Blue Book 2011
Blue Book 2011
Blue Book 2011
ANAESTHESIA
2011
AUSTRALASIAN
ANAESTHESIA
2011
Invited papers and selected
continuing education lectures
Editor:
Richard Riley
Department of Anaesthesia
and Pain Medicine
Royal Perth Hospital
Pharmacology and Anaesthesiology Unit,
School of Medicine and Pharmacology
University of Western Australia
Contents
Complex regional pain syndrome (CRPS), a brief review
Will Howard
The flimsy framework of methodology in the acute pain literature shaky structure in need of repair?
Mark Reeves
11
17
27
The disappointing spinal A review of the potential aetiologies for failure of spinal anaesthesia
Steven Koh
33
43
49
57
67
73
Jet Ventilation and Anaesthesia A practical guide to understanding jet ventilation and its
current applications in clinical anaesthetic practice
Sasanka S Dhara
79
Care of the potential lung transplant donor optimisation, prevention of decline and future prospects
Ian James Smith
93
The Last Frontier: Donation after Cardiac Death (DCD) reaches Western Australia
David Simes
103
115
125
135
145
157
163
171
179
189
197
203
209
AUSTRALASIAN
ANAESTHESIA
2011
Preface
Welcome to the 2011 edition of Australasian Anaesthesia. This marks the first edition wherein our Intensive Care
colleagues have officially departed and we are sad to see them go. However, this does not mean the end of articles
with a focus on Intensive Care and this issue of Australasian Anaesthesia has two authors who are Intensive Care
Physicians. Indeed, it will be our pleasure to continue to provide a vehicle for topics of mutual interest.
Perhaps I should mention again that articles from this book are published on the website of ANZCA and that there
is often some bonus material located there; such as video files or brochures. The authors have generously allowed
their articles to be distributed in this way to maximise the educational impact of their work.
Finally, this issue of the Blue Book once again provides a diverse range of topics for your interest. I thank the
authors, the regional editors and Katherine Goodwin for their work and support. It always surprises me that our
countries produce outstanding clinicians who are willing to share their experiences, knowledge and perspectives
with us. I hope you have the opportunity to thank those authors personally when you can and also consider writing
yourself for a future edition.
Richard Riley
CLINICAL COURSE
The clinical course is variable and unpredictable. Most patients present with pain which is regional and spreading
to adjacent regions e.g. pain affecting all of a hand spreading at times proximally to the forearm, or pain affecting
the knee and spreading towards the ankle. With time the pain may spread further. The pain is present both
spontaneously and in response to provocations such as using the limb, changes in temperature, and stress and
anger. Often the pain is worse at night; significant disturbance of sleep is common. Swelling may be mild or extreme;
commonly it fluctuates, again this can be both spontaneous or in response to the provocations which cause pain.
In the early stage of CRPS the affected part may be warm, red and sweaty; later it is likely to be blue and cold;
however some patients do not experience the warm phase; and others initially fluctuate between the two with cold
manifestations prevailing later. Swelling is usually more marked in the early stage. Variable motor manifestations
occur stiffness, weakness, tremor and impaired co-ordination; their severity tends to mirror the course of the
disease. Increased growth of hair and of the nails may be seen.
In some patients perhaps many patients spontaneous resolution occurs; in a very small proportion there is
an apparently inexorable progression to severe dystrophy with a wasted shiny cold and contractured limb; many
patients endure a persisting fairly stable condition of moderate pain, swelling and stiffness.
PATHOPHYSIOLOGY
The pathophysiology of both the onset and the maintenance of CRPS have not been defined; it may be that the
clinical entity, with its variable manifestations, is in fact the outcome of more than one pathophysiology. Amongst
the intriguing pieces of evidence are the following. Multiple groups have reported increased amounts of proinflammatory
cytokines (tumour necrosis factor alpha (TNF-alpha), interleukin-1beta and interleukin-6 ) and of neuropeptides
(substance P, calcitonin gene-related peptide (CGRP)) in tissue fluid from affected regions, or in plasma, or in CSF.
Abnormal or excessively sustained release of these agents after tissue damage might lead to CRPS. These cytokines
and neuropeptides can cause pain, swelling, vasodilatation, sweating, increased hair growth and osteoclastic
activity all phenomena seen in CRPS. Even in CRPS in which there is not injury to a major peripheral nerve, i.e.
CRPS-I, reduced density of C-fibres and Adelta-fibres has been reported by more than one research group. In the
past it was considered that excessive activity of the sympathetic nervous system (SNS) was contributory: however
evidence suggests that, in the affected region at least, there is reduced SNS outflow; however there may be
sympatho-afferent coupling, i.e. increased expression of adrenergic receptors on nociceptors and their afferent
fibres and at their cell bodies in the dorsal root ganglia (as is known to occur after nerve injury) so that the region
is more sensitive to catecholamines despite reduced SNS activity. There appears to be a lack of data, in humans
at least, whether central sensitisation occurs at the spinal cord. However there is evidence from multiple groups of
altered neural processing in the brain (see below graded motor imagery).
PREVENTION
A high quality study of 416 patients in a double-blind prospective multicenter trial by Zollinger et al. 2 found that
vitamin C in a dose of 500 mg or more per day reduced the prevalence of CRPS after wrist fracture from around
10% to less than 2%. Treatment was continued for 50 days. It has been speculated that the efficacy of vitamin C
was due to its anti-oxidant activity.
There is no robust evidence to guide, but expert opinion has recommended that patients with a history of CRPS
should avoid surgery on the affected part; if surgery is being undertaken, whether on the affected limb or other
body extremity, regional blockade might be preventative. The role of perioperative steroids or of ketamine is unclear;
in my opinion, their potential benefit would be expected to outweigh potential harm.
TREATMENT
There is a dearth of quality evidence regarding treatment of CRPS; where RCTs have been performed the studies
have tended to be small and/ or to be awaiting replication by other researchers. The lack of trials is perhaps due
to the variability of clinical presentations, the need for multiple modalities of treatment, the variability in response
to treatment with some patients seeming to improve spontaneously and others not improving regardless of an array
of treatments. Thus clinicians must turn to guidelines drawn from a consensus of experts.
Allied Health
As summarised succinctly by the Dutch clinician guidelines in 20061 The key to recovery seems to be in properly
adjusted movement and in learning to reintegrate the affected limb to everyday activity. Thus physiotherapists and
occupational therapists have the key roles in managing CRPS. In the majority of cases standard treatment, judiciously
modified and often protracted, suffices. Experience and judgement is required because activity of the affected part
can both mitigate and aggravate CRPS: the challenge is to achieve sufficient use to turn off the CRPS process but
not so much as to cause a flare of CRPS activity. Some patients have moderate or severe CRPS from early on, or
fail to respond to lengthy treatment: these patients require additional medical input but always the principle is for
the medical treatment to be facilitating activity of the affected part as this seems to be the key to reversing
the CRPS.
In addition to physical and medical measures, psychological support is often appropriate, to assist patients to
adjust to live with a significantly painful condition, and to develop strategies and implement behavioural changes
to optimise their situation. Many patients will have been let down badly by their medical experience: they will have
had surgery or other treatment which has failed, and often their complaints of pain will have been met with scepticism.
Medical treatments
Amongst medications with RCTs to support their use are: steroids, free-radical scavengers (dimethyl sulfoxide
cream, N-acetyl cysteine), biphosphonates. Evidence for calcitonin has been mixed. Agents used for neuropathic
pain opioids, gabapentinoids, and antidepressants blocking re-uptake of noradrenaline (amitriptyline, venlafaxine,
duloxetine) - have been used for CRPS. Recently infusions of ketamine have become quite widely used. The infusion
is often at doses causing actual or potential sedation; hence patients must be hospitalised; there is uncertainty
regarding optimal dose, duration, and frequency of treatments.
SYMPATHETIC BLOCK
Sympathetic blockade (stellate ganglion block and lumbar sympathetic block) has been used extensively. There
continues to be a lack of evidence to support its use: the most recent Cochrane review could find only one RCT
of adequate quality and that was for permanent sympathectomy. However sympathetic block continues to be
recommended in consensus guidelines. It is unclear whether permanent sympathectomy (i.e. ablation of the relevant
ganglia) is better than repeated temporary blockade by local anaesthetic; if the latter is undertaken there is uncertainty
regarding the optimal interval between blocks and the optimal duration of treatment. Long-lasting ablation can be
achieved surgically or by percutaneous delivery of heat or neurotoxic chemical. Intravenous regional guanethidine
(Biers block) has been demonstrated not to be effective and it seems to be little used these days. Epidural block
will provide both sympathetic and somatic block; whether somatic block is advantageous is unclear; generally
epidural treatment will require hospitalisation; duration of the infusion will be limited by apprehension regarding
infection.
Due to the severe pain and impaired function of this condition, major interventions are sometimes undertaken.
Usually they are reserved for the most severe cases. Their cost, the required expertise, and need for ongoing
supervision have tended to limit their use to compensable patients or well-resourced public clinics. There has been
a small RCT supporting the use of spinal cord stimulators (SCS) which showed a modest decrease in pain intensity,
a modest improvement in quality of life but no change in function (Kemmler 2000)3. The hardware for a spinal cord
stimulator plus one one lead costs approximately $25,000; in the past the implanted stimulator had to be replaced
when the battery was exhausted after several years, a recurring cost of about $18,000. Intrathecal pumps infusing
an opioid and sometimes other agents such as clonidine or baclofen are occasionally used; their use tends to be
limited to the lower limb because treatment of the upper limb necessitates higher positioning of the intrathecal
catheter or higher infusion rates or both and thus side-effects are more problematic. Such pumps necessitate
ongoing involvement with the patient to provide refills of the pump and monitor for complications of the intrathecal
device and intrathecal medications, e.g. granulomas causing neurologic compromise and hormonal suppression
secondary to chronic opioid use.
The past decade has seen the introduction of graded motor imagery (GMI). This technique was originally
investigated for use to relieve phantom limb pain. It uses techniques which retrain neural circuits in the brain.
Research by an Australian physiotherapist, Lorimer Moseley, has demonstrated that three components of retraining
should be undertaken and that the order in which patients perform them is important. In the first phase patients
practise lateral recognition which requires them to distinguish whether a limb (hand or foot) is left or right when
images are rapidly presented for a number of minutes, using flash cards or electronic means. Patients with CRPS
have impeded recognition of the affected side manifested by a time lag or higher rate of inaccuracy or both.
Improvement requires frequent and sustained practice. Once lateral recognition approaches normality, the patient
is encouraged to undertake phase two, imagined movements in which movements of the affected part is imagined.
When the patient is able do imagined movements without causing aggravation of the CRPS pain and swellingthey progress to phase three mirror movements in which the patient observes movements of the contralateral
limb in a mirror so that it is perceived by their brain to be movements of the affected limb. Remarkably this process
of neural retraining directed at brain circuitry can reduce or turn off the manifestations of CRPS in the periphery.
Further evidence of the role of brain neural processing has been the fascinating observation that CRPS is associated
with changes in the somatotopic representation of the affected limb: representation shrinks and shifts to a more
proximal part of the cortical somatotopic map. For example if the hand is affected, its representation becomes
smaller and is located closer to the shoulder and the face, and thus tactile stimulation of the hand may be perceived
in the shoulder or the face or both. These changes reverse when treatment is successful a stunning example
of neuroplasticity.
SUMMARY
CRPS remains an enigmatic disease. Its pathophysiology is unclear but there is increasing acceptance of the roles
of: firstly an interaction between peripheral nerves, peripheral neuropeptides and cytokines; and secondly reversible
changes in brain neural patterns. CRPS is particularly likely after injury to the distal upper or lower limb but there
appears to be a high rate of natural resolution. In those with severe or persistent symptoms, CRPS is disabling and
often very distressing. The key to turning off CRPS is believed to be actual or simulated use of the limb; the primary
objective of medical treatments should be to facilitate function. CRPS has a range of medical treatments including
neuropathic medications and various procedures; the evidence for most treatments of CRPS is weak. However
there is strong evidence for the prophylactic use of vitamin C to prevent CRPS after wrist fractures.
There are a number of recent very good reviews available for further reading.4,5,6
Causalgia
Sudecks atrophy
Algodystrophy
Sudecks osteodystrophy
Shoulder-hand syndrome
Spontaneous pain
Mechanical hyperalgesia
Thermal hyperalgesia
Deep somatic hyperalgesia
Vascular abnormalities
Vasodilatation
Asymmetric skin temperatures
Skin colour changes
Swelling
Hyperhidrosis
Weakness
Tremor
Dystonia
Impaired co-ordination
Nail or hair changes
Skin atrophy
Joint stiffness
Soft tissue changes
REFERENCES
1. http://pdver.atcomputing.nl/pdf/CRPS_I_Guidelines.pdf Guidelines complex regional pain syndrome type 1
Netherlands Society of Rehabilitation Specialists and Netherlands Society of Anaesthesiologists.
2. Zollinger P, Tuinebreijer W, Breederveld R, Kries R Can vitamin C prevent complex regional pain syndrome in
patients with wrist fractures? J Bone Joint Surg am 2007;1424-1431.
3. Kemmler MA, De Wet HC et al The effect of spinal cord stimulation in patients with reflex sympathetic dystrophy:
two years follow-up of the randomized control trial Am Neurol 2004;55:13-18.
4. Marinus J, Moseley L, Birklein F, et al Clinical features and pathophysiology of complex regional pain syndrome
www.thelancet.com/neurology2011;10:637-648.
5. Bruehl S An Update on the Pathophysiology of Complex Regional Pain Syndrome Anesthesiology
2010; 113: 713-725.
6. Maihofner C, Seifert F, Markovic K Complex regional pain syndromes: new pathophysiological concepts and
therapies European J Neurology 2010; 17: 649-660.
7. Moseley GL.Graded motor imagery for pathologic pain: a randomized controlled trial. Neurology. 2006;67:
2129-34.
8. Daly AE, Bialocerkowski AE. Does evidence support physiotherapy management of adult Complex Regional
Pain Syndrome Type One? A systematic review. Eur J Pain. 2009; 13: 339-53.
9. Baron R, Janig W Complex regional pain syndromes-how do we escape the diagnostic trap? Lancet
2004;364:1739-1741.
The flimsy framework of methodology in the acute pain literature shaky structure in need of repair?
The flimsy framework of methodology in the acute pain literature shaky structure in need of repair?
Validation of new endpoints is urgently needed: episodes of severe pain, constant moderate pain, development
of persistent pain, intolerable side-effects, functional disability, length of stay and satisfaction are all worthy of
investigation and have been variously included in studies, although usually as secondary endpoints. These outcomes
are non-parametric (frequency counts, ordinal scales, categories, etc). Trials comparing different strategies on
outcomes such as these will need far greater numbers than the most frequent types of studies populating the
current literature, nearly all of which have less than 100 participants.14 This will be challenging and will probably
require multi-centre approaches. In Australasia we have the capacity to do this kind of research, as the achievements
of the Trials Group at the Australia and New Zealand College of Anaesthetists have shown since the MASTER trial.
So, if someone taps you on the shoulder to be involved in a trial on postoperative pain, please dont scoff and
assume that we already have most of the answers we need. Weve barely scratched the surface.
REFERENCES
1. Shafer SL. Notice of retraction. Anesth Analg. 2009; 108(4):1350.
2. Website: http://en.wikipedia.org/wiki/Scott_Reuben accessed 31/5/11
3. Reeves M. The influence of age on sample size calculation in acute pain trials using morphine consumption as
an end point. Anesth Analg. 2010; 110(4):1186-90
4. Reeves M, Lindholm DE, Myles PS, Fletcher H, Hunt JO. Adding ketamine to morphine for patient-controlled
analgesia after major abdominal surgery: a double-blinded, randomized controlled trial. Anesth Analg. 2001;
93(1):116-20.
5. Subramaniam K, Subramaniam B, Steinbrook RA. Ketamine as adjuvant analgesic to opioids: a quantitative
and qualitative systematic review. Anesth Analg. 2004; 99(2):482-95.
6. Carstensen M, Mller AM. Adding ketamine to morphine for intravenous patient-controlled analgesia for acute
postoperative pain: a qualitative review of randomized trials. Br J Anaesth. 2010;104(4):401-6.
7. Bell RF, Dahl JB, Moore RA, Kalso E. Peri-operative ketamine for acute post-operative pain: a quantitative and
qualitative systematic review (Cochrane review). Acta Anaesthesiol Scand. 2005; 49(10):1405-28.
8. Myles PS, Troedel S, Boquest M, Reeves M. The pain visual analog scale: is it linear or nonlinear? Anesth Analg.
1999; 89(6):1517-20.
9. Myles PS, Urquhart N. The linearity of the visual analogue scale in patients with severe acute pain. Anaesth
Intensive Care. 2005; 33(1):54-8.
10. Rigg JR, Jamrozik K, Myles PS, Silbert BS, Peyton PJ, Parsons RW, Collins KS; MASTER Anaesthesia Trial
Study Group. Epidural anaesthesia and analgesia and outcome of major surgery: a randomised trial. Lancet.
2002; 359(9314):1276-82.
11. Macintyre PE, Jarvis DA. Age is the best predictor of postoperative morphine requirements. Pain. 1996; 64(2):
357-64.
12. Myles PS, Leslie K, Chan MT, Forbes A, Paech MJ, Peyton P, Silbert BS, Pascoe E; ENIGMA Trial Group.
Avoidance of nitrous oxide for patients undergoing major surgery: a randomized controlled trial. Anesthesiology.
2007; 107(2):221-31.
13. Chan M, Wan A, Leslie K, Myles P. Chronic post-surgical pain in the ENIGMA Trial. Australian Society of
Anaesthetists National Scientific Congress, Melbourne 2010.
14. Reeves MD. Increase in quality, but not quantity, of clinical trials in acute pain: 1992 versus 2007. Anesth Analg.
2009; 109(5):1656-8.
11
12
CONSTIPATION
This is probably the most frequently encountered side effect of opioids, occurring in 72% of cancer patients on
morphine in one study.15,16 Accurate measurements of incidence of constipation are probably not possible, but from
best estimates, constipation occurs in approximately 10% of the general population, 20% of those over 65 years
of age, 50% of those with cancer, 70% of patients with advanced cancer, rising to 90% or more in those with
advanced cancer being treated with opioids. Strictly speaking, the term opioid bowel dysfunction17 is perhaps
more accurate and often encountered in the literature, but the definition is problematic, and varies from publication
to publication. Perhaps the most practical definition for the patient is the experience of less frequent bowel motions
or the sensation that more frequent bowel movements are required.
In cancer patients, there are contributing factors to be considered: cancer related causes, medication related
and those due to other causes. For example, bed rest, pelvic cancers, bowel obstruction, hypercalcaemia and
dehydration are not uncommon in a cancer patient population. Some drugs such as chemotherapy agents (eg.
vincristine), some antiemetics such as 5HT3 antagonists, antispasmodics, anticholinergics, diuretics and iron
supplements can all contribute to constipation. Other conditions such as hypothyrodism, autonomic neuropathy
and diabetes may also exacerbate constipation from other causes.
The pathophysiology of constipation in patients with cancer treated with opioids is not fully understood, but
involves inhibition of opioid receptors in the myenteric plexus, where the circular smooth muscles are more affected
than longitudinal muscles18. Delayed gastric emptying can occur, and reduced peristalsis throughout the gastrointestinal
tract is thought to be common. Decreased mucosal secretion has been noted, and when this occurs in addition to
increased rectal tone, it is not surprising that opioid bowel dysfunction occurs almost universally. The implication
of an increased rectal tone is that some patients with stomas may only require stool softeners (without bowel
stimulants) to relieve their constipation.
The principles of management of constipation include exclusion of bowel obstruction, finding and treating the
underlying cause if relevant and treating the contributing factors. I find something as simple as intravenous fluids
for 24-48hrs, or encouraging patients to be as active as possible, preferably walking around the ward, can be very
helpful. If pharmacological treatment is required, then the combination of stool softeners and stimulants is a useful
start (eg. sennosides with docusate). Table 1 lists a suggested starting dose equivalent of laxatives for a given level
of opioid dose. There is no published literature except for Mancini et al19 who calculated a laxative/opioid ratio for
morphine of around 0.15 in a study of 49 patients admitted acutely to a hospice, based on the designation of 100mg
docusate plus 8mg senna as one laxative unit (containing more docusate than one Coloxyl with Senna tablet in
Australia). Using their calculations, one might predict a laxative dose of around 2 tablets twice a day for an opioid
dose of 60mg per 24hrs, not dissimilar to Table 1. It is important to note that the dose of laxatives needs to be
titrated according to individual response. Like nausea, constipation is best managed using laxatives on a preventative
basis: I usually recommend starting a laxative with, or even before, the first dose of opioid, since most laxatives
require 4-24hrs to work.
In the event of constipation not responding to preventative laxatives in about 2-3 days, Table 2 lists a suggested
escalation plan involving agents delivered per rectum. In general, oral laxatives are preferred before rectal
administration, though sometimes both are required. Oils (paraffin, olive oil) can be administered via the oral route
or as enemas, and are also occasionally useful in severe impaction, though manual evacuation is more reliable.
Oils are not recommended for chronic use. In patients in whom I am interested in taking an aggressive approach
to constipation, overcorrection of constipation may be acceptable before dose reduction of laxatives.
In practice, I like to use abdominal X-rays if patients have been constipated for some time, in order to rule out
bowel obstruction, though this is not always recommended in the literature. Most radiologists however, do not
comment on constipation or faecal loading, and reports generally focus on ruling out acute abdominal events such
as bowel obstruction. As a result, it is always best to visualise the X-rays directly. Also, overflow incontinence is
perhaps under-recognised, and without a careful history, one can be fooled by the apparent clearing of chronic
constipation.
SEDATION
Sedation is a common problem, but tends to be mild, occurs early and at increases of opioid dose20. Tolerance
typically develops in about 2-3 days. For this reason, and because continual changes in doses of narcotics are
unhelpful, any change in dose of opioids is best done only every 2-3 days, in my view, unless of course it becomes
clear that pain is not adequately controlled. In this situation however, sedation is not usually an issue, and the main
problem is inadequate analgesia. Occasionally, sedation fluctuates, in which case strategies could include small
doses of methylphenidate, possibly modafinil or even a small dose of steroids. If sedation is accompanied by
respiratory depression, then reducing the dose of opioid is the best way to manage the problem. Naloxone can be
titrated to effect if used judiciously, but in cancer patients in whom pain control has been an issue, naloxone is best
avoided altogether in view of the potential to cause severe rebound pain.
13
HALLUCINATIONS
Non-opioid causes for hallucinations are perhaps more common than narcotics in cancer patients. 20 Cerebral
metastases, particularly if hallucinations in the setting of advanced disease are the first presentation, sepsis, hypoxia,
and hypercalcaemia are not uncommon causes. Assuming these have been excluded, management includes dose
reduction of opioids, small doses of haloperidol (eg. 0.5mg bd), or risperidone (0.5-1.0mg bd). For more prolonged
episodes of hallucinations or delirium, palliative care physicians sometimes prescribe higher doses of haloperidol,
risperidone, olanzapine or chlorpromazine.
DRY MOUTH
This is a common, though generally mild, side effect associated with opioids. Symptomatic treatment is all that is
usually required if it is a feature in the patients complaints.
OTHER SIDE EFFECTS
Itch is occasionally an issue, and has been estimated to occur in around 1% of patients treated with opioids, rising
to 40% with the use of spinal opioids, suggesting a spinal opioid receptor mechanism.21 The cause is unclear, and
may be dose related. There is some evidence that opioids cause some histamine release from mast cells (though
this has not been demonstrated for fentanyl and sufentanil, though curiously, itching still can occur with the use of
these drugs). Treatment is again symptomatic, with a trial of antihistamines worthwhile. Physical treatments such
as cool compresses and moisturisers may be helpful.
Myoclonus may be more frequent with chronic use, and the risk appears to increase in the presence of spinal
cord lesions in patients.22 It may also be related to reduced clearance of opioid metabolites, though there is no
good evidence in this regard. In the presence of persistent myoclonus, opioid rotation (morphine, hydromorphone,
oxycodone, fentanyl, methadone) has been suggested.22 If this approach fails, gabapentin23 lorazepam or clonazepam
may be useful.
NEW DRUGS AND APPROACHES
In the last decade, a number of novel drugs have been developed that target the most common side effect of
opioids: constipation. Recent meta-analyses24,25 suggest that both methylnaltrexone and alvimopam have Level 1
evidence to show that they are better than placebo in treating constipation and post-operative ileus.
Methylnaltrexone is a peripheral mu-opioid receptor antagonist that does not cross the blood brain barrier in
appreciable amounts and as a result, does not antagonise opioid induced central nervous system effects such as
sedation.26,27 In Australia, it is approved on the pharmaceutical benefits scheme. A subcutaneous dose results in a
bowel movement around 4 hours later, but occasionally a second dose may be required. Given its apparent ability
to rescue patients with constipation, it is generally not used as first line treatment, and tends to be reserved for
patients who fail standard laxatives.
Alvimopam is also a peripheral mu-opioid receptor antagonist that does not cross the blood brain barrier in
appreciable amounts.27 It was approved by the American Federal Drug Agency (FDA) in 2008 for use for postoperative ileus.28 For this indication, it is commenced prior to surgery and administered twice a day for a week. The
drug is well-tolerated.
Phase III trials of an oxycodone/naloxone combination show that significantly less constipation occurs with its
use than oxycodone.29,30 The rationale behind this is the pharmacological advantage of giving naloxone orally, which
has low bioavailability and which exclusively inhibits gut opioid receptors. However, side effects from the oxycodone
component can occur, not unexpectedly.
Tapentadol is a mu-opioid receptor activator and noradrenaline reuptake blocker that acts in the central nervous
system.31 It is useful in a variety of pain conditions, including back pain and osteoarthritis.32 It has already been
FDA approved and appears to cause less constipation than oxycodone in clinical trials.
PHARMACOGENETICS
Although in its infancy, the study of pharmacogenetics of opioids appears to be taking shape. It may be possible
therefore, to identify patients who have a higher risk of severe or unusual reactions to opioids prior to the development
of these adverse events.33 For instance, genetic polymorphisms of cytochrome P4502D6 may help to determine
rapid metabolisers of codeine (into morphine, more side effects) from those who are poor metabolisers (more pain),
(see Kadiev et al, 2008 for review).34
CONCLUSIONS
Although opioids are extremely useful in the management of pain syndromes in many different diseases, patients
commonly experience side effects. Fortunately, most of these are either mild or manageable. The incidence of these
adverse events can only be estimated from large clinical trials, but these patient populations are unlikely to represent
the real world where patients have generally poorer performance status, or may have multiple co-morbidities
which increase the risk of side effects. If we assume recent pharmacogenetic work is a reasonable guide, then
approximately 10% of patients have unusual or more severe side effects than most patients, while 10% of patients
could be expected to have poor pain control with standard opioid and adjunct treatment approaches. It would
seem that these patients may benefit most from the novel drugs recently developed, which of course would also
be suitable for patients in whom side effects of opioids such as constipation are difficult to manage.
14
Table 1.
Suggested starting laxative dosing equivalents for given levels of morphine requirements. Laxatives should be
commenced with, or before, the first dose of opioid for optimum prevention of constipation. The overall aim is not
necessarily to produce normal bowel movements, but something close. In patients in whom constipation is a
potential issue (eg. recent hemorrhoidal bleeding, previous severe constipation), looser bowel movements may be
preferable.
Morphine equivalents Examples
per 24hrs
Laxative equivalents
10-30mg
40-60mg
80-100mg
>120mg
Table 2.
Suggested escalation strategy for constipation not responding to preventative laxatives. Clearly, the choice to use
any of these agents must be guided by patient preference and the clinical situation. At some stage, consultation
with gastroenterologists, colorectal surgeons or palliative care physicians might be prudent.
Level
Agent
Level 1
add lactulose
Level 2
Level 3
Impaction
REFERENCES
1. CLEARY, J.F. (2007). The pharmacologic management of cancer pain. J Palliat Med, 10, 1369.
2. DAVIS, M.P., LASHEEN, W. & GAMIER, P. (2007). Practical guide to opioids and their complications in managing
cancer pain. What oncologists need to know. Oncology (Williston Park), 21, 1229.
3. DRONEY, J. & RILEY, J. (2009). Recent advances in the use of opioids for cancer pain. J Pain Res, 2, 135.
4. AHLBECK, K. (2011). Opioids: a two-faced Janus. Curr Med Res Opin, 27, 439.
5. PIGNI, A., BRUNELLI, C. & CARACENI, A. (2011). The role of hydromorphone in cancer pain treatment:
a systematic review. Palliat Med, 25, 471.
6. KING, S.J., REID, C., FORBES, K. & HANKS, G. (2011). A systematic review of oxycodone in the management
of cancer pain. Palliat Med, 25, 454.
7. CHAN, B.K., TAM, L.K., WAT, C.Y., CHUNG, Y.F., TSUI, S.L. & CHEUNG, C.W. (2011). Opioids in chronic
non-cancer pain. Expert Opin Pharmacother, 12, 705.
8. HADI, I., MORLEY-FORSTER, P.K., DAIN, S., HORRILL, K. & MOULIN, D.E. (2006). Brief review: perioperative
management of the patient with chronic non-cancer pain. Can J Anaesth, 53, 1190.
9. ROZEN, D. & GRASS, G.W. (2005). Perioperative and intraoperative pain and anesthetic care of the chronic
pain and cancer pain patient receiving chronic opioid therapy. Pain Pract, 5, 18.
10. RICHEBE, P. & BEAULIEU, P. (2009). Perioperative pain management in the patient treated with opioids: continuing
professional development. Can J Anaesth, 56, 969.
15
11. HARRIS, J.D. (2008). Management of expected and unexpected opioid-related side effects. Clin J Pain,
24 Suppl 10, S8.
12. MCNICOL, E. (2008). Opioid side effects and their treatment in patients with chronic cancer and noncancer
pain. J Pain Palliat Care Pharmacother, 22, 270.
13. CHERNY, N., RIPAMONTI, C., PEREIRA, J., DAVIS, C., FALLON, M., MCQUAY, H., MERCADANTE,
S., PASTERNAK, G. & VENTAFRIDDA, V. (2001). Strategies to manage the adverse effects of oral morphine: an
evidence-based report. J Clin Oncol, 19, 2542.
14. QUIGLEY, C. (2004). Opioid switching to improve pain relief and drug tolerability. Cochrane Database Syst Rev,
CD004847.
15. DRONEY, J., ROSS, J., GRETTON, S., WELSH, K., SATO, H. & RILEY, J. (2008). Constipation in cancer patients
on morphine. Support Care Cancer, 16, 453.
16. ROSTI, G., GATTI, A., COSTANTINI, A., SABATO, A.F. & ZUCCO, F. (2010). Opioid-related bowel dysfunction:
prevalence and identification of predictive factors in a large sample of Italian patients on chronic treatment.
Eur Rev Med Pharmacol Sci, 14, 1045.
17. HOLZER, P., AHMEDZAI, S.H., NIEDERLE, N., LEYENDECKER, P., HOPP, M., BOSSE, B., SPOHR, I. & REIMER,
K. (2009). Opioid-induced bowel dysfunction in cancer-related pain: causes, consequences, and a novel approach
for its management. J Opioid Manag, 5, 145.
18. DAVIS, M.P. (2005). The opioid bowel syndrome: a review of pathophysiology and treatment. J Opioid Manag,
1, 153.
19. MANCINI, I.L., HANSON, J., NEUMANN, C.M. & BRUERA, E.D. (2000). Opioid type and other clinical predictors
of laxative dose in advanced cancer patients: a retrospective study. J Palliat Med, 3, 49.
20. VELLA-BRINCAT, J. & MACLEOD, A.D. (2007). Adverse effects of opioids on the central nervous systems of
palliative care patients. J Pain Palliat Care Pharmacother, 21, 15.
21. BALLANTYNE, J.C., LOACH, A.B. & CARR, D.B. (1988). Itching after epidural and spinal opiates. Pain, 33, 149.
22. MERCADANTE, S. (1998). Pathophysiology and treatment of opioid-related myoclonus in cancer patients.
Pain, 74, 5.
23. MERCADANTE, S., VILLARI, P. & FULFARO, F. (2001). Gabapentin for opioid-related myoclonus in cancer
patients. Support Care Cancer, 9, 205.
24. MCNICOL, E.D., BOYCE, D., SCHUMANN, R. & CARR, D.B. (2008). Mu-opioid antagonists for opioid-induced
bowel dysfunction. Cochrane Database Syst Rev, CD006332.
25. BECKER, G., GALANDI, D. & BLUM, H.E. (2007). Peripherally acting opioid antagonists in the treatment of
opiate-related constipation: a systematic review. J Pain Symptom Manage, 34, 547.
26. DEIBERT, P., XANDER, C., BLUM, H.E. & BECKER, G. (2010). Methylnaltrexone: the evidence for its use in the
management of opioid-induced constipation. Core Evid, 4, 247.
27. THOMAS, J. (2008). Opioid-induced bowel dysfunction. J Pain Symptom Manage, 35, 103.
28. OBOKHARE, I.D., CHAMPAGNE, B., STEIN, S.L., KRPATA, D. & DELANEY, C.P. (2011). The effect of alvimopan
on recovery after laparoscopic segmental colectomy. Dis Colon Rectum, 54, 743.
29. SIMPSON, K., LEYENDECKER, P., HOPP, M., MULLER-LISSNER, S., LOWENSTEIN, O., DE ANDRES,
J., TROY FERRARONS, J., BOSSE, B., KRAIN, B., NICHOLS, T., KREMERS, W. & REIMER, K. (2008). Fixed-ratio
combination oxycodone/naloxone compared with oxycodone alone for the relief of opioid-induced constipation
in moderate-to-severe noncancer pain. Curr Med Res Opin, 24, 3503.
30. LOWENSTEIN, O., LEYENDECKER, P., HOPP, M., SCHUTTER, U., ROGERS, P.D., UHL, R., BOND, S., KREMERS,
W., NICHOLS, T., KRAIN, B. & REIMER, K. (2009). Combined prolonged-release oxycodone and naloxone
improves bowel function in patients receiving opioids for moderate-to-severe non-malignant chronic pain: a
randomised controlled trial. Expert Opin Pharmacother, 10, 531.
31. VADIVELU, N., TIMCHENKO, A., HUANG, Y. & SINATRA, R. (2011). Tapentadol extended-release for treatment
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32. CANDIOTTI, K.A. & GITLIN, M.C. (2010). Review of the effect of opioid-related side effects on the undertreatment
of moderate to severe chronic non-cancer pain: tapentadol, a step toward a solution? Curr Med Res Opin, 26,
1677.
33. STAMER, U.M. & STUBER, F. (2007). The pharmacogenetics of analgesia. Expert Opin Pharmacother, 8, 2235.
34. KADIEV, E., PATEL, V., RAD, P., THANKACHAN, L., TRAM, A., WEINLEIN, M., WOODFIN, K., RAFFA, R.B. &
NAGAR, S. (2008). Role of pharmacogenetics in variable response to drugs: focus on opioids. Expert Opin
Drug Metab Toxicol, 4, 77.
17
18
Much of anaesthetist-administered pethidine is provided intraoperatively with the justification of lowering nausea
and vomiting rates. In this circumstance what is being observed is postoperative nausea and vomiting (PONV). On
the topic of PONV the anaesthetic literature provides us with quite a deal of information as to which factors impact
PONV rates. Leslie et al have identified use of nitrous oxide and a longer duration of anaesthesia as increasing the
observed incidence of PONV.9 Use of bispectral index monitoring was associated with a reduction in PONV,
apportioned to the lessening in anaesthesia exposure afforded by its use. From Gan et als Consensus Guidelines
for managing PONV, similar anaesthetist-modifiable factors such as use of nitrous oxide and use of volatile anaesthetic
are cited as being positive causative factors for PONV.10 These guidelines add a third contributor to PONV: use of
intraoperative and postoperative opioids. In this review, the preferential benefit of one opioid over another to reduce
PONV was not identified. The appropriate conclusion from the anaesthetic literature is that the contribution to PONV
by the opioids is a class effect with no one opioid consistently offering an advantage over another.
Anaesthetists may be presented with a patient reporting a history of being PONV-free only when pethidine is
administered - a claim that must at times be viewed with caution, as there may be innumerable alternative reasons
why this may have been so. Even the same anaesthetic administered on different days to the same patient can
have widely different outcomes. When the evidence is explored it becomes evident far more substantive reductions
in a patients PONV risk can be achieved by an emphasis on eliminating the factors known to promote PONV, rather
than by the preferential use of a drug that has little evidence in its support.
If a benefit in nausea and vomiting rates does exist with pethidine, but has not yet been demonstrated by the
research available, then this might be expected to have become evident through other means. There might have
been a noticeable spike in PONV rates coinciding with a hospitals sudden withdrawal of pethidine. In 2006 Royal
North Shore Hospital (Sydney, NSW) undertook just such a withdrawal of pethidine, however no rise in PONV
frequency was noted.
Sphincter of Oddi Dysfunction
It has been accepted dogma taught to generations of medical students that only pethidine should be used for
analgesia in patients with biliary disease, such as acute cholecystitis or pancreatitis. Any doctor who was foolhardy
enough to administer morphine to such patients, it was said, would witness a calamitous worsening of the patients
pain. This was taught on the basis pethidine did not possess sphincter of Oddi (SO) stimulating activity, whereas
morphine did.
In order to challenge this second justification for pethidine it is informative to first ask: what was the origin of
the belief in the SO` sparing actions of pethidine? To answer, it is necessary to take quite a step back in time.
In the 1930s, an open cholecystectomy involving operative exploration of the common bile duct (CBD) would
generally mandate the placement of a T-tube to allow percutaneous drainage of bile fluid. The presence of a T-tube
meant measurement of bile duct pressure was a relatively simple matter of connecting a fluid filled column. Using
this methodology, administration of morphine to the patient was noted to lead to a rise in bile duct pressure and
this rise often, but not always, was limited by the prior administration of atropine.11 Then in 1939 came the synthesis
and marketing of pethidine, a drug designed to have similar structure activity to atropine. These two events were
linked and soon pethidine was being promoted as the analgesic of choice for biliary tree pathology but based
largely on theory.
As early as 1947 Gaensler et al published work questioning the theoretical benefit of pethidine. 12 T-tube based
studies demonstrated pethidine was also capable of producing substantative rises in CBD pressures. Although
this was generally less than that seen with morphine, in 10% of patients this was noted to be greater than the
response to morphine. The authors concluded, based on their findings: preference should not be given to pethidine
over morphine for patients with biliary pathology. In fact, they went on to state morphine could be preferred because
it seemed to provide better analgesia to patients suffering biliary pain than pethidine was able.
Despite the publication of such early work challenging pethidines role as the analgesic panacea for biliary
disease, the belief was perpetuated in major textbooks of the late 20th century.
In 1984 came perhaps the most notable publication in the anaesthesia literature on the biliary pressure response
to different opioids. Using similar T-tube pressure methodology, morphine was observed to cause a greater rise in
CBD pressure than pethidine, however this was still much less than the increase in pressure seen following fentanyl
administration.13 This finding of fentanyl being the most potent provocateur of CBD pressure rise presented a
challenge to the prevailing clinical practice and so the understanding of CBD clinicopathology, fentanyl being the
predominant intraoperative opioid utilised for cholecystectomy in many centres, as well as being the recommended
agent for pain management of pancreatitis sufferers admitted to hospital requiring a PCA. For both these scenarios
and based on this evidence, use of fentanyl should have resulted in noticeable presentations of biliary-type pain.
The explanation for this perplexing paradox lies in one, or a combination of two possibilities. First, the threshold
for pain due to biliary distension varies from person to person. Secondly, it is not so much the distension that is
thought to lead to pain, but rather it is the exaggerated relaxation phase following an opioid-induced overstimulated
contraction that leads to pain (J. Kellow, personal communication, June 2011). Therefore, the emphasis on measuring
CBD pressure elevations may have been misleading all along. Increased CBD pressure may serve only as a marker
of opioid activity and is not the cause of the pain per se.
19
Rather than focusing on CBD pressure it becomes more informative to closely observe the most active site
where opioid smooth muscle stimulation is believed to occur: at the sphincter of Oddi. This is undertaken experimentally
by placing a pressure-transducing catheter within the lumen of the CBD at the level of the SO at the time of
endoscopic retrograde cholangiopancreatocography. Studies undertaken in such a way result in an equal number
reporting a response of the SO to morphine as to pethidine.14-17 The studies do not consistently find a sustained
increase in the basal pressure as might be expected. Rather, they demonstrate an increase in the phasic firing of
SO contractions produced by both pethidine and morphine equally (measured as contractions per minute). The
mechanism by which this increase in contraction rate leads to the coincident rise in CBD pressure observed by
earlier researchers lies in the way in which the SO functions. The SO not only has a valve-like function, but also
acts as a pump. When this pump is stimulated beyond its maximal efficiency rate, it begins to fail in both a forwards
and backwards direction, much in the same way the left ventricle fails in times of tachycardia.
The stimulating effect of the opioids on the biliary tree smooth muscle entirely mirrors their effect on the rest of
the gastrointestinal tract. This is seen most profoundly in a clinical sense for the small intestine and is contrary to
what is believed by many to be the effect of the opioids on bowel contractions, which is in fact stimulatory rather
than inhibitory. Administration of morphine leads to an increase in the phasic firing of the migrating motor complex18,
however the resulting contractions of the small intestine now become discoordinated. This leads to loss of normal
coordinated peristalsis and rather than luminal contents being propelled toward the rectum, they are merely squeezed
to and fro, leading to constipation.
There is no one opioid known to consistently lead to less constipation in all patients. Drawing parallels to this,
the preferential use of pethidine in patients with biliary disease has little evidence to support it. This argument is
further supported by reviews of the topic: Reevaluation of this preference of meperidine (pethidine) over morphine
shows that it is the medical equivalent of an urban legend.19 and No studies or evidence exist to indicate that
morphine is contraindicated for use in acute pancreatitis.20
Labour Analgesia
Pethidine comprehensively dominates as the injectable opioid for labour analgesia. Finding reason for this
status quo requires a look back in time of several decades, and again reveals a practice based on dogma rather
than science.21
The initiating paper thought to have thrust pethidine forward as the agent of choice in labour analgesia was
published in 1949 by Little and Tovell.22 They conducted a retrospective audit of associated factors for neonatal
asphyxia cases reported in Indiana, USA. Morphine use in the labouring mother was reported to be associated with
an incidence of neonatal asphyxia of 3.1%, whereas with pethidine the incidence was reduced to 2.8%. This
reduction in complications was ascribed to pharmacological advantage of pethidine over morphine. Only in more
recent years has an alternative hypothesis for the difference been put forward: bias due to use of non-equivalent
drug doses. The brand-new agent of pethidine was innovatively presented in a solution making it easy to measure
out a precise dose (and this was indeed one of the marketed advantages). Morphine dosing in comparison was
antiquated; being cumbersome and inaccurate due to presentation in a solid pelletised form, termed a grain. The
standard dosing of morphine for labour analgesia at the time was a quarter of a grain, or approximately 16 mg a
far more generous dose than we would administer today and greater than the equipotent recommended dose
of pethidine.
Evidence based medicine has now caught up with pethidines sanctified place in labour. A recent Cochrane
Review of parenteral opioids for maternal pain relief in labour analysed 54 comparative studies of opioid use in
labour.23 The review concluded there was insufficient evidence to advocate the preferential use of any one opioid
in labour when measured as effectiveness of pain relief or by occurrence of side effects. Favourable comparisons
were highlighted with the use of pethidine alternatives of fentanyl24, morphine25,26 and even remifentanil PCA27 for
labour analgesia.
From research of a non-comparative design, and therefore not included in the mentioned Cochrane Review,
comes reason to be concerned for pethidine use in labour. Pethidine, owing to a high lipid solubility has been
demonstrated to readily cross the placenta into the fetal circulation. High pethidine levels in umbilical blood of up
to two-thirds the level seen in analgesed adults have been recorded after single-dose pethidine administration to
the mother.28 Greater neonatal depression has been correlated with higher pethidine blood concentrations in the
newborn.29 Research has also focused on the effect of the nor-pethidine metabolite on the neonate. Kuhnert et al
reported a correlation between poorer neonatal behaviour scores and a prolongation of the drug delivery interval,
defined as the interval between pethidine administration and delivery of the baby. 30 A longer drug delivery interval
results in greater transfer and accumulation of nor-pethidine into the fetus and this is the mechanism thought to
underlie these findings. Although this is a complex area with ongoing research awaited, we should be aware of
these concerns nonetheless.
The concern for placental transfer does not exist with morphine. There has been only limited research conducted
on morphine use in labouring mothers so pervasive is the lingering fear of morphine use resulting from Little and
Tovells work but what has been conducted demonstrates a reassuringly minor placental transfer of morphine.
Gerdin et al found at the time of delivery, morphine could only be detected in 8% of umbilical cord vein samples
after administration of morphine to the mother during labour.31
Implementation of present day knowledge has seen pethidine successfully withdrawn from the labour floor and
replaced with morphine in at least two major teaching hospitals of Sydney (Westmead and RNSH).
20
21
2. Oxycodone.
Injectable oxycodone has been available in Australia since 2007. It is simple to administer (having similar numerical
dosages to morphine), is as effective as morphine, and has a tolerable side effect profile. Clinician preference
for the use of injectable oxycodone for their patients is increasingly encountered. Use carries the advantage of
simplicity of dose conversion since oral oxycodone, in immediate release or extended release forms, is a favoured
agent for step-down analgesia.
3. Hydromorphone.
Use in Australia of injectable hydromorphone tends to be limited to chronic and cancer pain and is infrequently
administered in the acute setting. The latter is for no particular reason, other than perhaps simply a lack of
familiarity or perceived need. Hydromorphone use in the perioperative period is commonly encountered in North
American hospitals. The main downside to hydromorphone is unfamiliarity and so potential for confusion with
morphine, leading to drug administration errors. This was the topic of a recent NSW Department of Health Safety
Alert. Orders for hydromorphone are recommended to include use of TALLman lettering (i.e. HYDROmorphone)
as well as addition of the commercial name Dilaudid, placed in brackets immediately next to the order.
DISADVANTAGES OF PETHIDINE USE
Much has already been published on the complications from pethidine use. The following discussion will aim
to summarise that which is already well known and provide an extended discussion on issues of current interest
to anaesthetists.
Pethidine Seizures
The seizure provoking activity of pethidine is unique as it is the only opioid for which this side effect is encountered
at the doses prescribed for acute pain. Pethidines predominate metabolite nor-pethidine is a neuroexcitant, lowering
the seizure threshold. At low blood levels nor-pethidine leads to nervousness, tremor and twitching. As nor-pethidine
accumulates and blood levels rise the seizure threshold is eventually reached. It is critical to appreciate that even
following the recommended dosage guidelines (upper limit 600 1200 mg per day) does not provide surety of
avoiding nor-pethidine toxicity. Seizures have been reported with doses as low as 540 mg/d.43 In order to prevent
seizures from nor-pethidine accumulation, pethidine should be avoided in: repeated doses, PCA delivery or in renal
impairment.44
Drug Incompatibilities
Concomitant use of pethidine with tricyclic anti-depressants, monoamine oxidase inhibitors and tramadol has
resulted in serotonin syndrome, a condition capable of causing seizures and rarely, death, due to the additive effect
of pethidines uptake inhibition of a number of neurotransmitters, predominantly serotonin. Patients medicated with
these agents often have an unfavourable co-existence of the psychological conditions that would also make them
attracted to pethidine use, making for a dangerous mix.
Addiction
It is in the area of addictive potential that pethidine so strikingly stands apart from the alternative opioids. This is
particularly noticeable when compared to the phenanthrene family of opioids of oxycodone, hydromorphone and
morphine, which all have a similar mid-range addiction potential.45,46 There is increasing awareness and much media
publicity of oxycodone misuse. The rapid rise in rates of oxycodone misuse is not thought to result from any greater
addictiveness possessed by oxycodone, but rather from the marked increase in prescribing of oxycodone for
non-cancer pain, combined with the large milligram content (e.g. 80 mg) of pharmaceutical-grade purity found in
the extended release formulation often prescribed. OxyContin subsequently has become an ideal agent for diversion
and supply to the recreational drug market.
Pethidines two structurally related synthetic phenylpiperidine opioids of fentanyl and alfentanil have been
purported to also possess high addictive potentials, based largely on their pharmacokinetic properties allowing
rapid entry into the CNS. Where these two agents diverge from pethidine, and hence why there have not been calls
for the removal of these agents, is in the lack of translation of this potential into a high number of reported addiction
cases in the general community. This may be due to availability issues, for example: fentanyl and alfentanil are not
prescribed by general practitioners, whereas pethidine often is, making for a more readily accessible supply source.
The exception to this is fentanyl misuse by operating theatre personnel, who, largely on account of their access to
a reliable supply source, demonstrate a preference for fentanyl (see below for further discussion).
Our knowledge of the powerful addictive qualities of pethidine stems from a multitude of sources. On an individual
basis each piece of information may be argued away, but when drawn together they build a consistent and concerning
argument.
22
Pethidine High
For many patients, administration of pethidine produces a profound and complex high and far more so than is
experienced with the alternative opioids.47 This euphoric high is in addition intensely reinforcing with a greater
potential to develop an uncontrollable urge to recreate the experience, leading to addiction. Generally, addiction
risk increases with repeated dosing. Pethidine however is so intensely reinforcing that concern is held by addiction
medicine specialists for even a brief exposure to pethidine (as brief as a single dose) because it will conceivably,
in individuals with an addictive personality, lead to a highly vulnerable state for opioid addiction (S. Jurd, personal
communication, 25 August 2011).
Similarities between cocaine and pethidine
The stimulant effects of pethidine observed in humans have long been compared to those seen with cocaine.48
This led to the proposal for a non-opioid receptor mediated mechanism to explain at least some of pethidines
actions. This is supported firstly by experimental research demonstrating incomplete reversal of pethidine actions,
including nociception, following administration of opioid antagonists. Further support for a non-opioid receptor
involvement lies in research with trained monkeys capable of discriminating cocaine from saline, whereby the
simultaneous administration of pethidine and the mu-antagonist naltrexone led to a response in the monkeys
identical to that seen with cocaine.49
The cocaine and pethidine molecules share a number of structural features, including a piperidine ring, which
are thought responsible for their similar actions. Notably, pethidine and cocaine have comparably high potencies
for dopamine uptake inhibition in rat brains. Morphine was found to be devoid of such actions. Dopamine is heavily
implicated in the neurobiology of addiction and so pethidines actions to inhibit dopamine uptake to a similar degree
as cocaine may explain its strong addictive potential.50
Lessons learnt from use in chronic pain
Pethidine is not recommended for use in chronic pain states owing to the high likelihood of developing addiction.51
Of all the patients who present to pain clinics, it is those who have been maintained on pethidine that are notoriously
more difficult to manage. Weaning of pethidine injections is far more difficult than for alternative opioids and
additionally is rarely accomplished without inpatient admission and close supervision of dosing. Pain medicine
specialists left to deal with such patients do so needlessly since the patients could and should have been
managed with a less addictive agent in the first instance. The anaesthetists who are frequently the initial prescribers
of pethidine are rarely involved in the subsequent management of the patient many weeks or months later and so
remain unaware of the harm caused by their actions.
Expert Opinion
Addiction medicine is a field in which there is not the ability to conduct large randomised controlled trials or
Framingham-styled longitudinal studies of the type we have grown accustomed to in other fields of medicine and
so we are heavily reliant on expert opinion. This expert opinion is overwhelmingly to avoid the use of pethidine,
owing to the greater risk of addiction. Some anaesthetists express their own counter opinion of pethidine use posing
no greater risk of addiction than any other opioid based on their absent recollections of addiction seen in their own
patients following many years of pethidine prescribing. Such assertions are challengeable on the basis of naivety.
Given that the interaction between anaesthetist and patient is usually relatively brief and at best episodic, it can
not be expected that anaesthetists would consistently conduct a thorough assessment of their patients psychosocial
history capable of uncovering the intimately personal nature of addictive behaviour toward opioids.
Medical profession misuse
Doctors detected to be self-administering opioids display a preference for the misuse of pethidine over morphine.
In the often-cited review of Cadman and Bell, pethidine was the main opioid abused by 84% of doctors disciplined
by the New South Wales Department of Health.52 Self-administering doctors brought to the attention of the authorities
stand the greatest chance of successful rehabilitation, however the associated mortality rate is still high at 13%.
Far more concerning is the doctors who do not receive treatment for their addiction. For these doctors, particularly
anaesthetists, the anecdotal experience is of a significant number to have their first presentation of opioid abuse
in the form of a fatality (G Knoblanche, personal communication, May 2011). Up until the 1980s, pethidine was the
abusing anaesthetists drug of choice, reflecting that of the medical and nursing professions as a whole.53,54 Then,
with the introduction of fentanyl came a change in behaviour of anaesthetists, with fentanyl replacing pethidine as
the most common opioid of abuse by anaesthetists.55
This change in preference to fentanyl away from pethidine by anaesthetists is ascribed to a number of reasons.
Firstly, the increased awareness and vigilance for aberrant pethidine prescribing makes diversion without drawing
suspicion quite difficult. Secondly, fentanyl is presented in ampoules containing very high doses and is indeed often
administered in very high doses. Diversion of even small proportional quantities therefore can readily go unnoticed,
but are still of sufficient potency to provide reward to the abuser. For example, the intentional diversion of 100 mcg
out of a 500 mcg ampoule intended for a patient will have barely detectable consequences for the patient whilst
providing a substantive effect for the abusing anaesthetist. Finally, an anaesthetist under the influence of fentanyl
is capable of a higher degree of function than if using pethidine.56 The present-day preference away from pethidine
by anaesthetists does not now justify an attitude of complacency. Instead it should be viewed as evidence of the
effectiveness of strategies to date, but strategies that need to be enhanced in order to reduce the rate of pethidine
abuse still further.
23
If we know our medical colleagues have a preference for the misuse of pethidine over the equally effective
alternative opioids then it becomes an abrogation of our duty of care to tolerate the availability of pethidine. We
are obliged to eliminate the hazardous occupational exposure of our anaesthetic colleagues in the operating theatre,
and we need to extend our concern to nursing staff in the operating room, the general wards and on the labour
floor. In 2006, out of concern for the personal misuse of pethidine by general practitioners, the Australian Medical
Association and Pharmaceutical Benefits Advisory Committee collaborated to enact just such a strategy, and had
pethidine removed from the Doctors Bag supply carried by general practitioners.
The withdrawal of pethidine is a simple and effective means of minimising harm from the occupational exposure
of doctors to the most addictive of opioids, particularly because there are suitable alternatives to pethidine. Concern
for fentanyl exposure on the other hand, would be somewhat impractical to address solely by advocating its
withdrawal since it is the cornerstone of many general and neuraxial anaesthesia practices. Continued vigilance
and education will provide the greatest protection from fentanyl misuse.57
SUMMARY
A critical examination of the evidence fails to find support for the commonly held beliefs as to the benefits of
pethidine use. In stark contrast is the significant evidence for harm resulting from pethidine use.
While evidence based medicine has provided, and will continue to provide real guidance for all doctors in
therapeutic decision making, it must be acknowledged that our own personal experience with different medications
is a powerful influence on patient management. Many anaesthetists have used pethidine for decades, possibly
without any (known) complications, and will find articles such as these somewhat unpalatable. However, it must
be acknowledged that the evidence against the continued use of pethidine is now so clear, and incontrovertible,
and has been disseminated in so many forums, that should any patient experience any untoward effects due to
pethidine use, it will be difficult to sustain a defence based on the credo that it has been my usual practice.
In many Australian states inroads have been made by major teaching hospitals to completely withdraw, or
severely restrict use of pethidine. Hospitals regarded for their expertise in pain management that have removed
pethidine from their formularies include Royal Adelaide in 1993 and Royal North Shore in 2006. Time will hopefully
see the private sector following in a similarly educated manner. Keys to the success of a hospitals withdrawal of
pethidine are the involvement of the Drug Committee as well as a transition period of tolerated use in extenuating
circumstances. For example, at the authors hospital when pethidine was withdrawn, provision was made to allow
the use of pethidine on an Individual Patient Use (IPU) basis largely to appease a minority who were adamant
practice was not possible without pethidine. In the 5 years during which access to pethidine was available under
IPU, there were reassuringly no applications for pethidine.
Figures from the International Narcotics Control Board for 2004 place Australia in a desirable position on the
international ranking of pethidine prescribing.58 On a per head of population per annum basis, Australia consumes
9 mg and is well behind our Canadian counterparts at the head of the table with 36 mg as well as the United States
with 19 mg. Data extracted by the New South Wales Department of Health tallied a total use of pethidine for that
state of over 14 kg for the year of 2010.59 Of this total: 4.5 kg is accounted for by administration in labour, assuming
one in two of the approximating 90 000 labouring mothers for that year was administered a 100 mg ampoule of
pethidine (or part thereof). Whilst on an international basis Australian anesthetists have demonstrated a commendably
enlightened practice, the substantative ongoing use (at least from NSW data) indicates there is still further work to
be done. This may lie particularly in educating our colleagues in the other medical professions to whom much of
the continued prescribing of pethidine is apportioned.
CONCLUSION
In 2011 we have reached the point where the case has been made for the appropriate and effective use of opioids
to manage pain, particularly in the acute setting. We need to continue these efforts to further refine our practice,
ensuring the agents used are as safe and effective as possible.
The seductive simplicity to the change in practice necessary to eliminate pethidine is that it is completely painless.
Clinicians will not suffer and more importantly nor will our patients.
24
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2008;101:498-505.
10. Gan TJ, Meyer T, Apfel CC, Chung F, Davis PJ, Eubanks S, Kovac A, Philip BK, Sessler DI, Temo J, Tramer MR,
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11. Best RR, Barr HJ. The administration of morphine and antispasmodics in biliary colic. Annals of Surgery
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13. Radnay PA, Duncalf D, Novakovic M, Lesser ML. Common bile duct pressure changes after fentanyl, morphine,
meperidine, butorphanol, and naloxone. Anesth Analg 1984;63:441-4.
14. Helm JF, Venu RP, Geenen JE, Hogan WJ, Dodds WJ, Toouli J, Arndorfer RC. Effects of morphine on the human
sphincter of Oddi. Gut 1988;29:1402-7.
15. Thune A, Baker RA, Saccone GT, Owen H, Toouli J. Differing effects of pethidine and morphine on human
sphincter of Oddi motility. Br J Surg 1990;77:992-5.
16. Elta GH, Barnett JL. Meperidine need not be proscribed during sphincter of Oddi manometry. Gastrointest
Endosc 1994;40:7-9.
17. Sherman S, Gottlieb K, Uzer MF, Smith MT, Khusro QE, Earle DT, Brunelle RL, Hawes RH, Lehman GA. Effects
of meperidine on the pancreatic and biliary sphincter. Gastrointest Endosc 1996;44:239-42.
18. Borody TJ, Quigley EM, Phillips SF, Wienbeck M, Tucker RL, Haddad A, Zinsmeister AR. Effects of morphine
and atropine on motility and transit in the human ileum. Gastroenterology 1985;89:562-70.
19. Lee F, Cundiff D. Meperidine vs morphine in pancreatitis and cholecystitis. Arch Intern Med 1998;158:2399.
20. Thompson DR. Narcotic analgesic effects on the sphincter of Oddi: a review of the data and therapeutic
implications in treating pancreatitis. Am J Gastroenterol 2001;96:1266-72.
21. Aly EE, Shilling RS. Are we willing to change? Anaesthesia 2000;55:419-20.
22. Little D, Tovell R. The role of analgesia and anesthesia in the production of asphyxia neonatorium. Journal of
the Indiana State Medical Association 1949;42:201-10.
23. Ullman R, Smith LA, Burns E, Mori R, Dowswell T. Parenteral opioids for maternal pain relief in labour. Cochrane
Database Syst Rev 2010:CD007396.
24. Rayburn WF, Smith CV, Parriott JE, Woods RE. Randomized comparison of meperidine and fentanyl during
labor. Obstet Gynecol 1989;74:604-6.
25. Prasertsawat OP, Herabutya Y, Chaturachinda K. Obstetric analgesia: comparison between tramadol, morphine
and pethidine. Current Therapeutic Research, Clinical and Experimental 1986;40:1022-8.
26. Sliom CM. Analgesia during labour: a comparison between dihydrocodeine and pethidine. S Afr Med
J 1970;44:317-9.
27. Volikas I, Male D. A comparison of pethidine and remifentanil patient-controlled analgesia in labour. Int J Obstet
Anesth 2001;10:86-90.
28. Tomson G, Garle RI, Thalme B, Nisell H, Nylund L, Rane A. Maternal kinetics and transplacental passage of
pethidine during labour. Br J Clin Pharmacol 1982;13:653-9.
25
29. Belfrage P, Boreus LO, Hartvig P, Irestedt L, Raabe N. Neonatal depression after obstetrical analgesia with
pethidine. The role of the injection-delivery time interval and of the plasma concentrations of pethidine and
norpethidine. Acta Obstet Gynecol Scand 1981;60:43-9.
30. Kuhnert BR, Linn PL, Kennard MJ, Kuhnert PM. Effects of low doses of meperidine on neonatal behavior.
Anesth Analg 1985;64:335-42.
31. Gerdin E, Salmonson T, Lindberg B, Rane A. Maternal kinetics of morphine during labour. J Perinat Med
1990;18:479-87.
32. Ngan Kee WD. Epidural pethidine: pharmacology and clinical experience. Anaesth Intensive Care 1998;26:247-55.
33. Paech MJ, Moore JS, Evans SF. Meperidine for patient-controlled analgesia after cesarean section. Intravenous
versus epidural administration. Anesthesiology 1994;80:1268-76.
34. Fanshawe MP. A comparison of patient controlled epidural pethidine versus single dose epidural morphine for
analgesia after caesarean section. Anaesth Intensive Care 1999;27:610-4.
35. Rosaeg OP, Lindsay MP. Epidural opioid analgesia after caesarean section: a comparison of patient-controlled
analgesia with meperidine and single bolus injection of morphine. Can J Anaesth 1994;41:1063-8.
36. Macarthur A, Imarengiaye C, Tureanu L, Downey K. A randomized, double-blind, placebo-controlled trial of
epidural morphine analgesia after vaginal delivery. Anesth Analg 2010;110:159-64.
37. van Laarhoven AI, Vogelaar ML, Wilder-Smith OH, van Riel PL, van de Kerkhof PC, Kraaimaat FW, Evers AW.
Induction of nocebo and placebo effects on itch and pain by verbal suggestions. Pain 2011;152:1486-94
38. Siddiqui N, Freidman Z, McGeer A, Carvalho JC, Davies S. Should gowning be the standard practise for epidural
anesthesia. Poster session presented at Canadian Anesthesiologists Society, Toronto, Canada 2011.
39. Kranke P, Eberhart LH, Roewer N, Tramer MR. Pharmacological treatment of postoperative shivering:
a quantitative systematic review of randomized controlled trials. Anesth Analg 2002;94:453-60.
40. de Witte J, Deloof T, de Veylder J, Housmans PR. Tramadol in the treatment of postanesthetic shivering. Acta
Anaesthesiol Scand 1997;41:506-10.
41. Bhatnagar S, Saxena A, Kannan TR, Punj J, Panigrahi M, Mishra S. Tramadol for postoperative shivering:
a double-blind comparison with pethidine. Anaesth Intensive Care 2001;29:149-54.
42. Mohta M, Kumari N, Tyagi A, Sethi AK, Agarwal D, Singh M. Tramadol for prevention of postanaesthetic shivering:
a randomised double-blind comparison with pethidine. Anaesthesia 2009;64:141-6.
43. Kaiko RF, Foley KM, Grabinski PY, Heidrich G, Rogers AG, Inturrisi CE, Reidenberg MM. Central nervous system
excitatory effects of meperidine in cancer patients. Ann Neurol 1983;13:180-5.
44. Hubbard GP, Wolfe KR. Meperidine misuse in a patient with sphincter of Oddi dysfunction. Ann Pharmacother
2003;37:534-7.
45. Kalso E. How different is oxycodone from morphine?[comment]. Pain 2007;132:227-8.
46. Murray A, Hagen NA. Hydromorphone. J Pain Symptom Manage 2005;29:S57-66.
47. Polonio P, Lisbon MB. Pethidine addiction. Lancet 1947;249:592-4.
48. Himmelsbach C. Further studies of the addiction liability of demerol. Journal of Pharmacology and Experimental
Theraputics 1943;79:5-.
49. Izenwasser S, Newman AH, Cox BM, Katz JL. The cocaine-like behavioral effects of meperidine are mediated
by activity at the dopamine transporter. Eur J Pharmacol 1996;297:9-17.
50. Daglish MR, Williams TM, Wilson SJ, Taylor LG, Eap CB, Augsburger M, Giroud C, Brooks DJ, Myles JS,
Grasby P, Lingford-Hughes AR, Nutt DJ. Brain dopamine response in human opioid addiction. Br J Psychiatry
2008;193:65-72.
51. Molloy A. Does pethidine still have a place in therapy? Australian Presciber 2002;25:12-3.
52. Cadman M, Bell J. Doctors detected self-administering opioids in New South Wales, 1985-1994: characteristics
and outcomes. Med J Aust 1998;169:419-21.
53. Ward CF, Ward GC, Saidman LJ. Drug abuse in anesthesia training programs. A survey: 1970 through 1980.
JAMA 1983;250:922-5.
54. Isbell H, White WM. Clinical characteristics of addictions. Am J Med 1953;14:558-65.
55. Bryson EO, Levine A. One approach to the return to residency for anesthesia residents recovering from opioid
addiction. J Clin Anesth 2008;20:397-400.
56. Bryson EO. Should anesthesia residents with a history of substance abuse be allowed to continue training in clinical
anesthesia? The results of a survey of anesthesia residency program directors. J Clin Anesth 2009;21:508-13.
57. Bryson EO, Silverstein JH. Addiction and substance abuse in anesthesiology. Anesthesiology 2008;109:905-17.
58. University of Wisconsin Pain and Policy Studies Group. Availability of morphine and pethidine in the world and
Africa. http://wwwpainpolicywiscedu/publicat/monograp/africa06pdf 2006.
59. NDS Transaction Data, Office of Chemical Safety, Australian Government on Health and Aging. Unpublished
data 2011.
27
28
These figures highlight an interesting discrepancy between pure lumbar punctures and spinal anaesthesia.
It has been postulated that the lower incidence of meningitis with spinal anaesthesia compared to lumbar punctures
may be due to the fact that people undergoing spinal anaesthesia are generally not infected (whereas those
undergoing LP generally have a source of infection) and also the bacteriostatic properties of local anaesthetics.2
Another issue is that post spinal meningitis is probably under-diagnosed. As mentioned, the most common symptom
(an isolated headache) may be confused with a post-dural puncture headache.
Abscess Formation
Like meningitis, the incidence of epidural abscess is low.10 Most appear as individual case reports or in retrospective
reviews. Based on current data, it appears that most epidural abscesses are due to infections of skin, soft tissue,
spine or haematogenous spread rather than due to catheter placement. The retrospective review of Baker et al
reported epidural abscess to account for 2-12 cases per 100 000 admissions to tertiary hospitals.11 The most
commonly identified organisms were S. aureus (57%), streptococci (18%) and Gram negative bacilli (13%). Out of
the 39 cases reported, only 1 was attributed to epidural catheter placement. Similarly, Ericsson et al reported 10
cases of epidural abscess occurring at one teaching hospital over 10year period.12 Of the 10 cases, only 1 was
attributed to epidural catheter placement. The remainder were due to repeated lumbar puncture in patients with
meningitis (2 cases), a paravertebral injection (1 case) and spontaneous (6 cases).
When reviewing the literature limited to neuraxial blockade, there is equal paucity of data. The incidence appears
to be dependent on a variety of factors including population sampled (eg obstetric versus surgical), duration that
catheter was in situ and whether the patient was immuno-compromised. The incidence quoted ranges from 1:1930
(Wang et al)13 to 1:100000 (Aromaa et al).14 Analysis of the patients who developed epidural abscess has led to
identifying various risk factors that may increase its likelihood. These include poor aseptic technique, immunocompromised patients (including diabetics, patients on steroids, alcoholism, cancer), multiple attempts at insertion,
type of surgery (urology and gynaecology more common due to risk of bacteraemia) and traumatic insertion.15
Although a theoretical risk, the reports of blood patch causing infectious complications appear to be limited to
superficial abscess (Collis et al).16 Pre-existing sepsis is regarded as a risk factor despite there being very little
evidence to support this.
As mentioned, despite the lack of data, pre-existing sepsis is regarded as a relative contraindication to neuraxial
blockade. In fact the current best evidence is that pre-existing sepsis does not increase the likelihood of infectious
complications. Two studies that showed this involved women with chorioamnionitis.
Bader et al investigated the use of regional anaesthesia in patients with chorioamnionitis.17 Out of 10047 women,
319 were identified as having chorioamnionitis based on the presence of 2 or more of the following: pyrexia
(>38 Celsius) on 2 or more occasions, maternal leukocytosis (white cell count > 20 000/L), tachycardia (pulse>120/
min), foul smelling amniotic fluid and uterine tenderness. Of the 319 women identified, 100 had blood cultures
taken, of which 8 were consistent with a bacteraemia. 293 of the 319 women had some form of neuraxial blockade
43 of these women had peri-procedural antibiotics. None of the 319 women, including those with a documented
bacteraemia, developed infectious complications.
Goodman et al also reported similar results.18 They retrospectively reviewed the records of 531 paturients who
had some form of neuraxial blockade and were then later identified as having chorioamnionitis. Of the 531 women,
146 had blood cultures taken. Thirteen of these were positive. Antibiotics were given prior to the block in
123 patients whilst one-third of patients had no antibiotics during the entire peripartum period. Like reported by
Bader and colleagues, there were no infectious complications identified in any of the patients.
Another paper that supports this conclusion is a retrospective audit conducted at a single centre over a ten-year
period.19 Forty-six epidurals were inserted in children who had a pneumonic empyema that required thoracotomy/
decortication. Of the 46 patients, 23 exhibited signs of sepsis (temperature >38 C and white cell count > 14 000);
21 had a leukocytosis but no pyrexia; 2 had a normal white cell count and were afebrile. These patients were
followed up for three years post discharge. None of the patients developed any infectious complications, even at
long term follow up. Whilst it may be argued that with 46 patients, it would be difficult to detect even one epidural
abscess (given its low incidence), the results are nevertheless compelling.
A retrospective review by Steffen et al highlighted the fact that bacterial colonisation does not translate into
infectious complications.20 Steffen et al performed a retrospective study of 502 epidurals inserted for abdominal,
thoracic or trauma surgery. A standardised aseptic technique and post insertion dressing was employed. There
was a daily monitoring of the puncture site. The catheter tips were removed in a sterile fashion and cultured. The
average catheterisation duration was 5 days. What was surprising was that despite an aseptic technique and
dressing, there was a unexpectedly high bacterial colonisation rate (5.8%). The predominant bacterium cultured
was S. epidermidis (76%). The patients were all followed up for 6 months post insertion. No patient developed
infectious complications despite the apparently high colonisation rate.
29
Recently, the results of a UK survey regarding epidural analgesia in patients with sepsis undergoing laparotomy
were published.22 This was a nation wide survey to 304 anaesthetic departments within the United Kingdom. The
survey consisted of questions as to whether a policy existed for the use of epidural analgesia in sepsis and questions
related to two vignettes. The response rate was 67% (211 departments). Only five hospitals (2%) had a policy
regarding the use of epidurals in the face of sepsis. This perhaps highlights the fact that many people still hold
conventional teachings to be true and thus do not require a policy. One hundred and fifty two (82%) of the 185
respondents who routinely use an epidural for a laparotomy reported that they would do so in a patient with a
suspected small bowel perforation but no signs of a systemic inflammatory response syndrome (SIRS). In patients
with clearly defined SIRS, forty-nine respondents (27%) said that they would use epidural analgesia. The main
reason cited for not using an epidural was fear of epidural abscess (116 respondents) followed by fear of haemodynamic
instability (102 respondents) and contraindication to potential use of activated protein C in management of sepsis
(23 respondents). Although no consensus was made, it did highlight the changing opinion regarding the use of
epidurals in the face of sepsis amongst anaesthetists in the United Kingdom.
RECOMMENDATIONS
The notion that neuraxial instrumentation is contraindicated during sepsis is controversial. The perceived increased
risk of infective complications is based on case series and older studies (of limited relevance). Whilst there is a
theoretical increase in risk, this is not seen when large retrospective studies are reviewed. The incidence of infective
complications remains low. Certainly, a high bacterial colonisation rate does not translate to a high infectious
complication rate. This then suggests that other factors also play a role in determining the likelihood of developing
infectious complications, such as diabetes, steroid therapy, alcoholism and cancer. The evidence that neuraxial
infection in the face of sepsis is limited, but may indicate that there is not an increased risk. As such the following
recommendations may be made:
1. Infectious complications as a result of neuraxial blockade are rare but potentially serious.
2. The rate of infection must be minimised by adhering to strict aseptic technique (i.e. gown/gloves/mask/hat/
drapes/alcohol based antiseptic).22
3. The use of aseptic technique does not eliminate the risk of infectious complications.
4. Rather than viewing sepsis as an absolute contraindication to neuraxial blockade (traditional view), it should
be viewed as a relative contraindication.
5. Each case should be reviewed on its merits. A risk-benefit analysis needs to be performed. If there is a
compelling reason to perform neuraxial blockade in the face of sepsis, it should be carried out using
periprocedural antibiotics.
6. The patient will need to be monitored closely postoperatively for signs of infection.
30
REFERENCES
1. Eissa D, Carton EG, Buggy DJ. Anaesthetic management of patients with severe sepsis. BJA 2010;105:734-43.
2. Wedel DJ, Horlocker TT. Regional Anaesthesia in the Febrile or Infected Patient. Reg Anes Pain Med 2006;31:
324-33.
3. Weed LH, Wegeforth P, Ayer JB, Felton LD. The production of meningitis by release of cerebrospinal fluid during
an experimental septicemia. JAMA 1919;72:190-93.
4. Wegeforth P, Latham JR. Lumbar puncture as a factor in the causation of meningitis. Am J Med Sci 1919;158:
183-202.
5. Carp H, Bailey S. The association between meningitis and dural puncture in bacteremic rats. Anesthesiology
1992;76:739-42.
6. Kilpatrick M, Girgis N. Meningitis-A complication of spinal anesthesia. Anesth Analg 1983;62:513-5.
7. Kane RE. Neurologic deficits following epidural or spinal anaesthesia. Anesth Analg; 1981 60:150-61.
8. Holloway J, Seed PT, OSullivan G, Reynolds F. Paraesthesia and nerve damage following combined spinal
epidural and spinal anaesthesia: a pilot survey. Int J Obstet Anesth 2000;9:151-5.
9. Moen V, Dahlgren N, Irestedt L. Severe neurological complications after central neuraxial blockades in Sweden
1990-1999. Anesthesiology 2004;101:950-59.
10. Grewal S, Hocking G, Wildsmith JAW; Epidural Abscess; BJA; 2006; 96;292-302.
11. Baker AS, Ojemann RG, Swartz MN, Richardson EP Jr. Spinal Epidural Abscess; NEJM; 1975; 293; 463-8.
12. Ericsson M et al; Spinal epidural abscesses in adults: review and report of iatrogenic cases; Scand J Infect
Dis; 1990; 22; 249-57.
13. Wang LP, Hauerberg J, Schmidt JF. Incidence of spinal epidural abscess after epidural analgesia: a national
1-year survey. Anesthesiology 1999;91:1928-36.
14. Aromaa U, Lahdensuu M, Cozanitis DA. Severe complications associated with epidural and spinal anaesthesias
in Finland 1987-1993. A study based on patient insurance claims. Acta Anaesthesiol Scand 1997;41:445-52.
15. Horlocker TT, Wedel DJ. Infectious complications of regional anesthesia; Best Prac Research Clin Anesth
2008;22:451-75.
16. Collis RE, Harries SE. Subdural Abscess and infected blood patch complicating regional anaesthesia for labour.
Int J Obstet Anesth 2005;14:246-51.
17. Bader AM, et al. Regional anesthesia in women with chorioamnionitis. Reg Anesth 1992;17:84-6.
18. Goodman EJ, et al. Safety of spinal and epidural anesthesia in parturients with chorioamnionitis. Reg Anesth
1996;21:436-41.
19. Kotze A, et al. Audit of epidural analgesia in children undergoing thoracotomy for decortication of empyema.
BJA 2007;98:662-6.
20. Steffen P, et al. Bacterial contamination of epidural catheters: microbiological examination of 502 epidural
catheters used for postoperative analgesia. J Clin Anesth 2004; 16:92-7.
21. Nightingale J, Burmeister L, Hopkins D. A National Survey of the use of epidural analgesia in patients with sepsis
undergoing laparotomy. Anaesthesia 2011;66:311-12.
22. Hebl JR. The importance and implications of aseptic techniques during regional anesthesia. Reg Anesth Pain
Med 2006;31:311-23.
31
33
34
ANATOMICAL VARIANTS
Anatomical variants have long been touted as the cause of failed and inadequate spinal anaesthesia. Although
difficult to ascribe to individual cases post hoc, numerous studies have demonstrated that the anatomy of the
intrathecal compartment is not simply a cylindrical structure allowing unimpeded flow of csf and introduced agents.
Subarachnoid trabeculae
Intrathecal subarachnoid trabeculae have been described and are formed from arachnoid trabecula cells surrounding
extracellular collagen. Arachnoid trabeculae appear to form a loose and indeed random arrangement, bridging the
subarachnoid space between the more tightly organised arachnoid barrier cell layer and the pia mater.11 However,
they may form more organised and extensive sheets and under examination the collagen content of the spinal
arachnoid trabeculae (or reticular layer) is often more substantial than that of its cranial counterpart.12 Furthermore,
the arachnoid barrier cell layer may at times come into close apposition with the pia mater, the arachnoid trabeculae
being compacted in between, and the subarachnoid space become all but obliterated. As a result of these morphological
characteristics, the free flow of exogenous substances introduced into the csf may be impeded resulting in a
suboptimal block.
subdural block
Certain authors refute the notion of a true potential subdural space.11 Histologically, the meninges, from outside in,
consist of the superficial periosteal dural layer, a meningeal dural layer, a dural border cell layer, arachnoid barrier
cell layer, arachnoid trabeculae, and ultimately the pia mater. The so called subdural space has been argued to
be an artifactual space formed within the dural border cell layer and therefore, intradural. This comes about because
of the existence of many cellular interconnections between the arachnoid (barrier cell layer) and the dura (border
cells). Histological evidence of blood between the cells of the dural border cells in de novo and experimental
subdural haematomas seems to confirm an intradural locale. The dural border cell layer represents a weak layer
of the meninges due to the paucity of intercellular connections, enlarged extracellular spaces, and lack of extracellular
collagen.11,12 Further, the existence of dural border cells lining the capsules of subdural haematomas lends credence
to the fact that the subdural space forms as a result of tearing and disruption of cells within the dural border cell
layer. This lack of a definitive true potential subdural space may explain why subdural injection of local anaesthetic
creates a block that is often patchy and high relative to dose, as the subdural space is artificially and pathologically
created rather than opened up.
Septae
Other anatomical variants have also been described in the literature including the existence of a posterior septum
of the cord formed from the arachnoid trabecula. In a study of human cadaver cords, the posterior septum was
described as progressing from a number of filaments and strands in the cervical area to becoming more extensive
caudad to form a finely-woven, fenestrated mesh in the lumbar region of the cord.18 The posterior septum was
noted to occupy the majority of the posterior subarachnoid space and arose perpendicularly from the pia cord
between the posterior nerve rootlets and even beyond their origins. Although largely fenestrated it is possible that
individual differences in the density of openings may limit the spread of local anaesthetic throughout the subarachnoid
space. The presence of a septum posticum has been demonstrated and was seen to occupy the midline in the
lower thoracic and upper lumbar region dividing the subarachnoid space into two sections. 19 In a clinical correlate,
complete unilateral anaesthesia was described following spinal injection in a 26 year old woman undergoing
caesarean section.20 Despite an uncomplicated procedure with easy identification and aspiration of csf, sensory
and motor blockade was achieved purely on the right side to the T2 level with no demonstrable block on the left.
This persisted into the recovery period after general anaesthesia was performed. The author postulated that the
existence of an imperforate posterior septum or thickening of the dorsolateral membrane surrounding posterior
nerve roots might have been responsible.
Csf volume
Many explicit patient and injectate factors have been postulated to affect the spread of local anaesthetics, however
none have been shown to explain more than 50% of the variability in patient response. However, one small study
demonstrated that both block height and sensory block duration were highly correlated with csf volume (r=0.91
and 0.83 respectively).13 The diluent effect of the csf on local anaesthetics injected into the intrathecal space and
the limitation of spread of effective concentrations of these agents is a plausible and attractive explanation for this
finding. This correlation was supported in a further study wherein removal of 5ml of csf prior to subarachnoid block
led to a higher block14, and a number of case reports have confirmed the presence of a large csf volume in instances
of failed spinal anaesthesia.15,16
Individual csf volumes can vary by a factor of three, and this large interindividual variability makes prediction of
extent and duration an inexact science.17 Unfortunately, correlation between csf volume (and therefore spinal effect
and necessary local anaesthetic dose) and any phenotypic patient characteristic is poor, with body mass index
being the best correlate identified (r=0.40). Increasing body mass index appears to negatively correlate with csf
volume, obese subjects having less csf. This finding may explain in part why obese and pregnant patients are
generally more susceptible to the effects of subarachnoid blockade at same dose compared to their lean counterparts.
35
Nerve roots
A further facet of human anatomy that may have a bearing on efficacy is the target nerve roots themselves and the
ease with which local anaesthetics can diffuse into them. Another cadaveric study demonstrated that the posterior
nerve roots exhibit significant variability in diameter between individuals, with the posterior L5 nerve root area
ranging from 2.33-7.71mm2.21 Anterior nerve roots are generally half as large in diameter, and nerve root diameters
are smaller in the thoracic region and largest in the lumbosacral region. This may explain the enhanced effect of
epidurals in the thoracic region compared to lumbar placement. Despite the dorsal nerve roots being larger, stranding
into individual components was pronounced and would serve to increase the surface area to volume ratio of nerve
roots and facilitate anaesthetic action. It is therefore possible that diffusion characteristics of nerve roots may
themselves affect spinal anaesthesia, and poor effect be partly explained by large diameter posterior nerve roots
that resist stranding.
Deposition
The existence of natural curvatures within the vertebral canal can contribute to inadequate spinal blockade. This
is a particular problem with solutions designed to be hyperbaric as their spread will be influenced by gravity and
thus patient positioning and site of injection. The lumbar lordosis of the spine typically occurs at the L4 level in men
and women22 and may be imagined as the apex down which hyperbaric solutions will flow. Depending on which
side of the apex the injection occurs, anaesthetic solution, in the absence of further patient positioning, will be
encouraged to flow either more cephalad or more caudad and thereby affect block efficacy. It would seem sensible
to aim to inject hyperbaric local anaesthetic solutions no lower than the L3/4 interspace in order to promote cephalad
spread, unless a saddle block is intended or patient positioning is to follow.
Changes in curvature
Alterations of these natural curves may influence the effectiveness of the spinal block. Interindividual differences
in the site of the lumbar apex appear to be small but should be considered as a potential problem. The lowest point
of the thoracic spinal canal will influence the number of thoracic segments blocked. Typically this occurs at the
body of the T8 vertebra. In contrast to the lumbar apex however, the lowest thoracic level of the spinal canal does
exhibit greater individual variability and ranges over the T7-T9 vertebral bodies.22 This may explain the differences
in cephalad spread amongst patients in which the same dose is used. Of greater import is the effect of the gravid
status on the vertebral curvatures. MRI studies have demonstrated that in the supine position with left tilt, the
pregnant patient near term has a lumbar apex in the L4/5 position and the lowest point of the thoracic spine was
more cephalad (at T6-7) compared to non-pregnant women.23 These findings could also account for the increased
efficacy of spinal anaesthesia in pregnant women and the potential problem of inadequate cephalad extent with
hyperbaric solutions when too low an injection site is used.
PATHOLOGY
Dural ectasia or ballooning of the lumbosacral dural sac is commonly found in conditions such as Marfans syndrome
and is a postulated cause of spinal failure. The incidence of dural ectasia in Marfans syndrome is estimated to be
63-92%24,25 and, along with ectopia lentis and aortic dilatation, is one of the major manifestations of the syndrome.
The presence of dural ectasia is not associated with aortic dilatation as such but is associated with back pain, and
the degree of ectasia with the severity of the pain. Similar in effect to the presence of a large csf volume, dural
ectasia has been described in two case reports.26 In these two obstetric cases, continuous spinal anaesthesia failed
to produce a satisfactory block for elective caesarean section despite large doses of bupivacaine, the block being
either patchy or inadequate in its cephalad extent, and reversion to general anaesthesia was required. Postoperative
computed tomography demonstrated dural ectasia in both cases. The authors concluded that dural ectasia resulting
in a large csf volume was the cause of an unsatisfactory block.
Tarlov cysts are an increasingly recognised anatomical variant most likely due to the more widespread use of
magnetic resonance imaging. These cysts are extradural outpouchings of the meninges encasing the posterior
nerve root sheaths and occur most frequently in the lumbosacral region. They may occur either de novo or as a
result of surgery or trauma. Their estimated incidence is between 4.6%27 and 9% and although generally asymptomatic
they may give rise to pain and neurological symptoms of parasthesia, bowel, and bladder disturbance. They
communicate with the intrathecal compartment and as a result contain csf. Enlargement of the cyst is often due
to increasing volumes of csf within them and the cause of the mass effect and symptoms. Furthermore, they may
eventually lose communication with the intrathecal space. Their existence may be another explanation for failure
to achieve satisfactory spinal anaesthesia. Entry of the spinal needle into a Tarlov cyst would lead to aspiration of
csf and deposition of local anaesthetic into the cyst rather than the intrathecal space. The spinal anaesthetic effect
will depend on how much of the solution is able to distribute to the appropriate neural structures from the cyst. If
the cyst has separated entirely from the intrathecal space, a complete failure of spinal block will predictably occur.
Although a postulated cause of spinal failure, to this authors knowledge Tarlov cysts have not been described in
patients following failure of spinal anaesthesia.
36
Pathology associated with previous surgery, spinal stenosis, and damage to nerve roots may also be contributory.
Despite adherence to good technique and apparent uncomplicated administration, spinal blockade may fail due
to inability of spread and/or diffusion into neural structures. A published account of inadequate spinal anaesthesia
after two apparently uncomplicated spinal punctures occurred in a male patient who had previously received
intrathecal chemotherapy.28 The authors suggested chemotherapy-induced nerve root changes may have been
responsible. Pathological conditions of the spinal cord itself, such as syringomyelia, may render subarachnoid block
unsuccessful and have also been reported.29 Adhesions between nerve roots or between the nerve root and the
arachnoid membrane have been demonstrated by spinaloscopy and may hinder local anaesthetic action.19 Diabetes
has also been suggested as a potential cause of failed subdural anaesthesia resulting from glycosylation of nerve
roots in a manner similar to the well-recognised damage of autonomic and peripheral nerves in this condition.
LOCAL ANAESTHETIC MALDISTRIBUTION
Spinal anaesthesia relies on the appropriate concentration of local anaesthetic acting on the appropriate neural
structures. Introduction of a spinal needle, demonstration of free flow of csf, and the ability to aspirate confirms
injection into the csf milieu. However, what concentration of local anaesthetic acts on nerve structures is indeterminate.
As has been suggested in other reports16, csf volume, and presumably thereby local anaesthetic concentrations,
play an important role in subarachnoid efficacy. One study reported on the csf concentrations of bupivacaine in 20
patients following failed spinal injection and preceding a repeat injection.30 Of these 20 patients, 60% had concentrations
greater than 73g/ml, this arbitrary threshold being the 5th percentile of csf concentrations producing effective block
in another study by Ruppen and colleagues.31 Of the 6 patients with a completely failed spinal, one had bupivacaine
csf concentrations in excess of this threshold [106g/ml]. Amongst the 14 patients with incomplete spinal anaesthesia,
eleven were above this threshold with one demonstrating a csf bupivacaine concentration of 1020g/ml!
The authors of this study conjectured that given 60% of patients with either incomplete or totally failed spinal
anaesthesia had csf bupivacaine concentrations above the threshold where one would expect satisfactory anaesthesia,
maldistribution of local anaesthetic was a possible major factor. In particular, the patient with a concentration of
1mg/ml after an injectate of 17.5mg of bupivacaine, would presuppose a csf volume of 17.5ml, well below the
volumes estimated in previous studies,13 and unlikely given the expectation of a high block with such a small csf
volume. This particular case strongly suggests maldistibution and non-uniform spread of local anaesthetic was
responsible.
Certainly anatomical considerations as alluded to above, may hinder effective spread of local anaesthetic
throughout the intrathecal compartment, and compartmentalisation would explain seemingly adequate csf
concentrations with inadequate block or even the absence of any block. Models of the intrathecal compartment
have demonstrated this as a potential issue.32
Ruppens particular study involved bupivacaine concentration estimations in 60 patients subjected to a 2nd
diagnostic lumbar puncture, all of whom had had a successful initial spinal block.31 He demonstrated highly variable
concentrations with no correlation between concentration and block extent at particular time points. Whilst
interpretation of their results is limited by methodology, the highly variable concentrations suggest non-uniform
spread of local anaesthetic within the csf may be a normal occurrence. Multiple factors dictating this spread have
been elaborated.33 Fortunately, the factors most significant are largely under the control of the anaesthetist, these
being local anaesthetic baricity, patient positioning following deposition, and dosage.
Aside from the development of a less than optimal block, the clinical significance of maldistribution of local
anaesthetic within the subarachnoid space is the possibility of neurotoxicity associated with high concentrations.
This potential is exacerbated with repeat injections since, if maldistribution is responsible and compartmentalisation
has resulted in high concentrations in restricted csf regions, a repeated injection could undergo the same process
and elevate concentrations further. The potential for neurotoxicity is thus augmented.
There is a longstanding concern within the anaesthetic community over neurotoxicity of local anaesthetic
solutions. In vitro and animal research has demonstrated this toxicity convincingly34,35,36 and many solutions have
been implicated. The local anaesthetic agent used, the concentration and dose, and the time of exposure to the
anaesthetic agent all appear significant. A higher concentration and dosage (presumably through a concentration
effect) are more neurotoxic, whilst lignocaine, particularly at high concentration, may be worse than bupivacaine
(although equipotent studies on neurotoxicity are lacking). Hyperbaricity may predispose to pooling and worsen
concentration-associated neurotoxicity.
In the clinical literature there are numerous reports of significant neurotoxicity predominantly involving high
concentrations of lignocaine37,38,39,40 through a continuous spinal catheter technique. A catheter may predispose to
both the use of higher doses than a single shot technique, and continuous or repeated delivery of local anaesthetic
that undergoes maldistribution as a practitioner attempts to achieve a satisfactory block. However, cauda equina
syndrome has also been reported in cases involving single shot techniques using 5% hyperbaric lignocaine41 and
following a repeat single shot of dibucaine.42 Conus medullaris injury has been described following tetracaine and,
subsequently, lignocaine spinal anaesthesia43, and numerous cases of severe neurologic deficits have been published
involving multiple older spinal agents, tetracaine included.44 In a prospective study of complications related to
regional anaesthesia, 12 cases of cauda equina syndrome were identified following uncomplicated subarachnoid
block.45 Nine of these had received hyperbaric lignocaine, and 3 had received hyperbaric bupivacaine. These latter
three however, had only transient neurological deficits.
37
Many of such reported cases have demonstrated clinical evidence of local anaesthetic maldistribution with a
restricted block. In the instance of a failed spinal if a repeat injection is to be is performed, it would seem prudent
to limit the total dose of local anaesthetic to that which is reasonable for a single injection. Furthermore, testing of
the sacral dermatomes in the circumstance of a totally failed block may give an insight into the problem of
maldistribution and the potential for neurotoxicity with repeat injection.
LOCAL ANAESTHETIC RESISTANCE
Local anaesthetic resistance is an intriguing postulated cause of spinal failure. Despite the lack of definitive molecular
or genetic evidence, there are multiple anecdotal reports within the literature that suggest resistance exists as a
true phenomenon.
Case reports within the literature vary in the local anaesthetic used, techniques, and attempts to redress failure.
Reports where patients have demonstrated failure to one type of anaesthetic and success subsequently with another
type and/or skin anaesthesia to the original local anaesthetic are more tenuous for complete resistance. This variable
response may suggest either technical failure, a selective resistance, or possibly a site concentration problem as
previously elaborated.
One report described the case of a 77 year old man who underwent continuous spinal anaesthesia for cystoscopy
with an end-hole catheter inserted without incident.46 Despite being able to freely aspirate csf and injection of a
total of 125mg of hyperbaric lignocaine in two aliquots over 25 minutes, the patient failed to develop any demonstrable
block. Csf was aspirated from the catheter following lignocaine injection and subsequent failure, and analysis
demonstrated concentrations too high to measure. 0.75% bupivacaine however was able to provide an adequate
block at a conventional dose. The patient returned a second time for a transurethral resection of the prostate and
again underwent continuous spinal anaesthesia. Lignocaine was used as before, and again failed to result in any
block, with successful anaesthesia achieved with bupivacaine. Interestingly, subcutaneous lignocaine from the
same vial resulted in skin anaesthesia. The authors concluded that the most likely explanation was the existence
of local anaesthetic resistance to lignocaine. However this conclusion would need to be explained by failure within
the same class of local anaesthetic since bupivacaine was used as the rescue drug after lignocaine. Additionally,
their conclusion does not explain why skin anaesthesia was achieved.
Another author published a case report of a 48 year old male who underwent continuous spinal anaesthesia on
two occasions with intrathecal tetracaine.47 Despite apparent successful insertion of the catheter, no sensory or
motor blockade resulted. On the second occasion following failure of the spinal anaesthetic, radiographic contrast
was injected through the catheter and demonstrated dispersion of the contrast throughout the csf. Subcutaneous
tetracaine was effective in producing anaesthesia, with the author concluding that anaesthetic resistance was
excluded by such means. However, as demonstrated by the previous case, complete failure of spinal anaesthesia
has been reported where the same anaesthetic agent produced skin anaesthesia.
A case report was published of a 55 year old female who presented with lower limb and perianal numbness and
an abnormal magnetic resonance imaging study suggestive of transverse myelitis.48 Attempts at lumbar puncture
were hampered by inability to produce skin anaesthesia with up to 15ml of 1% lignocaine being used. The procedure
was abandoned and performed under general anaesthesia. On further questioning the patient gave a history of
failure of local anaesthesia with dental treatments and a similar problem with her father.
Reports of the failure of patients to achieve demonstrable subarachnoid block using multiple forms of local
anaesthetics on multiple occasions and in multiple settings, is more convincing for true resistance to local anaesthetics.
Reports of such failure are summarised:
In a series of 71 patients, hyperbaric 5% lignocaine was used in 30 patients and in five of these there was
complete absence of motor or sensory block.49 In four of these five, csf lignocaine levels where measured and
found to be at high enough concentration to warrant a successful block. Successful anaesthesia was achieved
when 0.75% bupivacaine was used in four patients. However, one patient failed to develop any subarachnoid block
with neither hyperbaric lignocaine (csf concentrations adequate when tested) nor 0.75% bupivacaine and also gave
a history of multiple regional anaesthetic failures including failed brachial plexus and wrist blocks, and multiple
failures of local anaesthetics used for dental restorations.
In a further case report a female parturient failed to achieve any sensory or motor block with a single shot spinal
anaesthetic for a caesarean section despite evidence of technical proficiency.50 The local anaesthetic agent used
was 0.75% bupivacaine. Interestingly, she also failed to develop skin anaesthesia with 1% lignocaine sourced from
two different lots preventing attempts at a combined spinal-epidural technique as originally planned. General
anaesthesia was performed and no block was discernable on wakening. Subsequent history revealed the same
problems with her previous caesarean in which attempts to achieve skin anaesthesia were unsuccessful, the regional
block failed, and reversion to general anaesthesia was necessary. Furthermore, the patient related repeated failures
of local anaesthetics for intravenous line placement, and a series of dental procedures despite three different types
of anaesthetics being used. A published letter responded to this relating a case of a failed spinal in a patient having
a history of repeated failures of local anaesthetics for dental and dermatological procedures.51
38
The incidence of resistance to local anaesthetics was investigated in a pilot screening project.52 This investigator
had noted a significant number of patients in whom local anaesthetics were ineffective after well-performed pain
procedures. Patients with a history of poor response to local anaesthetic injections were tested with a panel of
lignocaine, bupivacaine, and mepivacaine using skin infiltration. Of 1198 patients seen over a one month period in
the clinic, 250 were tested after a suggestive history. 7.5% of these patients were found to be hypoaesthetic to
only mepivacaine, 3.8% to lignocaine, and the remainder hypoaesthetic to all agents, or bupivacaine. This pilot
study seemed to suggest a relatively high incidence of resistance to local anaesthetics in a pain clinic population.
Interestingly, other published reports suggest a high incidence of poor local anaesthetic efficacy in those with red
hair with the melanocortin-1 receptor gene variant.53.54
Local anaesthetics exert their action on the neural sodium channel and a channel mutation has been suggested
as the underlying aberration. The sodium channel site of local anaesthetic action is purported to be the alpha
subunit which is comprised of four homologous domains, each in turn comprised of six helical transmembrane
units. Mutations in the transmembrane segment s6 of domain iv resulted in near abolition of the effect of local
anaesthetic, confirming the significance of this location in local anaesthetic efficacy as well as demonstrating the
possibility of anaesthetic resistance due to receptor mutations.55 However, local anaesthetic activity is more complex
with other sites of the alpha subunit seeming to be important in local anaesthetic activity. Mutations of the
batrachotoxin binding site at s6 of domain i reduce local anaesthetic affinity,56 whilst other investigators have shown
enhanced affinity with disparate mutations.57 Conversely, mutations of other domains have been shown to affect
batrachotoxin binding but leave local anaesthetic activity intact.58
Recently, human mutations involving the TTX-sensitive voltage-gated sodium channel subtype Na1.7 have been
implicated in the condition primary hereditary erythromelalgia.59,60 In this condition, patients experience a painful
neuropathy characterised by intense burning pain and erythema of the peripheries. The Na1.7 subtype is expressed
at high levels in human dorsal root and sympathetic ganglia and the genetic mutations are multiple. The analgesic
response to treatment with lignocaine infusions in these patients is variable 61 and has been explained on the basis
of the different mutations which may variably affect the lignocaine binding site. One study on the N395K mutation,
which affects the local anaesthetic binding site of the sodium channel, demonstrated reduced lignocaine inhibition
in vitro.62 This is significant in that the association of a human mutation of a sodium channel subtype (demonstrated
in vitro to render lignocaine less effective) in a population of patients in whom treatment with lignocaine is recognised
to be variably effective, raises the very real possibility that genomic mutations affecting the local anaesthestic
binding site may lead to functional local anaesthetic resistance.
As the cause of spinal failure, local anaesthetic resistance must of itself be extraordinarily rare. Our understanding
of the normal sodium channel and the mechanisms of local anaesthetic efficacy are still in their infancy. However,
further study seems warranted in delineating the phenomenon of resistance given anecdotal reports and the evidence
of channel mutations able to influence local anaesthetic molecular binding.
CHEMICAL FAILURE
Chemical failure is a commonly touted aetiology of failed spinal anaesthesia. In the circumstance of a technically
straightforward procedure that results in a totally failed spinal or a block that is unsatisfactory, it is compelling to
ascribe blame to the injected material. So much so that many authors have published their experiences of such
failure.63,64,65,66 However problems with the local anaesthetic, after assays have been conducted on such samples,
have never been identified by the manufacturer. AstraZeneca examined 562 such samples within a 6 year period
to 2007 and all were found to be within the products specifications.10 Furthermore, the majority of case reports
published in the literature have demonstrated an effect of the local anaesthetic, albeit an unsatisfactory one, and
possibly chemical failure would be more likely to result in a totally failed spinal anaesthetic. Given the multiple
potential causes of spinal failure presented in this review and the repeated negative testing on failed samples, the
reality of chemical failure as a significant cause may be questionable.
CONCLUSION
As a specialty, anaesthetists have grown accustomed to spinal anaesthesia as an effective and reliable means of
rendering surgery possible. It is often with considerable surprise that a practitioner discovers the subarachnoid
block to have failed, partially or in its entirety. Hopefully, these relatively rare occurrences can be made more easily
explained by the host of potential problems elaborated in this review. And whilst the aetiologies presented are
mostly speculative and difficult to prove, perhaps the mystery of the failed spinal may be more acceptable, knowing
there are a myriad potential ways to have led to the disappointing spinal.
39
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41
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43
44
Figure 1. ASIA standard neurological classification of spinal cord injury chart. (American Spinal Injury
Association: International Standards for Neurological Classification of Spinal Cord Injury, revised 2011;
Atlanta, GA. Reprinted with permission 2011.)
45
AIRWAY MANAGEMENT
Emergency or semi-elective airway management may be required during the hospital stay of the patient with known
or suspected SCI. In Australia 53% of SCI cases involves the cervical segments. The most common cervical spine
injury is located at C4C5 level, accounting for 61% of all cervical SCI cases and 32% of all documented neurological
injuries.1 Up to 10% of patients with head injury will also have a cervical SCI. As such, a high index of suspicion
should be employed during airway management of the traumatically injured patient, especially with head injury.
In the normal cervical spine, direct laryngoscopy causes extension at upper cervical joints, minimal movement
at C4-C7, and flexion at the cervico-thoracic junction.3,4,5 Instability involving subaxial cervical vertebrae may act
as a second site for extension during laryngoscopy, leading to iatrogenic spinal cord injury.
Spinal immobilisation and Manual In Line Stabilisation (MILS) are logical choices and are recommended by
current ATLS guidelines as a standard for airway intervention in patients with known or suspected cervical injury.6
The goal of MILS is to apply equal opposing forces to the head and neck, limiting movement during airway
intervention. MILS reduces cervical movement better than a rigid collar during laryngoscopy, and an improved view
is obtained, owing to better mouth opening.7,8 The incidence of neurological impairment due to endotracheal
intubation when MILS is used has been reported to be extremely rare.9 Care should also be taken with mask
ventilation. The minimum of jaw thrust and chin lift should be used to maintain the patients airway.10,11 Cricoid
pressure remains controversial however, a cadaver model of upper cervical injury showed that cricoid pressure did
not result in significant cervical movement.12
The patient presenting to theatre for operative fixation of their spine or associated injuries affords time to plan
successful airway management. Patients with pre-existing cervical spinal pathology including spondylosis, rheumatoid
arthritis, Klippel-Feil, ankylosing spondylitis, tumor, pre-existing cervical fusion and upper (vs. lower) cervical disease
or physical obstacles such as cervical traction or halo may increase the difficulty of airway interventions.13
No single intubation technique has been proved superior to others. Patients without existing neurological
impairment and acceptable radiological findings can be managed with direct laryngoscopy with MILS. If the airway
is potentially difficult and the patient has an existing neurological deficit and C-spine instability, an alternative should
be considered. Awake intubation has not been shown to be superior to asleep intubation.14,15,16 Videolaryngoscopes
including the Airtraq (AT) (Prodol Ltd., Vizcaya, Spain), and Glidescope (GS)(Verathon Ltd., Bothell, USA) have
become a viable alternate technique. Numerous studies of their use in various scenarios exist but it is difficult to
draw conclusions due to the heterogeneity of the studied populations. Studies in normal subjects with either MILS
or hard collar in-situ to stimulate cervical immobilisation showed that AT performed better than direct laryngoscopy
(DL), but GS compared to DL yielded conflicting results. GS prolonged the intubation time for experienced
laryngoscopists, but not for new learners. Studies looking at cervical motion suggested less movement occurred
with AT, while GS again produced equivocal results.17
Reinforced endotracheal tubes are less likely to kink during patient positioning and also prevent tracheal
compression during anterior cervical procedures. The decision to extubate postoperatively is influenced by factors
including the extent of surgery, complications (e.g. recurrent laryngeal nerve injury), duration, prone positioning,
blood loss and subsequent fluid resuscitation, and ease of intubation. The presence of a cuff leak in the spontaneously
breathing patient has not consistently been shown to predict subsequent airway obstruction from edema. An airway
exchange catheter may facilitate emergent re-intubation in the event of obstruction from airway edema. Good
clinical judgment is necessary, and if concern remains, delayed extubation should be considered.
BLOOD PRESSURE MANAGEMENT
Traumatic SCI may be complicated by systemic hypotension and reduced spinal cord perfusion pressure (SCPP).18
Hypotension should be avoided to prevent the worsening of secondary neurologic injury.
Spinal cord perfusion is autoregulated in a similar fashion as cerebral blood flow.19 Systemic hypotension may
result either from hemorrhage from associated traumatic injuries (chest, intra-abdominal, retroperitoneal, pelvic or
long bone fractures) or neurogenic shock, or a combination. Neurogenic shock is hypotension and inadequate
tissue perfusion due to vasodilatation from loss of central sympathetic control.20 It is more common after cervical
SCI and is usually associated with bradycardia from unopposed vagal tone. Increased blood pressure leads to
improved axonal function both in motor and somatosensory tracts of the injured spinal cord.21,22 Current recommended
blood pressure targets include maintenance of mean arterial pressure (MAP) at 85-90mmHg and avoiding systolic
blood pressure below 90mmHg for up to five days post injury.18 These parameters should be maintained perioperatively
and will require judicious use of intravenous fluids, vasopressors and inotropes. Hypotension may also interfere
with neurophysiological monitoring. A retrospective review of anterior cervical fusion cases found that intraoperative
deterioration of evoked potential monitoring was associated with hypotension in 1% of cases.23
46
FLUID MANAGEMENT
Several strategies have been used to minimize intraoperative blood loss. Elevation of the intra-abdominal pressure
should be avoided. An operative table with the Jackson frame attachment is preferable, enabling the abdomen to
hang free. This reduces epidural venous bleeding when compared to positioning prone on the Wilson frame.24
Antifibrinolytic agents have been shown to decrease intraoperative and total perioperative blood loss in patients
undergoing spinal fusion. A randomised study showed an absolute but non-significant decrease in both total
perioperative blood loss and transfusion requirements using aminocaproic acid compared to control.25 A randomised
study of tranexamic acid versus placebo for spinal fusions showed significantly less perioperative blood loss
compared to placebo, but no difference in the amount of blood products transfused between the two groups.26
There was no increase in thromboembolic complications.
A small randomised dose escalation trial using recombinant factor VIIa (rFVIIa) in spinal fusion showed an
absolute but non significant decrease in intraoperative blood loss for the rFVIIa groups at any dose studied.27 One
thromboembolic event causing death was reported in the rFVIIa group.
Studies reporting the effectiveness of cell saver in reducing the need for homologous transfusion have shown
variable results. A recent systematic review of cell saver in routine elective spine surgery concluded that there is
insufficient evidence in the literature to support its cost-effective use.28
Optimal fluid therapy in SCI patients remains unknown. Hypotonic crystalloids such as 5% dextrose and 0.45%
normal saline however, may exacerbate cord swelling and should be avoided. Albumin use is contraindicated in
patients with concurrent traumatic brain injury following report of increased mortality from the SAFE-TBI study.29,30
EVOKED POTENTIAL MONITORING
Modern intraoperative neurological monitoring during spinal surgery includes evoked potential monitoring (sensory
and motor) and spontaneous electromyography (EMG).
Somatosensory evoked potentials (SSEP) are elicited by stimulation over peripheral nerves and recording
responses at some point along the sensory pathway, usually the somatosensory cortex. Motor evoked potential
(MEP) monitoring involves transcortical stimulation over the motor cortex and recording the muscle response. EMG
can detect nerve root irritation by electrode placement in the innervated muscle group.
The aim of evoked potential monitoring is the early detection of worsening spinal cord function, giving the
opportunity to correct offending factors such as: patient position (e.g. neck position, shoulder position), hypotension,
hypothermia, and factors related to the surgical intervention. A recent systematic review indicated that there is only
low level evidence that intraoperative neuromonitoring reduces the rate of new or worsening neurologic deficits.31
Total intravenous anaesthesia (TIVA) without muscle relaxation is required for MEP monitoring. Volatile anesthetics
and nitrous oxide are best avoided as they cause a dose-dependent reduction in MEP signal amplitude, commencing
at low concentrations.
Volatiles suppress cortical SSEPs in a dose dependant way, especially above 0.5 MAC. TIVA provides better
monitoring conditions. Volatile anesthetics may also be used for spontaneous EMG recording, provided muscle
relaxants are avoided. Opioids do not impact evoked potential monitoring and ketamine has been shown to enhance
evoked potential monitoring.32 Dexmedetomidine has been used as a supplement to TIVA, without detriment to
evoked potential monitoring.33,34 A stable anesthesia without significant changes in blood pressure or dosing of
anesthetic agents needs to be provided so that changes in evoked responses may be attributed solely to surgical
technique.
CONCLUSION
The anaesthetist plays a crucial role in the perioperative management of patients with spinal cord injury. The overall
goal of anaesthetic management is the prevention of secondary injury to the spinal cord. This paper presents
an overview to the assessment, and summarises evidence for successful anaesthetic management of the
cord-injured patient.
REFERENCES
1. Norton L. Spinal cord injury Australia 2007-2008. Australian Institute of Health and Welfare. 2010. p. 13,18.
2. Association ASI. Reference Manual of the International Standards for Neurological Classification of Spinal Cord
Injury. American Spinal Injury Association 2003.
3. Lennarson PJ, Smith DW, Sawin PD, Todd MM, Sato Y, Traynelis VC. Cervical spinal motion during intubation:
Efficacy of stabilization maneuvers in the setting of complete segmental instability. J Neurosurg 2001;94:265-70.
4. Lennarson PJ, Smith D, Todd MM, Carras D, Sawin PD, Brayton J, et al. Segmental cervical spine motion
during orotracheal intubation of the intact and injured spine with and without external stabilization. J Neurosurg
2000;92:201-6.
5. Sawin PD, Todd MM, Traynelis VC, Farrell SB, Nader A, Sato Y, et al. Cervical spine motion with direct
laryngoscopy and orotracheal intubation. An in vivo cinefluoroscopic study of subjects without cervical
abnormality. Anesthesiology 1996;85:26-36.
6. American College of Surgeons CoT. Advanced Trauma Life Support Student Course Manual. Advanced Trauma
Life Support Student Course Manual, 8 th ed. Chicago; 2008. p. 168.
47
7. Heath KJ. The effect of laryngoscopy of different cervical spine immobilisation techniques. Anaesthesia
1994;49:843-5.
8. Aoi Y, Inagawa G, Hashimoto K, Tashima H, Tsuboi S, Takahata T, et al. Airway Scope Laryngoscopy Under
Manual Inline Stabilization and Cervical Collar Immobilization: A Crossover In Vivo Cinefluoroscopic Study.
J Trauma 2010.
9. Manoach S, Paladino L. Manual in-line stabilization for acute airway management of suspected cervical spine
injury: Historical review and current questions. Ann Emerg Med 2007;50:236-45.
10. Aprahamian C, Thompson BM, Finger WA, Darin JC. Experimental cervical spine injury model: Evaluation
of airway management and splinting techniques. Ann Emerg Med 1984;13:584-7.
11. Hauswald M, Sklar DP, Tandberg D, Garcia JF. Cervical spine movement during airway management:
Cinefluoroscopic appraisal in human cadavers. Am J Emerg Med 1991;9:535-538.
12. Donaldson WF 3 rd, Heil BV, Donaldson VP, Silvaggio VJ. The effect of airway maneuvers on the unstable
C1-C2 segment. A cadaver study. Spine (Phila Pa 1976) 1997;22:1215-8.
13. Calder I, Calder J, Crockard HA. Difficult direct laryngoscopy in patients with cervical spine disease. Anaesthesia
1995;50:756-63.
14. Popitz MD. Anesthetic implications of chronic disease of the cervical spine. Anesth Analg 1997;84:672-83.
15. Crosby ET, Lui A. The adult cervical spine: Implications for airway management. Can J Anaesth 1990;37:77-93.
16. Suderman VS, Crosby ET, Lui A. Elective oral tracheal intubation in cervical spine-injured adults. Can J Anaesth
1991;38:785-9.
17. Cheyne D, Doyle P. Advances in laryngoscopy: rigid indirect laryngoscopy. F1000 Med Reports 2010, 2:61
18. AANS/CNS. Blood Pressure Management after Acute Spinal Cord Injury. Neurosurgery 2002;50:S58-S62.
19. Kobrine AI, Doyle TF, Rizzoli HV. Spinal cord blood flow as affected by changes in systemic arterial blood
pressure. J Neurosurg 1976;44:12-5.
20. Wuermser LA, Ho CH, Chiodo AE, Priebe MM, Kirshblum SC, Scelza WM. Spinal cord injury medicine. 2. Acute
care management of traumatic and nontraumatic injury. Arch Phys Med Rehabil 2007;88:S55-61.
21. Ploumis A, Yadlapalli N, Fehlings MG, Kwon BK, Vaccaro AR. A systematic review of the evidence supporting
a role for vasopressor support in acute SCI. Spinal Cord 2010;48:356-62.
22. King BS, Gupta R, Narayan RK. The early assessment and intensive care unit management of patients with
severe traumatic brain and spinal cord injuries. Surg Clin North Am 2000;80:855-70.
23. Lee JY, Hilibrand AS, Lim MR, Zavatsky J, Zeiller S, Schwartz DM, et al. Characterization of neurophysiologic
alerts during anterior cervical spine surgery. Spine (Phila Pa 1976) 2006;31:1916-22.
24. Bess RS, Lenke LG. Blood loss minimization and blood salvage techniques for complex spinal surgery. Neurosurg
Clin N Am 2006;17:227-34.
25. Urban MK, Beckman J, Gordon M, Urquhart B, Boachie-Adjei O. The efficacy of antifibrinolytics in the reduction
of blood loss during complex adult reconstructive spine surgery. Spine (Phila Pa 1976) 2001;26:1152-6.
26. Wong J, El Beheiry H, Rampersaud YR, Lewis S, Ahn H, De Silva Y, et al. Tranexamic Acid reduces perioperative
blood loss in adult patients having spinal fusion surgery. Anesth Analg 2008;107:1479-86.
27. Sachs B, Delacy D, Green J, Graham RS, Ramsay J, Kreisler N, et al. Recombinant activated factor VII in spinal
surgery: A multicenter, randomized, double-blind, placebo-controlled, dose-escalation trial. Spine (Phila Pa
1976) 2007;32:2285-93.
28. Elgafy H, Bransford RJ, McGuire RA, Dettori JR, Fischer D. Blood loss in major spine surgery: Are there effective
measures to decrease massive hemorrhage in major spine fusion surgery? Spine (Phila Pa 1976) 2010;35:S47-56.
29. Finfer S, Bellomo R, Boyce N, French J, Myburgh J, Norton R. A comparison of albumin and saline for fluid
resuscitation in the intensive care unit. N Engl J Med 2004;350:2247-56.
30. Choi PT, Yip G, Quinonez LG, Cook DJ. Crystalloids vs. colloids in fluid resuscitation: A systematic review.
Crit Care Med 1999;27:200-10.
31. Fehlings MG, Brodke DS, Norvell DC, Dettori JR. The evidence for intraoperative neurophysiological monitoring
in spine surgery: Does it make a difference? Spine (Phila Pa 1976) 2010;35:S37-46.
32. Erb TO, Ryhult SE, Duitmann E, Hasler C, Luetschg J, Frei FJ. Improvement of motor-evoked potentials by
ketamine and spatial facilitation during spinal surgery in a young child. Anesth Analg 2005;100:1634-6.
33. Anschel DJ, Aherne A, Soto RG, Carrion W, Hoegerl C, Nori P, et al. Successful intraoperative spinal cord
monitoring during scoliosis surgery using a total intravenous anesthetic regimen including dexmedetomidine.
J Clin Neurophysiol 2008;25:56-61.
34. Tobias JD, Goble TJ, Bates G, Anderson JT, Hoernschemeyer DG. Effects of dexmedetomidine on intraoperative
motor and somatosensory evoked potential monitoring during spinal surgery in adolescents. Paediatr Anaesth
2008;18:1082-8.
49
50
Anaesthetic management:
A history of connective tissue disease (rheumatoid arthritis) or previous cervical spine surgery is important to the
planning of airway management and intubation. A wire re-inforced (armoured) tube can be positioned to optimise
surgical access. Also, it withstands compression from retractors. Intra-arterial blood pressure monitoring is often
used. This allows for careful titration of the mean arterial blood pressure and provides early information on autonomic
stimulation during surgery. Finally, arterial blood gas analysis may assist in the assessment of potential postoperative
airway compromise.
Postoperative airway compromise is not common but may have several causes. Recurrent laryngeal nerve
dysfunction is usually unilateral. It may result in vocal cord palsy and cause postoperative hoarseness. Although
anterior fusion may include several levels, artificial disc insertion usually only involves one level. Postoperative
bleeding arising from the spine may form a retropharyngeal haematoma displacing and narrowing the trachea. The
risk of bleeding increases with the number of levels fused. Patients having undergone fusion of three or more
vertebrae generally require close postoperative observation in the intensive care or high-dependency unit.
INSTRUMENTED POSTERIOR LATERAL MASS AND CRANIO-CERVICAL FUSIONS
The patient is in the prone position, the head fixed in Mayfield skull pins, and the neck is flexed. The arms rest by
the patients sides and are inaccessible to the anaesthetist.
Anaesthetic management:
This procedure may involve C1and C2. In the event of odontoid process pathology, an unstable cervical spine should
be anticipated. Awake fibreoptic intubation may be the preferred method of airway management. This may dictate
the tube selection. If conventional intubation is possible, a wire re-inforced tube can be useful as the tube lumen
is generally preserved and patent for ventilation and suction in the prone position with a flexed neck. Care should
be taken to protect the patients eyes from the disinfectant solution used for the preparation of the neck. Excessive
flexion of the neck in combination with the prone position may result in swelling and oedema of the tongue, which
may become apparent following extubation.
Intra-arterial blood pressure measurement allows for careful monitoring of the mean arterial blood pressure and
facilitates blood pressure control. Arterial blood gas analysis may assist in the assessment of the severity of any
postoperative airway compromise. Intensive care admission may be considered following surgical procedures
involving C1 and C2.
LUMBAR SPINE SURGERY
Instrumented lumbar spine surgery includes anterior lumbar interbody fusion (ALIF), artificial lumbar disc insertion,
posterior lumbar interbody fusion (PLIF) and posterior lumbar decompression and fixation.
LUMBAR SPINE ANATOMY
The distal abdominal aorta lies to the left of and anterior to the L4 vertebral body where it divides into the common
iliac arteries. Above the L4 body the inferior vena cava lies slightly to the right. The internal and external iliac veins
form the common iliac veins anterior to the sacroiliac joints. The common iliac veins unite on the right hand side
of the L5 vertebral body. Hence, the iliac vessels must be pushed aside using retractors to expose the L4/L5 and L5/
S1 discs through an anterior (abdominal) approach and so may be vulnerable during L4/5 and L5/S1 surgery. Conversely,
during a PLIF procedure the postero-medial walls of the inferior vena cava and the aorta may be visible through
the L4/L5 interbody space.
ANTERIOR LUMBAR INTERBODY FUSION (ALIF) AND ARTIFICIAL DISC INSERTION
The patient is placed in the lithotomy position with the arms abducted. The operating table is placed in a slight
head-down position to facilitate surgical access and the surgeon stands between the patients legs. Anterior lumbar
spine procedures most frequently involve the L4/L5 and L5/S1 levels and are performed through an infra-umbilical
midline incision. A hybrid operation indicates a combination of an artificial disc insertion at one level and an ALIF
at the adjacent level. The bladder is drained by the insertion of an indwelling urinary catheter.
Anaesthetic management:
Reliable large-bore intravenous access is essential. Following induction and insertion of the appropriate lines the
patient is positioned in the lithotomy position with both arms abducted to nearly 90. In the presence of peripheral
vascular disease, perfusion of the lower legs may be borderline in this position. It has been suggested that the
presence of a satisfactory pulse oximetry signal from a toe is evidence of adequate perfusion.2 Monitoring is applied
as determined by the patients co-morbidities. Invasive arterial blood pressure monitoring may be useful in the
event of a major bleeding. Central venous access and central venous pressure monitoring are generally not required
for ALIF procedures. Bleeding may potentially occur from the iliac vessels during the initial exposure of the surgical
site or towards the end of surgery when the retractor pins are removed. Cell salvage may be employed in the event
of major blood loss. Postoperative intravenous fluid management is continued until bowel function has returned.
51
52
Inhibition of fibrinolysis
Acute normovolemic hemodilution
Cell salvage and autotransfusion
Hypotensive anaesthesia
Fibrinolysis inhibitors. These agents have been used to reduce blood loss during PLIFs. A recent study
demonstrated good effect on blood loss of intravenous tranexamic acid (TXA).9 A dose regime of TXA of 10mg/kg
bodyweight prior to skin incision followed by 1mg/kg/h has been suggested for instrumented spinal surgery.9
Acute normovolaemic haemodilution (ANH). The technique of ANH remains controversial. ANH has its
supporters but others are critical of its transfusion-reducing capacity.11 Some authors have found that ANH reduces
the number of patients needing allogeneic transfusion; others have found that ANH does not alter the number of
patients needing transfusion but ANH does reduce the number of units transfused.
ANH may be most efficacious in terms of avoiding allogeneic blood transfusion when the blood loss is moderate.12
This is because, firstly, the volume of withdrawn blood must be in the 1000-2000mL range in order to provide a
meaningful level of hemodilution12 and, secondly, the surgical blood loss occurs in addition to the volume of withdrawn
blood and should therefore probably not exceed 1000mL before re-transfusion is considered. In the clinical reality,
many patients present with a history of ischaemic heart disease and rarely have a preoperative haematocrit value
in the 0.40-0.45 range. If the blood loss is massive, allogeneic blood may be required regardless of ANH.
Intraoperative cell-salvage (CS). This may be useful in the setting of major blood loss. The advantages of cell
salvage include rapid availability, reduced immunomodulation, no risk of transmission of infectious agents and in
some cases reduced costs.13
The main issues associated with cell salvage are
Depletion of clotting factors.6
Hypothermia.
Sudden hypotension during re-infusion of salvaged blood.14,15
Cell salvage may reduce but not eliminate the need for allogeneic blood products.16
Logistics.
CS has been recommended to reduce the use of allogeneic blood products.17 Intuitively, the technique is
appealing and justified. The technique is used in 53% of British hospitals and it is recommended by the Association
of Anaesthetists in Great Britain and Ireland to reduce the need for allogeneic blood (product) transfusion for spinal
surgery.18 The proviso pertaining to cell salvage is that any reduction in the use of allogeneic blood products is
beneficial to the patient. The problem is that CS may be used for procedures and patients for whom the technique
itself may not be beneficial. The benefits of CS in orthopaedic, vascular and obstetric surgery are well documented.6,17
The benefits of CS for instrumented spinal surgery on the other hand are not well supported in the literature.16,19
One study found that the use of cell salvage doubled the costs of blood related charges.19 The authors also found
that the transfusion requirements could be satisfied by pre-donation. The cost issue is a sensitive one and only
relevant for cases in which the cell salvage does not avoid the use of allogeneic blood transfusion. The mean blood
loss in the study was 650mL and subsequently well within the volume that may be replaced by one unit of predonated blood. It is thus no surprise that CS did not have a role in this series.
Although the red blood cells (RBC) are returned to the patient, the washing procedure depletes the returned
blood of clotting factors and platelets.6 Regular monitoring of haemoglobin, total blood loss and coagulation profile
are required to ascertain the indication for blood products.6 A mathematic model of cell salvage suggests that a
healthy patient with a hematocrit of 45 can tolerate a blood loss of 7 litres using cell salvage with 57% recovery
rate and a bowl volume of 225 mL.20 In clinical practice, however, this amount of bleeding is likely to require
transfusion of packed red cells and fresh frozen plasma in order to preserve cardiovascular stability and clotting
factors.
Cell salvage requires anticoagulant solution to be added to the salvaged blood. The use of citrate (Acid Citrate
Dextrose Anticoagulant, ACDA) binds the calcium in the collected blood.21 Following the washing of the RBCs, the
blood is transferred to a collection bag and re-infused. Most centres use a filter for infusion of cell salvaged blood.
Some centres use a 40micron lipid and leucocyte filter that clears the RBC solution of non-cellular components
(bone and tissue fragments and fat droplets) as well as leucocytes when the RBCs are returned to the patient.22
Sudden severe hypotension following transfusion of washed RBCs has been reported.4,15 and indeed noticed by
the author on several occasions. This has been ascribed to mast cell activation and the subsequent release of
bradykinin caused by the filter surface.14 If re-transfusion is required urgently some authors advice that the filter be
omitted if severe hypotension occurs or alternatively that the filtered RBCs be stored for 60 min before
re-infusion.14,15,22
53
Hypotensive anaesthesia. The use of induced hypotension during anaesthesia has become controversial. The
Brain Trauma Foundations guidelines for management of the central nervous system perfusion pressure are also
applicable to the spinal cord. This means that the spinal cord perfusion pressure should be maintained in the 5070mmHg range.24 The recent awareness of postoperative blindness has further weakened the arguments for
hypotensive anaesthesia.25 In addition, a recent study found a significant increase of intraocular pressure from
13mmHg after induction of anaesthesia in the supine position to 40mmHg after 5 hours of spinal surgery in the
prone position.26
VISUAL LOSS
Visual disturbances have been quoted to occur in approximately 1 in 2000 spinal procedures.27,28 Visual loss has
also been reported following cardiac surgery and, head and neck surgery. 28 The aetiology remains unclear. The
American Society of Anesthesiologists Postoperative Visual Loss (PVL) Registry identified few common traits in
patients who have developed postoperative blindness.29 Eighty-two per cent of the patients sustained a blood loss
in excess of 1000mL, and 94% had been anaesthetised for more than 6 hours (mean 9.8 h). Large volumes of
crystalloids were used for blood replacement (9.7 l). In an earlier retrospective review of 37 cases of visual loss
after spinal surgery the authors compared a subgroup of 28 patients (with complete notes) with matching historical
controls. The authors found that the mean surgery time was 410 min (6h50min) with a mean blood loss of 3500mL. 30
Blood pressure changes were similar in both groups and the authors conclude that although hypotension may
increase the risk of PVL, moderate hypotension alone is rarely the cause. It is common-sense and generally accepted
that pressure on the eyes and eyeballs should be avoided during the prone positioning of the patient.
Anaesthetic risk management with respect to PVL in prone spinal surgery should consider:
Positioning of the head in the neutral position.25,30
The use of a soft head rest with cut-outs for eyes, nose and the tracheal tube.
Avoidance of direct pressure on the eyes.25,30
Correction of anaemia (Hb < 80g/L).
Avoidance of prolonged arterial hypotension (SAP <90mmHg).29,30
Balanced fluid replacement with crystalloids and colloids.25
Where possible, ensure the patients head is level with or slightly higher than the torso.
PERIOPERATIVE PAIN MANAGEMENT
Many patients presenting for instrumented spinal surgery may have experienced varying levels of pain. In addition
to paracetamol and NSAIDs many patients may require opioids, tramadol and pregabalin or gabapentin. Some
patients also use carbamazepine, valproic acid or amitriptyline for neuropathic pain. There is good evidence that
a preoperative dose of gabapentin may improve pain control after instrumented spinal fusion although the optimal
dose has yet to be determined.31 Pregabalin 150mg before and 12 hours after surgery has been found to reduce
the postoperative morphine consumption.32
Commonly used opioids in Australia include oral oxycodone and topical fentanyl or buprenorphine for nontraumatic, degenerative back pain. These patients are therefore opioid-tolerant when they present for surgery and
postoperative pain management may be challenging. Intraoperatively, short acting opioids like fentanyl, alfentanil
or remifentanil may be used in combination with tramadol, clonidine and a volatile agent to maintain pain control.
Surgery is very stimulating and high doses of opioids may be required. There is evidence that a small intraoperative
dose of ketamine may improve postoperative analgesia in patients undergoing spinal surgery.33 Many spinal
surgeons prefer to avoid COX2-inhibitors because of the possible effect on bone growth.
The postoperative pain level is generally high and an opioid-based patient-controlled analgesia (PCA) technique
combined with paracetamol, tramadol and perioperative oral pregabalin.32 is generally required. Gabapentin has
also been shown to improve the quality of postoperative pain relief.31 Opioid rotation describes a model of pain
management that replaces the patients regular opioid with an equi-analgesic combination of other opioids and/or
NMDA antagonists.34 If the patient has required opioids preoperatively, a PCA hydromorphone technique may
provide better analgesia than morphine. Occasionally, the patient may benefit greatly from a ketamine infusion of
0.1mg/kg/h for the first 24-48 hrs in addition to the PCA device.35 Subarachnoid injection of morphine may assist
in the management of postoperative pain. Doses of 100-200 mcg offer effective analgesia with a low risk of adverse
effects.36 Many surgeons are reluctant to use spinal techniques for pain management. Subcutaneous infusion of
local anaesthetic into the wound may reduce the requirements of systemic analgesia after lumbar fusion.37
In summary, instrumented spinal surgery is a rapidly growing branch of neurosurgery that requires a high level
of specialised anaesthetic involvement to manage the challenges of patient positioning, cardiovascular control, a
significant blood loss and postoperative pain.
54
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17. Reitman CA, Watters WC, Sassard WR. The cell saver in adult spinal fusion surgery. A cost-benefit outcomes
study. Spine 2004; 29: 1580-4.
18. Carless PA, Henry DA, Moxley AJ et al. Cell salvage for minimising perioperative allogeneic blood transfusion.
Cochrane Database of Systematic Reviews. 2010, issue 4, article number CD001888.
19. Blood Transfusion and the anaesthetist. Intraoperative cell salvage. Association of Anaesthetists in Great Britain
and Ireland, 2009.
20. Gause PR, Siska PA, Westrick ER, Zavatsky J, Irrgang JJ, Kang JD. Efficacy of intraoperative cell saver in
decreasing postoperative blood transfusions in instrumented posterior lumbar fusion patients. Spine 2008;
33: 571-5.
21. Waters JH, ShinJung J, Karafa MT. A mathematical model of cell salvage efficiency. Anesth Analg 2002; 95:
1312-7.
22. Kang Y, Aggarwal S, Virji M, Pasculle AW, Lewis JH, Freeman JA, Martin LK. Clinical evaluation of autotransfusion
during liver transplantation. Anesth Analg 1991; 72: 94-100.
23. Booke M, van Aken H, Storm M, Fritzsche F, Wirtz S, Hinder F, Fat elimination from autologous blood. Anesth
Analg 2001; 92: 341-3.
24. Hussain S, Clyburn P. Cell-salvage induced hypotension and London buses (Editorial). Anaesthesia 2010; 6: 661-3.
25. Brain Trauma Foundation Guidelines. J Neurotrauma 2007; Suppl 1: 1-95.
26. Goepfert CE, Ifune C, Tempelhoff R. Ischemic optic neuropathy: are we any further? Curr Opin Anaesthesiol
2010; 23: 582-7.
27. Cheng MA, Todorov A, Tempelhoff R, McHugh T, Crowder CM, Lauryssen C. The effect of prone positioning on
intraocular pressure in anesthetized patients. Anesthesiology 2001; 95: 1351-5.
28. Stevens WR, Maj MC, Glazer PA, Kelley SD, Bradford DS. Ophthalmic complications after spinal surgery. Spine
1997; 22: 1319-24.
55
29. Holy SE, Tsai JH, McAllister RK, Smith KH. Perioperative ischemic neuropathy. A case control analysis of 126,666
surgical procedures at a single institution. Anesthesiology 2009; 110: 246-53.
30. Lee LA, Roth S, Posner KL, Cheney FW, Caplan RA, Newman NJ, Domino KB. The American Society of
Anesthesiologists postoperative visual loss registry: Analysis of 93 spine surgery cases with postoperative
visual loss. Anesthesiology 2006; 105: 652-9.
31. Myers MA, Hamilton SR, Bogosian AJ, Smith CH. Visual loss as a complication of spine surgery: a review of
37 cases. Spine1997; 22: 1325-9.
32. van Elstraete AC, Tirault M, Lebrun T, Sandefo I, Bernard JC, Polin B, Vally P, Mazoit JX. The median effective
dose of preemptive gabapentin on postoperative morphine consumption after posterior spinal fusion. AA 2008;
106:305-8.
33. Kim JC, Choi YS, Kim KN, Shim JK, Lee JY, Kwak YL. Effective dose of peri-operative oral pregabalin as an
adjunct to multimodal analgesic regimen in lumbar spinal fusion surgery. Spine 2011; 36: 428-33.
34. Bell RF, Dahl JB, Moore RA, Kalso E. Perioperative ketamine for acute post-operative pain: a quantitative and
qualitative systematic review (Cochrane review). Acta Anaesthesiol Scand 2005; 49: 1405-28.
35. Mercadante S, Arcuri E. Hyperalgesia and opioid switching. Am J Hosp Pal Med 2005; 22: 291-4.
36. Subramaniam K, Subramaniam B, Steinbrook RA. Ketamine as adjuvant analgesic to opioids: a quantitative
and qualitative systematic review. Anesth Analg 2004; 99: 482-95.
37. Acute Pain Management: Scientific evidence. 3rd ed. 2010. Australian and New Zealand College of Anaesthetists
and Faculty of Pain Medicine, Melbourne Vic, Australia.
38. Bianconi M, Ferraro L, Ricci R, Zanoli G, Antonelli T, Guilia B, Guberti A, Massari L. The pharmacokinetics and
efficacy of ropivacaine continuous wound instillation after spine fusion surgery. Anesth Analg 2004; 98: 166-72.
57
58
Figure 1 shows a selection of the original diagrams from Bannister and Macbeths article (figure 1A), the MRI
scans from Adnets article22 (figure 1B) and the diagrams illustrating the three axes theory in Millers Anesthesia
textbook26 (figure 1C). Comparing these diagrams, there is obvious disagreement where these axes should be
drawn. A more scientific explanation for this critical point in airway management should be available.
A new theory is now timely. I have called this proposal the Two-Curve Theory.27,28 This theory not only supports
the sniffing position for direct laryngoscopy but also provides understanding of how other devices (e.g. video
laryngoscopes and optical stylets) function and, just as important, why they may fail. This is critical in difficult airway
management when each technique attempted takes time and multiple failures may lead to patient morbidity or
mortality.1-5,29
Figure 1. Diagrams illustrating the Three Axes Alignment Theory from A) Bannister and Macbeth
(1944)21, B) Adnet and co-workers (2001)22 and C) Millers Anesthesia (2000)26 (head and neck
positioning: upper figures in neutral, middle figures in extension and lower figures in sniffing).
Neutral position
Extension position
Sniffing position
The Three Column Model allows classification of the anatomical variations occurring with head and neck positioning during direct laryngoscopy by considering the airway passage as two curves (figure 2A).27 In a normal
patient extension of the head and neck leads to flattening of the Primary Curve with little effect on the Secondary Curve (figure 2B). Head elevation leads to flattening of the Secondary Curve with little effect on the Primary
Curve (figure 2C). Combination of head elevation and head and neck extension (i.e. the sniffing position) (figure
2D) causes flattening of both curves. Insertion of a laryngoscope and elevation of the mandible with compression of the submandibular space further flattens the Primary Curve improving direct laryngoscopy.
59
Figure 2. Airway passage (solid curved line) superimposed over MRI scan showing Primary and
Secondary Curves. The line of vision (dashed line) is drawn from top front incisors to glottis. Dotted line is
the laryngeal vestibule axis27
60
61
Figure 3. History, physical examination and investigations for airway assessment based on the Three
Column Model for Direct Laryngoscopy (elements of Model in clear boxes, airway assessment tests in
shaded boxes)
full explanation of this figure is found in the original publication in Anaesthesia and Intensive Care30
TMJ temporomandibular joint
Static
Limited
occipito-atlantoaxial complex
Posterior
Airway problems
History of current
Airway imaging
X-ray, CT Scan,
NasoAirway
Middle
Short Incisor-hyoid
(short thyromental)
Short TMJ-incisor
distance
Absolute
Model for
Direct
Short TMJ-TMJ
distance
Volume of
submandibular
Prominent upper
Relative
Large tongue
(Mallampati
Compliance of
submandibular
Low compliance
of submandibular
Range of
movement
Dynamic
Limited mouth
Anterior
Range of
movement of
stylo-hyoid
Poor mandibular
protrusion in front
Restricted
movement of
62
EXAMPLES OF AIRWAY MANAGEMENT BASED ON THE TWO-CURVES THEORY AND THE THREE
COLUMN MODEL
Anterior Column Problems
Anterior Column problems are a diverse group of pathological conditions which may be divided into (i) reduced
volume of the submandibular space (retrognathia/micrognathia), (ii) reduced compliance of the submandibular
tissues (including Ludwigs angina, post-radiotherapy to the submandibular space and tumour of the tongue base)
and (iii) restriction of temporo-mandibular joint function.
Optimising head and neck position is essential to ensure flattening of the Secondary Curve before focusing on
the Primary Curve with Anterior Column problems. With reduced volume or reduced compliance of the submandibular
space, the Primary Curve is the major focus of management. There are two potential management plans for dealing
with Primary Curve problems.
1) Paraglossal or retromolar insertion of a straight laryngoscope:
Magill described a technique later called by Bonfil38 homolateral retromolar intubation which allows the operator
to bypass the Primary Curve and enter the supraglottic space (rostral part of Secondary Curve). Henderson39,40
re-visited this concept, using a low profile straight blade with a paraglossal approach rather than the midline for a
patient with a hypoplastic mandible40,41 and limited forward movement of the hyoid.40
63
64
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6. Cook TM, Scott S, Mihai R Litigation related to airway and respiratory complications of anaesthesia: an analysis
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18. Borges BCR, Boet S, Siu LW, Bruppacher HR, Naik VN, Riem N, et al. Incomplete adherence to the ASA difficult
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19. Mihai R, Blair E, Kay H, Cook TM A quantitative review and meta-analysis of performance of non-standard
laryngoscopes and rigid fibreoptic intubation aids. Anaesthesia 2008; 63: 745-760.
20. Greenland K A proposed model of direct laryngoscopy and tracheal intubation. Anaesthesia 2008; 63: 156-61.
21. Bannister F, Macbeth R Direct laryngoscopy and tracheal intubation. Lancet 1944; 244: 651-4.
22. Adnet F, Borron SW, Dumas JL, Lapostolle F, Cupa M, Lapandry C Study of the sniffing position by magnetic
resonance imaging. Anesthesiology 2001; 94: 83-6.
23. Adnet F, Borron SW, Lapostolle F, Lapandry C The three axis alignment theory and the sniffing position:
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24. Adnet F, Baillard C, Borron SW, Denantes C, Lefebvre L, Galinski M, et al. Randomized study comparing the
sniffing position with simple head extension for laryngoscopic view in elective surgery patients. Anesthesiology
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25. Adnet F A Reconsideration of Three Axes Alignment Theory and Sniffing Position. Anesthesiology 2002; 97: 754.
26. Stone D, Gal T Airway Management, Anesthesia, 5th Edition. Edited by Miller R. Philadelphia, Churchill
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28. Greenland KB, Edwards MJ, Hutton NJ, Challis VJ, Irwin MG, Sleigh JW Changes in airway configuration with
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30. Greenland KB Airway assessment based on a three column model of direct laryngoscopy. Anaesth Intensive
Care 2010; 38: 14-9.
31. Greenland KB, Cumpston PHV, Huang J Magnetic resonance scanning of the upper airway following difficult
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32. Wilson ME, Spiegelhalter D, Robertson JA, Lesser P Predicting difficult intubation. Br. J. Anaesth. 1988; 61: 211-6.
33. Wilson ME Predicting difficult intubation. Br. J. Anaesth. 1993; 71: 333-4.
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39. Henderson JJ ENT Vs anaesthesia straight laryngoscopes. Anaesth Intensive Care 2002; 30: 250-1.
40. Henderson JJ The use of paraglossal straight blade laryngoscopy in difficult tracheal intubation. Anaesthesia
1997; 52: 552-60.
41. Semjen F, Bordes M, Cros A-M Intubation of infants with Pierre Robin syndrome: the use of the paraglossal
approach combined with a gum-elastic bougie in six consecutive cases. Anaesthesia 2008; 63: 147-50.
42. Milne AD, Dower AM, Hackmann T Airway management using the pediatric GlideScope in a child with Goldenhar
syndrome and atypical plasma cholinesterase. Paediatr Anaesth 2007; 17: 484-7.
43. Vitin AA, Erdman JE A difficult airway case with GlideScope-assisted fiberoptic intubation. J Clin Anesth 2007;
19: 564-5.
44. Christodoulou C, Hung O Blind Intubation Techniques, Management of the Difficult and Failed Airway. Edited
by Hung OR, Murphy MF. New York, McGraw-Hill Medical, 2008, p. 168.
45. Iseki K, Watanabe K, Iwama H Use of the Trachlight for intubation in the Pierre-Robin syndrome. Anaesthesia
1997; 52: 801-2.
46. Xue FS, Yang QY, Liao X, He N, Liu HP Lightwand guided intubation in paediatric patients with a known difficult
airway: a report of four cases. Anaesthesia 2008; 63: 520-5.
47. Hung OR, Pytka S, Morris I, Murphy M, Stewart RD Lightwand intubation: II--Clinical trial of a new lightwand
for tracheal intubation in patients with difficult airways. Can J Anaesth 1995; 42: 826-30.
48. Favaro R, Tordiglione P, Di Lascio F, Colagiovanni D, Esposito G, Quaranta S, et al. Effective nasotracheal
intubation using a modified transillumination technique. Can J Anaesth 2002; 49: 91-5.
49. Gabbott DA Laryngoscopy using the McCoy laryngoscope after application of a cervical collar. Anaesthesia
1996; 51: 812-4.
50. Laurent SC, de Melo AE, Alexander-Williams JM The use of the McCoy laryngoscope in patients with simulated
cervical spine injuries. Anaesthesia 1996; 51: 74-5.
51. Uchida T, Hikawa Y, Saito Y, Yasuda K The McCoy levering laryngoscope in patients with limited neck extension.
Can J Anaesth 1997; 44: 674-6.
52. Osborn I, Kramer D, Luney S The Difficult Airway in Neurosurgery, Benumofs Airway Management: Principles
and Practice, 2nd Edition. Edited by Hagberg CA. Philadelphia, Mosby Elsevier, 2007, p. 965-6.
53. Law-Koune JD, Liu N, Szekely B, Fischler M Using the intubating laryngeal mask airway for ventilation and
endotracheal intubation in anesthetized and unparalyzed acromegalic patients. J Neuro Anesth 2004; 16: 11-13.
54. Ovassapian A Acromegaly - Use of fiberoptic laryngoscopy to avoid tracheostomy. Anesthesiology 1981; 54:
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55. Southwick J, Katz J Unusual airwy difficulty in acromegalic patient: Indications for tracheostomy. Anesthesiology
1979; 51: 72-3.
56. Young M, Hanson C An alternative to tracheostomy following transsphenoidal hypophysectomy in a patient
with acromegaly and sleep apnea. Anesth Analg 1993; 76: 446-9.
67
68
69
COMPLICATIONS OF CP
There are limited data on reported complications of CP, these are listed in Table 1.
Table 1. Reported complications of CP
Oesophageal rupture (n=2).
Fracture of the cricoid cartilage (n=1).
Regurgitation.
Intrathyroidal bleeding (n=1).
Neck soft tissue haematoma.
Pharyngo-oesophageal trauma.
Traumatic recall due to patient awareness.
Airway difficulties.
The impact on airway management is the most important complication of CP. It not only impairs laryngoscope
insertion and intubation, but also the passage of a bougie and insertion of a laryngeal mask. It can cause airway
obstruction and decrease the tidal volume during bag mask ventilation; however, it can be used in cardiopulmonary
resuscitation to limit gastric inflation by limiting the tidal volume achieved. If applied incorrectly CP will cause airway
distortion, pharyngeal compression and misalignment of the larynx and the trachea.2
There are various recommendations proposed if CP interferes with laryngoscopy:
1. if it is applied correctly then decrease the pressure and review, if the view is still inadequate release the CP;
2. if it is incorrect adjust accordingly and review, if the view is still inadequate release the CP.
In the authors opinion if the view obtained at laryngoscopy is poor then release CP and intubate, to delay
intubation to adjust CP is poor clinical practice, because the purpose of a RSI is to intubate as soon as possible.
PREVENTION OF ASPIRATION
Majority of clinicians would agree that prevention of aspiration should not solely rest on the application of CP. Risk
factors for pulmonary aspiration (Table 2) should be identified prior to anaesthesia and appropriate action taken.
There should be a suitable pre operative fasting regime, although fasting does not guarantee an empty stomach.
Some studies suggest that safety can be improved by the use of drugs, which reduce gastric volume and increase
gastric pH. There has been only one study, from the Mayo Clinic, that assesses the value of using antacids in the
pre operative period. 2,10
Table 2. Known risk factors for regurgitation and pulmonary aspiration
Pregnant patients greater than 20 weeks gestation.
Patients who have had a recent meal within the last 6 hours.
Patients who have suffered a recent injury.
Patients with gut obstruction or dysfunction (hiatus hernia, GORD).
Patients receiving opioid medication.
Patients with head injury and/or a depressed level of consciousness.
Obesity.
Patients with in-coordination of swallowing.
Patients with a tracheostomy.
70
71
18. Patel PN. Effect of education on the application of Cricoid pressure during Rapid sequence Induction. Difficult
Airway Society Meeting, Cheltenham UK 2010.
19. Smith KJ; Dobransowski J, Yip G et al. Cricoid pressure displaces the oesophagus: an observational study
using magnetic resonance imaging. Anesthesiology. 2003; 99(1):66-64.
20. Toumadre J, Chassard D, Berrada KR et al. Cricoid pressure decreases lower oesophageal sphincter tone.
Anesthesiology. 1997; 86(1):7-9.
21. Vanner R. A presentation at the Difficult Airway Society Meeting, Cheltenham UK 2010.
73
74
Khine et al. published the first randomised trial comparing the use of cuffed and uncuffed tubes in the paediatric
anaesthetic setting in 1997.7 In all 488 children were recruited with an average age of 3 years in each group. Ages
ranged from term neonates to 8 years. Outcome measures included the number of intubations required to achieve
an appropriately sized tube, need for fresh gas flows greater than 2 L/min indicating a significant leak, atmospheric
pollution with nitrous oxide, and post-extubation croup. Khines study allocated a cuffed tube size according to
formula Age/4 + 3, and an uncuffed tube by Age/4 + 4. For children less than 1 year of age, a cuffed size 3.0 or
uncuffed 4.0 was used, although at the discretion of the anaesthetist a smaller tube was chosen for 15 of the 49
children randomised to a 4.0 uncuffed tube. This suggests that in infants, a one size fits all approach to choosing
an appropriate endotracheal tube is naive. Khines results demonstrated a correctly sized tube in 99% of patients
allocated to a cuffed tube but only 77% in the uncuffed group, necessitating reintubation with a better fitting tube.
Atmospheric pollution of nitrous oxide exceeding 25 ppm occurred in 37% cases with an un-cuffed tube but in no
cases where a cuffed tube was used. There was no difference in the number of patients with post-extubation stridor.
From these results, Khine concludes that cuffed endotracheal tubes may be used routinely in term neonates through
to older children. There is, however, no breakdown of ages in Khines analysis so the reader is left wondering how
applicable the results are to a neonatal population where most controversy exists regarding cuffed tubes.
Based on Khines publication, Murat reports a change in practice at a French Childrens Hospital.8 After 1997,
the institution changed to the use of cuffed endo-tracheal tubes exclusively. An audit conducted in 2000 showed,
9845 anaesthetics, of which 55% were intubated. Over 3400 were under 8 years, and 900 were infants. There was
no morbidity attributable to the use of cuffed tracheal tubes and when data was compared to a similar audit
conducted prior to the change in tube use there was considerable reduction in the operating theatre pollution with
nitrous oxide.
Another study by Newth et al in a paediatric intensive care setting reported outcomes from a 12 month period
for children intubated with either cuffed or uncuffed tubes. Tube selection was at the discretion of the clinician and
cuff pressure was regularly monitored to ensure a small leak at maximum inflation pressure. The outcome measures
used were the need for post-extubation adrenaline to treat stridor and the rate of failed extubation necessitating
reintubation. There was no significant difference in outcomes across 5 age sub-groups including neonates, however
numbers in each group were not even with only 20% of neonates receiving a cuffed tube.9 Despite this, Newth
makes the conclusion that traditional teaching of cuffed endotracheal tubes being contraindicated in children less
than 8 years of age is archaic.
MORBIDITY
All studies to date utilise surrogate outcome measures of laryngeal or tracheal morbidity when comparing cuffed
and uncuffed endotracheal tubes. These outcomes include post-extubation stridor, need for adrenaline nebulisers
post-extubation, or need for reintubation. While these outcomes provide some measure by which comparison has
been made, they differ from the more meaningful outcome of subglottic stenosis. The early descriptions of prolonged
intubation in children by McDonald and Stocks2, and Allen and Stevens3 included cases of subglottic stenosis from
which recommendations were made. However, improved materials and care of intubated patients has made
subglottic stenosis an extremely rare outcome seen almost exclusively in small premature infants, intubated and
ventilated in the neonatal intensive care for longer periods. Josef Holzki publishes an alternate point of view, stating
that stridor is not necessarily present in spite of significant airway mucosal injury.10 Holzki describes endoscopic
findings from children documented to have had airway trauma from intubation. Graphic pictures of airway morbidity
are presented, many from children intubated with cuffed endotracheal tubes. One of his criticisms of cuffed tubes
is the pressure that the ridges of an uninflated cuff can exert on the airway mucosa. Despite the compelling images,
Holzki fails to produce the statistical evidence that cuffed endotracheal tubes are more likely to cause airway injury.
What Holzki does raise is doubt that outcome measures used in studies are reflecting airway morbidity.
In spite of these concerns editorial opinion was shifting towards a less dogmatic view of cuffed tubes in paediatrics.
In 2001, Paediatric Anaesthesia published an editorial by James who examined the arguments for and against
cuffed tubes and in spite of a lack of evidence to support them being more dangerous, found there was not much
to be gained by using a cuffed tube.11
ADVANTAGES OF USING CUFFED TRACHEAL TUBES
There are, however, some instances where a cuffed endotracheal tube may be advantageous. The reduced number
of tube changes to achieve a satisfactory fitting tube has been demonstrated.7,16 Reduced atmospheric pollution,
reduced fresh gas flows7 and improved capnography have also been shown with cuffed endotracheal tubes. James,
in his editorial, raises another potential advantage. As the size of the cuffed endotracheal tube is generally one half
size smaller than with an uncuffed tube, there is less potential for pressure from the round tube against the posterior
portions of the larynx and cricoid. The inflated cuff will therefore tend to help the tube sit centrally in the trachea
further reducing pressure on the mucosa.11
75
Ventilatory mechanics are also altered by a leak around the endotracheal tube. Modern ventilators monitor leak
by sensing the difference between the inspiratory and expiratory volumes. In the neonatal intensive care unit using
uncuffed tubes, tracheal tube leaks greater than 5% of tidal volume (VT) are present in 75% of all ventilated
neonates.12 In over 40% of infants the leak was > 40% VT at some time during the period of ventilation. Since
modern lung protective strategies rely on targeted tidal volumes, a significant leak makes instituting these strategies
impossible. Furthermore, repetitive atelectasis and recruitment from loss of PEEP may result in mechanical stress
and inflammation. Tracheal tube leak was most significant in infants with lower birth weight and smaller diameter
tubes placing the most vulnerable lungs at risk of errors in measuring VT. The authors make the comment that the
use of cuffed endotracheal tubes would enable better monitoring of VT and avoid the need for multiple intubations
in attempts to optimise tube size. However, since the smallest available cuffed tube is 3.0 mm internal diameter
there would not be that option in preterm and low birth-weight neonates.
DISADVANTAGES OF USING CUFFED TRACHEAL TUBES
Disadvantages of the use of cuffed tubes include increased cost, the need for a smaller internal diameter tube
which has implications for suctioning and work of breathing in the spontaneously breathing child and the need to
monitor the pressure in the cuff. The ideal cuff pressure should provide a seal at inflation of the lungs but also permit
perfusion of the tracheal mucosa. Mucosal perfusion pressure in small children is not well known but it has been
shown that the presence of a leak at 25 cmH2O reduces the incidence of post-extubation stridor with uncuffed
tubes.13 Cuff pressure needs to be monitored at regular intervals, if not continuously. In the presence of nitrous
oxide, cuff pressures have been shown to increase above 25cmH2O within 12 minutes due to diffusion of nitrous
oxide into the cuff.14 Another disadvantage of cuffed endotracheal tubes is the small margin of error in depth of
insertion. When the cuff of some brands of tube is placed below the level of the glottis the tube tip lies perilously
close to the carina.15 Based on these findings, a new endotracheal tube (Microcuff) was developed with a shorter,
low pressure-high volume cuff and a short distance from the cuff to tube tip. This design gives a wider margin of
safety with respect to depth of insertion.
The Microcuff endotracheal tube was compared to uncuffed tubes of several varieties in a large multi-centre
randomised controlled trial of over 2200 children across Europe.16 The study included term neonates to children
aged 5 years. Outcome measures were post-extubation stridor and the number of tube exchanges required to find
an appropriately sized tube. The rate of post-operative stridor was around 4.5% for both cuffed and uncuffed
groups. When children were analysed in age groups 0 to <8mths, 8mths to < 18months, 18mths to < 36mths, and
36mths to < 60mth there was also no significant difference in the rate of post-extubation stridor. There was, however,
a need to alter the initially chosen tube size in 2.1% of those randomised to a cuffed tube compared with 30.8%
(p<0.0001) in the uncuffed group. It should be noted that the cuff pressure was kept below 20cmH2O by way of a
pressure release valve.
This large well designed study prompted further shift in editorial comment, such that in 2009 Lonnqvist makes
the statement that in the anaesthetic setting evidence now supports the use of appropriately designed cuffed
endotracheal tubes in paediatrics provided the cuff pressure is monitored.17
SIZING CUFFED TRACHEAL TUBES
So if Anaesthetists and Intensivists are to have a similar shift in opinion, how should these cuffed tubes be sized
to achieve a satisfactory fit? Weisss study used a 3.0 cuffed tube for term neonates to < 8mths, 3.5 for 8mths to
<18mths, 4.0 for 18mths to <36mths and 4.5 for 36mths to <5 years. This regimen had a satisfactory fit in over
97% patients. For older children, the formula - Age/4 + 3.5, has been validated. 18 While useful in predicting likely
tube requirements, clinical judgement is paramount and any resistance to insertion should prompt downsizing of
the endotracheal tube.
One area where evidence based practice is compromised is the example of the neonate intubated in theatre
with a cuffed tube and returning to intensive care intubated. Evidence for longer term intubation in this sub-population
is less strong, and in my own institution current practice is to return intubated neonates to intensive care with an
uncuffed tube. Further work is required to assess risks and benefits of cuffed tubes in this group.
SUMMARY
If we are to assume that airway morbidity can be accurately predicted from surrogate markers such as stridor, then
current evidence supports the use of cuffed endotracheal tubes in paediatrics from neonates up to older children.
The risk of airway trauma seems to be determined more by the technique of intubation, the size of the tube chosen
and the vigilance of monitoring for pressure on the airway mucosa. Further evidence is required in the intensive
care setting, particularly with regards to neonates and small ex-premature infants.
76
REFERENCES
1. Eckenhoff JE. Some anatomic considerations of the infant larynx influencing endotracheal anesthesia.
Anesthesiology 1951;12(4):401-410.
2. McDonald IH, Stocks JG. Prolonged nasotracheal intubation. BJA 1965;37:161-173.
3. Allen TH, Steven IM. Prolonged endotracheal intubation in infants and children. BMJ 1965; 37:566-573.
4. Holzki J. Laryngeal damage from tracheal intubation. Paediatric Anaesthesia 1997;7:435-437.
5. Flynn PE, Black AE, Mitchell V. The use of cuffed tracheal tubes for paediatric tracheal intubation, a survey of
specialist practice in the United Kingdom. European Journal of Anaesthesiolgy 2008;25:685-688.
6. Deakers TW, Reynolds G, Stretton M, Newth CJL. Cuffed endotracheal tubes in pediatric intensive care.
The Journal of Pediatrics 1994;125(1):57-62.
7. Khine HH, Corddry DH, Kettrick RG et-al. Comparison of Cuffed and Uncuffed Endotracheal Tubes in Young
Children during General Anesthesia. Anesthesiology 1997;86:627-631.
8. Murat I. Cuffed tubes in children: a 3 year experience in a single institution (Letter). Paediatric Anaesthesia
2001;11:748-749.
9. Newth CJ, Rachman B, Patel N, Hammer J. The use of cuffed versus uncuffed endotracheal tubes in pediatric
intensive care. The Journal of Pediatrics 2004;144:333-337.
10. Holzki J. Stridor is not a scientifically valid outcome measure for assessing airway injury. Pediatric Anesthesia
2009;19(Supp.1):180-197.
11. James I. Cuffed tubes in children. Paediatric Anaesthesia. 2001;11:259-263.
12. Mahmoud RA, Proquitte H, Fawzy N, et-al. Tracheal tube airleak in clinical practice and impact on tidal volume
measurement in ventilated neonates. Neonatal Intensive Care 2011;12(2):197-202.
13. Suominen P, Taivainen T, Tuominen N, et-al. Optimally fitted tracheal tubes decrease the probability of
postextubation adverse events in children undergoing general anesthesia. Pediatric Anesthesia 2006;16:641-647.
14. Felton M, Schmautz E, Delaporte-Cerceau S, et-al. Endotracheal Tube Cuff Pressure Is Unpredictable In Children.
Anesth Analg 2003;97:1612-1616.
15. Weiss M, Dullenkopf A, Gysin C, et-al. Shortcomings of cuffed paediatric tracheal tubes. BJA 2004;92(1):
78-88.
16. Weiss M, Dullenkopf A, Fischer JE, et-al. Prospective randomised controlled mutli-centre trial of cuffed or
uncuffed endotracheal tubes in small children. BJA 2009;103(6):867-873.
17. Lonnqvist PA. Cuffed or uncuffed tracheal tubes during anaesthesia in infants and small children: time to put
the eternal discussion to rest? BJA 2009;103(6):783-785.
18. Duracher C, Schmautz E, Martinon C, et-al. Evaluation of cuffed tracheal tube size predicted using the Khine
formula in children. Pediatric Anesthesia 2008;18:113-118.
77
79
Jacoby 1956
Use of the above technique for oxygenation in patients with airway obstruction.
Sanders 1967
Jet ventilation at 344 kpa (50 psi) through a rigid bronchoscope providing unhindered
Spoerel 1971
Earliest description of elective, percutaneous, trans tracheal jet ventilation (PTTJV) during
anaesthesia.
Oultol 1971
Jacobs 1972
Development of a fluid logic based jet ventilator capable of 60-100 breaths per minute.
80
81
82
83
Modern jet ventilators provide a display of the tidal and minute volume delivered out of the machine.
Humidification during HFJV
The prolonged use of dry gases for artificial ventilation is well known to cause damage to respiratory mucus
membranes with consequent morbidity.36 Heated humidification is provided in some modern jet ventilators.
APPLICATIONS OF JET VENTILATION IN ANAESTHETIC PRACTICE
The unique features of jet ventilation include delivery of ventilation through a narrow, unobtrusive conduit, adequate
gas exchange at low peak inspiratory pressure and with minimal thoracic excursion, non-interference with spontaneous
ventilation and a relative absence of the circulatory impairment that may be associated with conventional positive
pressure ventilation.
Jet ventilation in low frequency mode is mostly used for difficult airway management in the emergency setting
while HFJV has a broad range of applications in clinical anaesthesia.
The difficult airway
It is possible to provide emergent or prophylactic oxygenation and ventilation via a trans-tracheal cannula inserted
percutaneously through the anterior neck percutaneous transtracheal jet ventilation (PTTJV). This is of course a
recommended technique for emergency oxygenation in all published, national, difficult airway management
algorithms.37 This has actually been the catalyst for the development of jet ventilation3,5,7-9,38 and there are several
case series of its use in both emergency and elective situations.
The 1416G venous cannulae that have traditionally been used for trans tracheal delivery of jet ventilation can
kink easily. Vessel dilators from central venous access kits are firm, pliable and resist kinking and have been
successfully used for cricothyroidotomy and jet ventilation.39 The author has described the use of triple lumen
central venous catheters for monitored PTTJV.40
The VBM trans-tracheal cannulae (VBM Medizintechnik, Sulz a.N., Germany) designed for adults (13G) and
paediatric (15G) use, are more resistant to kinking, have extra holes at the tip, are resistant to stray laser beams
and offer the option of either a Luer lock or 15 mm ID connection. They are a useful addition to a difficult airway
trolley.
84
It is possible that supraglottic jet ventilation delivered through an LMA could provide adequate oxygenation in
a critically obstructed airway.41
It is often very useful in a less urgent setting where a difficult airway has been anticipated. For example, the
prophylactic use of PTTJV to ensure oxygenation during an anticipated difficult fibreoptic intubation or while teaching
the use of flexible fibreoptic intubation has been described.42-43 The sight of the catheter just beyond the vocal
cords has been used as a marker during difficult laryngoscopy in situations where the anatomy may be distorted
[44]. It has been the authors practice to place a trans-tracheal cannula under local anaesthesia and light sedation
prior to commencement of anaesthesia or airway manipulation in situations where major difficulties are anticipated.
Laryngeal surgery
HFJV is most frequently used during surgery on or around the larynx. Having no conduit or only a very small conduit
through the larynx offers optimum conditions for the surgical intervention while the airway is shared between the
surgeon and the anaesthetist.
General anaesthesia during these procedures is normally provided using a total intravenous (TIVA) method and
a muscle relaxant. Topical analgesia of the vallecula, epiglottis, laryngeal inlet and the vocal cords before the
introduction of the rigid laryngoscope is a very useful adjunct to blunt airway reflexes.
In this setting HFJV may be achieved using a supraglottic or a subglottic jet delivery. Subglottic jet delivery may
in turn be via a catheter passed trough the laryneal inlet (translaryngeal) from above or via a trans-tracheal catheter
or cannula (PTTJV).
Supraglottic jet ventilation
Supraglottic jet ventilation is done through an operating laryngoscope while the tip of the scope is aligned with the
laryngeal inlet. Jet delivery is done either with an injector clamped into the main lumen of the scope or through a
dedicated channel built into the wall of the scope. A technique delivering both a low frequency and a high frequency
jet stream through dedicated channels built into a modified laryngoscope has also been reported45 and is termed
combined frequency jet ventilation.
The main advantage of supraglottic jet ventilation is that view and access to the larynx is unhindered. However,
entrainment of air is large and accurate monitoring of FiO2, airway pressure and expired CO2 is difficult. Furthermore,
the large airflow not only causes a ripple movement of mucus membranes and vocal cords but can also blow blood,
smoke or tissue debris down the trachea. There has been a concern expressed of tumour implantation in more
distal airways. Finally, this technique may not be suitable in the presence of a compromised glottic aperture caused
by stenosis, tumour or paralysed vocal cords.6,46
The proper alignment of the rigid laryngoscope is very important as a misdirected jet may cause gastric insufflation
and a vagal reaction.
Subglottic methods
The value of subglottic jet ventilation without a large tracheal tube placed through the larynx obscuring most of it
from view and restricting room needed for surgical manipulation has long been appreciated (Figure 3). A range of
tubes, catheters and cannulae had been reported in the literature for delivery of translaryngeal subglottic jet
ventilation.47-56
The use of flexible catheters for subglottic HFJV is by far the most popular choice for endolaryngeal intervention.
Whipping of the tip of a catheter during jet ventilation is a concern as it can cause trauma to the tracheal mucosa,
leading to the spread of pressurized air into the mediastinum, lungs and soft tissues of the neck and upper chest
area. Jet induced movement of the catheter tip is reduced or eliminated by having multiple openings at the tip,
using a stiffer material and placing a minimum length of catheter inside the airway.
Figure 3. The view and workspace available with a shielded 7Fr (2.33 mm O.D) catheter through the larynx
of a child and a 5 mm (O.D) catheter through an adult larynx.
85
A cage design at the tip of the catheter to keep the catheter central inside the trachea, was first described
by Benjamin and Gronow.50 A catheter with modified cage design and a second channel designed by Hunsaker
(Mon- Jet TM tube Xomed-Treace, Jacksonville, FL, USA) is commonly used now.54
With the introduction of CO2 laser for endolaryngeal interventions, flammability of the jet conduits became an
issue. Long metal cannulae, various coverings for the catheters like metal foils and specially designed tapes that
could be soaked in water were used. The Hunsaker device has a fluoroplastic coating resistant to laser beams.
Recently use of a new device named the Jockjet tube system has been described.56 The design has the jet
flow encased in a segment of 4 mm teflon tube and a trailing double lumen catheter to measure distal airway
pressure and to sample gas for capnography.
HFJV has been successfully employed for airway management and anaesthesia in neonates, infants and
children.57-58
During subglottic ventilation one must ensure a clear expiratory pathway before the first breath is delivered. This
should be managed as described below in the section on PTTJV. The technique of subglottic HFJV using a catheter
may avoid tracheostomy or laryngectomy during endoscopic treatment and resection of various glottic and subglottic
tumours. It has also been used successfully to deliver ventilation during tracheostomy, tracheoplasty and tracheal
resection.59
Percutaneous trans-tracheal jet ventilation
While less common than a trans-laryngeal catheter approach, PTTJV is often used for endolaryngeal interventions
as the technique offers the best view and working space with no tubes at all in or around the laryngeal inlet
(Figure 4)
Figure 4. A narrow laryngeal inlet that may not have enough room for even the smallest catheter,
precluding safe translaryngeal ventilation.
The percutaneous transtracheal catheter is introduced using local anaesthesia and tested while the patient is awake.
After induction of general anaesthesia using TIVA an oropharyngeal or nasopharyngeal airway is inserted and the
neck extended before HFJV is delivered. Driving pressure is increased once the expiratory outlet is confirmed
patent. Jet ventilation is stopped transiently while the airway is taken out and the operating laryngoscope is
positioned in place. (figure 5)
There are several series of case reports describing the usefulness of this technique and a low incidence of
complications.60-65 Recently, a prospective audit of successful management of 50 cases with severe airway
compromise and stridor has been reported [65]. It should be stressed that there is a learning curve and all reports
strongly recommend that HFJV should be monitored closely and conducted in presence of experienced operators.
Figure 5. PTTJV for endolaryngeal surgery
86
87
88
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85. Okada M, Mimura T, Ikegaki J, Katoh H, Itoh H, Tsubota N. A novel video- assisted anatomic segmentectomy
technique: selective segmental inflation via bronchofiberoptic jet followed by cautery cutting. J Thorac Cardiovasc
Surg. 2007;133 (3):753-8.
86. Arima H, Nakamura T, Sobue K. High frequency jet ventilation through a fibreoptic bronchoscope channel during
lung lavage. Anaesth Intensive Care 2005; 33: 274-276.
87. Hauntmann H, Gamarra F, Hencke M, Diehm S, Huber R. High frequency jet ventilation in interventional fibreoptic
bronchoscopy. Anesth Analg 2000; 90(6): 1436-1440.
88. Benumof JL. Airway exchange catheters. Simple concept, potentially great danger. Editorial Anesthsiology
1999; 91(2): 342-344.
89. Carlon GC, Miodownik S, Ray C Jr, Kahn RC. Technical aspects and clinical implications of high frequency jet
ventilation with a solenoid valve. Crit Care Med. 1981; 9(1): 47-50.
90. Satyanarayana T, Capan L, Ramanathan S, Chalon J, Turndorf H. Bronchofibrescopic Jet Ventilation. Anesth
Analg 1980; 59: 350-354.
91. Jaquet Y, Monnier P, Van Melle G, Ravussin P, Spahn DR, Chollet-Rivier M. Complications of different ventilation
strategies in endoscopic laryngeal surgery: a 10-year review. Anesthesiology. 2006;104 (1):52-9.
92. Sdrales I, Benumof JL. Prevention of kinking of a percutaneous transtracheal intravenous catheter. Anesthesiology
1995; 82:288-91.
93. Ihra G, Gockner G, Kashanipour A, Aloy A. High-frequency jet ventilation in European and North American
institutions: developments and clinical practice. Eur J Anaesthesiol. 2000; 17 (7): 418-30.
94. Cook TM, Alexander R. Major complications during anaesthesia for elective laryngeal surgery in the UK:
a national survey of the use of high-pressure source ventilation. Br J Anaesth. 2008; 101(2): 266-72.
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DONOR AGE
Little evidence exists to support a specific upper age limit however older donors of kidney, heart and liver are well
established as associated with lower graft survival and it is unlikely that lungs are not similarly affected. De Perrot
et al in Toronto have shown higher rates of bronchiolitis obliterans syndrome (BOS) in recipients of older grafts.7
Generally older donor lungs are used for older recipients when possible. It is thought that older lungs may be less
immunologically active however the older donor tolerates ischaemia less well than younger donors. The International
Society for Heart and Lung Transplantation (ISHLT) data registry supports this in their current guidelines.6
ARTERIAL BLOOD GAS
The minimum of 300 for PaO2:FiO2 appears to have been accepted as standard based on one case report from
1987. This report showed a single case of graft failure where the preoperative donor ratio was less than 250. Since
this case, the ratio of 300 has been adhered to without further evidential testing.
Multiple factors exist in the critically ill and brain dead patient to impair the ratio. Aspiration, atelectasis, neurogenic
pulmonary oedema (NPO), sepsis and fluid management all can impair gas exchange.
CHEST RADIOGRAPH
A clear chest radiograph (CXR) has been included in current ISHLT recommendations despite this being a weak
estimator of abnormalities.
CXR may be an indicator of aspiration, fluid loading, pulmonary oedema, sepsis or structural abnormality/trauma.
Inter observer error is significant with regard to this reporting and may be done out of normal hours by non radiology
clinicians. Unilateral infiltrates are likely acceptable whereas diffuse bilateral infiltrates have a higher rate of primary
graft dysfunction. Currently there is no clear evidential basis on what CXR findings are acceptable. The marginal
CXR is best considered in combination with other criteria.
BACTERIAL COLONISATION
Bronchoscopy is performed prior to initiating the donor procedure. Presence of gross inflammation or purulence
generally precludes lung donation. Sterile secretions are uncommon so a quantitative assessment by the donor
procurement team of secretion load is usually undertaken. Microbiological specimens are taken that may help tailor
treatment should infection become established in the recipient. Length of time on mechanical ventilation influences
colonisation of the tracheobronchial tree; however no absolute time limit exists for exclusion. Most important is the
management of the patient whilst ventilated. This will be discussed in further detail later.
Bacterial infection is not uncommon in the recipient but carries a lower risk than viral or fungal infection. Current
guidelines do not include the routine administration of antibiotics as part of the donor procurement however many
teams employ broad spectrum antibiotics immediately prior to retrieval. Given the weakness of predicting VAP
based on CXR compared to histology this seems prudent. If unilateral infection exists, this does not preclude single
lung transplant should there be a suitable recipient.
GRAFT ISCHEMIC TIME
It is endeavoured to maintain the time from donor aortic cross clamp to reperfusion as short as practically possible.
Cold ischemic times are ideally less than 6 hours. Again however, little evidence supports this arbitrary time.
Combined age over 55 and longer ischemic times do have increased one year mortality but considered alone,
prolonging times does not influence early graft function or long term mortality. The upper limit has not been
determined, case reports of times as long as 11 hours exist. It is possible that with new developments such as
ex-vivo lung perfusion that longer ischaemic times will become more common.
THE PATHOPHYSIOLOGY OF BRAIN DEATH AND ITS EFFECTS
Brain death testing is outlined in the document The ANZICS statement on death and organ donation. A .pdf check
list is available to clearly record this.8 Injury to the neuron results in loss of membrane function. As a consequence,
the neuron cannot maintain its internal homeostasis and oedema will develop within the neuron. The more severe
the injury, the greater the oedema that will develop. As the cranium is non elastic, the rise in brain tissue volume
must be at the expense of blood and cerebrospinal fluid volumes, the so called Monro-Kellie doctrine. Once
intracranial compliance limits are reached, intracranial pressure rises. Cerebral blood flow falls as intracranial
pressure rises, further worsening cellular oedema. Once intracranial pressure has risen above mean arterial pressure,
perfusion pressure will be zero and blood flow to the brain will cease. Further oedema will develop resulting in
compression of the brainstem with subsequent brainstem death.
HEMODYNAMIC CHANGES
Compression of the brain stem occurs in a rostral to caudal progression. Pontine compression and ischaemia leads
to a Cushing reflex, hypertension with bradycardia due to mixed sympathetic and reflex vagal discharge. As
ischaemia progresses further, the medulla oblongata is rendered ischaemic with loss of the vagal nuclei causing
unopposed sympathetic tone, the sympathetic storm of hypertension and tachycardia. Progression of ischaemia
then involves the spinal cord with loss of all sympathetic tone, complete vasoplegia and cardiovascular collapse.
The sympathetic stimulation may reduce coronary perfusion through vasoconstriction and cause contraction band
necrosis of cardiac myocytes.9 There may be multiple arrhythmias and significant ST-segment changes compatible
with strain or ischaemia.
Care of the potential lung transplant donor optimisation, prevention of decline and future prospects.
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PULMONARY EFFECTS
Severe pulmonary effects can occur during the sympathetic storm. NPO is a common consequence and has a
significant effect on gas exchange. It is a major cause of lung donor unsuitability. Intense systemic vasoconstriction
raises systemic vascular resistance (SVR). This shifts the systemic blood volume (usually 76%) to the pulmonary
compartment, raising it from 24 to 72% of total blood volume.10 The rise in both SVR and left atrial pressure (from
pulmonary volume loading) may lead to acute severe functional mitral regurgitation, possibly made worse by
myocardial ischaemia. Right ventricular work elevates and it may become volume overloaded. The rapid rise in
pulmonary capillary hydrostatic pressure results in endothelial leak and alveolar oedema.
A separate mechanism is also known to contribute to NPO. Direct alpha stimulation of the pulmonary circulation
despite pulmonary normotension can cause capillary leak and alveolar oedema. It is unclear which of these two
mechanisms dominates, however the end result is pulmonary oedema and impaired gas exchange. Patients with
complete high cervical cord injury may manifest less severe pulmonary injury due to loss of direct neuronal pathways.
The speed of brain stem death or coning may also influence the intensity of the sympathetic storm. When coning
is rapid, the effects may be more severe.
SYSTEMIC INFLAMMATION
Brain death results in a systemic inflammatory response with rises in acute phase cytokines, particularly IL1, IL6
and IL8. These cause neutrophil aggregation and activation and mediate endothelial and alveolar injury. Whilst
these cause direct organ injury, possibly contributing to organ non acceptance, they are also associated with
increased early graft dysfunction in the recipient.9
COAGULOPATHY
Brain death may also be associated with exposure of tissue thromboplastin to the circulation due to disruption of
the blood brain barrier and endothelial dysfunction. This activates the coagulation and fibrinolytic cascades and
may result in further lung injury.
ENDOCRINE FAILURE
The hypothalamic pituitary axis may also be affected by brain stem death. Significant hormonal derangements
contribute to further cardiovascular decline. Anterior pituitary function is less commonly affected than posterior.
More commonly, in up to 80% of donors, there is severe depletion in posterior pituitary hormones, i.e. those of
hypothalamic origin. Most significant haemodynamically is the fall in antidiuretic hormone (ADH) which also contributes
to diabetes insipidus (DI). DI is present in 80 to 90% of donors post brain death. Antidiuretic hormone expression
causes aquaporin channel insertion into the collecting ducts of the distal tubule. This prevents water reabsorption
and results in large volumes (>1L/hr) of dilute urine being passed. The effect of this is hypovolaemia, hypernatraemia,
hypomagnesaemia, hypophosphatemia, and hypocalcaemia. This should be differentiated from diuresis caused
by mannitol or diuretic therapy. Correction should not be delayed by waiting for serum and urine osmolality results.
Hypernatraemia is important to correct as it is associated with impaired outcomes in both liver and kidney
transplantation.
Anterior pituitary impairment may result in falls in thyroid and corticoid hormones.
The fall in thyroxin, cortisol and insulin levels is associated with a shift from aerobic to anaerobic metabolism
and rises in serum lactate and hydrogen ion levels. Various studies have been performed looking at hormone
replacement therapy. These will be addressed later.
HYPOTHERMIA
Brain death results in loss of upper motor neurons and vasomotor tone so there is an inability to conserve heat and
shiver. There is reduced muscle and brain metabolism. Hence, hypothermia is a common feature. This may have
adverse effects on coagulation, oxygen delivery (left shift of the oxyhaemoglobin dissociation curve reduces
peripheral oxygen unloading from haemoglobin), arrhythmias and end organ function. Forced air warming blankets,
fluid warmers and humidified ventilator circuits are useful adjuncts to maintain normothermia.
MULTIFACTORIAL LUNG INJURY
Other events may contribute to pulmonary dysfunction. Events leading to brain death such as aspiration prior to
and during attempted airway protection, atelectasis and cardiopulmonary resuscitation (CPR) causing pulmonary
contusion will worsen lung injury, function, and increase infection risk. Micro aspiration can occur around endotrachael
tube cuffs despite appropriate inflation.
Whilst receiving invasive ventilation, still further injury is possible. Volutrauma and barotrauma are possible from
ventilator management leading to ventilator associated lung injury (VALI). Intentional hypocapnea achieved through
hyperventilation as a therapy for intracranial hypertension uses high tidal volumes (10-12ml/kg) and respiratory
frequency, both of which are associated with VALI.
Gastric decompression via oro or nasogastric drainage may reduce reflux and pooling in the hypopharynx and
also improve ventilator mechanics. Ventilator acquired pneumonia (VAP) is increasingly likely with prolonged invasive
ventilation. VAP incidence is approximately 1-3% per day ventilated.
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Care of the potential lung transplant donor optimisation, prevention of decline and future prospects.
97
Physiotherapy is also vital to maintaining donor lungs. Two to three hourly percussive physiotherapy, closed
circuit suctioning, 30 degree head up positioning and hourly turns are strongly recommended. Without physiotherapy
and postural drainage, further collapse and consolidation are likely with increasing shunt and worsening gas
exchange. Frequent bronchial toilet with suctioning of secretions after physiotherapy is required.
Retrieved secretions should be sent for early microscopy culture and staining. Though bacterial infection is
rarely spread to the recipient, this does allow tailoring of antibiotic therapy if required. Consideration should be
given to broad spectrum antibiotic treatment. Discussion with transplant physicians or donor coordinators is
encouraged if doubt exists over management.
HAEMODYNAMIC MANAGEMENT
Aims should be to normalise organ perfusion and oxygen delivery. Any form of low output or hypotension should
be aggressively managed. Mean arterial blood pressure aim is 60-80mmHg. This can be achieved through preload,
afterload, rate, rhythm and contractility manipulation.
Monitoring should include invasive arterial blood pressure and central venous pressure (CVP). Sterility is as
critical in the donor as in the living patient. Recipients will be immunosuppressed; all invasive procedures must be
treated as sterile.
PRELOAD
CVP catheterisation should ideally be in a jugular vein as this will be most accurate. Accuracy is relevant in terms
of not fluid overloading donors with resultant increases in lung water. Many papers advocate haemodynamic
algorhythms based on pulmonary capillary wedge pressure (PCWP) monitoring.14 However it is recognised that this
increases cost and complexity of care, often in units unfamiliar with pulmonary artery catheter use. Misinterpretation
of data when unfamiliar with a monitoring modality can lead to incorrect changes in therapy. Also, given the presumed
normal pulmonary vascular resistance in donor lungs, the accepted deficiencies in using CVP as a surrogate for
PCWP and hence left ventricular filling are probably insignificant. Preload can be maintained through fluid boluses
taking into account maintenance of a haemoglobin concentration near 10g/L, serum sodium concentration and
urine output. A target CVP of 6-8 mmHg is the consensus recommendation of the Crystal City Conference that
aimed to maximise all donor organ utilisation.
RATE AND RHYTHM
Arrhythmias should be aggressively treated as per standard care. Correction of all electrolytes and acid base
abnormalities are first line steps. Indirect acting agents such as atropine will be ineffective post brain stem death.
Temporary transvenous pacing may be required for severe bradycardia. Amiodarone and beta agonist infusions
may be required.
AFTERLOAD AND CONTRACTILITY
Post brain stem death, vasoplegia induced low afterload may render the donor severely hypotensive. Attempts
should be made to distinguish low cardiac output hypotension from vasoplegic hypotension. Pure alpha1 agent
use to maintain perfusion pressure to tissues may accentuate anaerobic acidosis and lactate accumulation if
hypotension is due to a low output state rather than vasodilation. It has however been a mainstay of support and
organ protection. Throughout Australia and New Zealand, noradrenaline use is common for donor haemodynamic
support and has not been associated with worsened donor kidney and liver graft function though this has not been
reviewed for lung donors. High dose catecholamines are to be avoided as their infusion in the donor causes up
regulation of beta receptors in the heart which may mandate the use of higher inotrope requirements in the heart
transplant recipient.
Dopamine administration to the donor has been shown to improve function in cadaveric kidney grafts and also
to prolong graft survival. It is also thought that the alveolar membrane is receptive to catecholamine induced sodium
and water reabsorption.15 Beta2 stimulation in both the donor and recipient can accelerate water clearance from
the alveolus. This can be achieved with dopamine administration or inhaled beta agonist therapy.
A retrospective review has however shown an association between worsened early graft function (PaO2:FiO2)
and catecholamine administration.16 However this paper included those donors receiving high dose alpha 1 agonists
which may have been an indicator of more severe acute lung injury and sympathetic storm.
The use of triiodothyronine and arginine vasopressin should be considered. These may be combined with low
dose dopamine as needed.
Should hypertension (MAP >90mmHg) require pharmacological intervention, it is important to use short acting
agents as the haemodynamic status of the donor may change rapidly. Sodium Nitroprusside is ideal. Esmolol may
also be used, however pure beta antagonism in the face of high afterload may cause heart failure so should be
combined with a vasodilator.
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FLUID MANAGEMENT
Resuscitation should aim to correct sodium levels to less than 155mmol/L. Hypotonic glucose containing fluid
replacement or even sterile water may be necessary if hypernatraemia, hyperglycaemia and hypovolaemia are
problematic. Large volumes may result in hypothermia and hyperglycaemia which again should be aggressively
corrected to within their normal ranges. Ideally all organs should be managed together from a haemodynamic
perspective though when specific organs have been rejected, therapy may be more focused on the target organs.
If the lungs have been rejected more aggressive fluid loading is acceptable. The debate about colloid versus
crystalloid use is far from complete and no clear recommendation can be made.
Optimal haematocrit for oxygen delivery should be considered, 30% being acceptable. If transfusion is required
to achieve this, cytomegalovirus negative blood should be requested.
Conventional management of the liver and kidney donor favours relative hypervolaemia. Pennefather et al
however, showed that crystalloid fluid loading to a CVP of 8-12cmH2O had a significantly negative impact on the
alveolar to arterial (A-a) gradient.17
A recent publication from Spain challenges this approach to the kidney donor. The effect of aggressive fluid
restriction (target CVP <6 mmHg) versus conventional fluid management (CVP 6-10 mmHg) was examined in brain
dead kidney donors. No detriment to graft survival was seen in the aggressively managed group. This study lacks
detail regarding experimental design so no recommendation can be made at this stage. It does however imply that
avoiding fluid overload in the multi organ donor to protect lung function is not detrimental to renal graft survival.18
If haemodynamic parameters permit and CVP is elevated, cautious frusemide use is warranted to attempt a reduction
in excess body water.
HORMONE REPLACEMENT THERAPY
As discussed earlier, a brain stem death endocrinopathy may develop. The data supporting aggressive hormone
replacement yields mixed results, some studies strongly supporting it,19 others failing to reproduce the effects.20
Those patients demonstrating significant hypotension despite adequate preload, inotrope and vasopressor support
should be trialled with hormonal support. Triiodothyronine (T3) may be given as a 4 microgram intravenous bolus
followed by 3 micrograms per hour continuous infusion. Some evidence suggests that peripheral conversion of
thyroxine to T3 fails post brain stem death, supporting T3 rather than T4 usage. T3 also has a faster onset of action
allowing potentially faster catecholamine weaning. Vasopressin maybe given as a cautious 0.5-1 unit intravenous
bolus, followed by an infusion of 0.5 to 4 units per hour. This may be titrated to MAP 60-80mmHg whilst aiming to
wean noradrenaline and adrenaline infusions. If this fails to meet haemodynamic targets, dopamine may be added.
Treatment of DI is by volume replacement and infusion of a 2-4 mcg bolus of desamino arginine vasopressin
(DDAVP). This stimulates aquaporin formation, allowing the kidney to concentrate urine without the vasocontrictive
effects of arginine vasopressin. Should the donor be requiring high doses of noradrenaline at this point, the addition
of a vasopressin infusion may be justified and will also reverse DI effects. This has no adverse effect on kidney
donation.14
Correction of serum blood glucose to within normal limits is recommended. Hyperglycaemia can cause damage
to pancreatic beta cells rendering the pancreas less suitable for transplant.
Early after brain death has been certified, but after blood for tissue typing and serology has been taken, methyl
prednisilone 15 mg/kg intravenous bolus should be administered. This has multiple beneficial effects though will
contribute to hyperglycaemia. Steroids are highly effective in the suppression of the systemic inflammatory effects
of brain death. They also reduce neutrophil accumulation and activation with a reduction in ischaemia reperfusion
injury.21 Both animal and human studies have repeatedly shown improved early graft function when the donor is
treated with methyl prednisilone. This is partly the anti inflammatory effect, but is also related to accelerated clearance
of alveolar oedema and reduced capillary leak.10
NURSING
Further aspects that are important for optimal organ care from a nursing perspective include oral care and hygiene
to reduce aspiration risk and frequent repositioning to assist postural drainage of the lungs and vary the dependant
areas. Strict infection control care should be continued also.
ANAESTHESIA FOR ORGAN PROCUREMENT
Some transplant centres may send teams including an anaesthetist to oversee the conduct of care during organ
retrieval. In those hospitals where the resident staff provide care for the donor, this may be an unfamiliar procedure.
In centres where donation is uncommon, the donor procedure may attract greater numbers of spectators to the
operating room. This should be strictly controlled to reduce traffic and airborne debris as in any theatre. Only those
directly involved should be present.
Prior to starting, the operating theatre should be checked. This includes anaesthetic machine check, presence
of adequate infusion pumps, intravenous fluid warmer, forced air warmer and invasive monitors. The operating
theatre should also be warmed.
Care of the potential lung transplant donor optimisation, prevention of decline and future prospects.
99
Upon receiving the donor, the anaesthetist should check all documentation. This includes patient identity label,
brain death documentation, and consent for donation. The patient should be examined checking endotracheal tube
insertion depth and adequate cuff inflation, fluid balance, recent chest radiograph and blood gas results. Also,
coagulation tests, biochemistry, haematology and cross match should be reviewed. Invasive arterial blood pressure
monitoring and central venous access are required. Internal jugular central venous access is preferable, once
abdominal organ retrieval begins, femoral venous access may be unreliable. A large bore intravenous cannula is
required as large rapid volume loss may occur.
A bronchoscopy is usually performed by the retrieving thoracic team to assess anatomy and secretions prior
to the surgical procedure.
During retrieval it may be necessary to control hypertension and tachycardia, volatile anaesthetics may be useful
in this regard.
It is well recognised in cardiac anaesthesia that volatile anaesthetics, isoflurane and sevoflurane in particular,
have beneficial effects in diminishing ischaemia-reperfusion (IRI) injury, so called ischaemic preconditioning. IRI
and early graft dysfunction are predictors of early and late mortality. If severe, early graft dysfunction in the recipient
may require massive support. This may include extra corporeal membrane oxygenation, a very expensive and
resource consuming therapy. Animal studies demonstrate similar effects of volatile anaesthetics in IRI lung models
and also anti inflammatory effects. Whilst no trials have been done to determine an improvement in early graft
function in human lung transplantation, it is likely that exposure to volatiles prior to ischaemia may reduce inflammatory
and IR injuries. Similar evidence is emerging in both liver and kidney transplantation.
Spinal reflexes may cause involuntary movement in the donor, operating theatre staff may feel uncomfortable
seeing this. These movements may include shoulder shrugging, extension-pronation of upper limbs, lower limb
flexion and head turning. Long acting deep muscle relaxants such as pancuronium are recommended.
The same level of intensive care support should continue until organ procurement is complete. This includes
protective ventilation and optimising haemodynamics through the measures already discussed. If used, antibiotics
should be given 30 minutes prior to incision to achieve maximal tissue levels.
THE DONATION PROCEDURE
Depending on which organs are to be retrieved, the procedure may take three to four hours. Usually two surgical
teams will operate simultaneously, a thoracic and an abdominal team. Sternotomy is continued caudally as a midline
laparotomy. The anaesthetic circuit should be disconnected during sternotomy to reduce the chance of lung injury
with the sternal saw. The thoracic organs are inspected visually for any abnormality and all mobilisation is performed.
Direct pulmonary vein blood gas sampling may be performed if the donor is considered for single lung donation
as in the case of unilateral donor lung unsuitability. Lifting the heart and retraction of organs may cause significant
haemodynamic instability that is usually short lived. The abdominal team then continue the procedure, the thoracic
team scrubbing out as abdominal organ mobilisation may take sometime. If haemodynamic collapse occurs
during this phase, the thoracic team should be called back to theatre to allow immediate thoracic organ retrieval
as the heart and lungs are most sensitive to prolonged ischaemia. Once abdominal mobilisation is complete, the
thoracic team return and preparation is made for aortic cross clamping and infusion of organ preservation solutions.
The donor is then anticoagulated with 300u/kg of heparin. After cross clamping the aorta, Plegisol is infused into
the aortic root to achieve cardioplegia and Perfadex into the main pulmonary artery for lung preservation. The donor
coordinator must be informed and the time recorded.
For lung retrieval the donor is hand ventilated and full recruitment under direct vision is confirmed using FiO2
0.5 or less. Oxygen concentrations over 50% are associated with greater lipid peroxidation and lung injury.23 The
airway pressure is then held at a constant 10-15cmH2O whilst tracheal stapling is performed. The endotrachael
tube may require partial withdrawal without cuff deflation at this point to avoid entrapment. It is important that the
lungs are retrieved and stored without atelectasis or hyperinflation. Hyperinflation may be exacerbated with air
transport to the transplant centre.
Some institutions may use a 500mcg prostaglandin E1 infusion directly into the pulmonary artery during the final
phase prior to aortic cross clamping. This is intended to cause full pulmonary vasodilation to maximise washout
of blood and emboli and maximal distribution of Perfadex lung preservation solution. If this agent is used, profound
systemic vasodilation requiring pressor support may be necessary until the cross clamp is in place.
To prevent unnecessary concern from monitor alarms, the anaesthetic monitors may be switched off. The thoracic
team will then usually leave with the procured organs as soon as possible to minimise ischaemic times.
ALTERNATIVE THERAPIES
Despite all current efforts, lung donor numbers still lag behind those awaiting transplantation. Some intended
recipients may die whilst waiting for a suitable donor. Alternate strategies are emerging to attempt redress this
imbalance.
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101
REFERENCES
1. http://www.donatelife.gov.au/News-and-Events/News/Media-Releases/DonateLife-Week-2012.html.
2. http://www.facebook.com/DonateLifeAustralia).
3. http://www.anzdata.org.au/anzod/ANZODReport/2011/2011Pages01-36.pdf.
4. Bugge JF. Brain death and its implications for management of the potential organ donor. Acta Anaesthesiol
Scand 2009; 53:1239-50.
5. Kootstra G, Daemen JH, Oomen AP. Categories of non-heart-beating donors. Transplant Proc 1995;
27: 2893-2894.
6. Orens JB. Boehler A, de Perrot M, Estenne M et al. A review of lung transplant donor acceptability criteria.
Pulmonary Council, International Society for Heart Lung Transplantation. J Heart Lung Transplant 2003;
22: 1183-1200.
7. de Perrot M, Waddell T, Shargall Y, Pierre A et al. Keshavjee S. Impact of donors aged 60 years or more on
outcome after lung transplantation: results of an 11-year single-center experience. J Thorac Cardiovasc Surg
2007; 133: 525-531.
8. http://www.anzics.com.au/downloads/cat_view/12-death-and-organ-donation.
9. Novitzky D, Cooper D K, Rosendale J D, Kauffman HM. Hormonal therapy of the brain-dead organ donor:
experimental and clinical studies. Transplantation 2006; 82:1396-1401.
10. Avlonitis V, Fisher A, Kirby J, Dark J. Pulmonary transplantation: the role of brain death in donor lung injury.
Transplantation 2003; 75: 1928-33.
11. Angel L, Levine D, Restrepo M, Johnson S, Sako E, et al. Impact of a lung transplantation donor-management
protocol on lung donation and recipient outcomes. Am J Respir Crit Care Med 2006; 174:710-6.
12. Gabbay E, Williams T, Griffiths A, Macfarlane L, et al. Maximizing the utilization of donor organs offered for lung
transplantation. Am J Respir Crit Care Med 1999;160: 265-71.
13. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the
acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network. New Eng J Med
2000; 342:1301-8.
14. Wood K, Becker B, McCartney J, DAlessandro A et al. Care of the potential organ donor. New Eng J Med
2004; 351:2730-9.
15. Ware L, Fang X, Wang Y, Sakuma T et al. Selected contribution: mechanisms that may stimulate the resolution
of alveolar edema in the transplanted human lung. J Appl Physiol 2002; 93:1869-74.
16. Mukadam M, Harrington D, Wilson I, Mascaro J et al. Does donor catecholamine administration affect early
lung function after transplantation? J Thorac Cardiovasc Surg 2005;130:926-7.
17. Pennefather S, Bullock R, Dark J. The effect of fluid therapy on alveolar arterial oxygen gradient in brain-dead
organ donors. Transplantation 1993; 56:1418-22.
18. Minambres E, Rodrigo E, Ballesteros M, Llorca J et al. Impact of restrictive fluid balance focused to increase
lung procurement on renal function after kidney transplantation: Nephrol Dial Transplant 2010;25:2352-6.
19. Rosendale J, Kauffman H, McBride M, Chabalewski F et al. Aggressive pharmacologic donor management
results in more transplanted organs. Transplantation 2003; 75: 482-7.
20. Randell T, Hockerstedt K. Triiodothyronine treatment in brain-dead multiorgan donors--a controlled study.
Transplantation 1992; 54: 736-8.
21. Follette D, Rudich S, Babcock W. Improved oxygenation and increased lung donor recovery with high-dose
steroid administration after brain death. J Heart Lung Transplant 1998; 17: 423-9.
22. Liu R, Ishibe Y, Ueda M. Isoflurane-sevoflurane adminstration before ischemia attenuates ischemia-reperfusioninduced injury in isolated rat lungs. Anesthesiology 2000 92; 3: 833-40.
23. de Perrot M, Liu M, Waddell T, Keshavjee S. Ischemia-reperfusion-induced lung injury. Am J Respir Crit Care
Med 2003 167; 4: 490-511.
24. Steen S, Sjoberg T, Pierre L, Liao Q, et al. Transplantation of lungs from a non-heart-beating donor: Lancet
2001; 357: 825-9.
25. Cypel M, YeungJ, Liu M, Anraku M, F et al. Normothermic ex vivo lung perfusion in clinical lung transplantation.
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26. Cypel M, Liu M, Rubacha M, Yeung J et al. Functional repair of human donor lungs by IL-10 gene therapy.
Sci Transl Med 2009;1: 1-9.
The Last Frontier: Donation after Cardiac Death (DCD) reaches Western Australia
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104
After 1962, immunology and pharmacologys advances (prednisone, azathioprine and then cyclosporine in 1972)
helped control acute organ rejection and the era of successful cadaveric transplantation began. The emergence of
specialised medical units for supporting patients with respiratory failure (the current term would be Critical or
Intensive Care Units) led to a group of patients being supported on artificial ventilation despite having no clinically
detectable signs of brain activity. To allow doctors to legally withdraw artificial ventilator support on these patients,
the condition of brain death had to be legally accepted.
In 1968, the Harvard Medical Schools Ad Hoc Committee established the definition of brain death,8 and American
legislatures took up acceptance of the legal standing of brain death as death. Transplantation from brain dead
patients met with far better results than transplantation after cardiac death, and has become the standard way that
organs may be obtained for transplant in Australia, under the strictly defined guidelines of the ANZICS Statement. 9
But transplantation improvements meant that the waiting lists ballooned. Every avenue of supply needed to be
re-explored.
And Donation after Cardiac Death, refined and re-tuned, has re-risen.
THE PHOENIX ARISES
Why would you re-invent any procedure with a poor track record?
Donation after cardiac death arose in parallel with living directed donation, with far inferior results. With the
acceptance of death by neurological criteria, the inferior DCD results led to its abandonment in favour of donors
with an intact circulation. In countries where the concept of brain death was problematic on social and religious
(Japan, China), ethical or legal grounds, DCD and living donation were the only sources of organs for transplant,
and those countries experience and modifications of technique have helped the re-emergence of functional DCD
programmes.
Close to 50% of organ donation comes from DCD in countries as advanced as the Netherlands and closer to
100% in Japan. China is said to have a high DCD rate, with their prison system reportedly the major contributor
since 1965. The Chinese DCD programme is said to be modernising by the end of the year with the imminent
use of lethal injection, rather than the reputed current use of acute lead poisoning.10*
* The Chinese organ donation programme appears to differ from the Australian programme. It is less transparent,
and while it is difficult to obtain official details, it appears to run a system which can guarantee the donors time of
death, and has achieved a high consent rate. A DCD programme consistent with international ethical lines has been
piloted in 2010.
INTERNATIONAL EXPERIENCE
Countries such as the Netherlands and Spain have had DCD programmes running in parallel with DBD for more
than 30 years, while China and Japan have pursued donation programmes relying almost exclusively on DCD. The
experience of these countries has been invaluable for countries looking at re-adopting DCD as a means of increasing
donation rates.
Where DCD has been added to an existing DBD organ donation system, there has been a jump in donor rates
of between 10 and 30%. Other than a substantial increase in organs available for transplant, DCD brings a greater
awareness of organ donation as an integral part of end-of-life care.
The late 1990s saw DCD re-emerge in many European countries, the UK and the USA, where the procedural
differences from DBD led to vigorous discussion. High profile government debate and ethical questions were raised
in prominent public fora.11 The West Australians recent attention-grabbing headline is an echo of more ferocious
earlier lay press articles in the USA. More serious ethical discussions and court cases prompted the US Institute
of Medicine (IOM) to publish three reports on the implementation and ethical aspects of DCD as far back as
2000,12culminating in a list of Recommendations and Obstacles to the Implementation of DCD programmes. If
only wed read them.
Every obstacle WA has encountered so far has been described before; including accusations of using euthanasia
to obtain organs for transplant, or facilitating organ operations on the nearly-dead. Misconstruing the DCD Protocol
to this extent was a source of bewilderment, until we reviewed similar misperceptions from the United States.
These accusations hit the USA as far back as 1997, and served as a catalyst in garnering administrative, legal
and governmental support for DCD. A bio-ethicist at Ohio learned of the proposed DCD protocol coming to the
Cleveland Clinic, and rather than explore the process with the participants, took her concerns to the district attorney
and the television show 60 Minutes.13 Thanks to her intervention and consequent exposure of DCD, legal, medical
and governmental advisors reviewed the process in detail. Under intense public, legal, ethical and administrative
scrutiny, it galvanised the parties to define their support for DCD.
NATIONAL EXPERIENCE
Under what circumstances does Australia consider retrieving organs from the recently deceased? The Maastricht
DCD categories, established in 1995 to classify the likelihood of significant ischaemic damage (and so likely viability)
of the organs to be retrieved and transplanted,14 establishes the conditions:
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Category I:
The patient is dead on arrival to hospital:
This is an uncontrolled circumstance, with an unquantifiable warm ischaemic injury.
Category II:
Unsuccessful resuscitation either in the ward, theatre or Emergency Department:
Again, uncontrolled circumstance, but the warm ischaemic time is known
Category III:
Cardiac arrest following withdrawal of support in ICU:
Controlled circumstances; known and limited warm ischaemic time.
Category IV:
Cardiac arrest following brain death (before planned organ procurement):
Largely controlled circumstances; known and potentially limited warm ischaemic time.
Only the controlled categories (3 and 4) are considered for Australia. The risks to the patient, their family and
the recipients in implementing DCD in Categories 1 and 2 appear too great, and also allow very limited time to
obtain valid informed consent from grieving families.
The only DCD setting being considered in Australia is in an ICU when artificial supportive measures have been
judged to be pointless, and artificial support is deemed to be only delaying inevitable death. Treatment is futile.
The clinicians and the patients family have to be clear and unified in this opinion. Additionally, third parties (clinicians
removed from the organ donation process) are usually called in to provide an independent assessment and opinion.15
If all parties are in agreement, and the patient is likely (based on previous verbal or written communication) to
have supported organ donation, futile treatment can be stopped at an agreed time, with the family and the operating
theatres in readiness in case the patients circulation stops within set time limits.
Hospitals in Australia and New Zealand developed their own local DCD protocols before there was any central
prescriptive standard. Australias National Organ Donation Collaborative (2006 to 2009) brought together interested
participants across Australia-New Zealand, fostering the hope of a unified approach to Organ Donation. The National
Authority for Organ and Tissue Donation (2009, NAOTD) achieved this with its National DCD Protocol,16 giving a
broad structure for delivering a nationally uniform approach.
But before this national standard could be proclaimed, the community spoke.
In Victoria, a family suggested legal action might be taken against a hospital for the lack of availability of an
organ donation service as an option for their enthusiastically-supportive (but imminently-deceased) family member.
The hospitals DCD capability was accelerated. That specific hospital had researchers in lung transplant who were
able to build on their experience16 to perform the first Australian lung transplant from a donor after withdrawal of
therapy in Intensive Care (DCD). While it was by no means a world first, they continued their careful practice until
they had accumulated the largest published case series of successful DCD lung transplant worldwide.3
Their results could not be ignored. It was argued that this improvement in transplant organ availability would be
to the detriment of organ donation as a whole, given that DCD was perceived as a complex and inherently risky
practice. This argument claimed that DCD was risky for the patient (deceased), and for the family (who have
consented and supported the DCD procedure on behalf of the deceased patient).
It became apparent that the real discomfort lay within the medical practitioners themselves.
We were ethically disturbed and legally anxious.
While the procedure in Australia has always been in the clinical context of an Intensive Care Unit, after an
independent decision to withdraw futile treatment, there were issues that would need to be explored if DCD was
to gain a foot-hold in Western Australia.
WA-SPECIFIC CHALLENGES
DCD has been running successfully in Europe for decades, in the USA over the last 15 years or so, and in the
Australian eastern states since 2006. The worlds success with the procedure meant we no longer had anywhere
to hide. Even Rogue States would have to participate.
LEGAL QUANDRY
In WA there was no specific legal support for the removal of futile therapy. As West Australians are mortal, limitation
of therapy in some fashion is intrinsic to daily Intensive Care practice, with or without specific legal support. But
clinicians felt that if there was no specific legal support for their usual practice of withdrawal of ineffective therapy,
they couldnt be engaged in any activity that was dependent upon it. While flawed in logic, it was a common stance.
But the clinicians even greater fear was that they could be accused of withdrawing therapy for the purpose of
organ donation. As long as the law failed to protect clinicians for withdrawal of futile therapy, they werent prepared
to stick their necks out further by assisting subsequent organ donation.
But if you could clearly separate the decision to withdraw therapy from any discussion of organ donation, most
Intensivists were prepared to consider DCD. And as of February 2010, the law changed in WA 18 to specifically
address decriminaliasation of withdrawal of futile therapy.
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loss of
circulation
death
documented
proceed to
Operating
Theatre
10
11
12
13
14
surgery
15
16
17
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The Theatre Timeline is the important one for effective donation retrieval surgery.
The ICU Timeline describes the events leading up to withdrawal of therapy, and is the cornerstone for everyone
involved feeling comfortable that the right thing has been done for the deceased. The DCD Protocols15 for the
individual hospitals provide a detailed description of the donation process.
Operating Theatre involvement usually comes at the end of a protracted stay in the Intensive Care Unit, where the
patients outcome has become more and more apparent to everyone involved in their care, as well as to the patients
relatives. The patient may have been in the ICU for a week or more, and it is a common feeling at the bedside vigil
that the patient should be allowed to pass away without too much delay.
The hours or days of coming to terms with inevitable death are often not visible to the theatre or anaesthesia
staff involved in the final retrieval surgery. The efficiency of withdrawal of therapy and subsequent close analysis
of the patients progress, and declaration of death if it occurs, may then seem cold and calculated, maybe even
rushed and undignified. This should be far from the case for the relatives. They must be informed of every step
needed for a successful transplant outcome, and may see organ donation as the only positive to be drawn from
the patients passing. Most relatives do not choose to stay with the deceased for the optional time after declaration
of death, as they may well have said their farewells at the bedside over the preceding days, or choose to say their
final farewell during the 5 minutes observation of cardiac standstill. Infrequently, the family has been unable to
relinquish contact with the deceased, and the donation process is consequently abandoned. The family then stays
to grieve at the bedside in the ICU, and the theatre staff are informed of cancellation of the potential donation.
TIME PRESSURES IN THE PROCEDURE
The practice of DCD involves organ donation after the patients heart has stopped beating, and since there is
progressive organ damage the longer someone is left with impaired circulation, it can only be successful in patients
who have gone from an intact circulation to circulatory arrest over a relatively short period of time. The anaesthetist
will be asked to accompany the patient from the Intensive Care Unit (ICU) to the Operating Theatre (OT), or to be
prepared to receive the patient in the OT without a great deal of proximate warning. Timing and co-ordination with
ICU are crucial to successful donation. The anaesthetist has a critical role in facilitating lung retrieval surgery, by
timely re-intubation of the patient in the OT and possibly careful lung re-inflation as directed by the surgeon, to
allow dissection and optimise early lung function in the recipient.
The patient will only be transferred to theatre if his/her circulation stops within 90 minutes of withdrawal of
artificial ventilatory and circulatory support.
Time-limits for ischaemia have been set based on experience of organ function in recipients:
For the liver, cardiac arrest within 30 minutes of withdrawal of therapy is the maximum warm ischaemia assessed
as tolerable, to avoid ischaemic strictures in the finer biliary connections.
For the kidneys, the limit of this warm ischaemic time is set at 60 minutes in WA at present, although there is
on-going review of acceptable criteria.
The DCD patients lungs have proven the most resilient organ to warm ischaemic damage, possibly because of
the proximity of oxygen-containing air and the lesser need for circulating blood to get this oxygen to the cells to
maintain viability. In fact, lungs retrieved from DCD donors perform at least as well as lungs retrieved after brain
death3, with conjecture that the massive release of cytokines and catecholamines showering through the pulmonary
circulation at the time of brain herniation might be a major contributor to DBD lung injury.
ANAESTHESIA FOR THE DECEASED
While the deceased patient does not require sedation, analgesia or anaesthesia, airway skills will be needed if there
is the hope of lung retrieval. Depending on the donor hospital, anaesthetists may or may not be required for purely
abdominal organ retrieval.
Anaesthetists in most hospitals will be welcome to attend, to enhance familiarity, comfort and understanding
of the process.
There should be few or no medications to administer, other than heparin subsequent to donation surgery. Gentle
ventilation (with extreme caution to avoid major thoracic excursions that might generate forward flow of the circulation)
may be requested by the surgeon.
Other than securing the airway in a timely fashion, to protect the lungs from passive soiling that would preclude
transplant, there is little role for the anaesthetist other than to ensure that resuscitative efforts (against the patients
wishes and interests) do not occur.
THE ROLE OF ANAESTHESIA: LUNG DONATION
The Alfred Hospitals DCD lung transplant experience in Melbourne has suggested that DCD lungs may work better
than lungs from Donation after Brain Death (DBD) donors,3 results that have been confirmed by overseas publications.
We had to include the potential for lung donation in our WA protocols, and this would mean re-intubation and
careful, delayed re-inflation, if it were to be successful.
So DCD lung retrieval will require active participation by an anaesthetist.
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Perhaps the greatest fear in the DCD procedure is over-vigorous ventilation of the patients lungs, potentially
resulting in transient return of the patients recently ceased circulation.19,20 Most patients will have suffered a primary
brain injury, stroke or trauma, but their cardiovascular system may have been unharmed. Young patients who have
recently suffered a circulatory arrest could conceivably get venous return and transient restoration of circulation if
their thoracic cage is unnecessarily inflated and deflated.
So while re-intubation may be needed for lung retrieval surgery, early re-ventilation is not to be performed. The
minimum gentle delayed re-inflation required by the surgeon for clear dissection margins or lung function is all that
should be contemplated. This may amount to applying PEEP alone.
ENGAGING ANAESTHETISTS
With a little trepidation, we set out to describe DCD to Anaesthesia Departments. They would surely take pleasure
in pointing out non-sequiturs, mutually exclusive ethical conundra and potential catastrophes. It was just the perfect
storm for DCD.
So how did it go?
We werent disappointed! Lively exchanges of opinion, reluctant participation, antagonism, enthusiasm and
left-field ideas came freely. The suggestion that we were asking anaesthetists to be complicit in murder took us by
surprise (its hard to kill a deceased person). Or that we were asking anaesthetists to help perform procedures on
the nearly-deceased. These reactions, while isolated, were very unsettling.
There will always be people who do not feel comfortable with organ donation. While the general public may be
more comfortable with the idea of organ donation after cardiac death, sustained exposure to brain-dead donation
by the medical profession has left doctors more comfortable with that route.
Anaesthetists we contacted were more comfortable with the idea of taking a pink person with an intact circulation,
on a ventilator, who had been declared deceased by brain death criteria (a declaration in which they had taken no
part, and which they had not witnessed), to the operating theatre to assist with organ donation surgery, than they
were to consider taking a cool, grey, pulseless, apnoeic deceased person to the operating theatre for the same
surgery.
DCDS PLACE IN ORGAN DONATION AND SOCIETY
DCD has already contributed to the increase in lung and kidney cadaveric donation by about 10-30% in Australia
over the last few years, and to an additional alternative in end-of-life care in the ICU. This 30% share of deceased
donation should persist, and increased awareness of the donation option is vital at a medical and community level.
The financial benefits for successful renal donation amount to a recurring saving of at least $80,000 per annum
per person released from a dialysis unit, minus the initial costs of donation surgery and immuno-surveillance.
Successful lung donation occurs in an age-group where not only is there improved quality of life and activity
and longevity, but increased productivity in terms of active participation in the work-force.
These financial benefits are quite aside from the overwhelming personal benefits.
Living related donation and paired-exchange programmes for kidney donation should exceed these benefits
from DCD, and already in North America and parts of Europe, living kidney donation accounts for between 30 and
50% of all kidney donation.
CONCLUSION
DCD does present ethical and philosophical questions to participants. It does commit an operating theatre to the
donation process for a session, and there is only an 80% chance that the procedure will go ahead.
It can free two people from dialysis machines, improving both quality of life and longevity, and it can give decades
of good quality life to young lung recipients.
Organ donation is possibly the only procedure in Intensive Care medicine for which a Business Plan can have
financial merit. And thats quite aside from the personal and social effects on one young patient with respiratory
failure, and two other patients disconnecting themselves from renal units.
Carried out carefully, following the wishes of the deceased person, it should provide benefit to their family,
participants, recipients, and respect for the deceased.
While the concept of cardiac death may be better accepted by the public than the concept of brain death, lack
of familiarity with DCD has left doctors uncertain about its place in health care. By the time of going to press, W.A.
should be more comfortable with offering DCD as an infrequent but almost routine end-of-life option.
POST-SCRIPT
WA has now ventured forward with three successful DCD procedures in early 2011. A few barriers were broken,
including transfer of one of the patients from the private sector to a DCD-performing hospital, based on the patients
clear ante-mortem discussions with family. One patient successfully donated her lungs after suffering a cardiac
arrest from pulmonary embolism. One patient became a kidney donor where the primary injury had been nonneurologic. Our donor co-ordinators have gone from ambivalence to proprietary in their attitude to DCD, while the
support for DCD in the Intensive Care Units continues to reflect long-held views on organ donation in general.
Anaesthesia has participated effectively in all three events, thanks to strong leadership and a positive attitude at
the performing hospital.
110
REFERENCES
1. Australian New Zealand Organ Donation (ANZOD) Registry 2011.
2. Snoeijs MG, Schaubel DE, Hene R et al. Kidneys after Cardiac Death Provide Survival Benefit. J.Am.Soc.
Nephrol.Jun 1, 2010 21: 888-890.
3. Snell GI, Levvey BJ, Oto T, McEgan R, Pilcher D, Davies A, Morasco S, Rosenfeldt F. Early lung transplantation
success utilizing controlled donation after cardiac death donors. Am J Transplant.2008 Jun;8(6):1282-9.
4. B Harvey, State Political Editor. Hospitals take organs before brain death. The West Australian, Wednesday,
May 18th, 2011. Front Page headline.
5. Australian Law Reform Commission, 1977. (is there more to this citation where would I access it?).
6. Keller MR, Burlingham WJ. Loss of tolerance to self after transplant. Sem in Immunopathol. 2011 Mar;33(2):
105-10. Epub 2011 Feb 6.
7. Merrill JP, Murray JE, Harrison JH, Guild WR. Successful homotransplantations of the human kidney between
identical twins. J Am Med Assoc. 1956 Jan 28;160(4)277-82.
8. Report of the Ad Hoc Committee of the Harvard Medical School to Examine the Definition of Brain Death.
A Definition of Irreversible Coma. JAMA. 1968 Aug 5;205(6):337-40.
9. Australian and New Zealand Intensive Care Society. The ANZICS Statement on Death and Organ Donation.
3rd ed. Melbourne: ANZICS 2008.
10. BBC News. News.bbc.co.uk/2/hl/8222732.stm Cached. China reportedly admits that most transplant organs
come from executed prisoners, as a scheme to promote donation is launched. 26 Aug 2009.
11. Ethics Committee, American College of Critical Care Medicine: Recommendations for Non- heartbeating Organ
Donation. Crit Care Med 2001;29:1826-1831.
12. Institute of Medicine, National Academy of Sciences. Non-heart-beating organ transplantation: Practice and
protocols. Washington, DC: National Academy Press, 2000.
13. Agich GJ. From Pittsburgh to Cleveland:NHBD Controversies and Bioethics. Cambridge Quarterly of Healthcare
Ethics (1999),8,269-274.
14. Kootstra G, Daemen J, Oomen AP. Categories of non-heart-beating donors. Transplant Proc. 1995 Oct:27(5):
2893-4.
15. RPH/FH/SCGH Protocols for DCD, 2011.
16. National Protocol for Donation after Cardiac Death. Organ and Tissue Authority. July 2010.
17. Snell GI, Levvey BJ, Williams TJ. Ethics in Medicine Non-Heart Beating Organ Donation. Internal Medicine
Journal 2004; 34:501- 503.
18. Acts Amendment (Consent to Medical Treatment) Act 2008 (No. 25 of 2008).
19. Hornby K, Hornby L, Shemie SD. A systematic review of autoresuscitation after cardiac arrest. Crit Care Med.
2010 May;38(5):1246-1253.
20. Adhiyaman V, Adhiyaman S, Sundaram R. The Lazarus Phenomenon. J R Soc Med. 2007 Dec;100(12):552557.
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APPENDIX 1
THE INTENSIVISTS CONCERNS
Much of the Intensivists discomfort comes from being asked to consider the patient as a donor rather than a
potential survivor. If the Intensivist or the family harbour hopes of salvage for that individual, organ donation cannot
be considered. Talk of organ donation signals an abandonment of that hope, and may be misperceived as an
abandonment of that person.
Concerns raised by the Intensivist can be addressed by going through the DCD procedure, and anyone with
residual concerns is free to opt out of participation in specific aspects of DCD, or the whole event. These include:
Concerns: Do I look after the patient, and then look after the organ donation process?
I feel compromised and conflicted by that.
Im prepared to withdraw treatment appropriately, but Im not comfortable having anything to do with organ donation
after that.
I wont make the decision to withdraw treatment if theres any risk anyone might think it was for the purpose of
organ donation.
Response: The conflict of roles (looking after the patient while looking after donation) can be alleviated by asking
a second intensive care specialist to either be present to observe the period of cardiac arrest and declare life extinct,
withdraw therapy, or both.
Concern: Im prepared to withdraw treatment appropriately, but Im not comfortable declaring death by these
circulatory criteria.
Response: A genuinely held discomfort with the declaration of death after 5 minutes of observed circulatory
standstill can be similarly alleviated by having a second party perform the withdrawal and declaration of death.
Concern: I usually give an opioid and sometimes a sedative to my patient, so that they wont suffer. I wont know
how much to give, in case anyone thinks Im giving these drugs to hasten death and allow organ donation.
Response: The amount, if any, of pain relief or sedation deemed appropriate during the dying process has to be
a conscience decision by the doctor in charge of the patient, as it always has been.
Concern: I wont give anything before death that might cause harm or hasten death (i.e. heparin).
Response: There are no ante-mortem procedures in most DCD protocols in Australia.
Other un-linked concerns include:
Is the patient really deceased?
If anyone has such concerns, they should not participate in the declaration of death, or any other part of the
procedure where they feel ethically compromised. Exposure to DCD in an observational role will hopefully help
resolve any conflicts.
Q. Im not comfortable declaring death by these new criteria.
Dont do it. Someone comfortable with the procedure will be sought, and if available, be introduced to the family
and participate where the primary doctor has concerns.
Q. It all seems too rushed, where is the respect?
Only extensive clear communication with the family will reduce the risk of hurting their feelings during the process.
The ICU staff will be briefed, but this intrinsically time-dependent procedure will offend the sensibilities of anyone
who is not very aware of the timelines for a successful donation. And aware of the patients wishes.
Q. The relatives only get 3 minutes with the deceased?
Well, not really. Their family has been aware of the inevitable outcome for some time, maybe days. Withdrawal of
therapy occurs at a time when all available family members have had their time to say good-bye. They may stay
overnight, they may stay through the withdrawal of therapy, they may stay through the observed 5 minutes of
circulatory arrest, and they may even elect to stay with the patient through the 3 minute optional period after life
has been declared extinct.
In practice, they tend not to stay for those last three minutes.
If they cannot bring themselves to leave the bedside, despite knowledge of the patients wishes, then organ donation
does not proceed, and palliation continues in the ICU.
I wont have anything to do with DCD/organ donation.
This is a personal decision. The reasons may be obvious or unfathomable. An alternative practitioner can usually
be substituted in the larger institutions.
And there may be an opportunity for the non-participating staff member to observe the procedure.
What happens if the pulse returns after declaration of death?
Ah..watch out for Lazarus.
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APPENDIX 2
LAZARI
Its easy to get your Lazari confused, from phenomena, to signs, syndromes and reflexes. Historically and medically,
Lazarus lived and died (twice) in the Middle East between the year 0 and the year 33AD. To clarify, here is his story:
Lazarus of Bethany (near Jerusalem) appears in the Gospel of St John.21 Hes one of Jesus Christs friends,
and when he falls ill, Lazarus two sisters (Mary and Martha) send word to Jesus Christ that all is not well. Jesus
Christ dawdles and arrives 4 days too late! Lazarus has died and been entombed, and the sisters arent happy.
Jesus Christ sets them straight, saying I am the Resurrection (Jesus Christ does something similar himself, a bit
later) and the Life. He who believes in Me shall live, even if he dies. And everyone who lives and believes in Me
shall never die in eternity.
Jesus Christ goes to the tomb and gets some muscle to shift the stone away from the tombs entrance, says a
prayer, and tells Lazarus to get up and out of his grave clothes. Which he does! There are a number of devout Jesus
Christ followers to witness and document the event, but also a bunch of Jewish skeptics who apparently reported
the event to the authorities.
Lazarus went on to be a priest in Cyprus, they say, dying again quite some time later, in tomb #2 in a church in
Larnaca, bearing the inscription Lazarus the friend of Christ. His bones/remains were squabbled over and eventually
ended up in France after the fourth crusade (in 1204). There is no record of his remains re-assembling to any
Lazarean likeness again.
Lazarus reflex or sign is an example of a reflex arc or neural pathway which passes by the spinal cord but not
the brain. The reflex is often preceded by slight shivering motions of the patients arms, or the appearance of
gooseflesh on the arms and torso. The arms then begin to flex at the elbows before lifting to be held above the
sternum. They are often brought from here toward the neck or chin and touch or cross over. Short exhalations have
also been observed coinciding with the action.
It has been observed soon after withdrawal of mechanical ventilation, or during the apnoea test to determine
brain death on clinical grounds.
These movements occur mostly within 24 hrs of the diagnosis of brain death, and have not been observed
beyond 72 hours of the declaration of brain death.22 About 20 to 40% of brain dead patients may exhibit spinal
reflexes of variable complexity.
While the Lazarus sign or reflex is very disquieting in the setting of the declaration of brain death, and pushes
clinicians to request perfusion studies to clarify the presence or absence of blood flow to the brain, it is the Lazarus
phenomenon (or syndrome) which is of greater concern in DCD.
The Lazarus Phenomenon (or syndrome) refers to auto-resuscitation, the return of circulation spontaneously
after a period of circulatory arrest.19,20 It is reported to occur most frequently after a period of CPR (high intrathoracic
pressures, poor venous return, particularly in young patients who may have received adrenaline during the resuscitative
efforts).
Without CPR, the literature on autoresuscitation is scant. It is at best anecdotal.
So whats the truth about autoresuscitation, the Lazarus syndrome or phenomenon?
Do people come back to life after withdrawal of therapy?
How long should we wait, before declaring life extinct?
A systematic review of autoresuscitation after cardiac arrest published in 2010 gives us the medically recorded
information, if not the exact answer.19
The authors reviewed 1,265 citations of autoresuscitation, narrowed them to 27 articles describing 32 cases of
autoresuscitation: most of the reports in this sub-group were still of very low quality. All 32 reported cases were
after failed CPR, with times to pulse restoration ranging from a few seconds to up to 33 minutes. However,
continuity of observation and methods of monitoring were highly inconsistent. For the eight studies reporting
continuous ECG monitoring and exact times, autoresuscitation did not occur beyond 7 minutes after CPR.
No cases of autoresuscitation were reported in the absence of CPR.
Zero.
But how often and for how long do we usually monitor patients when they lose their respiration and circulation
after withdrawal of therapy?
And how often do we report unsettling events, knowing that they may rightly disrupt clinical practice, if the data
and observations are less than absolutely accurate?
DCD may become, effectively, the first prospective monitored study of the potential for autoresuscitation.
Coming to a balanced position between the fear of autoresuscitation and the detrimental effects on transplantable
organs of leaving the circulation arrested for too long, the National Authority for Organ and tissue donation chose
a period of observation of between 2 and 5 minutes of arrested circulation as the acceptable time prior to doctors
declaring life extinct by circulatory criteria.
REFERENCES FOR APPENDICES:
21. The New Testament, Chapter 11, St John.
22. Bueri JA, Saposnik G, Maurino J, Saizar R, Garetto NS. Lazarus sign in brain death. Mov Disord. 2000
May;15(3):583-6.
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In evaluating the evidence, there were three studies referenced in the ANZCA statement which made claims
about recent quitters.17-19 The first was a 1982 prospective study from Mitchell et al which sought to identify risk
factors for postoperative respiratory morbidity in 200 general surgical patients.18 Among the findings were that 7
out of the 14 patients (50%) who had stopped smoking within 8 weeks of surgery had purulent sputum postoperatively
compared to ex-smokers >8 weeks (many of whom could have had years of abstinence), where the prevalence of
purulent sputum was only 22% (10 out of 45 patients).18 This result just reached statistical significance (2=4.02
p=0.045) and the difference in sputum rate between recent ex-smokers and those with prolonged abstinence (28%)
had a wide 95% confidence interval (95%CI: 0 to 50%). The Mitchell et al study did not analyse those who continued
to smoke with the 14 recent quitters but had this been done, no significant differences in sputum would have been
found. Furthermore, the actual quit times of the recent quitters (less than 8 weeks) was not stated and it may have
been just a few days in some cases. Data on arguably more important pulmonary complications than purulent
sputum such as bronchospasm, fever and segmental lung collapse was not reported in the Mitchell study.18
The second study cited in the ANZCA statement was a 1989 study of cardiac surgical patients by Warner et al.
It found that 12 out of 21 recent quitters (<8 weeks) had postoperative respiratory complications (57%) compared
with 6 out of 18 patients (33%) who continued to smoke.17 Patients who stopped smoking longer that 8 weeks had
a 14.5% pulmonary complication rate which was similar to the rate in patients who never smoked (11.9%).17 While
there is no argument that longer periods of cessation before surgery are preferable, the data from this paper does
not provide evidence that short periods of cessation were harmful, as is sometimes stated.19 No statistics were
done on the difference in complications between the current smokers and recent ex-smokers. Had this been done,
the 24% difference in complications between the groups in the small sample size (95% CI: -10 to 50%) would not
have been statistically significant (2=2.2; p=0.2).
The third study was by Bluman et al who found that the 36 patients who self-reported that they had reduced
their cigarette intake in the preoperative period had 6.7 times (95%CI: 2.6 to 17.1) more postoperative respiratory
complications than the 105 who said they smoked their usual amount.19 This extraordinary claim is undermined by
the difficulty in verifying self-reported cigarette reductions or cessation.23 It also ignores a well-described phenomenon
called compensatory smoking whereby smokers may consume fewer cigarettes but extract a similar smoke volume
by modifying the pattern of inhalation.24 In lay terms, they suck the life out of the cigarette. The patients total
smoke exposure is thus not simply a function of cigarette numbers, but behavioural characteristics which can
achieve a greater yield per cigarette.24
Citing the Mitchell and Warner papers, the ANZCA document PS12 states that compared to non-smoking
patients, production of purulent sputum in the postoperative period is 50% higher in patients who stopped smoking
< 8 weeks prior to surgery, 25% higher in those who ceased to smoke > 8 weeks prior to surgery and no different
to non-smokers if cessation of smoking occurred > 6 months.16 At face value, this would seem enough to encourage
any smoker to keep lighting up, but a critical look at their data shows that the sputum production of recent quitters
is little different from continuing smokers. This is supported by the largest study to date on the relationship between
smoking, quitting and intra-operative sputum volumes which involved over 1000 participants in Fukushima, Japan.25
Sputum volumes were determined by endotracheal tube suctioning during elective surgery. As expected, the
prevalence of current smokers with increased sputum volumes (18.2%) was higher than non-smokers (9.3%).
However 18.8% of recent quitters (>2 weeks but <2 months) had increased sputum which was not significantly
different from 18.2% in current smokers.25 The prevalence of patients with increased sputum was not significantly
higher than current smokers for those quitting for between 1-day and 2 weeks (22.9%) and no differences in
postoperative pulmonary complications were found based on length of smoking abstinence.25
The issue of timing smoking cessation before surgery was recently reviewed by Myers et al who published a
meta-analysis of studies that compared complication rates between smokers who stopped <8 weeks before surgery
with those who continued to smoke.11 Myers et al indentified 9 studies for inclusion in the meta-analysis totalling
448 recent quitters and 441 continuing smokers, most of which did not report statistically significant results. 11
Analysing results of all studies together, the composite endpoint for total complications was 22% lower in recent
quitters (Relative risk 0.8, 95% CI: 0.6 to 1.1).11 Pulmonary complications were reported endpoints of five studies,
occurring in 115 of 261 recent quitters and 75 of 251 continuing smokers; a relative risk of 1.2 (95% CI: 0.9 to 1.5)
meaning recent quitters were at slightly higher risk.11 However statistically minded readers will note that as the
confidence intervals for these risk ratios include the number one, they were not statistically significant. Thus the
question of optimal timing of smoking cessation before surgery still cannot be answered without larger studies.26
The bottom-line from critical analysis of the studies is that recent quitters have fewer postoperative complications
overall10. It would seem they are no worse off than continuing smokers in terms of pulmonary complications, but
may be no better off.11,26,27 Further data is needed on this important question but current available evidence should
not dissuade anaesthetists and surgeons advising patients to quit at any time before surgery.
The ANZCA Statement on Smoking is due for revision in 2012 (K Leslie, personal communication). Its current
wording may have undesirable consequences including reducing the enthusiasm for clinicians to deliver a smoking
cessation message when surgery occurs within an 8-week time-frame. Other consequences include the potential
for surgery to be delayed in order to achieve a certain period of smoking abstinence that is based on an inaccurate
interpretation of the data.
117
118
A=Ask. Patients should always be asked about their smoking status. One suggestion is to always ask even
when the answer is already known as it reinforces the opinion that their tobacco use is a significant issue. Asking
about smoking is frequently not done. One large audit showed hospital doctors asked about smoking status in less
than half the cases.42 Anaesthetists documented smoking status in only 25% of cases in another audit.43
A=Advise. An Australian study showed that at a Newcastle preoperative clinic, 39% of smokers received smoking
cessation advice from the anaesthetist.44 The situation may be worse elsewhere as many clinics in Australasia and
elsewhere do not routinely give smokers cessation advice or quitting literature.45 We cannot assume surgeons or
general practitioners (GP) perform this role as Myles et al found that stop-smoking advice was given in 6.5% of
cases by surgeons and 3% of cases by GPs.31 Most smokers are aware of the risks that are printed on the packet
regarding future cardio-respiratory disease and cancer, but data shows that few have awareness of the specific
perioperative risks that their habit poses for them.7 Smokers deserve to know this information. Unless they understand
that the potential benefit of quitting before surgery outweighs the perceived unpleasantness of cessation, it is not
reasonable to expect smokers to make behavioural change prior to surgery.
R=Refer. Compared to the provision of self-help material alone, multi-session counselling delivered via telephone
quit lines increases the chance of smoking abstinence at 12 months by a significant 25-50%.46 A Victorian study
showed that multi-session Quitline counselling resulted in 24% of participants being abstinent at 3 months.47 In
Australia, self-referral to Quitline on 13 7848 (13 QUIT) or physician referral via fax is available. A standard Quitline
service consists of 6 counselling sessions via telephone, usually 2 before the quit date and 4 afterwards (I. Ferreter,
personal communication). Quitline staff can also give advice regarding smoking cessation pharmacotherapy. New
Zealand Quitline can be contacted on 0800 778 778 and offer access to low-cost nicotine pharmacotherapy in
addition to counselling.
Meta-analysis of the evidence of effectiveness of various smoking cessation interventions is shown in table 1
below. Most studies have been done on patients meeting criteria of nicotine dependence, which include smoking
within 30 minutes of waking, smoking more than 15 cigarettes a day and significant withdrawal symptoms during
previous quit attempts.48
Table 1. What works for smoking cessation from the Cochrane Library of Systematic Reviews
Intervention
Effectiveness
Relative Risk*
(95% Confidence
interval)
Comments
1.7
(1.5 to 1.8)
DRUG TREATMENTS
Nicotine patch51
Anxiolytics55
Bupropion (Zyban)52
1.7
(1.5 to 1.9)
Nortryptyline52
2.0
(1.5 to 2.8)
6 studies. Tricyclic
side-effects.
Selective serotonin
reuptake inhibitors
(SSRI) e.g.: Fluoxetine52
0.9
(0.7 to 1.2)
No
Clonidine (oral or
transdermal)54
1.7
(1.2 to 2.8)
Yes.
119
Intervention
Effectiveness
Relative Risk*
(95% Confidence
interval)
Comments
2.3
(2.0 to 2.7)
NON-DRUG TREATMENT
Hypnotherapy56
Individual counselling50
1.4
(1.2 to 1.6)
Yes.
2.0
(1.6 to 2.5)
Yes.
2.0
(1.4 to 3.0)
Yes.
1.1
(0.8 to 1.4)
*Relative risk (RR) refers here to the risk of successful cessation, usually measured at 12 months. Thus a RR of
1.7 for nicotine patches means patients receiving patches were 70% more likely to succeed at 12 months than
control group patients.
Counselling is highly effective, whether individual or group based.49,50 Effective drug treatments include nicotine
replacement therapy (NRT), bupropion and varenicline, while the place of nortryptyline and clonidine in smoking
cessation is limited by side-effects.51-54 Varenicline is generally commenced one-week before the patients quit date
and bupropion commenced two-weeks before the quit date.40 This may cause practical difficulties in cases when
the timing of surgery is imminent.
NRT is commenced on the patients quit date, making it use easier.40 There is no evidence that NRT has a
negative effect on postoperative outcome.59 Given the known cardiovascular side-effects of nicotine, it is somewhat
counter-intuitive that the safety of NRT has been firmly established, even in the presence of cardiac disease.60
Guidelines from The Royal Australian College of General Practitioners state there is no evidence of increased risk
for patients using NRT with stable cardiovascular disease, but it should be used with caution in recent MI, unstable
angina or recent CVA.48 In many cases the benefit that NRT gives cardiac patients in stopping smoking outweighs
the harm of continued smoking or the NRT itself.60
It is likely that components of cigarette smoke other than nicotine contribute significantly to the increased
cardiovascular risk of smokers.27 Furthermore, peaks and troughs of blood nicotine levels after smoking are far
greater with cigarettes than NRT.27 Nicotine patches do not appear to induce vasoconstriction resulting in poor
wound healing and infection as wounds in abstinent smokers wearing NRT patches were no more likely to become
infected or rupture than abstinent smokers without NRT.59
Studies comparing different forms of NRT (transdermal patches, gum, inhalers etc) did not strongly favour one
form over another but studies using NRT combinations showed higher effectiveness (e.g. patch for baseline nicotine
requirement and gum for breakthrough cravings).51 The initial dose of a sustained-release nicotine patch usually
approximates the current daily nicotine intake so that a 20 cigarettes per day patient would be prescribed patches
delivering 21mg/day.40 Nicotine (eg. gums) for breakthrough cravings 12mg/day.40 Tapering of patch doses generally
occurs over a 4-week period.40
SMOKING CESSATION: THE PUBLIC HEALTH CHALLENGE FOR ANAESTHETISTS AND SURGEONS.
The consistent and routine application of a smoking cessation strategy represents a challenge for anaesthetists,
surgeons and health services. The first challenge is overcoming personal attitudes that prevent us from engaging
with patients to inform them of the harms of smoking and giving encouragement and support to quit. This includes
perceptions that smoking is a social rather than medical problem, assumptions that physicians advice lacks effect
on cessation outcomes, a deficit of knowledge or training and a reluctance to raise the topic because it may upset
patients.3,41,44
The second challenge is time. The smoking status of a patient may only be discovered by the anaesthetist on
the day of surgery. Systems to have alerting information available earlier should be considered. Despite political
and media agendas that focus on long elective surgical waiting lists, the reality is that there is relatively little time
to act in most cases as half of elective surgery at Australian public hospitals being currently done within 36 days.22
Whether smokers should have elective surgery delayed in order to participate in a smoking cessation program is
a debate long overdue when one considers that since 1944 there have been over 300 papers showing the adverse
effects of smoking on surgical outcomes.33
120
The third challenge is to advocate within our health systems for effective and sustainable programs for smoking
cessation based on established evidence-based models. Fund providers of acute care in hospitals may balk at
funding requests for hospital-based interventions where the savings are not immediately apparent. This is unfortunate
as even an intensive preoperative smoking cessation clinic model was shown to be cost-effective in terms of
reducing overall hospital costs.61 More long-term community savings could be expected than reported in a hospitalcost analysis as many patients remain smoke-free 12 months or more after discharge from these programs.10
Anecdotally, very few health services in Australasia have systematic programs for patients joining surgical waiting
lists that identify smokers and give them information and support on how to quit before surgery. Peninsula Health
in Melbourne is currently commencing and evaluating a program where all smokers on the surgical waiting list will
receive a brochure explaining the benefits of quitting as well as a reply-paid referral letter to enable Quit Victoria to
commence free preoperative telephone counselling sessions*. No other Victorian health service systematically
refers elective surgical patients to quit (I. Ferreter, personal communication), yet referral to Quitline is an integral
part of smoking cessation guidelines for Australian general practice.48
The scale of the task is a challenge but also a significant opportunity for public health improvement. In the
2009/10 year there were 1.9 million elective operations in Australia, two thirds of which were in the private sector.22
In New Zealand public hospitals, there were 137,279 elective operations over the same period (C. Lewis, personal
communication). Based on the current smoking prevalence it is likely that at least 360,000 smokers have elective
surgery in our region each year. As cardiothoracic, vascular and certain cancer surgery is over-represented amongst
smokers, this figure is probably conservative. Worldwide, an estimated 70 million smokers undergo major surgery
each year.26
CONCLUSION
Before he died of lung cancer at the young age of 45, the great US musician Nat King Cole asked his doctor to
get me well so I can get on television and tell people to stop smoking62. It was too late for Nat and his cancer
denied him that opportunity. Yet by routinely enquiring about smoking habits, advising to stop and referring for
further help, anaesthetists can act on their favourable opportunity to end the misery that tobacco inflicts on many
lives. Regarding smoking and surgery, it is time to clear the air.
*Further information, brochure template and fax referral form, visit clinicians area at
www.stopbeforetheop.blogspot.com
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123
125
126
In 2000 the Watchtower Society also published the article Questions from Readers 5 which redefined the
guidelines for the use of blood products. It detailed which products are unacceptable and which are for the Christian
to decide.
Unacceptable products included:
1) Pre-operative autologous blood donation
2) Transfusion of the primary components of blood, namely whole blood, packed red cells, plasma, platelets
and white cells
However, in a policy change, fractions of all the primary components red cells were now permitted as a matter
of personal decision; beyond that, when it comes to fractions of any of the primary components, each Christian,
after careful and prayerful meditation, must conscientiously decide for himself.5 The list of acceptable products
includes, but is not limited to, albumin, cryoprecipitate, clotting factors, immunoglobulins, recombinant human
erythropoietin, interferon, interleukins and even haemoglobin based blood substitutes or oxygen carriers. The most
profound impact from this change will be seen if and when haemoglobin based oxygen carriers are introduced into
general use.
As can be seen the blood ban is in a state of evolution and change, with the number of acceptable blood products
ever increasing.
Indeed, within the Jehovahs Witness faith itself there are dissident groups who believe the blood ban is
unacceptable, has no biblical basis and is flawed by inconsistency. One such group is The Associated Jehovahs
Witnesses for Reform on Blood.6 The founder of this group maintains his status as a Jehovahs Witness but writes
under a pseudonym to avoid being expelled or disfellowshiped. The group argues:
If the scriptures ban blood transfusions why does the Watchtower Society allow transfusion of all minor blood
fractions?
Why are minor components like platelets (0.17% blood volume) and white cells (1% blood volume) forbidden
yet a larger component like albumin (2.2% blood volume) is permitted?
Why are Jehovahs Witnesses permitted to accept ever increasing numbers of blood products (and transplants)
yet are forbidden from contributing to the donor supply?
Ultimately it is essential to seek the views of the individual patient. However, many Jehovahs Witnesses are not
aware of the numerous blood products that can now be accepted as a matter of conscious. Without such
knowledge, decision making regarding blood products can not be considered informed or autonomous without
undue influence from others. A detailed discussion of the evolution of the blood policy may be necessary before
any consent can truly be considered informed.
The Hospital Liaison Committee for Jehovahs Witnesses is comprised of a group of educated elders, who may
assist a patient in making a decision. However it is imperative that Jehovahs Witness patients, where possible, are
also interviewed alone (including away from family members) so that they may make a decision free from coercion
or guilt.
Some may request to receive a blood transfusion secretly after visiting hours or agree to a contingency plan
such that they will only accept transfusion in the event of imminent death without transfusion. Confidentiality in
these situations needs to be respected to avoid social and religious repercussions.
THE DANGERS OF BLOOD TRANSFUSION
The lessons learnt from treating Jehovahs Witness patients may benefit society as a whole.
As the deleterious effects of blood transfusion become more apparent, costs escalate and donor numbers
decline, there has been an increase in transfusion avoidance strategies.
Many of the techniques developed for use in these patients will likely become standard practice in time, in an
effort to conserve low blood stocks and minimise exposure to transfused blood.
The disadvantages of transfusion are many.
a. Infection
Although improvements in screening have reduced the risk of transmission of HIV, HBV and HCV, these infections
do still rarely occur. In addition, severe acute respiratory syndrome (SARS), West Nile Virus, protozoa and prionrelated disease are the latest to join the list of potentially transmissible diseases.
b. Suppression of Immune System Function
So-called Transfusion Related ImmunoModulation or TRIM, may now be one of the greater disadvantages of
transfusion. Transfusion predisposes to infection, as seen in a study of 102 patients undergoing spinal fusion
procedures. The patients received either autologous transfusion, allogeneic transfusion or neither. The infection
rate of 4% in patients receiving no blood products was comparable to those receiving autologous blood transfusion
(3.3%). However, patients receiving allogeneic blood transfusions had infection rates in excess of 20%. The number
of allogeneic units transfused was the only significant predictor of in-hospital infection (p = 0.016) or days on
antibiotics and length of stay.7
The effect of immunomodulation on malignancy remains unclear. In animal studies transfusion increases metastatic
formation. Human studies are divided, but some have shown a correlation between transfusion and increased risk
of tumour recurrence after potentially curative surgery. In particular, perioperative blood transfusion has been
demonstrated to be a significant independent prognostic factor for colorectal cancer recurrence.8
127
Vincent et al performed a multicentre prospective observational study of 3534 critically ill patients admitted to
146 western European intensive care units during a 2 week period in 1994. Patients receiving transfusion had an
increased intensive care length of stay, organ dysfunction score and overall 28-day mortality (29% vs 14.9%)
compared to similar non-transfused patients.9
The TRICC trial (Transfusion Requirements In Critical Care) randomly allocated critically ill patients to either a
liberal (<10g/dl) or restrictive (<7g/dl) transfusion threshold. There was a non-significant trend towards lower mortality
in the restrictive group overall (18.7% vs 23.3%, p= 0.1). In addition these patients had a lower incidence of multiple
organ dysfunction, myocardial infarction and acute pulmonary oedema.10
c. Others
Immunological and allergic reactions may complicate transfusion. ABO incompatibility through human error may
have disastrous consequences. In addition, the metabolic consequences of transfusion (particularly massive
transfusion) are well known and include acidosis, hyperkalaemia, hypocalcaemia and hypothermia.
The storage defect results in red blood cells with increased fragility and reduced ability to transport oxygen.
Finally, respiratory failure may complicate transfusion due to either cardiogenic pulmonary oedema, transfusion
associated circulatory overload or Transfusion Related Acute Lung Injury (TRALI).
PRINCIPLES OF BLOODLESS SURGERY
The term bloodless surgery refers to a series of measures in the pre-, peri- and post- operative care of patients
that aims to reduce the need for allogeneic blood transfusion.11 There are over 230 Bloodless Hospitals worldwide12,
however there is only 1 in Australia, Kaleeya hospital, East Fremantle, West Australia; it is a small hospital without
an intensive care unit and provides mainly day surgery.
Bloodless surgery requires a coordinated multidisciplinary approach. Medical, anaesthetic and surgical teams,
phlebotomists, pharmacists, physiotherapists and dieticians all need to be involved, where available.
Senior surgical and anaesthetic staff should be made aware of a pre-operative Jehovahs Witness patient as
soon as possible. A thorough discussion between patient, surgeon and anaesthetist should occur, detailing the
risks, including intensive care stay and death. Which products will and will not be accepted should be documented
in the notes and witnessed. The patient may agree to a contingency plan should death without transfusion become
inevitable. The patient should be interviewed both with friends/ family and alone to avoid coercion. If the risk of
bleeding and death is high, consider involving the hospital ethics committee, legal department, risk management
group and Hospital Liaison Committee for Jehovahs Witnesses.
Both anaesthetists and surgeons have the right to refuse to anaesthetise or operate on an individual in the
elective situation provided they refer the case to a suitably qualified colleague who would be prepared to accept
it.13
In the emergency situation however, both the anaesthetist and surgeon are obliged to provide care and legally
must respect the patients views with respect to blood products.14
To administer a blood product to a competent adult after it has been explicitly refused is both illegal and ethically
unacceptable.
PRE-OPERATIVE MANAGEMENT
Pre-operative patient assessment should include a thorough history and examination to allow estimation of
physiological reserve and ability to withstand hypovolaemia and anaemia. Pre-existing cardiac and respiratory
disease should be optimised. Medications that may promote bleeding, such as antiplatelet agents, heparin, warfarin,
dabagatrin, NSAIDS and fish oil, should be reviewed and ideally stopped. Coagulopathy should be corrected.
Nutritional status should be reviewed and optimised with the use of enteral nutritional supplements and even
consideration given to total parenteral nutrition if nutritional status is poor.
Enhanced haematopoiesis requires supplementation of iron, folate, vitamin B12 and ascorbic acid. Even in the
absence of anaemia, recombinant human erythropoietin (rhEPO) can be used to improve red cell mass. The use of
erythropoietin requires additional iron supplementation, usually intravenous, to be most effective. Erythropoietin
has been demonstrated to half the rate of exposure to blood transfusion but requires approximately 4 weeks for
maximal erythropoiesis to occur. Erythropoietin however is not devoid of side effects, with hypertension and
thrombosis complicating its use.
INTRA-OPERATIVE MANAGEMENT
1. Surgery
With respect to intra-operative surgical technique; only senior personnel should perform procedures that carry a
significant risk of bleeding. Where possible a minimally invasive technique should be employed, such as laparoscopic,
endoscopic or staged procedures. For example a bilateral procedure should be performed as 2 separate unilateral
procedures to minimise acute blood loss at each surgery.
Meticulous haemostasis is essential. The use of diathermy dissection or the harmonic scalpel can minimise
bleeding depending on operator expertise.
Local haemostatic agents such as bone wax, fibrin glue, cellulose and collagen may also reduce haemorrhage.
Where possible, drains should be placed to facilitate early detection of post operative bleeding.
128
2. Anaesthesia techniques
With respect to anaesthetic technique, again senior or consultant personnel should be involved. The patient, room
and fluids should be warmed to prevent hypothermia and subsequent coagulopathy.
Venous congestion and venous ooze may be minimised by careful positioning and avoidance of high
intra-thoracic pressures and hypercapnia.
Where feasible, tourniquets and infiltration of vasoconstrictor agents should be used.
Regional techniques, where possible, will minimse blood loss.
Serial measurement and correction of coagulation profile and ionized calcium should be considered in long
cases.
Invasive monitoring should be considered to optimise tissue oxygen delivery, which is dependent upon haemoglobin
concentration, cardiac output and haemoglobin saturation. These factors may be manipulated using fluids, inotropes
and increasing the FiO2.
O2 delivery (DO2) = cardiac output x (1.39 x Hb x SaO2) + 0.02 x PaO2
3. Anaesthesia drugs
A number of drugs may be used peri-operatively to minimise bleeding.
a. Systemic antifibrinolytic agents, including tranexamic acid and eicoso-aminocaproic acid, inhibit plasminogen
activity and promote coagulation. Tranexamic acid is given as a 1g infusion followed by 1g Q8H. The infusion rate
should not exceed 100mg/min.
b. Desmopressin or DDAVP induces the release of Factor VIII, prostacyclin, tissue plasminogen activator and
von Willibrand Factor from vascular endothelium. It has been demonstrated to reduce peri-operative blood loss
associated with uraemic and aspirin-induced platelet dysfunction.15 The dose given is 0.3mcg/kg as an infusion
over 30 minutes.
c. Prothrombin Complex Concentrate or Prothrombinex contains recombinant factors II, VII, IX and X. It may be
acceptable to some Jehovahs Witness patients. The recommended dose is 25-50IU/kg. It is relatively deficient in
factor VII so works best when given along with a small amount of FFP and/ or rFVIIa.
d. Recombinant activated Factor 7 or Nova7 (rFVIIa) is reported to be effective in clinical situations associated
with severe haemorrhage including cardiac surgery, trauma and obstetrics, but controlled clinical trials are scarce.
Most case reports claim its use is associated with a reduction in blood loss and/ or transfusion requirements.
Randomised controlled trials using rFVIIa in intra-cerebral haemorrhage demonstrate reduced growth of the
hematoma but no improvement in survival or functional outcome.16 Likewise trials in blunt trauma demonstrate
benefit on blood loss and transfusion requirements but not mortality.17 Its use is complicated by the occurrence of
arterial and venous thromboses, especially in the elderly population and those with risk factors for peripheral
vascular disease. As it is an off-license indication, there is no recommended dose, but between 50 and 90mcg/kg
is generally given.
e. Individual clotting factors may be acceptable to some Jehovahs Witnesses.
f. Haemoglobin based oxygen carriers (HBOCs) could be employed in the future where available. They have
been in development for over 70 years; however interest has been renewed since the 1980s, prompted by both
the emergence of HIV and the death of trauma victims from exsanguination in the pre-hospital setting; including at
accident scenes, in ambulances and on the battlefield. Despite this there are currently no haemoglobin based
oxygen carriers approved for human use in Australia, the US or European Union; reflecting both a controversial
history and the challenge of creating an ideal blood substitute.
HBOC DEVELOPMENT
Haemoglobin based oxygen carriers contain purified haemoglobin derived from either bovine red cells, expired
human red cells or from recombinant technology. Free human haemoglobin has a tetrameric structure of 2 alpha
and 2 beta polypeptide chains. It rapidly dissociated into alpha/beta dimers which are cleared by glomerular filtration
with an intravascular half life of only 30 minutes. Dissociated haemoglobin causes renal failure and scavenges nitric
oxide causing hypertension. In addition, due to low concentrations of 2,3 DPG, free haemoglobin is ineffective at
oxygenation due to its high affinity for oxygen, with a P50 of 10 to 14mmHg. In order to become therapeutically
useful, free haemoglobin requires modification by polymerisation and/ or cross-linkage to prevent dissociation into
alpha/beta dimers, right shift the oxyhaemoglobin dissociation curve and to increase its half life in the circulation.
The modified haemoglobin is then incorporated into an electrolyte solution.
HBOC ADVANTAGES
Haemoglobin solutions have the advantage of being non-immunogenic. They do not contain any intact red blood
cells, which express ABO antigens, therefore cross-matching the product or typing the patient is not necessary.
The products undergo an extensive purification process to remove potential contaminants including proteins,
red blood cell stroma, bacteria, endotoxins, viruses and prions and are therefore guaranteed to be disease free.
Haemoglobin based oxygen carriers may be stored far longer than the 42 days permitted for packed cells,
between 12 months to 3 years, depending on the product. Hemopure is the easiest product to store and transport
as it does not require refrigeration and may be stored for up to three years at room temperature.
129
Haemoglobin solutions are developed to right shift the oxyhaemoglobin dissociation curve compared to native
haemoglobin. Hemopure contains bovine haemoglobin; it has a P50 of 40mmHg compared to 27mmHg for human
red blood cells. It therefore releases oxygen more readily to the tissues and, on a gram-for-gram basis, restores
oxygenation three times more effectively than a transfusion of stored human red blood cells. PolyHeme contains
human haemoglobin, it has a P50 of 20-22mmHg which is comparable to packed cells.
HBOC DISADVANTAGES
There are a number of disadvantages of haemoglobin based oxygen carriers compared to blood. Despite modification,
they have a short intravascular half life of 16 to 24 hours, compared to 60 to 90 days for red blood cells, making
repeat administration necessary. Cost is also higher than transfused red blood cells when compared on a unit-tounit basis.
Use of haemoglobin based oxygen carriers also interferes with many common laboratory tests, especially those
which are measured spectrophotometrically. Albumin, alkaline phosphatase, bilirubin and creatinine may all be
inaccurate. Optical methods of measuring coagulation will be misleading. Plasma will have a pink discoloration
and routine laboratory tests will not be able to differentiate between haemolysis and the presence of a haemoglobin
solution. Plasma free haemoglobin levels are measured to determine the amount of haemoglobin based oxygen
carrier present in the specimen but the decision to give additional doses must be determined clinically.
The incidence of adverse effects is not insignificant (approximately 5%), with complaints of jaundice, nausea,
mild to moderate increases in blood pressure, vomiting, oliguria, dysphagia and flatulence.
There are also reports of serious adverse events including myocardial infarction and death, however these risks
may be acceptable when allogeneic blood is either not available or effective or not acceptable to the patient.
Furthermore, haemoglobin solutions have a maximum recommended dose, reflecting the maximum dose studied
in clinical trials to-date, which may provide temporary oxygen-carrying support, or an oxygen bridge but may not
be sufficient to completely avoid red cell transfusions in patients experiencing massive or continued blood loss.
HBOC PRODUCT HISTORY
There have been a number of haemoglobin oxygen carriers in production over the last 30 years but PolyHeme is
probably the most controversial and Hemopure possibly the most promising.
PolyHeme is a haemoglobin based oxygen carrier derived from human hemoglobin and developed by Northfield
Laboratories, Inc. Northfield was predominately a research and development company; PolyHeme was their only
product. PolyHeme was the first blood substitute to reach a Phase III clinical trial in the US.
The trial was designed to assess the survival benefit of administering PolyHeme to severely injured trauma
patients in hemorrhagic shock, beginning in the pre-hospital setting and continuing for 12-hours post-injury in
hospital. It had two primary endpoints of superiority and non-inferiority to standard treatment. It was undertaken
between January 2004 and July 2006 at 29 Level I trauma centers across 19 states in the US under a Food and
Drug Administration (FDA) special category (21CFR 50.24) that allowed its use without consent. The waived informed
consent rule was established by the FDA in 1996 and stipulated that to be used available treatments . (must be)
unproven or unsatisfactory. The only way to opt out from the study was by wearing a special bracelet prior to
needing emergency care. The study was highly criticised due to the absence of consent. Indeed continuation of
the study into the in-hospital period was considered unethical as blood was then both readily available and a proven
and satisfactory therapy for haemorrhagic shock.
The results were published in the Journal of the American College of Surgeons in January 2009.18 They concluded
there was no significant difference in outcome between the conventionally-resuscitated group and the PolyHemetreated group. However PolyHeme was associated with an increased risk of myocardial infarction (3% versus 1%).
In May 2009 PolyHeme failed to receive FDA regulatory approval, with the FDA stating the risks of PolyHeme
outweighed the benefits. In June 2009 Northfield Laboratories Inc ceased operation and filed for bankruptcy.
Hemopure, or HBOC-201, is developed from highly purified bovine haemoglobin. It is a third generation product
developed by Biopure. It has been available for human use in South Africa since 2001 and in Russia since 2011.
There is also a compassionate use program in the US which makes Hemopure available when a life-threatening
situation exists and compatible red blood cell transfusion is either 1) not available 2) not effective or 3) not acceptable
to the patient. Approval by the FDA is made on a case-by-case basis.
Following a motor vehicle accident in October 2010, Australian Jehovahs Witness Tamara Coakley received a
life sustaining transfusion of 10 units of Hemopure, flown in from the US and made available via this compassionate
use scheme. Permission to use the product was granted by The Alfred Hospital Ethics Committee and the
Therapeutic Goods Administrations special access scheme. The manufacturer OPK Biotech paid for the costs
involved.
Hemopure has undergone a Phase III clinical trial evaluating its ability to reduce or eliminate perioperative
transfusion in orthopaedic patients.19 Hemopure reduced the need for packed cell transfusion in 59% of patients
but was associated with a significantly higher incidence of both adverse events (rate of adverse event/ patient 44%
higher, p<0.03) and serious adverse events (rate of serious adverse event/ patient 36% higher, p< 0.016).
130
In 2008 a controversial meta-analysis comparing 16 clinical trials involving 5 different HBOC products used on
over 3500 patients was published in the Journal of the American Medical Association.20 The study was led by
Charles Natanson, a scientist at the US National Institute of Health. It concluded that patients treated with a HBOC
had a 30% increased risk of death and 2.7-fold increased risk of myocardial infarction. Biopure responded by
claiming there were fundamental errors in the calculations and analysis. Biopure then sued Natanson, claiming he
had made false and defamatory statements about Hemopure. Following this South Africas Medicines Control
Council temporarily de-registered Hemopures approved use for the treatment of acute surgical anaemia.
A 2009 application to the FDA for clinical approval of Hemopure in the US was declined. In August 2009 Biopure
ceased operation and filed for bankruptcy.
Biopure has since been bought by OPK Biotech, a Russian owned company who has recently obtained approval
for Hemopure to be used in Russia. OPK Biotech has also bought the intellectual property of Northfield Laboratories
Inc, the company that developed PolyHeme. These acquisitions will likely make OPK Biotech a leading company
in the field of oxygen therapeutics.
ANAESTHESIA BLOOD SAVING TECHNIQUES
In addition to the use of drugs there are a number of anaesthetic techniques available to minimise blood loss.
a. Controlled hypotension or hypotensive anaesthesia is a technique whereby the mean arterial pressure is
maintained at a low level during surgery to minimise bleeding. It may decrease bleeding by as much as 50% but
is controversial due to the risk of cerebral, renal and myocardial ischaemia. In addition, haemostasis that is adequate
during controlled hypotension may not prove adequate when the patient returns to their normotensive, or worse
still hypertensive, state.21 As such, the avoidance of marked haemodynamic shifts intra-operatively is more accepted.
b. Acute normovolaemic haemodilution involves the removal of whole blood from the patient pre-operatively
and replacement with crystalloid or colloid to maintain intravascular volume. Blood lost intra-operatively has a
reduced haemoglobin concentration resulting in fewer red cells lost overall. Provided the blood is kept in continuity
with the patient the removed blood may be re-infused at the end of the case. This technique requires adequate
respiratory and cardiac reserve to compensate for acute blood loss.
c. Acute hypervolaemic haemodilution uses the rapid infusion of fluid to achieve haemodilution without venesection.
Again blood lost contains fewer red cells. Although acceptable to some Jehovahs Witness patients it is poorly
tolerated by those with cardiac disease, due to risks of fluid overload and heart failure.
d. Red cell salvage is a technique that can be used both intra-operatively and in the post-operative period to
replace blood in proportion to the volume lost. Shed blood is collected, washed, mixed with anticoagulant and then
re-infused via a filter. Many, but not all, Jehovahs Witnesses will accept red cell salvage, again provided the circuit
is not interrupted and remains in continuity with the patient. Red cell salvage is relatively contraindicated if there
is the possibility of contamination with urine, fat, amniotic fluid, bone chips, bowel contents or infected material.
Definite contraindications include re-infusion of anything that results in red blood cell lysis. This would include sterile
water, hydrogen peroxide, and alcohol.
POST-OPERATIVE MANAGEMENT
a. Early Detection of Blood Loss
In the post-operative period, early detection of blood loss is essential and can be facilitated by close monitoring
in a critical care area and serial clinical examination of both the patient and their drains.
b. Minimise Iatrogenic Blood Loss
Blood loss can be minimised by avoidance of hypertension and marked haemodynamic shifts, and by reducing
iatrogenic blood loss by infrequent and low volume blood sampling.
Two epidemiological studies of critically ill ICU patients have demonstrated similar figures for the mean volume
of blood taken daily; 42.5ml/day in 1 study22 and 41.1ml/day in the other.23 The more unwell the patient, the more
blood is likely to be taken.
Unnecessary blood loss can be avoided by abandoning routine tests which are not strictly indicated. When
available, paediatric or small volume tubes should be used. If these are not available then small volumes should
be used for all samples except coagulation profile, which is the only test that requires a full tube. Use of point of
care micro-testing should also be employed where available.
c. Promote Haematopoiesis
Haematopoiesis can be enhanced in the post operative period with the use of nutritional supplements, iron, folate,
vitamin B12, vitamin C and recombinant erythropoietin if necessary.
131
132
17. Boffard KD, Riou B, Warren B, et al. Recombinant factor VIIa as adjunctive therapy for bleeding control
in severely injured trauma patients: two parallel randomized, placebo-controlled, double blind clinical trials.
J Trauma 2005; 59: 8-15.
18. Moore EE, Moore FA, Fabian TC et al. Human Polymerized Hemoglobin for the Treatment of Hemorrhagic Shock
when Blood Is Unavailable: The USA Multicentre Trial. J Am Coll Surg. 2009; 208: 1-13.
19. Jahr JS, Mackenzie C, Pearce LB et al. HBOC-201 as an Alternative to Blood Transfusion: Efficacy and Safetly
Evaluation in a Multicentre Phase III Trial in Elective Orthopedic Surgery. J Trauma. 2008; 64: 1484-1497.
20. Natanson C, Kern SJ, Lurie P et al. Cell-Free Haemoglobin-Based Blood Substitutes and Risk of Myocardial
Infarction and Death. A Meta-analysis. JAMA. 2008; 299 (19): 2304-2312.
21. Gohel MS, Bulbulia RA, Slim FJ, et al. How to approach major surgery where patients refuse blood transfusion
(including Jehovahs Witnesses). Ann R Coll Surg Engl. 2005; 87: 3-14.
22. Smoller B, Kruskell M. Phlebotomy for diagnostic laboratory tests in adults: Pattern of use and effect on
transfusion requirements. N Engl J Med 1986; 314: 1233-1235.
23. Vincent J, Baron J, Reinhart I et al. Anaemia and blood transfusion in critically ill patients. JAMA 2002; 288:
1499-1507.
133
135
2600mg
Iron Stores
500 1000mg
Myoglobin / Cytochromes
400mg
Transferrin
3mg
136
137
Treatment points
Dietary iron alone (e.g. high red meat intake) is inadequate to treat established iron deficiency anaemia.3
Common medications such as H2 antagonists or proton pump inhibitors decrease the effectiveness of oral
iron therapy.3
Gastrointestinal iron is poorly absorbed in patients with raised hepcidin levels (inflammatory disease,
malignancy, immediate postoperative period)
Ferritin is an acute phase protein, which is often raised in patients with inflammatory disease processes and
so may not accurately reflect body iron stores. Some anaemic patients, with high or normal ferritin, may still
have true iron deficiency or functional iron deficiency, which will often respond to intravenous iron therapy.
A useful algorithm for assessing anaemia in pre-operative patients has been developed by the Western Australia
Department of Health Patient Blood Management Program a copy of which is provided at the end of this article.
TREATMENT OPTIONS FOR ANAEMIA
Oral Iron
The traditional first line treatment for iron deficiency anaemia (IDA) is oral iron therapy. In appropriate dosage and
given enough time, oral iron is an effective treatment for simple iron deficiency anaemia. Some important considerations
in the anaemic perioperative surgical patient include:
Oral iron requires sufficient time to produce an adequate response. In IDA an increase of 20g/L every 3 weeks
is the maximum to be expected. In practical terms this implies weeks to months of treatment.
30 50% of patients may experience gastrointestinal adverse effects and non-compliance is high.
Oral iron will be ineffective in patients with raised hepcidin levels, (e.g. immediate postoperative period,
chronic inflammatory disease)
H2-antagonists and proton pump inhibitor medications will reduce the efficacy of oral iron therapy.
It is important that patients take an oral preparation which contains an adequate dose of elemental iron
with100-200mg / day recommended (e.g. 12 Ferro grad). There are more than 100 iron containing over the
counter preparations available in Australia many of which contain woefully inadequate amounts of elemental
iron (often < 5mg). Many would require 20 tablets for a therapeutic dose!3
Red Cell Transfusion
There is evidence that transfusion to correct iron deficiency anaemia is still an overused treatment.5 Targeted use
of transfusion is an appropriate strategy when severe anaemia compromises organ function (e.g. cardiac failure,
angina pectoris) or there is ongoing serious bleeding. Iron therapy to fully replenish haemoglobin and iron stores
will still be required.
Intramuscular Iron
Intramuscular injection of iron polymaltose is not recommended in most circumstances,6 unless other approaches
are impractical (e.g. in remote communities). It is painful, causes skin discolouration, repetitive injections are required,
and it is less effective but no safer than IV administration.
Intravenous Iron
Pharmacology7
Administration of unbound inorganic ferric (Fe+3) iron in the early 1930s was observed to cause profound toxicity.
Therefore all modern intravenous iron preparations are colloids consisting of a protective spheroidal carbohydrate,
which encapsulates an inner iron hydroxide core. After IV injection the iron carbohydrates distribute in the plasma,
from where the majority then enter the reticuloendothelial system (mainly liver, spleen and bone marrow). From here
iron is either stored as ferritin or transferred out via transferrin to the bone marrow to produce haemoglobin. A small
amount of free iron from the IV iron may be released directly onto transferrin in the plasma; this is more so with
the smaller molecules such as iron sucrose, which explains why it cannot be used for total dose infusions.
Variation in the molecular weight of the encapsulating carbohydrate explains most of the differences in the
pharmacological properties of the different preparations. The rate of clearance from the plasma and the rate of
release of iron from the ferric hydroxide core are inversely related to the total molecular weight. The general rule is
the smaller the molecule the more rapid the release of the iron, and the lower the maximum dose you can give.
Adverse Effects and Toxicity8
Reactions During Infusion
During administration of an intravenous iron polymaltose infusion a number of adverse effects can occur occasionally.
The vast majority are not serious, are self-limiting in nature and have been described to varying degrees with all
the other intravenous iron preparations. These include nausea, rash, headache, mild hypotension, myalgia, arthralgia,
chest and back pain. The mechanism of these adverse reactions is hypothesised to be related to the small amount
of free or labile iron released during an infusion.
138
139
140
Oral Iron
Preoperative oral iron: 2 positive studies one in colorectal surgery and the other orthopaedic surgery found
preoperative oral iron reduced transfusions.
Postoperative oral iron: 5 RCTs (4 orthopaedic and 1 cardiac surgery) found that postoperative oral iron was
not beneficial.18
Intravenous Iron
Orthopaedics: Intravenous iron use was beneficial in most studies. It was associated with fewer transfusions, less
anaemia, decreased length of stay, and decreased postoperative infections. In some studies it was combined with
other modalities such as EPO or cell salvage. This is the most well studied surgical group (mainly joint replacement
surgery).
Cardiac Surgery: One RCT and one observational study failed to confirm any benefit from postoperative
intravenous iron.
Gynaecological Surgery: One RCT of 76 patients found preoperative iron sucrose superior to oral iron in correcting
the anaemia of women with menorrhagia and Hb<9g/L prior to surgery.19
Colorectal Surgery: One small preoperative RCT failed to show a benefit to intravenous iron sucrose 600mg
prior to surgery. This study has been criticised for having only a small proportion of patients with anaemia (i.e. those
patients most likely to benefit from intravenous iron).20
PUBLISHED LITERATURE OTHER INDICATIONS
Intravenous iron has also been shown to be an effective treatment in :
Congestive heart failure (improves NYHA status and fatigue scores)
Restless legs syndrome
Chronic Kidney Disease (adjunct to EPO)
Chemotherapy induced anaemia (+/- EPO)
As an MRI contrast agent (iron ferumoxytol)
GENERAL RECOMMENDATIONS
Patients scheduled for major surgery (or childbirth) with predicted moderate to major blood loss should be
screened for anaemia preoperatively, and if clinically feasible this should be corrected.
Patients without a clear physiological explanation for iron deficiency (especially men and postmenopausal
women) should be investigated to exclude serious underlying disorders especially occult GI malignancy. This
should take priority over purely elective surgical procedures.
With confirmed iron deficiency anaemia, intravenous iron should be considered in preference to oral iron if:
there is fewer 30 days to surgery
when it is reasonable to assume oral iron will be ineffective (e.g. postop)
Intravenous iron may be useful in anaemia of chronic disease, and it will improve the response to
erythropoietin if this is used.
Intravenous iron should be considered in the treatment of antepartum and postpartum iron deficiency
anaemia, especially if a rapid response is desirable or oral iron has failed.
Avoid intravenous iron during acute infections.
If the overall goal is avoiding perioperative blood transfusions this probably best accomplished by combining
intravenous iron with a range of other techniques (e.g. intraoperative cell salvage).
HYPOTHETICAL SCENARIOS TO PONDER:
How do you think these patients could be managed? How do you think they would actually be managed currently
in the hospital you work in?
1. You see a 64 yr old woman in the anaesthetic preadmission clinic 3 weeks prior to a planned anterior
resection for a recently diagnosed rectal cancer. On reviewing her recent blood tests you note she has a
microcytic anaemia with a Haemoglobin (Hb) of 94g/L.
2. A 74 yr old male presents for a left total hip replacement having undergone a right total hip replacement 6
months earlier. He is diabetic, with mild renal impairment (Creatinine 150) and you note he has a normocytic
anaemia with a Hb 102 g/L.
3. A 47 yr old woman with longstanding menorrhagia and fibroids presents to preadmission clinic 2 weeks prior
to a planned elective total abdominal hysterectomy. She states her gynaecologist advised her to take
ferrograd C two months ago but she stopped after 3 days because of nausea and constipation. A FBC from
her GP 2 weeks ago shows a microcytic anaemia with a Hb 81g/L.
4. A fit and healthy 27 yr old parturient develops an atonic uterus following emergency caesarean section for
twins, and has a 1.5 L blood loss which is successfully managed in theatre. You check her haemoglobin in
recovery and it is 76 g/L. You note her full blood count on admission to labour ward yesterday that she had a
microcytic anaemia with a Hb 104 g/L. She isnt that keen on the idea of a blood transfusion but the obstetric
registrar wants to top her up so shell have plenty of energy to look after two newborn twins when she is
discharged home in a few days.
Iron deficiency
anaemia Evaluate
possible causes.
If other causes are
excluded (eg dietary,
malabsorption,
menstruation, etc)
referral for GI
investigation is
appropriate.
Commence iron
therapy.+
MCV <80 fL
Thalassaemia or
Possible anaemia
of renal impairment.
Consider
Elevated creatinine
Transferrin saturation
Anaemia of chronic
disease/inflammation
Anaemia of chronic
disease/inflammation +
iron deficiency Consider
Diagnose cause
and treat B12/
This algorithm has been reproduced with permission the Western Australian Department of Health Patient Blood Management Program.
*Iron therapy
Oral iron in divided daily doses
if surgery >2 months and if oral
iron not contraindicated. Evaluate
response after 1 month. Provide
patient information material.
IV iron if <2 months to surgery
or oral iron is contraindicated.
Note: 1g/L of ferritin is equivalent
to 8 10 mg of storage iron. It will
take approximately 165 mg of
storage iron to reconstitute 10g/L
of haemoglobin in a 70 kg adult.
If preoperative ferritin is <100 g/L,
blood loss resulting in a
postoperative haemoglobin drop of
Preoperative tests:
Full blood picture (FBP) &
reticulocyte count CRP, creatinine
& eGFR
Iron studies
Use of this algorithm should always take into account the patients history and clinical assessment, and the nature of the proposed surgical procedure
142
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consensus statement on the role of intravenous iron. British Journal of Anaesthesia 2008; 100(5): 599-604.
19. Kim YH, Chung HH, Kang SB, Kim SC, Kim YT. Safety and usefulness of intravenous iron sucrose in the
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143
145
Haem molecule
with iron atom
chains
chains
Haem molecule
with iron atom
146
SCD comprises a collection of autosomal recessive genetic disorders characterised by the presence of an
abnormal haemoglobin S (HbS).
The abnormal Hb S molecule arises from a point substitution of one amino acid. The gene coding for synthesis
of the globin chain lies on the short arm of chromosome 11, and in Hb S, this defective gene codes for the amino
acid valine to be present in position 6 of the globin chain instead of glutamine.
Hb S represents one of many abnormal haemoglobins in existence, another clinically important one being
haemoglobin C (Hb C). In this mutated haemoglobin, the amino acid lysine replaces glutamine in this position 6.
Currently, over 475 globin gene variants have been identified1, but most of these genotypes do not result in
clinically significant phenotypes.
Table 1. The major sickle genotypes
Condition
Genotype
Disease expression
Moderate to severe
HbS/0 thalassaemia
Double heterozygote
Moderate to severe
HbSC
Double heterozygote
Moderate
HbS/+ thalassaemia
Double heterozygote
Mild to moderate
HbS/HPFH
Double heterozygote
HbS + hereditary persistence
of fetal Hb
Asymptomatic
HbS/HbE
Double heterozygote
Mild
As an autosomal recessive disorder, a carrier state exists whereby an individual inherits one gene for Hb S and the
other for the normal Hb A. This state is called sickle trait.
Rarer combinations of Hb S with a number of other abnormal haemoglobins also exist e.g. Hb D Los Angeles,
Hb O Arab, Hb G Philadelphia.
Disease expression appears dependent on genotype, globin haplotype2 and fetal Hb levels3, although the
balance of these determinants on disease severity is not fully understood.
HISTORY
In 1904, Melvin Dresbach published a letter in Science, noting a peculiar anomaly in human red blood corpuscles
that were elliptical and not circular.4
These cells had been visualised in the blood film of an apparently healthy medical student, who a year later,
was reported to have died suddenly from cardiac failure subsequent to an attack of acute inflammatory rheumatism
preceded by tonsillitis.5 Dresbachs account likely describes typical SCD complications; an infective trigger leading
to a pain crisis with subsequent acute chest syndrome and death.
The term sickle cell anaemia was used first by Vernon Mason in 19226 but it was not until 1949 that Linus Pauling
linked sickle cell disease with an abnormality of the haemoglobin molecule. His paper, Sickle Cell Anaemia
A Molecular Disease was the first to link a disease to a single molecular flaw.7
ORIGINS OF THE SICKLE GENE
Genetic studies indicate the sickle gene arose as an independent mutation in at least four separate geographical
locations; the Central African Republic, Benin, Senegal and either Saudi Arabia or central India.8
Hb S and to a lesser extent Hb C strongly protect against clinical Plasmodium falciparum malaria in a dose
dependent manner. Heterozygotes present a lower risk of infection than non-carriers; homozygotes even less of
an infection risk but with the increased risk of fatality if infected.9
This correlation between malarial parasite immunity and the prevalence of the Hb S and Hb C genes is reflected
in the geographical distribution of both conditions.
From http://en.wikipedia.org/wiki/File:Malaria_distribution.jpg
Figure 3. Map showing the distribution of the sickle cell gene. Darker shading denotes higher
gene frequency
From http://en.wikipedia.org/wiki/File:Sickle_cell_distribution.jpg
147
148
DEMOGRAPHICS
Persons of African descent have the highest frequency of the Hb S gene, but also those of southern Mediterranean,
Caribbean, South and Central American, Arab and Indian descent demonstrate high frequencies of this Hb S gene.1
The prevalence of the sickle cell trait ranges from 10-40% across equatorial Africa, decreasing to 1-2% on the
north African coast and <1% in South Africa. In west African countries such as Nigeria and Ghana, the carrier rate
is 15-30% of the population, and in Nigeria alone, around 150 000 children are born with sickle cell anaemia annually.
In parts of east Africa, the disease shows marked tribal variation in prevalence; for example, the Baamba tribe in
western Uganda exhibit a carrier rate of 45%.10
In the USA, 70-100 000 people have sickle cell disease, making it one of the most prevalent genetic disorders.
The UK has around 10 000 disease sufferers.
In Western Australia, immigration has seen an increase in numbers of these at-risk populations. Government
figures from 2006 give the following analysis of ethnicity by birthplace:11
Table 2. Snapshot population data based on Australian census information from 2006
Southern and
East Europe
Americas
Sub-Saharan
Africa
W. Australia
22, 400
4, 771
10, 791
21, 992
Perth
20, 800
4, 545
8, 868
18, 735
Interestingly, a case series published in the Medical Journal of Australia in 1978 described 11 cases of sickle cell
disease in the Sydney area. Patients were from Lebanese, Greek, Cypriot, Spanish, Portuguese and French origins.
The article concluded by warning that sickle cell disease is already a significant health problem within the Sydney
area, and likely to increase in incidence with increasing migration from endemic zones.12
PATHOPHYSIOLOGY
The historic concept of the disease purely as a state of inflexible sickle cells causing microvascular occlusion has
been challenged over the last 30 years. SCD may be more accurately described as a chronic inflammatory vascular
disease13, with potential novel avenues for treatment.
Haemoglobin S forms polymers under deoxygenated conditions, and also exhibits deranged solubility and
molecular instability. The myriad clinical manifestations of SCD stem from this abnormality.
Red blood cells containing polymerized Hb S adopt the characteristic sickle shape due to cell membrane damage.
Re-oxygenation will enable cells to resume their normal biconcave shape until recurrent sickling episodes render
them irreversibly sickled and rigid. These cells are prone to intravascular haemolysis and phagocytosis by
macrophages.
Sickle cells express antigen on their surface which interact with vascular endothelial proteins and cause increased
cell adherence to the endothelium.14 Endothelial activation follows, the result of which, is further erythrocyte adhesion,
thrombus formation and microvascular occlusion. Ischaemia, microinfarction and pain follow. The process is
accelerated by hypoxia and inhibited by nitric oxide. Free Hb molecules released by haemolysed sickle cells bind
nitric oxide avidly15 and thus contribute to vasoconstriction.
CLINICAL FEATURES
SCD is a multisystem disease characterised by a chronic, haemolytic anaemia, painful crises and progressive organ
damage resulting from microinfarction.
Presentation is usually in early childhood for those with Hb SS disease, although this is not universal, and patients
with Hb SC have presented in their 2nd and 3rd decades of life.
Fetal Hb comprises 2 and 2 globin chains and switches to the adult form at around six months of age. In
normal adult Hb (Hb A) the 2 subunits are replaced by 2 subunits. In Hb SS disease, the predominant Hb in the
red blood cells is Hb S, characterised by the mutated globin chains described earlier.
Haematological
Anaemia is universally present in SCD. In Hb SS disease, the Hb level is around 60-70 g/L and this level of anaemia
is normally well tolerated.
It may be complicated by megaloblastic changes from folate deficiency as red cell turnover outstrips folate
availability for new cell synthesis.
Severe, acute anaemia can be caused by:
Aplastic crises - infection with Parvovirus B-19 causes marrow cessation of erythropoiesis. The already short
RBC lifespan of around 20 days, coupled with reduced erythropoiesis results in a precipitous drop in Hb. The
marrow recovers spontaneously within 7-10 days but red cell transfusion may be needed.
Splenic or hepatic sequestration crises occur when large numbers of sickled cells pool in the liver and/or
spleen causing severe pain, rapid enlargement and severe anaemia often requiring red cell transfusion.
149
Over time, the spleen is subject to repeated infarction, exacerbated by the conditions of low oxygen tension in
the sinusoids, leading to eventual fibrosis. During this process, patients are rendered functionally hypo- or asplenic.
This places them at high risk of infection from encapsulated microorganisms such as Streptococcus pneumoniae
and Haemophilus influenza.
Pain
Vaso-occlusive crises are accompanied by severe, deep pain occurring typically in the long bones, axial skeleton
and abdomen. Their frequency can be extremely variable between individuals and even within the same patient.
Attacks can be triggered by infection, abrupt changes in temperature and dehydration; often no trigger is
identified. Crises can last hours to days with many individuals requiring opioid analgesia for symptom relief.
Pulmonary
The second commonest cause of admission in sickle cell patients is acute chest syndrome (ACS), defined as the
onset of new lobar infiltrates on chest x-ray, excluding atelectasis, with fever >38.5oC, respiratory distress or chest
pain.16 The aetiology is multifactorial; infection, both bacterial and viral, fat embolism (from bony infarction) and
pulmonary infarction or sequestration have been implicated. It is the most common, serious complication in SCD
in the peri-operative period.
Figure 4. Chest x ray showing the changes seen in acute chest syndrome. Image reproduced with
permission from Dr Donald J.Innes, Jr.,MD,: University of Virginia School of Medicine
Deoxygenated blood in the pulmonary circulation results in higher levels of Hb S polymer formation and irreversible
sickling with resultant areas of microinfarction.
Around 40% of adults with SCD have been found to have pulmonary hypertension.17
Cardiovascular
Chronic haemolysis and repeated red cell transfusion lead to myocardial haemosiderin deposition.
Children and young adults are prone to chronic leg ulcers, resulting from minor trauma with skin breakage, poor
peripheral circulation and delayed healing.18
Patients with Hb SC disease are more prone to thromboembolic complications than their Hb SS counterparts.
Neurological
Children with SCD have a 10% risk of overt stroke, a 20-25% risk of silent cerebral infarction and a 90% risk of
recurrence after a first CVA.19 A history of CVA in childhood is a strong indicator of severe disease and poor prognosis.
150
Musculoskeletal
In infants with SCD, a common presentation is with hand-foot syndrome; a painful dactylitis with radiological
evidence of cortical destruction of the metacarpal and metatarsal bones 3-5 weeks after the swelling begins.
Repeated infarction of joints, bones and growth plates results in aseptic necrosis, particularly of the femoral
and humeral heads. Areas of infarcted bone can develop Salmonella osteomyelitis.20
Gastrointestinal
Gallstone disease is common in SCD secondary to chronic haemolysis, with cholecystectomy being the most
common surgical procedure carried out in these patients.
Renal
Renal disease is not uncommon in SCD21; defective urine concentrating ability causes enuresis and can precipitate
dehydration in an already unwell patient. Renal papillary necrosis results in haematuria and renal or ureteric colic.
Nephropathy tends to be more common in Hb SC disease.
DIAGNOSIS
Testing for SCD occurs in several clinical scenarios; pre-natal testing to facilitate genetic counselling, newborn
screening and opportunistic testing after, for example, detection of anaemia or abnormalities on a blood film, or in
individuals presenting to healthcare services from at risk groups with an unknown sickle status.
Basic laboratory tests include a full blood count to detect anaemia and peripheral blood film examination to
search for sickled erythrocytes.
Elective testing can employ several different tests depending on local expertise and availability. Three commonly
used tests detect the globin gene product, haemoglobin. They are performed on blood samples, which can
include umbilical cord blood and dried blood spots from neonatal heel prick tests. These methods are listed below
alongside their sensitivity and specificity for detecting sickle cell disease.1 Detailed description of each method is
beyond the scope of this article.
Table 3 Haemoglobin variant detection methods
Method
Sensitivity (%)
Specificity (%)
93.1
99.9
Isoelectric focusing
100
100
100
100
In an emergency setting, for example prior to anaesthesia and surgery, sickle results need to be obtained rapidly
to inform peri-operative management.
The peri-operative period is a well-recognised, predictable time of disease exacerbations. SCD complications
range from 0-19% depending on the surgical procedure being carried out, with a peri-operative mortality of 1.1%.22
Identification of SCD and trait patients prior to anaesthesia is important to enable planning of peri-operative
care. This would include decisions regarding transfusion requirements, adequate hydration, analgesic options,
suitability of cell salvage techniques and tourniquet use, prevention of post-operative sickle complications and the
appropriate level of post-operative care i.e. high dependency unit.
Pre-anaesthetic testing for SCD in the emergency setting requires a rapid, easily accessible and accurate means
of determining whether a patient with an unknown sickle status is likely to be a carrier or homozygote for Hb S.
This can be readily achieved using a combination of a full blood count, sickle solubility testing +/- blood film
interpretation. A diagnostic flow chart is outlined below.23
151
Figure 5. A protocol for pre-anaesthetic sickle cell disease testing. FBC, full blood count; HPLC,
high performance liquid chromatography. Reproduced with modification with permission from
Blackwell Publishing
Assess if surgery
and anaesthesia
are urgent or
non-urgent
Surgery is
Surgery is
urgent
Assess patient,
perform FBC,
blood film, sickle
solubility test, Hb
electrophoresis or
Clinical features
suggestive of
Proceed to
surgery when
investigations
Clinical
features
Clinical
features
FBC, sickle
solubility test
and examine
No clinical
features,
-ve sickle
solubility and
No clinical features,
normal or abnormal
Hb, blood film not
indicative of SCD
but +vesickle
Clinical features
+/- blood film
suggest SCD
+/- positive sickle
Clinical features
+/- blood film
suggest SCD
+/- positive
sickle solubility
Treat pt as
Treat pt as
sickle cell
trait. Avoid
Treat patient as
SCD. Consult
haematologist, avoid
hypoxia, hypotension,
hypothermia and
Treat patient as
SCD. Consult
haematologist, avoid
hypoxia, hypotension,
hypothermia and
152
Sickle cell solubility testing relies on the relative insolubility of Hb S in high concentration phosphate buffers
compared with Hb A and other variant Hb. Hb S precipitates in this solution to form a cloudy, turbid solution.
Figure 6. The Itano sickle solubility test. Images reproduced with permission from Dr Donald J.Innes,
Jr.,MD,: University of Virginia School of Medicine
153
MANAGEMENT
As with any chronic illness, a multidisciplinary team approach is ideal to manage these patients, with close liaison
between primary care, haematologists, chronic pain services and specialist nurses.
In general, chronic management has seven elements:
1. Management of vaso-occlusive crises
2. Management of chronic pain syndromes
3. Management of haemolytic anaemia
4. Prevention and treatment of infections
5. Management of end organ damage and complications
6. Stroke prevention
7. Detection and treatment of pulmonary hypertension
Vaso-occlusive crises are often managed by the patient at home with rest, increased fluid intake and simple
analgesics. Severe crises warrant admission, investigation for an infective trigger, intravenous fluid therapy, oxygen
and often parenteral opioids.
Chronic, haemolytic anaemia requires folic acid supplementation and exclusion of concurrent iron deficiency
anaemia. Red cell transfusion is typically reserved for acute chest syndrome or stroke management, children with
abnormal transcranial dopplers who are at risk of stroke, major surgery and pregnancy.25
Penicillin V prophylaxis is administered lifelong from infancy with regular vaccination against Pneumococcus,
Haemophilus influenza type B, Meningococcus group C and influenza virus. Suspected infections should be treated
promptly, initially with broad spectrum agents until causative organisms are identified and targeted agents used.26
Acute chest syndrome requires treatment with oxygen and appropriate respiratory support, incentive spirometry27,
intravenous broad spectrum antibiotics, analgesia, bronchodilators if airway hyperreactivity is present and in
refractory cases, exchange transfusion.
All children with SCD require transcranial doppler studies annually. Those with abnormal studies are placed on
a blood transfusion regime to prevent stroke.28 29
All adult patients require regular echocardiography to assess their tricuspid regurgitation velocities as a marker
of pulmonary hypertension.30
Hydroxyurea is currently the only agent shown to modify disease expression in SCD. It increases fetal Hb levels
and decreases the frequency and severity of vaso-occlusive crises.31
Trials of inhaled nitric oxide for pain crises and ACS treatment are ongoing.
Bone marrow transplantation is currently the only curative option in SCD, but remains a high risk intervention,
reserved at present for children with severe disease.32 Trials of gene therapy via stem cell transfusion continue.33
PERI-OPERATIVE MANAGEMENT
As discussed earlier, the peri-operative period poses significant risks to SCD patients.
Predictors of higher morbidity include: major surgery, increased patient age, more frequent complications and
hospitalisations, abnormalities on chest x-ray, pregnancy, intercurrent infection and the patients haplotype (Central
African Republic > Benin > Senegal).34
Pre-operative assessment should focus on establishing the frequency and severity of disease exacerbations,
existence of end organ damage and whether the patient has predictors of high risk as listed above.
Optimisation of the patient should involve haematology input for guidance on the need for prophylactic red cell
transfusion (to achieve a haematocrit of >30%) or exchange transfusion (to achieve an Hb S % of <30) or neither.
SCD patients are at risk of alloimmunisation, the incidence of which can be reduced by extended phenotype
matching for Rhesus, Kell and Lewis antigen groups.35
Hydroxyurea has also been given pre-operatively to increase fetal Hb levels.
Patients should be adequately hydrated.
Intra-operative goals are to maintain homeostasis, with avoidance of episodes of hypoxia, hypotension, acidosis
and hypothermia. Arterial tourniquet use is not contra-indicated36 but the duration should be minimised as far as
possible. Autologous blood transfusion via cell salvage techniques has been used in these patients, despite evidence
of sickling occurring with the reservoir.
Multimodal analgesia should be utilised and regional techniques are useful adjuncts.
Post-operative vigilance for vaso-occlusive crises and acute chest syndrome is essential. ACS complicates
10-15% of intra abdominal37 and joint replacement38 surgeries in these patients, and can present up to 72 hours
post procedure.
154
CONCLUSIONS
Decisions regarding which individuals should be tested for sickle cell disease should be informed by consensus
guidelines based on disease patterns in the general populace. In the US, since the late 1980s, universal neonatal
screening has been advocated by the Agency for Health Care Policy (AHCPR). The agency stated that targeting
only high risk racial groups would not identify all affected infants, as health officials could not reliably determine an
infants race by appearance, name or parental report.
Analysing disease risk by presumed ethnic origin alone presents a potentially dangerous oversimplification.
Migration of black Africans to Britain has been documented since Roman times, resulting in genetic mixing that is
not obviously apparent.
A group of indigenous British men from Yorkshire were found to have genetic markers originating from West
Africa.39
In the UK over 10 years ago, a case of unexpected sickle cell trait emerged in a white woman with no discernable
African heritage. On donating blood, she was notified by the National Blood Service about her sickle cell trait status.
Further investigation revealed she was descended from a Jamaican slave who had lived in Liverpool in the 18th
century. The story made the UK national press and was not an isolated case.
With growing evidence of this genetic disease in a population not previously thought to be at risk, it is now UK
policy to universally screen all newborns for sickle cell disease, regardless of their presumed ethnic origin. This is
aside from the increased numbers of interracial relationships, bringing together heterozygote alleles from different
populations, be it sickle or the thalassaemias.
DOES THIS EXPERIENCE EXTRAPOLATE TO THE AUSTRALIAN POPULATION?
Certainly, historically at-risk groups are present in the Australian population and their numbers will only increase
with further immigration. In addition, ethnic groups with other clinically significant haemoglobinopathies, such as
the and thalassaemias, are well established in the community, and it is not inconceivable that with population
mixing, presentations of double heterozygotes will increase.
Knowledge within the wider medical community needs to increase in line with this change. These patients will
present to primary care and to other specialities of secondary care aside from haematology. They require lifelong
surveillance, prophylaxis, vaccination and psychosocial support to manage their chronic illness as well as
knowledgeable clinicians to manage acute complications and adequately prepared peri-operative teams to safely
negotiate surgery and anaesthesia.
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American Journal of Epidemiology 2000; 151 (9): 839-845.
2. Nagel RL, Ranney HM. Genetic epidemiology of structural mutations of the beta-globin gene. Semin Hematol
1990: 27:342-59.
3. Thomas PW, Higgs DR, Serjeant GR. Benign clinical course in homozygous sickle cell disease: a search for
predictors. J Clin Epidemiol 1997; 50:121-6.
4. Dresbach M. Elliptical human red corpuscles. Science 1904; 19: 469-70.
5. Dresbach M. Elliptical human red corpuscles (a supplementary statement). Science 1905; 21: 473-5.
6. Mason VR. Sickle cell anemia. J Am Med Assoc 1922; 79:1318-20.
7. Pauling L, Itano HA, Singer SJ, Wells IC. Sickle cell anemia. Science 1949; 110: 543-8.
8. Pagnier J, Mears JG, Dunda-Belkodja O, Schaefer-Rego KE, Beldjord C, Nagel RL, Labie D. Evidence for the
multicentric origin of the sickle cell hemoglobin gene in Africa. PNAS. 1984;81 (6):1771-73.
9.
Aluoch JR. Higher resistance to Plasmodium falciparum infection in patients with homozygous sickle cell disease
in western Kenya. Trap Med Int Health 1997;2:568-71.
10. World Health Organisation. Sickle-cell anaemia Report by the Secretariat to the 59th World Health Assembly
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11. Government of Western Australia, Department of local government and regional development(http://www.dlgrd.
wa.gov.au/Publications/Docs/StatSnapshot_populationDemographics.asp).
12. Harley JD, Concannon AJ. Eleven cases of sickle cell disease in Sydney. Med J Aust 1978; 2(9): 401-4.
13. Firth PG. Anaesthesia for peculiar cells-a century of sickle cell disease. British Journal of Anaesthesia.
2005;95(3):287-99.
14. Hebbel RP, Vercelloti GM. The endothelial biology of sickle cell disease. J Lab Clin Med 1997; 129: 288-93.
15. Lancaster JR jr. Reaping of nitric oxide by sickle cell disease. Proc Natl Acad Sci USA 2002; 99:552-3.
16. Vichinsky EP, Neumayr LD, Earles AN, et al. Causes and outcomes of the acute chest syndrome in sickle cell
disease. National Acute Chest Syndrome Study Group. N Eng J Med 2000; 342:1855-65.
17. Ataga K, Sood N, De Gent G, et al. Pulmonary hypertension in sickle cell disease. Am J Med 2004;117(9):665-9.
18. Eckman JR. Leg ulcers in sickle cell disease. Hematol Oncol Clin North Am 1996;10(6):1333-44.
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19. Quinn CT et al. Prognostic significance of early vaso-occlusive complications in children with sickle cell anaemia.
Blood 2007:109(1):40-45.
20. Smith JA. Bone disorders in sickle cell disease. Hematol Oncol Clin North Am 1996;10(6):1345-56.
21. Saborio P, Scheinman JI. Sickle cell nephropathy. J Am Soc Nephrol 1999;10(1):187-92.
22. Koshy M, Weiner SJ, Miller ST, et al. Surgery and anaesthesia in sickle cell disease. Cooperative Study of Sickle
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23. Bain BJ. 2006. Haemoglobinopathy Diagnosis. 2nd ed. London: Blackwell Publishing.
24. Ryan K et al. Significant haemoglobinopathies: guidelines for screening and diagnosis. British Committee for
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26. Overturf GD. Infections and immunizations of children with sickle cell disease. Adv Pediatr Infect Dis. 1999;14:
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28. Adams RJ, McKie VC, Hsu L, et al. Prevention of a first stroke by transfusions in children with sickle cell anemia
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158
The effects of oxytocin on uterine tone are likely to be due to the density of receptors in the uterus, rather than
the plasma concentration.11 Oxytocin also acts on receptors on the mammary ducts to facilitate milk letdown.9
Oxytocin receptors are also found outside of the uterus, in particular in the heart (atrial and ventricular tissue) and
the vascular endothelium, and have also been identified in the thymus, adipose tissue and pancreas.8 Oxytocin
means quick birth in Greek, presumably due to its effects on uterine tone.
Oxytocin receptors are G-protein coupled receptors found on the myometrial and myoepithelial cells. Stimulation
causes an increase in the force of contraction. Oxytocin has unknown effects in males but it is stored in similar
levels to women. It has a small antidiuretic effect, but only 1/200th that of vasopressin.9
Oxytocin has an elimination half-life in plasma of 3-5 minutes and is removed from the plasma via hydrolysis in
the kidneys and the liver (by the action of oxytocinase).9,12
SYNTOCINON
Syntocinon, the synthetic form of oxytocin, is a nonapeptide identical in structure to oxytocin. It is wholly synthetic
and has minimal vasopressor activity. One mg of Syntocinon is equivalent to 450 IU of hormone.9
The effect of Syntocinon infused at a low dose is a rhythmic uterine contraction, which is indistinguishable from
labour. Higher doses cause a sustained tetanic uterine contraction.13
The effect of Syntocinon lasts 30 to 60 minutes after intramuscular injection, and is likely shorter after intravenous
injection. Its half-life is approximately 30-60 minutes after intramuscular injection and 410 minutes after intravenous
injection. Syntocinon distributes into the extracellular fluid, has low plasma protein binding and is eliminated in the
liver and kidneys.13
Oxytocinase is a glycoprotein aminopeptidase produced during pregnancy, which degrades Syntocinon. Enzyme
activity increases until term, rises steeply at term, and then declines post delivery. There is little or no degradation
of Syntocinon in men, non-pregnant women or cord blood.13 The plasma levels of oxytocinase are raised in women
receiving Syntocinon infusions, during prolonged labour and in multiple pregnancies. Plasma oxytocinase is derived
predominantly from the placenta.14
In Australia and New Zealand, Syntocinon (Novartis) is supplied in 1 mL ampoules with either 5 IU or 10 IU of
hormone. The formulation also contains sodium acetate, glacial acetic acid, chlorobutanol, ethanol and water. A
study in 1998 investigated the effect of oxytocin and its preservative, chlorobutanol, on (non pregnant) human right
atrial tissue samples. Chlorobutanol alone inhibited myocardial contractility, as well as synthetic oxytocin containing
chlorobutanol. The magnitude of the negative inotropic effect on the atrial preparations was no different from
chlorobutanol alone versus oxytocin and chlorobutanol. Thus, some of the haemodynamic changes witnessed may
not be due solely to Syntocinon, as one of its preservatives may be contributing to the negative haemodynamic
effects.15
CONSIDERATIONS WHEN ADMINISTERING OXYTOCIN
Dose
In the triennium 1997 1999, the British National Formulary recommended a 5 IU dose of Syntocinon, given slowly.16
Despite this, the CEMACH report suggested that a request from the surgical team for a 10 IU bolus was a common
request. This was the dose that was administered to a woman that was hypotensive as a result of a high spinal
block and a post partum haemorrhage, and the injection was followed by cardiovascular collapse and death.4 The
current United Kingdom Royal College of Obstetrics and Gynaecology and the NICE guidelines are to administer
a 5 IU intravenous bolus, regardless of the indication for caesarean delivery.17
Interestingly, a survey of Fellows of the Royal Australian and New Zealand College of Obstetricians and
Gynaecologists resident in Australia and New Zealand and published in 2010, noted that the most common dose
of IV oxytocin used at caesarean delivery was 10 IU (67% of respondents). Two of the 700 Fellows who responded
gave or requested a 20 IU IV bolus dose. This survey did not ask anaesthetists what dose was actually administered.18
There is currently no evidence to support better efficacy from a bolus dose of 5 IU compared with smaller doses,
and side effects are common with a dose of 5 IU. There are studies that evaluated smaller doses in elective and
non-elective caesarean deliveries. These studies were all performed in patients that received regional anaesthesia,
with no studies investigating the dose given during general anaesthesia.
All dose-response studies concluded that a dose of less than 5 IU of Syntocinon was adequate to maintain
uterine tone, but none have been adequately powered to show a difference in clinical outcome (such as blood loss
or incidence of post-partum haemorrhage). A brief summary of three papers follows:
1. Sartain JB, et al. Intravenous oxytocin bolus of 2 units is superior to 5 units during elective caesarean section.
Eighty patients undergoing elective caesarean delivery were recruited and the patients were randomized to
either 2 or 5 IU of oxytocin followed by an infusion of 10 IU per hour. All the patients had their surgery
performed under spinal anaesthesia with a phenylephrine infusion. There was no difference between the two
groups in blood loss, uterine tone or requests for additional uterotonic drugs. In the 5 IU group, there was a
greater increase in heart rate, a larger decrease in mean arterial pressure and a higher rate of nausea and
vomiting.19
2. Carvalho JAC, et al. Oxytocin Requirements at Elective Cesarean Delivery: A Dose-Finding Study. Forty
women having elective caesarean deliveries under spinal anaesthesia were studied and the ED90 of oxytocin
was reported to be 0.35IU. These women had no other risk factors for uterine atony.20
159
3. Butwick AJ, et al. Minimum effective bolus dose of oxytocin during elective caesarean delivery. The study aim
was to quantify the lowest effective bolus dose of oxytocin to produce adequate uterine tone during elective
caesarean delivery. Seventy-five patients were recruited and randomized to placebo, 0.5, 1, 3 or 5 IU of
Syntocinon. All patients received a spinal anaesthetic with intrathecal morphine. If uterine tone was deemed
adequate by the obstetrician 2 minutes after administration, an oxytocin infusion was started. Seventythree percent of patients in the placebo group had adequate uterine tone at 2 minutes (these patients also
received uterine massage at delivery), although nearly 50% required rescue dose of oxytocin during the study
period. The ED50 and ED90 of sytocinon were unable to be calculated due to this high rate of adequate uterine
tone after placebo and low dose boluses. There were no significant differences in the prevalence of adequate
uterine tone among the study groups, although there was a higher rate of hypotension in the 5 IU group (vs.
the placebo).21
Tachyphylaxis
The oxytocin G-protein coupled receptor undergoes desensitization in the face of persistent agonist stimulation.
There are numerous potential cellular mechanisms responsible for this. Initially, the receptor and the G protein
uncouple. This occurs within a matter of seconds to minutes. Once uncoupled, the receptor undergoes internalization
or sequestration. Once internalized, the receptor can undergo degradation within lysosomes.8 The oxytocin receptor
undergoes rapid internalization in the setting of persistent agonist stimulation, which probably partly explains why
women having a non-elective caesarean delivery require more Syntocinon than those having an elective caesarean.9
The internalization of oxytocin receptors with agonist exposure has been postulated as a cause for the reduced
effect of Syntocinon after either repeat dosing or among patients who have received a Syntocinon infusion. In a
study of haemodynamic changes among women in the first trimester receiving a 10 IU bolus of oxytocin, less
pronounced changes in haemodynamics occurred after a second dose.22
Infusions
It is the authors experience that it is relatively standard practice to combine a Syntocinon bolus with a postoperative
sytocinon infusion at caesarean delivery. The short half-life of Syntocinon suits the administration of an infusion.
A recent study came to the conclusion that a 5 IU bolus prior to an infusion (at 1.3 IU/min for 30 minutes, followed
by 0.04 IU/min for 8 hours) did not alter the need for additional uterotonic drugs within the first 24 hours among
women with at least one risk factor for uterine atony.23
The recommendation from the CEMACH report for 2003-2005 is that IV oxytocin and/or ergometrine are the
treatment of choice for uterine atony and should be followed by an oxytocin infusion for 2-4 hours. The infusion
dose rate recommended is 40 IU over 4 hours (0.16 IU/min).24
SIDE EFFECTS OF OXYTOCIN
Cardiac
Mean Arterial Pressure. Intravenous oxytocin injections cause a biphasic change in mean arterial pressure. Initially,
there is a rise in the mean arterial pressure that may be associated with a reflex bradycardia and subsequent
decrease in cardiac output. This is followed by a prolonged fall in mean arterial pressure and increased pulse and
cardiac output. These changes are dose dependent.22, 25
Studies in the 1970s of women in the first trimester having termination of pregnancy demonstrated oxytocininduced hypotension, tachycardia and increased cardiac output.22 More recent studies confirm these changes,
which were due to a reduction in systemic vascular resistance among women presenting for caesarean delivery.26
ECG changes. A bolus of 10 IU has been shown to produce ST-T depression in both women undergoing caesarean
delivery under spinal anaesthesia and women who were neither pregnant nor anaesthetised. The ECG changes
were associated with symptoms such as flushing, chest pain and shortness of breath. This is now recognised to
be a large dose but it suggests some of the ECG changes are likely related to the oxytocin administration, rather
than the regional anaesthesia or pregnancy.27
Oxytocin-induced ECG changes are thought to be due to hypotension, tachycardia and possibly coronary artery
vasoconstriction.27,28 The incidence is greater after a 10 IU bolus, but is still possible after a 5 IU dose.28
Pulmonary Haemodynamics
The effects of oxytocin on the pulmonary vasculature have not been studied well. In a study of nine women in the
first trimester who received either a 5 IU or a 10 IU dose of oxytocin, there were significant changes in the pulmonary
pressures. The pulmonary artery pressure increased by a maximum of a third, peaking 150 seconds post administration,
at a time when the systolic blood pressure had returned to baseline. The elevation in pulmonary artery pressure
persisted for 10 minutes. The effects were almost as pronounced after 5 IU as after 10 IU.22
Hyponatraemia
Despite the antidiuretic effect of oxytocin being much less pronounced compared with vasopressin, there is a small
effect such that high doses, have been associated with water intoxication, due to increased water reabsorption
from the glomerular filtrate. Case reports usually also note an association with administration of large volumes of
low solute fluids.12,13
160
Anaphylaxis
There are numerous case reports implicating Syntocinon as the cause of an allergic reaction but few where this
reaction has been confirmed by skin testing. Oxytocin is a skin irritant if injected subcutaneously. It has been
postulated that some of the cases of allergy attributed to syntocinon were more likely to have been a reaction due
to latex.29
CARBETOCIN
Carbetocin is a synthetic analogue of oxytocin, with structural modifications. These modifications protect the
carbetocin molecule from degradation by oxytocinase, therefore prolonging its half-life and pharmacological effect.
Carbetocin (Duratocin, Ferring) is supplied in a 1 mL ampoule, containing 100 micrograms of the drug, which is the
recommended bolus dose when administered intravenously or intramuscularly.30
The half-life of Carbetocin is approximately 40 minutes after an intravenous injection. The tonic uterine activity
is 60 minutes after intravenous injection and 120 minutes after intramuscular injection. There have been minimal
adverse effects associated with carbetocins use and its side effect rate is likely similar to Syntocinon.31
A Cochrane Review from 2007 looked at four studies (three at caesarean delivery and one at vaginal delivery)
that compared carbetocin to Syntocinon to prevent postpartum haemorrhage. Carbetocin resulted in a statistically
significant reduction in the need for therapeutic uterotonic agents (in the caesarean delivery groups), but there was
insufficient evidence that carbetocin was as effective as Syntocinon to prevent postpartum haemorrhage. There
was no significant reduction in need for therapeutic uterotonic drugs after vaginal delivery. There was no difference
in adverse events.32
The proposed advantages of carbetocin over Syntocinon are its longer half-life and the subsequent need for a
single IV or IM injection, rather than an infusion. Further studies looking at its effect in cardiac patients, women with
pre-eclampsia and in women already bleeding are required.
SUMMARY
Syntocinon remains an important drug for the prevention and treatment of post partum haemorrhage. The evidence
supporting injection of a 5 IU dose at delivery is scant and this dose causes transient but profound cardiovascular
side effects when given as a rapid bolus. Recent studies suggest that a smaller dose at both elective and nonelective caesarean delivery is sufficient to improve uterine tone, and these doses potentially reduce the severity of
haemodynamic side effects.
The international guidelines for the dosage of Syntocinon after caesarean delivery are varied. There are also
warnings about this drug, both with a black box warning from the United States FDA33 and inclusion on a list of
high alert medications from the Institute for Safe Medication Practices.34
The haemodynamic effects of a 5 IU bolus are unlikely to cause significant problems in healthy women, but it
seems appropriate to use a lower dose of 2-3 IU bolused slowly and titrate further doses to effect. An editorial
published in 2010 in the International Journal of Obstetric Anaesthesia recommends an initial dose of less than
5IU, as a slow bolus.35 It is encouraging to know that smaller doses result in adequate uterine tone in women with
cardiac conditions or hypovolaemia who are unable to produce a compensatory increase in cardiac output.
A recent study by King and colleagues23 also suggests that an initial high dose infusion, rather than a bolus,
produces satisfactory uterine tone. Unfortunately, this study was not powered to assess side effects from the high
dose initial infusion. An adequate and safe dose rate of Sytnocinon by infusion post delivery is yet to be clarified.
It is important to remember women with prolonged labour prior to presenting for caesarean delivery and those
receiving a Syntocinon infusion prior to delivery are likely to require a higher dose of Syntocinon. They may also
require other uterotonic drugs that act on the myometrium via other mechanisms, such as Ergomterine or Misoprostol.
The present data supports a dose of 2 IU given as a slow bolus for elective caesarean sections, with an increase
to a 3 IU bolus for non-elective caesarean deliveries. These women should receive infusions post delivery.
What is not clear at the present time, is the most suitable dose of Syntocinon in the context of a general
anaesthetic, particularly when using volatile agents which relax the myometrium. It has not been established what
bolus doses or infusion rates should be used in women who have more than one risk factor for uterine atony, other
risk factors for post partum haemorrhage or women with pre-eclampsia.
REFERENCES
1. Saving Mothers Lives: Reviewing maternal deaths to make motherhood safer: 20062008. The Eighth Report
of the Confidential Enquiries into Maternal Deaths in the United Kingdom. British Journal of Obstetrics and
Gynaecology, 2011. 118, supplement 1.
2. Sullivan, E., B. Hall, and J. King, Maternal Deaths in Australia 2003-2005, 2008, Australian Government: Australian
Institute of Health and Welfare.
3. Al-Zirqi, I., et al., Prevalence and risk factors of severe obstetric haemorrhage. BJOG : an international journal
of obstetrics and gynaecology, 2008. 115(10): p. 1265-72.
4. Why Mothers DIe. Report on Confidential Enquiries into Maternal Deaths in the United Kingdom 1997 1999,
in Royal College of Obstetricians and Gynaecologists2001, London.
5. Du Vigneaud, V., et al., Oxytocin: Synthesis. Journal of the American Chemical Society, 1954. 76(12): p. 3115
3118.
6. http://www.nobelprize.org.
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7. Prendiville, W., The effect of routine oxytocic administration in the management of the third stage of labour: an
overview of the evidence from controlled trials. British Journal of Obstetrics and Gynaecology, 1988. 95: p. 3-16.
8. Gimpl, G. and F. Fahrenholz, The Oxytocin Receptor System: Structure, Function and Regulation. Physiological
Reviews, 2001. 81(2): p. 629-683.
9. Harrisons: Principles of Internal Medicine. 17th. ed, ed. B. Fauci, Kasper, Hauser, Longo, Jameson,
Loscalzo.2008, New York.: McGraw Hill Medical.
10. Fuchs, A., et al., Oxytocin receptors in the human uterus during pregnancy and partuition. American Journal of
Obstetrics and Gynaecology, 1984. 150: p. 734-41.
11. Wray, S., Uterine contraction and physiological mechanism of modulation. American Journal of Physiology,
1993(264): p. C1-18.
12. Sasada, M. and S. Smith, Drugs in Anaesthesia and Intensive Care. Third Edition ed2003, New York: Oxford
University Press.
13. Novartis Drug Pamphlet: Syntocinon, in Novartis Pharmaceuticals Australia Pty. Ltd.2009.
14. Mathur, V.S. and J.M. Walker, Oxytocinase in Plasma and Placenta in normal and prolonged labour. British
Medical Journal, 1968. 3: p. 96-97.
15. Rosaeg, O.P., N.J. Cicutti, and R.S. Labow, The effect of oxytocin on the contractile force of human atrial
trabeculae. Anesthesia and analgesia, 1998. 86(1): p. 40-4.
16. http://www.bnf.org.
17. http://www.rcog.org.uk.
18. Mockler, J.C., D.J. Murphy, and E.M. Wallace, An Australian and New Zealand survey of practice of the use
of oxytocin at elective caesarean section. The Australian & New Zealand journal of obstetrics & gynaecology,
2010. 50(1): p. 30-5.
19. Sartain, J.B., et al., Intravenous oxytocin bolus of 2 units is superior to 5 units during elective Caesarean section.
British journal of anaesthesia, 2008. 101(6): p. 822-6.
20. Carvalho, J.C., et al., Oxytocin requirements at elective cesarean delivery: a dose-finding study. Obstetrics and
gynecology, 2004. 104(5 Pt 1): p. 1005-10.
21. Butwick, A.J., et al., Minimum effective bolus dose of oxytocin during elective Caesarean delivery. British journal
of anaesthesia, 2010. 104(3): p. 338-43.
22. Secher, N.J., P. Arnsbo, and L. Wallin, Haemodynamic effects of oxytocin (syntocinon) and methyl ergometrine
(methergin) on the systemic and pulmonary circulations of pregnant anaesthetized women. Acta obstetricia et
gynecologica Scandinavica, 1978. 57(2): p. 97-103.
23. King, K., et al., Five Unit Bolus Oxytocin at Cesarean Delivery in Women at Risk of Atony: A randomized, DoubleBlind, Controlled trial. Anesthesia and analgesia, 2010. 111: p. 1460-1466.
24. Why Mothers Die. Report on Confidential Enquiries into Maternal Deaths in the United Kingdom 2003-2005.
Royal College of Obstetricians and Gynaecologists, 2007.
25. Mukaddam-Daher, S., et al., Negative inotropic and chronotropic effects of oxytocin. Hypertension, 2001. 38(2):
p. 292-6.
26. Pinder, A., et al., haemodynamic changes caused by oxytoxin during caesarean section under spinal anaesthesia.
International Journal of Obstetric Anaesthesia, 2002. 11: p. 156-159.
27. Svanstrom, M., et al., Signs of myocardial ischaemia after injection of oxytocin: a randomised double-blind
comparison of oxytocin and methylergometrine during caesarean delivery. British journal of anaesthesia, 2008.
100(5): p. 683-9.
28. Jonsson, M., et al., ST depression at caesarean section and teh relation to oxytocin dose. A randomised controlled
trial. British Journal of Obstetrics and Gynaecology, 2009. 117: p. 76-83.
29. Schnider and Levinsons Anesthesia for Obstetrics. 4th edition ed, ed. L.G. Hughes S, Rosen M.2002, Philadelphie:
Lippincott Williams & Wilkins.
30. Duratocin: Carbetocin. Single injection for lasting prevention, F.P.P. Ltd, Editor.
31. Werner, R., Prevention of postpartum haemorrhage with the oxytocin analogue carbetocin. European Journal
of Obstetrics & Gynecology and Reproductive Biology, 2009. 147(1): p. 15-20.
32. Su, L.L., Y.S. Chong, and M. Samuel, Oxytocin agonists for preventing postpartum haemorrhage. The Cochrane
Database of Systematic Reviews, 2007(3).
33. Formweb. FDA Black Box Warnings. http://www.blackboxrx.com/app/display.php?id=277.
34. Practices, I.f.S.M. High Alert Medications. http://www.ismp.org 2010.
35. Tsen, L. and M. Balki, Oxytocin Protocols during Cesarean Delivery: time to acknowledge the risk/benefit ration?
International Journal of Obstetric Anaesthesia, 2010. 19: p. 243-245.
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60
50
40
30
20
10
0
4
-5
52
-6
58
-6
64
-7
70
-7
76
-8
82
-9
86
-9
94
-0
00
-0
06
Triennium
From UK Data.1, 4
Congenital heart disease (CHD), often already corrected, is the most prevalent heart disease in pregnancy (0.8%)
in western countries, but acquired disease is the major cause of mortality.3, 5, 6
PHYSIOLOGY
Pregnancy is a hypervolaemic, hyperdynamic and pro-coagulant state.3, 6 The precise initiating roles of various
placental or maternal hormones, including progesterone, oestrogens, corticotrophin releasing hormone and prolactin,
remains unclear.7 However, the result is an increase in nitric oxide production and endothelial prostacyclin; activation
of the renin-angiotensin-aldosterone system; increased cortisol levels and decreased responsiveness to angiotensin
II and noradrenaline.7 In addition there is an increase in clotting factors with decreased levels of Protein S and
increased resistance to Protein C.7 Haemodynamic changes reflect both humorally mediated vasodilation and the
development of the high flow, low resistance utero-placental unit.7 Blood volume and cardiac output both increase
30-50% by mid-term, usually accompanied by a slight increase in heart rate and lower blood pressure, with a
decrease in both systemic and pulmonary vascular resistance.3, 6 A reduction in cardiac output (by 20-25%) occurs
in the supine position from caval compression.7 Labour results in a fluctuating 25-30% increase in cardiac output
from pain-related catecholamines and contraction-related auto-transfusion. Pushing (Valsalva) can result in rapid
changes, first increasing and then decreasing cardiac output from impaired venous return, with compensatory
tachycardia.7 After delivery, cardiac output may increase a further 25-50% from auto-transfusion of the contracted
uterus and removal of caval compression.7 This increase in output persists for 1-2 days, is 80% resolved after
2 weeks and returns to normal after 2-3 months.7, 8 It is easy to see why these profound physiological changes, as
well as pregnancy-related disorders such as haemorrhage or pre-eclampsia, can precipitate complications in
patients with cardiac disease.
164
Overall Risk
Low
5%
Moderate
30%
>1
High
70%
# Risk factors:
History of cardiac complications eg pulmonary oedema; symptomatic arrhythmias
Dyspnoea (NYHA 3 or 4) or cyanosis (SpO2 < 90%)
Impaired left ventricular function (EF < 40%)
Left heart obstruction (aortic or mitral valve area < 1.5 cm2)
* Complications: pulmonary oedema, symptomatic arrhythmias or stroke
SPECIFIC CONDITIONS
1. Congenital heart disease (CHD)
Most minor or corrected conditions have normal outcomes for mother and baby.13
Women with uncorrected cyanotic or complex CHD are much more problematic, with the highest mortality (approx
40%) in patients with Eisenmengers syndrome (reversal of left-to-right shunt). 13, 14 In other complex CHD, the
mortality rate is generally less than 5%, though the incidence of miscarriage (40%) premature delivery (30%) and
fetal mortality (15%) is high.13 Antibiotic prophylaxis for endocarditis (ampicillin 2g) is currently indicated only for
complicated CHD or prosthetic grafts in the presence of prolonged or infected labour.3 The incidence of CHD in
the infants of mothers with CHD is ten times the community risk.3, 13
2. Pulmonary hypertension (PHT)
PHT is poorly tolerated in pregnancy, because the right ventricle is unable to cope with the additional load imposed
by the physiological changes of pregnancy.15 If PHT is secondary to a remediable cause such as mitral stenosis, a
good outcome can be expected with appropriate treatment.6 However, in idiopathic pulmonary arterial hypertension
(formerly called primary pulmonary hypertension), or when PHT is secondary to pulmonary vasculitides (eg scleroderma,
SLE), severe respiratory disease, or uncorrectable heart disease, the mortality is 25-40%. Death is usually from
right heart failure or thromboembolism, most commonly in the first week post-partum.3, 6, 15 Treatment is of the
specific cause (if secondary), plus general therapy for cardiac failure (eg diuretics) and anticoagulation. Vasodilators
such amlodipine, sildenafil and intravenous or inhaled prostacyclin are useful for some sub-categories of PHT.3, 15
3. Rheumatic heart disease (RHD)
Rheumatic heart disease (RHD) remains a major problem in indigenous communities of northern Australia (1-3%),
and some immigrant groups.16 Outcomes are predictable based on assessment of known CARPREG risk factors
(especially mitral stenosis and a history of pulmonary oedema) and the presence of PHT.10, 12, 16 Exacerbation is
usually associated with a clear precipitant such as sepsis, pre-eclampsia or IV fluid loads. Medical therapy is usually
adequate, though percutaneous balloon mitral valvuloplasty can be performed safely during pregnancy for severe
or symptomatic mitral stenosis.12, 16 Previously undiagnosed patients still occur, so RHD should always be considered
with new onset cardio-respiratory symptoms in pregnant indigenous patients.16
165
4. Management of anticoagulation
The care of anticoagulated patients with prosthetic heart valves requires balancing the substantial risks of maternal
haemorrhage, maternal thrombosis (including stroke) and fetal loss or embryopathy, all of which are in the 10-20%
range.12, 16 Accepted management involves maintaining warfarin until pregnant (low teratogenic risk before 6 weeks),
then one of three options: (i) therapeutic dose low molecular weight heparin (LMWH) with anti-Xa monitoring plus
aspirin; (ii) warfarin until 36 weeks, then changing to unfractionated heparin (UFH) or LMWH; or (iii) LMWH during
1st trimester (to minimise teratogenic risk) then revert to warfarin regimen. LMWH is stopped 36 hours before labour
or surgery; UFH 6 hours beforehand.16, 17 The choice should be individualised based on a range of factors: LMWH
is favoured for a well motivated patient, requiring high warfarin dose, with ready access to anti-Xa monitoring;
warfarin is favoured with likely poor compliance, high thrombotic risk and a required warfarin dose of <5mg, which
has a low risk of embryopathy ( less than 10%).16, 17 Caesarean section is often performed in these patients, either
to enable timing of anticoagulation cessation, or if the woman labours within two weeks of stopping warfarin, as it
is still active in the fetus after normalisation of maternal coagulation, who is then at risk of intracranial bleeding
during labour.17
5. Ischaemic heart disease (IHD) and myocardial infarction (MI)
IHD is reported to occur in only 1 in 10,000 pregnancies, but is thirty times more likely in patients over 40 years
compared to those less than 20 years.3 Risk factors include age over 35, obesity, smoking, family history, hypertension
and diabetes. Appropriate investigations (Troponin levels, serial ECGs) should be performed in patients with typical
ischaemic symptoms. Patients with known IHD should be assessed and treated based on standard criteria with
delivery planned to minimise haemodynamic stress (see delivery section).18 Pregnancy-associated MI may be due
to coronary artery dissection or spasm rather than atherosclerosis.19 During the stress of the peripartum period or
post-partum, dissection accounts for 35-50% of MIs, compared to only 10% antepartum.19 Consequently percutaneous
coronary intervention (with possible stenting) is the treatment of choice rather than thrombolysis.3, 19 Bare-metal
stents, which do not require prolonged treatment with clopidogrel, may be preferable in the antepartum period.3, 19
Standard treatments in addition to antiplatelet agents include nitrates, beta blockade and LMWH.3, 5 Angiotension
converting enzyme inhibitors (ACE inhibitors), angiotension II receptor blockers (ARBs), statins and amiodarone
are class D drugs causing fetal abnormalities or death, so should not be given while still pregnant. 5 Metoprolol is
preferred over atenolol, as the latter may cause fetal growth retardation. 5 In a recent literature review the mortality
of myocardial infarction was 18% in the immediate peripartum period, but 9% when it occurred more than 24 hours
before or after labour.19 Historic data also suggests that delivery within 2 weeks of a myocardial infarction is
associated with a high mortality a period of stabilisation may be preferable if both cardiac and obstetric considerations
permit.6 Care must also be taken with the use of uterotonic agents (see delivery section).6
6. Aortic dissection
This is most commonly idiopathic, but may be secondary to Marfans syndrome or bicuspid aortic valve disease.1,
3
It should be suspected with severe back or left sided chest pain, diminished left sided pulses or a widened
mediastinum on chest X-ray. CT angiogram with contrast or transoesophageal echocardiography will show the
diagnosis. It is important to investigate appropriately if suspected rather than having inordinate fear of radiation to
the fetus.1 Patients with Marfans syndrome require beta blockade and frequent echocardiography during pregnancy.
Aortic arch replacement is recommended if aortic diameter is greater than 40mm, at which stage the risk of
spontaneous rupture is 10%.3, 11
7. Peripartum cardiomyopathy (PPCM)
PPCM occurs in 1 in 4000 pregnancies.3, 6, 9 It is a diagnosis of exclusion, with progressive systolic left ventricular
dysfunction developing 1 month pre-partum to 5 months post-partum. Management involves anti-failure treatment
plus anticoagulation; heart transplant is a last-ditch option. Patients who recover should be counselled that it recurs
in 30% of subsequent pregnancies.3, 6
8. Hypertrophic (obstructive) cardiomyopathy (HCM or HOCM)
This is an autosomal dominant condition, with an incidence of 1 in 500. 20 There is a wide range of severity from
essentially benign to immediately life-threatening. The majority of patients have an uneventful pregnancy, with
adverse outcomes predictable based on severity of symptoms (dyspnoea, syncope) and the degree of ventricular
outflow obstruction.20, 21 If required, treatment may involve beta blockade, with phenylephrine or metaraminol for
first-line treatment of hypotension rather than beta agonists.20
9. Cardiac surgery during pregnancy
The requirement for cardiac surgery and cardio-pulmonary bypass during pregnancy is associated with maternal
mortality of 5-10% and a fetal/neonatal death rate of 30%.5, 11 Although these rates probably reflect the maternal
condition primarily, other ill-defined factors such as cardiopulmonary bypass flows may also be relevant.5, 11 Therefore,
if the fetus is viable, consideration should be given to delivering the baby before the cardiac operation.11
10. Previous heart transplant
Despite the expected infection risk from immunotherapy and the lack of intact cardiac autonomic innervation,
outcomes are generally positive.6 In a series of 22 patients, hypertension or pre-eclampsia occurred in nearly half
166
and infections in 27%, but there were no maternal deaths or instances of heart failure and no fetal abnormalities. 22
Overall management plan
An overall management plan outline is given in figure 3. It should be individualised based on the severity of disease.
In general terms, low risk patients can be treated as standard obstetric patients. At the other extreme, high risk
patients may require transfer to a unit with access to immediate interventions including percutaneous valvuloplasty
or cardiac surgery.3, 5, 6
Figure 3. Overall management of obstetric patients with cardiac disease
Determine diagnosis
Assessment of severity
Specific high risk conditions
CARPREG risk score (history and echocardiography)
Cardiologist assessment
Medication or other intervention as required
Collaboration between relevant disciplines
obstetrics, cardiology, anaesthesia, ICU, paediatrics, haematology
Co-ordination of delivery
Appropriate location (expertise, resources)
Dependent on cardiac and obstetric factors
DELIVERY PLAN
A plan for delivery and labour is outlined in figure 4. It is clear that vaginal delivery is achievable (and generally
preferable) for the vast majority of patients with cardiac disease if obstetric considerations permit.3, 5, 6 In patients
at moderate to high risk, the use of well-conducted epidural analgesia (to minimise the haemodynamic perturbations
of labour), strict avoidance of caval compression (eg left lateral position), and assisted delivery (to minimise pushing)
are rational strategies,3, 5, 6 though there are no data from randomised trials. The anaesthetist should be present for
delivery as the person most able to manage haemodynamic changes. Great care must be taken with all uterotonic
agents.3, 5, 6 Ergometrine can cause myocardial ischaemia from coronary artery spasm and pulmonary oedema from
venoconstriction.6, 23 Oxytocin causes tachycardia and hypotension with decreased systemic and increased pulmonary
vascular resistance.6, 24 Prostaglandins have a similar effect.6 However, a balance must be achieved to avoid
inadequate uterine contraction and excessive blood loss. An infusion of oxytocin (eg starting at 0.5 -1 units/minute),24
titrated to haemodynamics and uterine tone, is recommended as the first line uterotonic for high risk patients.
Figure 4. Labour and delivery plan for moderate to high cardiac risk patients
Labour:
Consider epidural pain relief
Wedged or lateral position
Avoid excessive IV fluids
Antibiotic prophylaxis indicated with prosthetic valves, complex CHD, history of endocarditis or obstetrics
reasons
Consider invasive monitoring for high risk patients
Delivery:
Consider assisted vaginal delivery
Anaesthetist present for delivery
Avoid ergometrine
Oxytocin infusion eg 0.5-1 U/ minute initially +/- 1 unit increments IV (omit with severe disease)
Consider delivery in monitored situation (eg operating theatre) for high risk patients
Post Delivery:
IV fluids to replace blood loss only
Cease IV fluids once bleeding stopped
Consider frusemide IV or orally if at risk of pulmonary oedema
Observe in high dependency unit or intensive care overnight
167
CAESAREAN SECTION
A summary of indications for Caesarean Section and anaesthesia recommendations are given in Figure 5. Cardiac
indications for Caesarean section are based on logic or practical issues (eg anticoagulation management or planned
high risk delivery in daylight hours) rather than convincing data.3, 5, 6 It is far more likely that obstetric considerations
will be the determining factor for operative delivery, though many obstetricians have a lower threshold for intervention
in patients with co-existing pathology. Should Caesarean Section be indicated, general principles of maintaining
haemodynamic stability and oxygenation are more important than specific techniques.3, 6 For instance, worsening
of pulmonary hypertension or right-to-left shunt, can be avoided through cardiac general anaesthesia and controlled
ventilation (despite the effect of increased airway pressure), or by epidural anaesthesia plus the use of peripheral
alpha agonists and judicious fluids.6, 25 Similarly, preventing tachycardia and maintaining systemic vascular resistance
in patients with left-sided obstructive lesions can also be achieved through opioids and volatile agents or with
regional anaesthesia and alpha agonists.20, 25 Consequently, there are many series demonstrating the successful
use of either regional (incremental epidural) or general anaesthesia for obstetric patients with severe cardiac disease
of virtually any kind.6, 15, 25, 26 The wishes of the patient, her ability to lie flat without dyspnoea, contraindications to
regional anaesthesia (eg anticoagulation), and the individual expertise of the anaesthetist may be decisive factors.
Figure 5. Caesarean Section for moderate to high risk cardiac patients
Indications:
Obstetric
Cardiac:
Unstable situation (patient likely to be improved after baby delivered)
Decompensated heart failure despite treatment
Aortic dissection
?dilated aortic root
?severe pulmonary hypertension
Anticoagulation
Prosthetic valves: to fit with timing of stopping anticoagulation
Warfarin within last 2 weeks (fetal protection)
High risk patient with labour epidural relatively contra-indicated
Logistical issues (timing of high risk delivery when resources available)
Anaesthesia:
Either general or regional (incremental epidural) depending on contraindications, specific patient factors
and anaesthetist expertise
Invasive monitoring indicated for high risk cases
Avoid excessive IV fluids (primarily use to replace fluid losses)
Maintain haemodynamics with vasopressors
Oxytocin via titrated infusion (eg start 0.5-1 unit/ minute)
+/- 1 unit increments IV (omit with severe disease)
Observe in high dependency unit or intensive care overnight
SUMMARY
Maternal heart disease occurs in approximately 1% of pregnancies, but causes 15% of maternal mortality. Specific
high risk conditions and maternal cardiac risk factors are well established, so the prognosis for patients with known
disease is predictable. However, a high index of suspicion and a low threshold for appropriate investigations are
required to reduce mortality in patients without previously recognised cardiac disease. Multi-disciplinary collaboration,
with tailoring of cardiac therapy and delivery plan to the diagnosis and severity of disease, is associated with a
good outcome for the majority of patients. Vaginal delivery is generally preferred if obstetric indications allow. There
are very few cardiac indications for Caesarean section and both general and regional anaesthesia are acceptable
in most cases.
168
REFERENCES
1. Centre for Maternal and Child Enquiries (CMACE). Saving mothers lives: reviewing maternal deaths to make
motherhood safer: 20062008. The eighth report on confidential enquiries into maternal deaths in the United
Kingdom. Br J Obstet Gynaecol. 2011;118(suppl.1):1-203.
2. Sullivan EA Hall B & King JF. Maternal deaths in Australia 2003-2005. Sydney: AIHW. National Perinatal statistics
unit; 2008.
3. Curry R, Swan L, Steer PJ. Cardiac disease in pregnancy. Curr Opin Obstet Gynecol. 2009 Dec;21(6):508-13.
4. Confidential Enquiry into Maternal and Child Health. Why Mothers Die 20002002. London: RCOG Press; 2004.
5. van Mook WN, Peeters L. Severe cardiac disease in pregnancy, part II: impact of congenital and acquired cardiac
diseases during pregnancy. Curr Opin Crit Care. 2005 Oct;11(5):435-48.
6. Ray P, Murphy GJ, Shutt LE. Recognition and management of maternal cardiac disease in pregnancy.
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7. Foley MR. Maternal cardiovascular and hemodynamic adaptations to pregnancy. In: UpToDate, Lockwood
CJ & Gersh BJ (eds). UpToDate, Waltham MA, 2011.
8. Robson SC, Hunter S, Moore M, Dunlop W. Haemodynamic changes during the puerperium: a Doppler and
M-mode echocardiographic study. Br J Obstet Gynaecol. 1987 Nov;94(11):1028-39.
9. Elkayam U, Akhter MW, Singh H, Khan S, Bitar F, Hameed A, et al. Pregnancy-associated cardiomyopathy: clinical
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10. Siu SC, Sermer M, Colman JM, Alvarez AN, Mercier LA, Morton BC, et al. Prospective multicenter study of
pregnancy outcomes in women with heart disease. Circulation. 2001 Jul 31;104(5):515-21.
11. Barth WH, Jr. Cardiac surgery in pregnancy. Clin Obstet Gynecol. 2009 Dec;52(4):630-46.
12. Reimold SC, Rutherford JD. Clinical practice. Valvular heart disease in pregnancy. N Engl J Med. 2003
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in women with congenital heart disease: a literature review. J Am Coll Cardiol. 2007 Jun 19;49(24):2303-11.
14. Khairy P, Ouyang DW, Fernandes SM, Lee-Parritz A, Economy KE, Landzberg MJ. Pregnancy outcomes in
women with congenital heart disease. Circulation. 2006 Jan 31;113(4):517-24.
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172
warning sign of haemodynamic instability, but does not identify the cause.
Echocardiography can be used to identify patterns of abnormality (such as hypovolaemia), systolic failure or
vasodilatation), and when integrated with the clinical scenario, can help identify the cause of haemodynamic
instability. Royse has described a methodology for the evaluation of haemodynamic state using limited TTE.1
Critically ill patients require urgent diagnosis. This is facilitated if the practitioner managing the patient performs
the TTE, rather than relying on third party providers such as cardiology, where timely access to their services may
be limited or not available.
A third use of cardiac ultrasound is as a perioperative haemodynamic monitor. Echocardiography allows the
assessment of both right and left sided preload, of right and left ventricular systolic and diastolic function, of
pulmonary artery pressures (in most cases) and of cardiac output. No other haemodynamic monitor is able to
measure all of these parameters. TTE, unlike either TOE or a pulmonary artery catheter, is non-invasive and there
are no safety issues in image acquisition. It can also be used in an awake patient. Other monitors using pulse
pressure variation or transoesophageal doppler devices are arguably easier to use but provide a less complete
picture. An example of using TTE for haemodynamic monitoring during a caesarean section is described by Ferguson
et al.2
Fourthly, the anaesthetic perspective should be born in mind. It is rare for a cardiac sonographer or cardiologist
to have patient in whom there are sudden and significant changes in preload, afterload or contractility, as occurs
during anaesthesia. Anaesthetists will view echocardiograms with a different perspective to cardiologists, focusing
on ventricular function and haemodynamically important valve lesions to answer specific questions, rather than a
comprehensive study aimed at identifying all aspects of the echocardiogram.
Learning to perform and interpret echocardiography requires an additional knowledge base that is not currently
part of anaesthesia training. Performing echocardiography also provides the practitioner with a powerful feedback
tool, which serves to improve understanding of the pathophysiology and how anaesthesia influences it. Many
anaesthetists read only the conclusions of formal report, but the black and white conclusions often hide a greater
subtlety in the numbers, findings and the interpretation of the study. The anaesthetic paradigm mentioned earlier
can result in a different interpretation for our specialty even though the conclusions are totally appropriate from a
cardiology perspective.
An example could be a report of a large pericardial effusion without echocardiographic evidence of tamponade.
In another personal example, the patient had undergone a pericardial window 1 month earlier. The cardiologist had
reassured the surgeon that tamponade was no longer a risk. The anaesthetist performed a limited TTE and identified
a warning sign of a small degree of right atrial collapse, leading the anaesthetist to consider tamponade a significant
risk during the forthcoming anaesthetic. A 1500 mL fluid loading and vasopressor with the induction was administered.
Despite this, there was a significant, but not life threatening, haemodynamic change on induction. The echo findings
were the same for both cardiologist and anaesthetist, but the images were seen from a different perspective.
GOAL DIRECTED CARDIAC ULTRASOUND
Echocardiography examinations performed by cardiology services are (almost always) comprehensive diagnostic
studies. Studies are conducted for other practitioners and, irrespective of the indications for a study, the expectation
is that all findings will be included in the report. Conversely, in anaesthesia, echocardiography is an extension of
the clinical assessment. The echo results are often directly and immediately integrated with other clinical information.
Cardiologists need to follow trends overtime so quantification is important, but in anaesthesia, long term trends
are unimportant and a qualitative assessment will often suffice, especially in time critical situations.
These differences have led to a paradigm of goal-directed studies to answer only one or more specific clinical
questions (and often no more). Terms such as limited or focused, bed-side or point of care are also used because
of their location, or hand-held because of the equipment often used.3,4
They may take only five minutes while a comprehensive study may take half an hour. Goal-directed studies may
only use one or two echocardiographic windows and fewer than the expected number of views through each
window than would be expected in a comprehensive study. Quantification may be minimal or non-existent, pattern
recognition being more important than measurement. A goal-directed study may need no more than 2D imaging if
only haemodynamic state needs to be assessed, while a global assessment of valvular function requires colour
flow imaging as well. The term cardiac ultrasound is used by some to cover both types of examination while the
term echocardiography is reserved by others for comprehensive studies only.
There are some issues with goal-directed studies. First, it must be accepted that some information will be missed.
A study by Rugolotto et al5 showed that using clinical examination alone, a cardiologist missed some 40% of
significant abnormalities when compared with a comprehensive TTE. Using a hand-held bedside cardiac ultrasound
with 2D and colour flow Doppler capabilities only, they still missed 20% of significant abnormalities. However, by
using the results of the bedside study they were able to institute earlier treatment and discharge patients a day
earlier on average. Importantly, the authors reported no errors in treatment using the bedside studies. Other studies
have had similar findings.6-8 Missed information is potentially important but may not be significant in critical care.
A minor regional wall motion abnormality might be missed, but will not be the cause of haemodynamic collapse.
There is an increasing body of evidence for the efficacy of point of care, physician and sonographer performed,
goal directed studies, using with portable or hand carried machine. These studies are in many fields including
cardiology,7,9,10 general medicine,11 emergency medicine (many specialties),12-14 intensive care15-18 and anaesthesia,19,20
However, not all authors agree its utility in all fields or all circumstances.21,22
173
The potential advantages of goal directed studies should not be understated. In anaesthesia, when faced with
a systolic murmur, it is important23 to exclude haemodynamically significant aortic stenosis with reasonable certainty.
This cannot be done clinically. A review by Etchells and colleagues,24 showed that while effort syncope with a
systolic murmur has the highest positive predictive value, the lack of effort syncope is not helpful in differentiating
severe aortic stenosis. The lack of radiation of the murmur to the right carotid is the most useful of the negative
clinical sign, but there is a false negative rate of 5 10%. They showed cardiologists are better than non cardiologists,
but that even cardiologists were no better than about 90% certain. Reichlin et al25 assessed the ability of emergency
physicians to diagnose systolic murmurs. The study included 203 consecutive patients admitted to an emergency
department and noted to have a systolic murmur. Some 35% of these had significant valvular heart disease shown
on TTE within an hour of the clinical examination (equal distribution of mitral regurgitation, aortic stenosis and other
lesions). Sensitivity and specificity for the correct diagnosis by clinical examination were only 82% and
69% respectively.
In 1975 using M-mode echocardiography, Weyman and Feigenbaum26 showed that a cusp separation of 15mm
or more in the parasternal long axis view excludes moderate or severe aortic stenosis. Since then 2D imaging has
dramatically improved, and restricted leaflet movement in the parasternal long and short axis views readily identifies
haemodynamically significant moderate or severe aortic stenosis.
There is controversy regarding qualitative versus quantitative grading of ventricular function or valve lesions. If
long term trends are important, then quantification is important. For example, if a patient has had a myocardial
infarction and an ejection fraction of 40%, they may be put on an angiotensin converting enzyme inhibitor. In three
months a cardiologist will be interested if the ejection fraction is now 35, 40 or 45%. But in anaesthesia, all have
about the same degree of systolic impairment. An anaesthetist wants to know if the systolic function of a heart is
normal, somewhat impaired or severely impaired. These patterns are easy to distinguish by 2D pattern recognition
alone. With aortic stenosis, we are accustomed to peak and mean gradients and aortic valve area. But do we really
need this data? Anaesthetists need to know whether the stenosis could be haemodynamically significant, so that
we can plan the anaesthetic and postoperative care appropriately. In elective surgery, quantification may be important
in those few cases in which it would be more appropriate to consider valve surgery prior to their planned operation.
But when surgery is urgent and there is little choice but to proceed and anaesthetists will treat moderate and severe
stenosis in a similar manner.
Quantification for less experienced operators also has the potential to underestimate severity. The jets are often
eccentric and may require the use of non-standard views to obtain the peak velocity and the use of a non-imaging
probe. If the peak velocity is not interrogated, the valve area is overestimated and gradients underestimated. An
area of active research in preoperative assessment is to determine the learning curves required for the safe
quantification of aortic stenosis in comparison to qualitative 2D and colour flow pattern recognition. In a small study
by Cowie et al,27 TTE nave anaesthetic trainees were able to measure peak velocity and potentially gain useful
information in addition to that available from 2D and colour flow imaging alone.
TRAINING IN TTE FOR ANAESTHETISTS IN AUSTRALASIA
The penetration of TTE into anaesthesia can be gauged by training numbers. Courses, conferences and workshops
in TOE appeared in the late 1990s. Formal training was offered in Australia in 2004 with the establishment of a
Postgraduate Diploma in Perioperative and Critical Care Echocardiography by the University of Melbourne (PGDipEcho).
The original diploma included a component of TTE, but was largely designed for cardiac anaesthetists performing
TOE. The call for training for general anaesthetists and TTE resulted in modifications in 2009. The first six months
became a Postgraduate Certificate in Clinical Ultrasound (PGCertCU) with a strong emphasis on TTE with TOE
largely consigned to a second six months now a Postgraduate Diploma in Clinical Ultrasound (PGDipCU). The
knowledge base for the PGCertCU is aimed at a good basic sonographer and the PGDipCU at diagnostic level.
To date 460 clinicians have completed the PGDipEcho, 297 have completed the PGCertCU with another 135
enrolled. Forty-nine have now completed the PGDipCU with 40 more enrolled.
For skills based (i.e. hands-on) TTE training, the University of Melbourne has offered a large number of workshops.
The Point of Care Courses which ran from 2005 to 2009 (353 participants), included two stations (about 40%) on
TTE. Since 2005, the H.A.R.T.Scan courses have provided training in goal-directed TTE for 577 doctors. The majority
of doctors attending these courses have been anaesthetists.
Alternative qualifications are also available. The National Board of Echocardiography in the USA has examinations
and certification (but no specific training courses) in perioperative transoesophageal echocardiography (PTXeXAM)
and in adult echocardiography (ASCeXAM). The PTXeXAM is designed for cardiac anaesthetists while the ASCeXAM
is for cardiologists. There are 90 physicians in Australia and 25 in New Zealand with the PTXeXAM and 2 anaesthetists
with the ASCeXAM.
The Australian Society of Ultrasound Medicine (ASUM) offers a Diploma in Diagnostic Ultrasound with an option
of cardiac ultrasound. This course has both knowledge and skills base training. ASUM also provides one of the
primary qualifications held by sonographers in Australasia. Other universities are starting to offer training and
qualifications that could be of interest to goal-directed TTE.
Comprehensive echocardiography requires extensive training and experience. The joint American College of
Cardiology and America Heart Association (ACC/AHA) guidelines on the clinical competence28 require a minimum
of 150 personally performed and an additional 300 supervised reports for independent practice. However, many
studies have shown that goal-directed TTE can be taught with significantly less training, but with the proviso that
any findings may also be limited and integrated with other clinical information as discussed earlier.
174
Royse et al29 studied the learning curve in an echo nave medical student. They showed 20 studies were required
to conduct a basic haemodynamic state assessment. Price et al30 studied physicians attending a one-day training
course in peri-resuscitation echocardiography. A test of knowledge base showed an improvement in image
interpretation (pre 62%, post 78%, p < 0.01) and 100% of participants were able to obtain a subcostal view of
diagnostic quality by the end of the course, most in under 10 sec.
Vignon et al30 reported on the efficacy of training of nave non-cardiology residents in limited echocardiography
in an ICU. Each was given 3 hours of lectures and 5 hours of hands on training. In a study of 61 consecutive patients
and comparing residents with an experienced intensivist, they were significantly slower and answered significantly
fewer of the 366 clinical questions (3 vs. 27%). However, when addressed, left ventricular systolic function, left and
right ventricular dilatation, pericardial effusion and tamponade were all correctly appraised.
Hellman et al31 reported on the training of 31 residents in the use of a hand carried cardiac ultrasound machine
for limited echocardiographic studies. They were given a 30 minutes lecture followed by one-on-one instruction
and supervision. A linear regression model plotting an overall assessment index against the number of scans
showed a learning curve of 20 40 scans. However, the authors did note significant differences between residents
in their rate of learning.
These studies show that goal-directed limited transthoracic echocardiography is within the reasonable reach
of a significant proportion of the anaesthetic community.
TTE IN AUSTRALASIAN ANAESTHESIA
Some specific examples give an overview of TTE usage in Australasian anaesthesia. The first case series was
reported by Canty et al in 200920. They reported on 87 TTE and 14 TOE examinations in 97 patients at Royal Hobart
Hospital (75 studies were conducted pre-operatively). Three patients had their surgery changed or cancelled, and
in 18 patients there were significant changes in anaesthetic management.
Cowie in 201119, at St Vincents Hospital in Melbourne, has reported on three years experience in anaesthetists
performed goal-directed echocardiography. He reports adequate images obtainable in 167 out of 170 patients
(98%). Just over half the studies were conducted because of a systolic murmur. Changes in peri-operative
management occurred in 140 out of 170 (82%) patients. Major findings correlated with a formal cardiology
transthoracic echocardiogram in 52 out of 57 (92%) patients.
Joondalup Hospital in Perth has established a formal perioperative echocardiography service. Comprehensive
echocardiograms are conducted by a cardiac sonographer and reported by an anaesthetist. The most common
indications are undiagnosed systolic murmurs or poor exercise tolerance (or an inability to assess it). If an
echocardiogram has been conducted elsewhere in the preceding year and a copy of the report can be obtained,
it is not repeated unless there is a specific indication to do so. Abnormal findings are referred to cardiologists for
follow up with the images and report provided so that the study does not need to be repeated.
In the first 22 months, nearly 700 echocardiograms have been performed. Preliminary results show 26.7% of
patients had moderate or severe echocardiographic findings such as significant valvular dysfunction or valvular
heart disease. Half of these findings were totally unexpected on clinical grounds. Around 36% of the murmurs were
the results of moderate or severe disease. In sixty patients with a murmur, surgery proceeded as planned because
haemodynamically significant valvular heart disease was confidently excluded.
Sir Charles Gairdner Hospital, also in Perth, has embraced all forms of ultrasound. One third of the consultant
staff have experience and a formal qualification in echocardiography with others in training. The majority are general
anaesthetists and most perform only TTE, while three are cardiac anaesthetists practicing only TOE (with two more
meeting the grandfather requirements of PS4632). The department has seven TTE capable ultrasound machines.
Both limited goal-directed and comprehensive echocardiograms have been conducted as required over the past
five years. The hospital is considering extending anaesthetist performed goal-directed limited examinations to the
preoperative clinic on a more regular basis. With two different models being used in the one city, it is hoped to be
able to compare and contrast the efficacy and community costs of each model.
THE NEXT CASE
So you performed a goal-directed TTE for our elderly gentleman who fell and injured his lower leg. This showed a
heavily calcified aortic valve with an obvious restriction in opening. In addition, there was mild to moderate aortic
regurgitation, obvious concentric left ventricular hypertrophy, hypokinesis of the inferior septal wall (consistent with
an old right coronary artery territory myocardial infarction) and a huge left atrium typical of significant diastolic
impairment. Further questioning of the patient revealed a couple of episodes of possible syncope. Although he
walked the dog every day, the dog walked but he rode in a buggy. Although the ejection fraction appeared to be
relatively well preserved and the peak and mean gradients across the valve were only 39 and 26mmHg pressure
in the moderate range, the aortic valve area was 0.6cm2 and dimensionless index 0.20,33 both suggesting severe
if not critical aortic stenosis. However, the 2D appearance was that of severe, not just moderate stenosis, consistent
with normal ejection fraction low-gradient severe aortic stenosis. Despite initial patient reluctance, the surgery was
successfully conducted under local anaesthesia.
175
176
27. Cowie B, Kluger R: Evaluation of systolic murmurs using transthoracic echocardiography by anaesthetic
trainees. Anaesthesia 2011.
28. Quinones MA, Douglas PS, Foster E, Gorcsan J, 3rd, Lewis JF, Pearlman AS, Rychik J, Salcedo EE, Seward JB,
Stevenson JG, Thys DM, Weitz HH, Zoghbi WA, Creager MA, Winters WL, Jr., Elnicki M, Hirshfeld JW, Jr., Lorell
BH, Rodgers GP, Tracy CM: ACC/AHA clinical competence statement on echocardiography: a report of the
American College of Cardiology/American Heart Association/American College of Physicians-American Society
of Internal Medicine Task Force on clinical competence. Journal of the American Society of Echocardiography
: official publication of the American Society of Echocardiography 2003; 16: 379-402.
29. Royse CF, Seah JL, Donelan L, Royse AG: Point of care ultrasound for basic haemodynamic assessment: novice
compared with an expert operator. Anaesthesia 2006; 61: 849-55.
30. Vignon P, Dugrad A, Abraham J, Belcour D, Gondran G, Pepino F, Marin B, Franois B, Gastine Herv Focused
training for goal-oriented hand-held echocardiography performed by noncardiologist residents in the intensive
care unit. Intensive Care Med (2007) 33:1795-1799.
31. Hellmann DB, Whiting-OKeefe Q, Shapiro EP, Martin LD, Martire C, Ziegelstein RC: The rate at which residents
learn to use hand-held echocardiography at the bedside. Am J Med 2005; 118: 1010-8.
32. Recommendations for Training and Practice of Diagnostic Perioperative Transoesophageal Echocardiography
in Adult. ANZCA 2004.
33. Dimensionless index is the ratio between the LVOT peak velocity or velocity time integral and the aortic valve peak
velocity or velocity time integral. A dimensionless index of 0.25 or less is consistent with severe aortic stenosis.
177
179
Perfusion pressure
(Preload)
(Afterload)
Fluids/
Volume
Cardiac
output
Inotropes &
Chronotropy
Vascular
Resistance
Vasopressors
180
Principles of measurement:
Arterial pressure waveform methods:
The different variations of this approach convert a pulse pressure waveform into a measurement of stroke volume,
as originally developed from the work of Wesseling.1 The arterial tree behaves like a Windkessel, converting pulsatile
ejection to continuous flow in small vessels in the periphery by modifying the rise in pressure that accompanies
systolic ejection by virtue of its compliance and resistance characteristics. The mathematics of this approach must
incorporate all these factors to estimate stroke volume from arterial pressure (Figure 2). Wesseling pointed out that
for most robust accuracy, compliance and resistance should be identified in a given patient using a calibration
measurement, such as an indicator dilution measurement. This is an integral part of the technique for some devices,
such as PiCCO (Pulsion Medical Systems, Germany) which uses a transpulmonary thermodilution measurement
using a central venous line and femoral arterial line for the calibration measurement. The LiDCO system (LiDCO
Ltd, UK) uses a bolus intravenous injection of lithium, employing the dye dilution principle, for the calibration. In
between calibrations, beat-to-beat stroke volume and cardiac output measurement is provided from the pulse
contour algorithm.
mmHg
Figure 2. Pulse contour calculation of cardiac output (PCCO) used by the PiCCO.
Time
PCCO = cardiac output, cal = patient specific calibration factor, HR = heart rate, P(t) = arterial pressure at time t,
SVR = systemic vascular resistance, C = arterial compliance.
The calibration manoeuvre has been omitted in the Vigeleo/FloTrac pulse contour system (Edwards Lifesciences,
USA), which uses a proprietary stochastic (statistical) algorithm incorporating the data from the skewness (tilt) and
kurtosis (spread) of the pulse waveform along with patient height, weight and age to estimate circulatory compliance
and resistance and thus the baseline stroke volume. The FloTrac transducer is a single use peripheral component
which replaces the normal arterial pressure transducer and functions using a standard peripheral arterial catheter.
The patient compliance and resistance is recalculated every minute or more frequently on newer software versions.
Pulse pressure variation (PPV) with the respiratory cycle is a useful dynamic indicator of left ventricular preload
and volume status in ventilated patients who are in a regular cardiac rhythm. Pulse contour devices readily derive
a measurement of stroke volume variation (SVV) from this to estimate left ventricular preload. Along with cardiac
output and afterload calculations, this provides further data to guide fluid resuscitation. PPV of greater than 13%
is considered to indicate a low preload state, and less than 9% adequate fluid loading.
OESOPHAGEAL DOPPLER
These devices such as the Hemosonic (Arrow International, USA) or CardioQ ODM (Deltex Medical Ltd. UK) are
adapted for use in patients under general anaesthesia, and use a disposable ultrasound transducer positioned
mid-oesophagus to generate profiles of blood velocity in the descending aorta.2 The area under the velocity curve
is integrated with respect to time for each heart beat (velocity-time integral or stroke distance) and then multiplication
by the aortic cross-sectional area gives a measurement of aortic stroke volume. An arbitrary adjustment for the
proportion of blood flow that goes to the head and upper body is made to get an estimate of cardiac output. These
measurements are automated but the incident angle of the probe relative to the direction of aortic flow is critical
and must be adjusted to optimize the Doppler spectral envelope, and then kept steady.
Indices of preload, afterload and left ventricular function are obtained by these devices from the shape of the
velocity profile (Figure 3). The width of the velocity envelope is the flow time (corrected for the heart rate) or FTc. A
shorter FTc (less than 350 msec) indicates reduced preload, but in combination with a lower peak velocity indicates
increased afterload. A low peak velocity and flatter upstroke on the velocity profile indicates reduced left ventricular
contractility. Various other factors such as age affect the normal values for these indices. The learning curve with
these devices involves some pattern recognition by the user, and changes in waveforms in a patient are more easily
181
Stroke distance
Velocity
Peak velocity
Time
FTc
182
Baseline
period
Partial
rebreathing
Time >
183
The percentage errors shown by this meta-analysis represent the combined effects of a number of sources of
error of agreement with thermodilution. There are systematic sources of error for some methods, for example, the
tendency of thermodilution to overestimate low cardiac output values due to thermal decay during slow right heart
passage.13-15 There is inter-patient variability, reflecting a wide variety of sources of error, and there is intra-patient
variability.
In general, intra-patient variability is smaller, but most important. Most technologies are able to track changes
or trends in cardiac output, at least qualitatively, and arguably this is the most important function of a monitor.16,17
A device which gives misleading data on the direction of change of cardiac output may be of more harm than
benefit in clinical practice. Statistical methods have been discussed recently for assessing concordance between
a method and thermodilution in measuring changes in cardiac output.18,19 The ability of devices to track sudden
dramatic changes in cardiac output is hard to study in the clinical setting, and relies on animal studies and occasional
case reports of critical events. Some methods, including thermodilution itself, have not performed well in these
reports.20-22
USE IN MANAGEMENT OF PATIENTS
A growing number of studies have used these devices to influence patient management during surgery. Most of
these studies have used the data to guide fluid administration and use of vasopressors. A few have included the
use of inotropes to improve cardiac output as well. Where fluid and drug administration is guided by specific
measures of preload, cardiac output or afterload, the term goal directed management has been coined.
Dynamic indices such as SVV appear to be more reliable than static measurements of preload such as central
venous pressure.23 Along with systolic pressure and pulse pressure variation,24 SVV appears to be a useful index
of intravascular volume depletion in patients ventilated at tidal volumes of 500 mL or more and who are in a regular
cardiac rhythm. Kungys et al showed that SVV increase correlated with a reduction in cardiac index and transoesophageal echocardiography-based left ventricular end-diastolic volume in patients during acute normovolaemic
haemodilution involving removal of 15% of estimated blood volume and subsequent replacement with colloid.25
The reliability of PPV or SVV in patients with severe ventricular dysfunction is still unclear, however.
For both indices of preload and cardiac output measurement, changes in a given patient appear to be more
meaningful than does any isolated value. For this reason, fluid responsiveness has been central to most algorithms
using these devices to guide management. Increases in stroke volume (SV) and cardiac output of 10% or more
decrease in PPV or SVV in response to fluid challenge are considered significant. If preload is judged to be adequate
on the basis of a reduced response to fluid administration, hypotension is then treated with vasopressors, (and low
cardiac output is treated with inotropes in more aggressive protocols). A simple approach, targeting blood pressure,
is given in Figure 5.
Figure 5. A simple goal directed haemodynamic strategy targeting blood pressure
Yes
No
Fluid bolus
No
Vasopressor
Maintenance fluid
& replace losses
184
A more intensive algorithm targeting blood flow, or cardiac index (CI) first, and blood pressure second, is as shown
in Figure 6.
Figure 6. An intensive goal directed haemodynamic strategy targeting cardiac index first, and
incorporating the possibility of using an inotrope/chronotrope (such as dobutamine for example),
where preload appears adequate but cardiac index remains low, implying cardiac dysfunction.
No
Yes
No
SVI<35 ml/m2
HR low?
Yes
Fluid bolus
Inotrope/
chronotrope
No
Maintenance fluid
& replace losses
Indices of ventricular dysfunction measured by these devices include stroke volume index or SVI (CI/heart rate).
A SVI of less than 35 mL/m2 is considered suboptimal.
In essence these approaches are not very different from traditional management of the inadequate circulation
during anaesthesia: first give fluid, and supplement with vasopressor or other supportive drugs if necessary. The
new paradigm is that the triggers for each of these interventions are based on dynamic measurements of volume
status, and perfusion, which provide information to guide the optimal balance of fluid and vasoactive agents. A
better targeted balance of resuscitation strategies is obtained. It is logical to postulate that this may translate into
better perioperative outcomes. A recent meta-analysis focusing on studies which target tissue perfusion in a goal
directed manner has shown improved outcomes,26 although recent randomised trials using dopexamine have not
found this.27,28
FUTURE DIRECTIONS IN HAEMODYNAMIC MONITORING AND MANAGEMENT
Data from a number of studies, in particular in bowel surgery, suggest that major complications are reduced and
outcomes improved by use of a more restricted fluid administration strategy.29 The availability of less invasive
devices for haemodynamic monitoring has prompted numerous studies into improved outcome in patients using
goal directed therapy. There have been various reviews and meta-analyses published incorporating randomised
controlled studies, which have suggested that goal directed fluid management improves outcomes in abdominal
surgery.3,26,29-34 A recent editorial has suggested that failure to employ goal directed fluid management may represent
substandard care.35 In the United Kingdom, the National Institute for Health and Clinical Excellence (NICE) have
recently issued recommendations that the CardioQ-ODM should be considered for use in patients undergoing
major or high-risk surgery or other surgical patients in whom a clinician would consider using invasive cardiovascular
monitoring.36
185
However, there are still reasons to question these conclusions. All the randomised controlled trials (RCTs) using
minimally invasive monitors included in these meta-analyses have been small single centre studies, few with greater
than 100 200 patients. Trials of this size are typically efficacy studies which can reflect the intense interest of a
centre or research group in an intervention, but may not reflect the results of that intervention in more widespread
practice. Research funded by commercial interests or negative studies in a field of research can encounter publication
bias and this can affect the results of meta-analyses.37 There are a number of salient examples in the anaesthetic
and medical literature of failure of a meta-analysis of small RCTs to be confirmed by a subsequent large RCT
conducted across a large number of centres.38,39 There is a need for a large multicentre RCT of goal directed fluid
and haemodynamic management in major surgery, to confirm the findings of research to date in this field. The
increasing availability of minimally invasive monitors in clinical practice should make this feasible in the near future.
A higher standard of evidence for the benefits goal directed management will assist in the wider adoption of these
devices.
The slow penetration of these technologies into routine clinical practice up till now has been limited by other
factors as well. These include lack of familiarity of the clinician and cost considerations, particularly of single-use
disposable components. These devices add to the complexity of the conduct of anaesthesia and may be perceived
as a distraction to the anaesthetist. Most of the available devices are marketed as stand-alone systems, and lack
of integration with the rest of the patient monitoring system, contribute to this perception.
Better integration into anaesthesia delivery and monitoring platforms will improve this. For example, integration
with invasive or non-invasive blood pressure measurement allows automatic calculation of haemodynamic indices
such as SVR which gives further data to guide fluid and vasopressor therapy. Indices of oxygen delivery are
automatically available when oximetry data is incorporated. Full integration allows optimal data display and alarm
settings and prevents overcrowding of the anaesthetists work space and better ergonomics.
CONCLUSION
No one device for cardiac output measurement is ideal in all circumstances. The best option depends on the patient
and anaesthetic technique chosen by the clinician.40 Devices adapted to use in patients under general anaesthesia
such as partial CO2 rebreathing and oesophageal Doppler can provide data without the necessity for arterial
cannulation. Methods compatible with the awake patient such as pulse contour and bio-impedance may be useful
under neuraxial blockade and in the postoperative recovery or high dependency unit, but await formal validation
in these settings. The widest choice should be available to the anaesthetist to explore and exploit the potential
improvements in patient care that routine comprehensive haemodynamic monitoring promises. The need for this
is likely to grow in the future as the trend to more prolonged and aggressive surgery in patients with significant
co-morbidities increases.
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a nonlinear, three-element model. Journal of Applied Physiology 1993; 74: 2566-73.
2. Schober P, Loer SA, Schwarte LA: Perioperative Hemodynamic Monitoring with Transesophageal Doppler
Technology. Anesth Analg 2009; 109: 340-53.
3. Funk DJ, Moretti EW, Gan TJ: Minimally Invasive Cardiac Output Monitoring in the Perioperative Setting. Anesth
Analg 2009; 108: 887-97.
4. Jaffe MB. Partial CO2 rebreathing cardiac output - operating principles of the NICO2 system. J ClinMonit 1999;
15: 387-401.
5. Gedeon A, Forslund L, Hedenstierna G, Romano E. A new method for noninvasive bedside determination of
pulmonary blood flow. Med & Biol Eng & Comput 18: 411-8, 1980.
6. Peyton P, Thompson D, Junor P. Non-invasive automated measurement of cardiac output during stable cardiac
surgery using a fully integrated differential CO2 Fick method. J Clin Monit Comput. 2008 Aug; 22(4):285-92;
oi.org/10.1007/s10877-008-9131-2.
7. Bland JM, Altman DG: Statistical methods for assessing agreement between two methods of clinical
measurement. Lancet 1986; i: 307-10.
8. Stetz CW, Miller RG, Kelly GE, Raffin TA: Reliability of the thermodilution method in the determination of cardiac
output in clinical practice. Am Rev Resp Dis 1982; 126: 1001-4.
9. Critchley LAH, Critchley JA: A Meta-Analysis of Studies Using Bias and Precision Statistics to Compare Cardiac
Output Measurement Techniques. J Clin Monit Comput 1999; 15: 85-91.
10. Botero M, Kirby D, Lobato E, Staples E, Gravenstein N. Measurement of Cardiac Output Before and After
Cardiopulmonary Bypass: Comparison Among Aortic Transit-Time Ultrasound, Thermodilution, and Noninvasive
Partial CO2 Rebreathing. J Cardiothorac and Vasc Anesth 18(5): 563-72, 2004.
11. Bajorat J, Hofmockel R, Vagts D, Janda M, Pohl B, Beck C, Noeldge-Schomburg G. Comparison of invasive
and less-invasive techniques of cardiac output measurement under different haemodynamic conditions in a
pig model. Eur J Anaesthesiology, 23: 23-30, 2006.
186
12. Peyton P, Chong SW. Minimally invasive measurement of cardiac output during surgery and critical care:
A meta-analysis of accuracy and precision. Anesthesiology, 2010; 113 (5): 1220-35.
13. Runciman, W. B., A. H. Ilsley, J. G. Roberts. Thermodilution cardiac output a systematic error. Anaesth Intens
Care 9: 135-9, 1981.
14. Tournadre, J.P., D. Chassard and R. Muchada. Overestimation of low cardiac output measured by thermodilution.
Br J Anaesth 79: 514-6, 1997.
15. Van Grondelle, A., R. V. Ditchey, B. M. Groves, W. W. Wagner and J. T. Reeves. Thermodilution method
overestimates low cardiac output in humans. Am J Physiol (Heart Circ Physiol) 14: H690-2, 1983.
16. Bein B, Renner J, Scholz J, Tonner PH: Comparing different methods of cardiac output determination: A call
for consensus. Eur J Anaesthesiol 2006; 23: 710.
17. Linton NWF, Linton RA, Della Rocca G, Costa MG: Is comparison of changes in cardiac output, assessed by
different methods, better than only comparing cardiac output to the reference method? Br J Anaesth 2002;
89: 336-7.
18. Feldman JM: Is It a Bird? Is It a Plane? The Role of Patient Monitors in Medical Decision Making. Anesth Analg
2009; 108: 707-10.
19. Critchley LA, Yang XX, Lee A. Assessment of Trending Ability of Cardiac Output Monitors by Polar Plot
Methodology. J J Cardiothorac Vasc Anesth 2011; 25(3): 536-546.
20. Bein B, Meybohm P, Carvus E, Renner J, Tonner P, Steinfath M, Scholz J, Doerges V. The Reliability of Pulse
Contour-Derived Cardiac Output During Hemorrhage and After Vasopressor Administration. Anesth Analg, 105
(1): 107-13, 2007.
21. Collange O, Xavier L, Kuntzman H, Calon B, Schaeffer R, Pottecher T, Diemunsch P, Pessaux P. FloTrac for
monitoring arterial pressure and cardiac output during phaeochromocytoma surgery. Eur J Anaesthesiology.
25: 779-80, 2008.
22. Vannucci A, Krejci V, Kangrga I: Performance of Vigileo and LiDCOplus cardiac output monitors during a prolonged
cardiac arrest and resuscitation. Eur J Anaesthesiol 2009; 26: 885-7.
23. Marik PE, Cavallazzi R, Vasu T, Hirani A. Dynamic changes in arterial waveform derived variables and fluid
responsiveness in mechanically ventilated patients: a systematic review of the literature. Crit Care Med
2009;37:26427.
24. Bendjelid K, Romand JA. Fluid responsiveness in mechanically ventilated patients: a review of indices used in
intensive care. Intensive Care Med 2003; 29:352-360.
25. Kungys G, Rose DD, Fleming NW. Stroke Volume Variation During Acute Normovolemic Hemodilution. Anesth
Analg 2009;109:182330.
26. Gurgel ST, do Nascimento P Jr. Maintaining tissue perfusion in high-risk surgical patients: a systematic review
of randomized clinical trials. Anesth Analg 2011; 112:1384-91.
27. Davies SJ, David Yates D, Wilson RJT. Dopexamine Has No Additional Benefit in High-Risk Patients Receiving
Goal-Directed Fluid Therapy Undergoing Major Abdominal Surgery. Anesth Analg 2011;112:130-8.
28. Gopal S, Jayakumar D, Nelson PN. Meta-analysis on the effect of dopexamine on in-hospital mortality.
Anaesthesia 2009;64: 589-94.
29. Brandstrup B. Fluid therapy for the surgical patient. Best Practice & Research Clinical Anaesthesiology 2006;
Vol. 20(2): 265-283.
30. Abbas SM, Hill Ag. Systematic review of the literature for the use of oesophageal Doppler monitor for fluid
replacement in major abdominal surgery. Anaesthesia, 2008, 63, pages 44-51.
31. Giglio MT, Marucci M, Testini M, Brienza N. Goal-directed haemodynamic therapy and gastrointestinal
complications in major surgery: a meta-analysis of randomized controlled trials. British Journal of Anaesthesia
2009; 103 (5): 637-46.
32. Rahbari NN, Zimmermann JB, Schmidt T, Koch M, Weigand MA, Weitz J. Meta-analysis of standard, restrictive
and supplemental fluid administration in colorectal surgery. British Journal of Surgery 2009; 96: 331-341.
33. Roche AM, Miller TE, Gan TJ. Goal-directed fluid management with trans-oesophageal Doppler. Best Practice
& Research Clinical Anaesthesiology. 2009; 23: 327-334.
34. Hamilton MA, Cecconi M, Rhodes A. A systematic review and meta-analysis on the use of preemptive
hemodynamic interventionto improve postoperative outcomes in moderate- and high-risk surgical patients.
Anesth Analg 2011; 112:1392-402.
35. Miller TE, Roche AM, Gan TJ. Poor Adoption of Hemodynamic Optimization During Major Surgery: Are We
Practicing Substandard Care? Anesth Analg 2011; 112(6): 1274-6.
36. www.nice.org.uk/guidance/MTG3.
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37. Pogue J, Yusuf S. Overcoming the limitations of current meta-analysis of randomised controlled trials. Lancet
1998; 351: 47-52.
38. LeLorier J, Grgoire G, Benhaddad A, Lapierre J, Derderian F. Discrepancies between meta-analyses and
subsequent large randomised, controlled trials. N Engl J Med 1997; 337: 536-542.
39. Rigg JRA, Jamrozik K, Myles PS, Silbert BS, Peyton PJ, Parsons RW, Collins KS, for the MASTER Anaesthesia
Trial Study Group. Epidural Anaesthesia and Analgesia and Outcome of Major Surgery: a Randomised Trial.
Lancet, 2002; 359: 1276-82.
40. Slagt C, Breukers RM, Groeneveld ABJ. Choosing patient-tailored hemodynamic monitoring Critical Care 2010,
14:208-13.
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with attendance on courses such as the Effective Management of Anaesthetic Crises (EMAC),9 its unclear the
extent to which this has impacted on the functioning of the operating room team as a whole. No surgeons are
involved in EMAC. A crisis management course devised for surgeons from Imperial College, London, has an actor
playing the role of the anaesthetist, with a cardboard cut-out of an anaesthetic machine (personal communication).
Stereotypical representation of other professional groups may be inaccurate or even derogatory and can potentially
be reinforced during single profession team training, for example through consistently simulating negative aspects
of other professions, or through language permitted in single profession discussions (e.g. unhelpful, obstructive,
idle). We work in multidisciplinary teams and some of the bigger challenges in teamwork are likely to come from
interactions across these disciplines. Understanding the capabilities of other professional groups, how they process
and prioritise information, and the information they need to know to do their job, may be limited in members of the
operating room team. Learning how to negotiate these differences would seem a fundamental requirement for
developing teamwork.
In order for teams to share information, team leaders need to be open to suggestion. Where a power gradient
inhibits team members for speaking up, mistakes will go unchallenged. Bleakely10 describes the need for democracy
in healthcare teams, where all members have a voice. He further describes the monologic leader, who does all
the talking and doesnt invite input. This undemocratic culture provides a further challenge for developing effective
teams. By way of contrast, the dialogic leader, engages in open conversations and encourages suggestions from
the team members.
HARD FACTS
Medical error is the third biggest killer, after cancer and heart disease, in North America. 2 Between 6 and 16% of
all hospital admissions are associated with an adverse event, resulting in disability or longer hospital stay.11-13 Its
becoming clear that the majority of these medical errors and adverse events are not due to failures in training,
medical knowledge or technical proficiency, but to the so-called non-technical factors. Failures in teamwork and
communication make a substantial contribution.14-20 Miscommunication both within teams and across teams is
most acute in surgical settings.21
Observational studies in the operating room have identified communication problems. Lingard et al22 classified
over 25% of all communications between members of the operating room team as failures, due to poor timing,
wrong or incomplete content, or failure to resolve issues. Many of these were observed to result in deleterious
effects on the efficiency, use of resources and led to delays, procedural errors or tension between team members.
BETTER TEAMS HAVE BETTER RESULTS
In a meta-analysis of studies of 2650 non-clinical teams, nearly 20% of the differences in team processes and
outcomes could be accounted for by prior participation of team members in team training.23 This suggests team
training can lead to a change in team behaviour. These improved processes and outcomes also applied to teams
who did or did not regularly work together. A review of published studies on leadership and healthcare teams
supports the proposal that well functioning teams with good leadership can improve patient safety.24 In a metaanalysis of controlled trials on post-discharge non-pharmacological interventions in patients with heart failure,
involving a multidisciplinary team was associated with reduced rates of re-hospitalisation and mortality. 25 There is
some evidence that medical team training initiatives exhibit similar effects to those observed in aviation and laboratory
teams.26 While there are unique factors affecting operating room teams, it seems likely that there will be some
similarities in the way teams function across different contexts. Indeed in a survey of participants of a simulationbased course in crisis management, anaesthetists reported very specifically the changes theyd made to their
practice, and the way they managed their team in critical clinical events following the training.27
The WHO Surgical Safety Checklist has, as one of its components, an intention to improve the way the operating
room staff functions as a team, for example, introduction of team members and sharing of information about
significant patient and case issues. Reports of substantial reductions in post-operative morbidity and mortality are
compelling.23
SOFT SKILLS
However, teams do not just happen. As in other contexts, collecting a group of highly skilled health practitioners
together in the operating theatre does not ensure optimal outcomes for every patient. The undeniable evidence on
suboptimal teamwork, and resultant bad outcomes for patients, obliges us to look at some of the soft, non-technical
skills.
Based on an extensive review and analysis of the published studies on teamwork across different contexts,
Salas29 identified a number of dimensions that were requirements for a well-functioning team. These are: team
leadership; mutual performance monitoring; backup behaviour; adaptability; and team orientation. Salas proposed
a number of underlying conditions that were requirements for teams to be achieve these capabilities: mutual trust;
shared mental models; and closed loop communication (Table 1).
191
Definition
Behavioural markers
Team leadership
Mutual performance
monitoring
Backup behaviour
Adaptability
Team orientation
Mutual trust
Information sharing.
Willingness to admit mistakes and
accept feedback.
Closed-loop
communication
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193
Leadership: In anaesthesia, the role of the leader is to centralise communication and co-ordinate tasks. If the
team has previously clarified their roles and capabilities, established a common understanding of the pertinent
issues, and the goal of treatment, and has the skills to communicate efficiently, the leaders job is facilitated.
Mutual performance monitoring /Backup behaviour: A common understanding of others roles and clarity about
the goals of treatment enables team members to recognise when others are task overloaded, not coping or not on
the right track. Mutual trust and respect enables team members to speak up. A shared goal with whole team
responsibility facilitates speaking across professional boundaries in the interests of achieving the goal.
Adaptability: In the operating room, team members may not know each other, and the situation can change
rapidly. Processes that support understanding of who is in the team and their tasks and responsibilities, and
structures to ensure information is shared and updated, enables the whole team to move rapidly to a new
understanding of the changed situation and modify their actions accordingly.
Team orientation: When making decisions about patient care, surgeons and/or anaesthetists with a team
orientation will take others views into consideration when determining whats best for the patient or for the running
of the day.
A SYSTEMS APPROACH TO TEAMWORK IN THE OPERATING ROOM
Following the initial publication of the report To Err is Human with calls for doctors to improve the way they worked
in healthcare teams, progress has been frustratingly slow.33 Most effective public health interventions have taken
a systems approach. Roads are made safer not by asking drivers to be careful, but by installing traffic controlling
functions such as speed humps, traffic lights, median barriers. Anaesthesia has become safer by, for example, the
introduction of pulse oximetry and capnography, and design of gas delivery systems. In the same way, to improve
collaboration between members of operating room team we are likely to require systems and organisational structures
that support, or indeed require, collaboration by team members. These could include scheduling a brief and debrief
into the theatre day, implementing the WHO Surgical Safety Checklist, regular multidisciplinary departmental training
days.
There is a problem and we need to fix it, working alongside our surgical and nursing colleagues to firstly better
understand the requirements of teamwork in the operating theatre, develop a more democratic operating room
environment, and hone up on some of those hard skills of teamwork.
REFERENCES
1. Weaver SJ, Lyons R, DiazGranados D, Rosen MA, Salas E, Oglesby J, et al. The anatomy of health care team
training and the state of practice: a critical review. Academic Medicine. 2010;85(11):1746-60.
2. HealthGrades I. Health Grades Quality Study. Patient Safety in American Hospitals. Health Grades Incorporated;
2004 [cited 2011 December ]. Available from: http://www.healthgrades.com/media/english/pdf/HG_Patient_
Safety_Study_Final.pdf.
3. Bosch M, Faber MJ, Cruijsberg J, Voerman GE, Leatherman S, Grol RPTM, et al. Effectiveness of patient care
teams and the role of clinical expertise and coordination: A literature review. Medical Care Research & Review.
2009;66(6 Suppl):5S-35S.
4. Health and Disability Commissioner. A Report by the Health and Disability Commissioner. (Case 00/06857).
Health and Disability Commission; 2002 [cited 2010 17.4.2010]. Available from: www.hdc.org.nz/
media/2695/00HDC06857%20surgeon.pdf.
5. Institute of Medicine. To Err Is Human: Building a Safer Health System. Washington DC: National Academy
Press; 2000.
6. Accreditation Council for Medical Graduates. ACGME Core Competencies. ACGME 2001.
7. Jason R Frank, editor. The CanMEDS 2005 Physician Competency Framework: Better standards. Better
physicians. Better care. Ottawa: The Royal College of Physicians and Surgeons of Canada; 2005.
8. Agency for Healthcare Research and Quality. TeamSTEPPS: National Implementation. US Department of Health
and Human Services; [cited 2011 22.9.2011]. Available from.
9. Weller J, Morris R, Watterson L, Garden A, Flanagan B, Robinson B, et al. Effective Management of Anaesthetic
Crises: development and evaluation of a College accredited simulation-based course for anaesthesia education
in Australia and New Zealand. Simulation in Healthcare. 2006;1:209-14.
10. Bleakley A. Social comparison, peer learning and democracy in medical education. Medical Teacher.
2010;32(11):878-9.
11. indicative findings. New Zealand Medical Journal. 2001;11(114):203-5.
12. Leape L, Brennan T, Laird N, Lawthers A, Localio A, Barnes B, et al. The nature of adverse events in hospitalised
patients: The results of the Harvard Medical Practice Study II. New England Journal of Medicine. 1991;324:377-84.
13. Wilson R, Runciman W, Gibberd R, Harrison B, Newby L, Hamilton J. The Quality in Australian Health Care
Study. Medical Journal of Australia. 1995;163:458-71.
14. Alvarez G, Coiera E. Interdisciplinary communication: An uncharted source of medical error? Journal of Critical
Care. 2006;21:236 -42.
194
15. Bognor M. Human Error In Medicine. 1st ed. New Jersey: Lawrence Erlbaum Association Inc; 1994.
16. Helmreich R, editor. Threat and error in aviation and medicine: Similar and different. Special Medical Seminar,
Lessons for Health Care: Applied Human Factors Research; 2000. Australian Council of Safety and Quality in
Health Care & NSW Ministerial Council for Quality in Health Care.
17. Manser T. Teamwork and patient safety in dynamic domains of healthcare: a review of the literature. Acta
Anaesthesiologica Scandinavica. 2009;53:143-51.
18. Reader TW, Flin R, Cuthbertson BH. Communication skills and error in the intensive care unit. Current Opinion
in Critical Care. 2007;13(6):732-6.
19. Reason J. Human Error. 1st ed. Cambridge: Cambridge University Press; 1990.
20. Webb RK, Currie M, Morgan CA, Williamson JA, Mackay P, Russell WJ, et al. The Australian Incident Monitoring
Study: an analysis of 2000 incident reports. Anaesthesia & Intensive Care. 1993;21(5):520-8.
21. Greenberg CC, Regenbogen SE, Studdert DM, Lipsitz SR, Rogers SO, Zinner MJ, et al. Patterns of
Communication Breakdowns Resulting in Injury to Surgical Patients. Journal of the American College of
Surgeons. 2007;204(4):533-40.
22. Lingard L, Espin S, Whyte S, Regehr G, Baker G, Reznick R, et al. Communication failures in the operating room:
an observational classification of recurrent types and effects. Quality & Safety in Health Care. 2004;13:3304.
23. Salas E, DiazGranados D, Klein C, Burke CS, Stagl KC, Goodwin GF, et al. Does Team Training Improve Team
Performance? A Meta-Analysis Human Factors: The Journal of the Human Factors and Ergonomics Society.
2008;50:903-33.
24. Kunzle B, Kolbe M, Gudela G. Ensuring patient safety through effective leadership behaviour: A literature review.
Safety Science. 2010;48:1-17.
25. Raman G, DeVine D, Lau J. Non-Pharmacological Interventions for Post-Discharge Care in Heart Failure.
Rockville: Agency for Healthcare Research and Quality; 2008. Contract.
26. Salas E, DiazGranados D, Weaver S, King H. Does team training work? Principles for health care. Academic
Emergency Medicine. 2008;11:1002-9.
27. Weller J, Wilson L, Robinson B. Survey of change in practice following simulation-based training in crisis
management. Anaesthesia. 2003;58(5):471-3.
28. Haynes A, Weiser T, Berry W, Lipsitz S, Breizat A, Dellinger E, et al. A surgical safety checklist to reduce morbidity
and mortality in a global population. New England Journal of Medicine. 2009;360:491-9.
29. Salas E, Sims D, Burke C. Is there a Big Five in Teamwork? Small Group Research. 2005;36:555.
30. Gaba D, Fish K, Howard S. Crisis Management in Anesthesiology. 1st ed. Churchill Livingston; 1994.
31. Marshall S, Harrison J, Flanagan B. The teaching of a structured tool improves the clarity and content of
interprofessional clinical communication. Quality & Safety in Health Care. 2009;18(2):137-40.
32. Weller J, Torrie J, Hendersdon K, Frengley R. The Anaesthetist as a Team Player: Speed Dating and Other Useful
Skills. In: ANZCA, editor. Australian and New Zealand College of Anaesthetists Annual Scientific Meeting; 2010;
Christchurch. 2010.
33. Leape L, Berwick D, Clancy C, Conway J, Gluck P, Guest J, et al. Transforming healthcare: a safety imperative.
Quality and Safety in Health Care. 2009;18:424-8.
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LIMITATIONS OF CME
Dressing up old CME materials in new technology does not, however, address longstanding criticism that CME in
general fails to change physician practice or improve patient-oriented outcomes.2,3 Nonetheless, studies comparing
the performance of internet-based CME to traditional formats do demonstrate equal effectiveness in imparting
knowledge 4. Indeed, some studies do report that internet-based CME may be more effective at changing physician
behavior than its traditional equivalent.5,6
Whether it is delivered in traditional or electronic formats, CME in general faces several debilitating limitations.
Using new technologies to improve CME requires an understanding of how practicing physicians learn as well as
an appreciation for inherent variation among individual learning styles. No matter how advanced education technology
becomes, it will never obviate the prerequisite for quality content and skilled educators. Poorly prepared and
delivered content will always fail, no matter how sophisticated the technology used to deliver it becomes.
Another overarching limitation of CME is its lack of relevance to immediate questions and dilemmas that
physicians face in their daily practice. It has long been assumed that physicians-in-training learn most effectively
from their supervised clinical practice. Practicing physicians, however, rarely have the time or luxury to immediately
address gaps in their medical knowledge as they are discovered in real-time. Diligent physicians will take the first
opportune moment to redress these deficits but still may not have the resources to do so, for example, when a
quick internet search is not enough to answer a complex medical question.
The production of electronic CME faces challenges similar to those inherent in traditional CME. To be effective,
CME content must, at a minimum, be reliable, accurate, current, and relevant. If a practitioner identifies a knowledge
or skill deficit during their practice, the ideal CME product will have relevant materials immediately available to
address and remedy this deficit. Furthermore, content must be continually updated to reflect major changes in
accepted practice. It is impossible for a single author or lecturer to produce this breath and depth of content. Many
successful CME programs recruit and utilise a team of physician and faculty educators, often in exchange for
academic publication credit, a small stipend or royalty. However, ethical considerations should remain unchanged;
whether electronic or traditional, we believe that CME should be free of commercial bias, including any funding
from pharmaceutical and medical device companies.
CHALLENGES TO ELECTRONIC CME
Traditional CME offers the advantage of real-time or synchronous learning, but by design it is focused on the teacher
rather than the student. The material covered and discussed is restricted to what the educator has prepared and
chosen to present. This may be of limited relevance and usefulness to individual physicians as learners. Electronic
CME, on the other hand, is able to offer the user a huge selection of topics and archived material to choose from,
thereby focusing more on the needs of the learner.
Nonetheless, electronic CME suffers from delayed or asynchronous interaction in that there is a loss of physical
face-to-face time between facilitators and participants. This limitation has been reported to negatively affect user
perceptions of the effectiveness of internet-based CME.7,8 More importantly, regardless of whether it is synchronous
or asynchronous, education is more effective when it features an interactive component that engages the learner.9
Even face-to-face lectures in real-time that do not engage the learner with an interactive component will almost
certainly fail to change physician practice and ultimately have little effect on patient outcomes. With advancements
in internet technology, electronic CME can now engage learners with a variety of interactive features including
quizzes, assignments, chat, and email. To be truly effective, two-way interaction must occur to make learners active
participants in their education.
Because it lacks the face-to-face physical interaction of traditional CME, high quality electronic CME should
offer multiple formats for online education consumption, including video, audio, text, as well as interactive features.
Availability of multiple formats allows electronic CME to effectively disseminate educational information without a
real-time physical instructor. Many of these lectures can be recorded digitally at one of the many live CME conferences
held annually, then enhanced with audio format conversion, text summaries, and post-test quizzes. Video and audio
recording technology has advanced so that this can be accomplished with a simple setup using a laptop, cameras,
microphones, and relatively inexpensive software programs.
Making large amounts of digital content accessible in a clear and intuitive online format presents its own
challenges. Users must feel confident that the CME product search function returns accurate and relevant results
so that they can use it to immediately answer a clinical question or address a knowledge deficit. At the same time,
the content should be presented so that users are constantly exposed to and enticed to explore material they have
not reviewed recently. For more novice learners, it is helpful for the CME program to offer a step-by-step curriculum
of material with proposed timelines for completion. Meeting these challenges by providing features either through
a website or mobile device application requires a large investment in software programming time and expertise.
Lastly, information or materials that are no longer available or not easily accessible are of limited value. Therefore,
any successful CME will need to be enduring, that is available at any time after it is initially accessed.
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200
Pros
Cons
Notes
Ubiquitous,
archived, passive
Overused
Mass transmission to
phone and internet
2 way communication
more difficult
Streaming Video
Real time
Archived video
No live interaction
Able to be viewed on
multiple occasions from
multiple devices
Archived audio
Extremely portable
not time dependent
No live interaction
Ubiquitous access on
compact disc, MP3 players,
etc
Social Networking
Spaced Education
Interactive, adapts to
learners level of knowledge
and retention
Really Simple
Syndication (RSS)
201
REFERENCES
1. ACCME Annual Reports 1998-2009. Accreditation Council for Continuing Medical Education.
http://www.accme.org/index.cfm/fa/home.popular/popular_id/127a1c6f-462d-476b-a33a-6b67e131ef1a.cfm
(accessed February 9, 2010).
2. Davis D, OBrien MA, Freemantle N, et al. Impact of formal continuing medical education: do conferences,
workshops, rounds, and other traditional continuing education activities change physician behavior or health
care outcomes? JAMA 1999; 282:867-874.
3. Davis D, Thomson MA, Oxman AD, et al. Changing physician performance. A systematic review of the effect
of continuing medical education strategies. JAMA 1995; 274: 700-705.
4. Wutoh R, Boren SA, Balas EA. eLearning: a review of Internet-based continuing medical education. J Contin
Educ Health Prof 2004; 24:20-30.
5. Weston CM, Sciamanna CN, Nash DB. Evaluating online continuing medical education seminars: evidence for
improving clinical practices. Am J Med Qual. 2008; 23: 475-483.
6. Fordis M, King JE, Ballantyne CM, et al. Comparison of the instructional efficacy of Internet-based CME with
live interactive CME workshops: a randomized controlled trial. JAMA 2005; 294:1043-1051.
7. Sargeant J, Curran V, Jarvis-Selinger S, et al. Interactive on-line continuing medical education: physicians
perceptions and experiences. J Contin Educ Health Prof. 2004; 24:227-236.
8. Sargeant J, Curran V, Allen M, et al. Facilitating interpersonal interaction and learning online: linking theory and
practice. J Contin Educ Health Prof. 2006 Spring; 26: 128-136.
9. Fox RD, Bennett NL. Learning and change: implications for continuing medical education. BMJ. 1998; 316:
466-468.
10. Abdolrasulnia M, Collins BC, Casebeer L, et al. Using email reminders to engage physicians in an Internet-based
CME intervention. BMC Med Educ. 2004; 4:17.
11. Boulos MN, Wheeler S. The emerging Web 2.0 social software: an enabling suite of sociable technologies in
health and health care education. Health Info Libr J. 2007; 24: 2-23.
12. Cepeda NJ, Vul E, Rohrer D, Wixted JT, Pashler H. Spacing effects in learning: a temporal ridgeline of optimal
retention. Psychol Sci 2008; 19:1095-1102.
13. Guan J, Tregonning S, Keenan L. Social interaction and participation: formative evaluation of online CME
modules. J Contin Educ Health Prof. 2008; 28 :172-179.
14. Swadron SP, Herbert ME. How do I effectively use electronic continuing medical education? CJEM 2011;13:40-43.
203
204
in the media.5,6
Anaesthesia has been applauded for its progressive improvement in patient safety. Mortality, directly attributed
to anaesthesia, is probably 1 in 100,000 patients having anaesthesia. This figure has propelled anaesthesia to be
a leader in patient safety. It seems difficult, or even unnecessary, to spend further resources on reducing the very
low rate of anaesthesia related mortality. However, this mortality rate is only a short-term measure. Emerging
evidence now indicates that anaesthesia has an important influence on long-term morbidity and mortality.7 This
can be months or years after surgery. Although our anaesthetic drugs are shorter and shorter acting, they can have
important consequences due to interference with organ function in the perioperative period. Examples of anaesthesia
related long-term morbidity include cognitive dysfunction8 wound infection, persistent pain9 and cancer recurrence.10
This effect is further exacerbated by undertaking surgery in sicker patients who have diminished ability to withstand
these effects. What of the potential effects of the general anaesthetic state itself? Accumulating evidence from
several observational trials indicates that deep, prolonged general anaesthesia increases long-term mortality. 11
Future improvements in anaesthesia care will need to measure and improve these long-term outcomes. Long-term,
disability-free survival is an important goal for future anesthesia care.
COST OF HEALTHCARE
The escalating cost of healthcare is an increasing concern, and it has no clear solution. The rate of medical inflation
continues to outpace general inflation. It is fueled by the introduction of new drugs and technologies that are more
expensive than the older ones they replace, and the care of elderly patients near the end of life. Unfortunately, while
we would all wish for the best possible treatments, there are economical limits to what even the wealthiest societies
can provide. All scarce economic resources are rationed and this is accepted in other areas of our lives. If the
current growth of medical inflation is to continue unchanged, then the proportion of GDP in Western societies will
economically cripple future generations. The Australian Treasury estimates that by 2050 spending on healthcare
for those aged over 65 will increase 7 times and for those aged over 85 will increase by 12 times present-day
levels.12 Recent US data shows that the elderly undergo high rates of surgery towards the end of their life. 31.9%
had surgery within the last year of life and 18.3% within the last 30 days of life. Interestingly this treatment intensity
at the end of life varied by a factor of three across regions and was strongly associated with the number of hospital
beds and surgeons per capita. This calls for all physicians to identify and recommend appropriate treatment goals
for the elderly and their families.13
Each of us has a maximum price we would pay for treatment that will extend our life by an extra year. This has
been examined by the eminent bioethicist, Peter Singer, at Princeton.14 A suggested approach is for each speciality,
including our own, to decide on which tests or treatments are expensive, yet make no improvement to patient
outcome.15 For anaesthesia this could begin with reviewing preoperative testing, choice of anaestheic drugs and
techniques, and then extend to preventing futile surgery. The decision to operate is traditionally left to the surgeon
and their consultation with the patient. However from time to time these decisons may not benefit the patient for
either a cure of disease, or palliation. Surgeons may feel more comfortable to operate than to advise the patient
not to have surgery.
The treatment of the very elderly has caused a reassessment of the benefit of medical treatment regarding life
expectancy and quality of life. It has been argued that treatment of single-organ diseases in the very elderly does
not increase longevity due to the concurrent effect of multiple diseases in the elderly patient. For example, the
treatment of hyperlipidaemia with statins in the elderly reduces cardiac deaths, but does not reduce all-cause
mortality.16 Consequently, the focus on treating one isolated illness in a very elderly patient may produce no benefit
in longevity. This is because one of the other multiple morbidities of the elderly will step in to take its place.
RISK AND OUTCOME
Major surgery in the elderly typical carries a 5%, 30-day mortality. 17 This problem has been referred to as the
forgotten group in surgery.18 This issue is further exacerbated when the high-risk elderly patient has a prolonged,
stormy and expensive recovery in the intensive care unit. Ultimately this produces no benefit for the elderly patient
and diverts resources away from other more beneficial areas of care.
How can we predict which patients are at high risk having surgery and anaesthesia, and how can we reduce
this risk? The multi-factorial cardiac risk assessment index was first published in 1977 and the most recent update
was in 1999.19 However, since then there have been significant changes in the techniques of surgery and anaesthesia
along with the characteristics of patients presenting for surgery. The VISION study is an observational study of
40,000 patients that is aiming to answer some of these questions. It will develop a new predictive model of patient
risk and particularly look at the value of biomarkers such as brain natriuretic peptide (BNP) and high-sensitivity
troponin. When a high cardiac-risk patient is presented for surgery what preventive drug strategies do we have
available? Until recently, perioperative beta-blocker therapy was commonly advocated as beneficial, but doubt
about this therapy has followed the findings of the POISE I trial. The POISE II trial, which is currently recruiting, will
examine the effects of other drugs such as aspirin, clonidine or their combination to reduce cardiac events.
205
The approach of using a single-therapy intervention to improve patient outcome and recovery after surgery has
been criticised.20 This has lead to the growing adoption of multimodal interventions. These are commonly referred
to as fast-track surgery or enhanced recovery after surgery (ERAS). They typically involve a combination of pre,
intra, and postoperative interventions (bundles of care) to improve patient outcome. This has seen significant
uptake in several European countries with initiation of government-funded programs. This approach is yet to see
specific government or non-government financial support in Australia but this would be likely to change in the
future. The components include interventions such as regional anaesthesia, minimising systemic opioids, nutrition,
goal-directed fluid therapy, pain relief, and early mobilisation. Anaesthetists, by having a central role throughout a
patients surgical care, are well placed to lead in this reorganisation of practice. In the future there is a need to
determine which components are the most important and which are not worthwhile.
ROLE OF THE ANAESTHETIST
What are the attributes that an anaesthetist should have in the future? Is it enough to be an expert in the knowledge
and skills of anesthesia alone? This is being addressed through the development and introduction of the new
ANZCA curriculum. Traditionally, the role of the anaesthetist is considered to be a medical expert. This is covered
by the attributes of knowledge and skill in the realm of direct patient care. With the changes that have occurred in
healthcare, society and patient expectation there is a recognised need to broaden the attributes of a good anaesthetist.
These broader roles have been developed and promoted by the Royal College of Physicians and Surgeons of
Canada in 1996 and were updated in 2005. This framework has had widespread acceptance in medical education
and has been adopted in many universities and medical colleges. Importantly it emphasises the non-traditional
attributes which make up the broader role of a medical specialist in contemporary society. These include
the attributes of scholar, educator, communicator and manager. These are described further in the CanMEDS
documentation.21
INFORMATION TECHNOLOGY
Healthcare has lagged behind in the adoption of information technology (IT). We are familiar with and use the
benefits of modern IT in our lives every day. Most of us are users of internet banking, social media, email, Wikipedia
and Google. We all expect banks, insurance companies and major companies to use IT in their activities. Yet
hospitals and healthcare still cling to paper-based records. Patient records are called patient notes because they
really are on paper. X-rays and pathology results are still mostly paper or film based. Medications are prescribed
in barely legible handwriting on medication charts. Medication errors are a common cause of preventable patient
harm. Electronic medication management systems can have inbuilt decision support to prevent allergic reactions,
drug interactions and wrong doses. This physical record system is made more problematic when patients have
attended several hospitals, doctors and pharmacies in the past. This results in fragmentation of patients health
information and the risk of losing critical information. This has left us stuck in the traditional practice of each
undertaking and redoing, a clinical history, a medication history and a physical examination. Tests are repeated just
because old results are lost, or not readily accessible. Old patient files are not easily obtainable especially in an
emergency. These are the obvious weaknesses and risks of continuing with our current paper-based work-practices.
Why have anaesthesia and the rest of medicine been so reluctant to adopt IT systems? Key reasons are the need
for mobile access and adequate software design. Unlike workers in the corporate world, we do not stay working
in one location. Throughout the day we move from wards, to clinics, to operating rooms and recovery rooms. The
conventional work practice of sitting in front of a PC at each location is time consuming and distracting. Typically
the software available has a sub-optimal user-interface that further adds to non-acceptance. However these hurdles
now seem to be surmountable. We are now seeing the widespread uptake of affordable mobile computing, such
as tablets and smart phones, which are easy to use and carry throughout the day. When coupled with wireless data
access it seems that we may soon see the acceptance and widespread uptake of this new technology in our
clinical practice.
Will technology eventually replace the anaesthetist? Current developments suggest the introduction of computing
to replace the decision making of the anaesthetist could happen. This seems likely, with Ethicon seeking FDA
approval for its SEDASYS system for propofol sedation during colonoscopy.22 This system has recently been given
approval for use in patient sedation for endoscopy in Europe, Canada and Australia. A recent study showed the
system produced better and safer sedation for colonoscopy than physician-administered sedation. 23 A further
development is the fully computerised delivery of general anaesthesia using a system developed at McGill University
called McSleepy.24 Recently, McSleepy has been teamed up with the Da Vinci surgical robot, to together treat a
patient having a prostatectomy.25 Fortunately the aim of the researchers who developed McSleepy is to ensure the
delivery of consistently high quality anaesthesia despite any idiosyncratic human vagaries.
CONCLUSION
The future is approaching us whether we pay attention or not. With the changes in politics and society, we neglect
it at our peril. For the advancement of anaesthesia as a specialty, and for better patient care, we must be proactive
about our own future. To ignore this call is to leave our profession at risk. Peter Drucker, the preeminent management
thinker, said The best way to predict the future is to create it.26 We should heed his advice.
206
REFERENCES
1. Editorial. The New York Times. Who should provide anesthesia care? 6/9/2010. http://www.nytimes.
com/2010/09/07/opinion/07tue3.html (accessed 31/10/2010).
2. Doctor substitutes for a leaner health system. Ruth Pollard and Nick O'Malley. Sydney Morning Herald.
December 12, 2005. http://www.smh.com.au/news/national/doctor-substitutes-for-a-leaner-healthsystem/2005/12/11/1134235951316.html.
3. Turf war as nurses eye bigger role. Ruth Pollard. Sydney Morning Herald. May 9, 2005. http://www.smh.com.
au/news/Health/Turf-war-as-nurses-eye-bigger-role/2005/05/08/1115491047100.html.
4. Story, D et al. "Effect of an anaesthesia department led critical care outreach and acute pain service on
postoperative serious adverse events. (2006) vol. 61 (1) p. 24-8." Anaesthesia 61, no. 1 (2006): 24-28.
5. Patients wake in fright after anaesthetic gas. Julie Robotham. Sydney Morning Herald. May 5, 2005. p. 1-2.
6. Dunn, A. Aid to keep patients knocked out. The Age (29/05/2004).
7. Sessler, D. Long-term consequences of anesthetic management. Anesthesiology (2009) vol. 111 (1) p. 1-4.
8. Cottrell, JE. We care, therefore we are: anesthesia-related morbidity and mortality: the 46th Rovenstine Lecture.
Anesthesiology (2008) vol. 109 (3) p. 377-88.
9. Chan, MT et al. Chronic postsurgical pain after nitrous oxide anesthesia. Pain (Pain 2011 Nov 152 (11), 2514-20.
10. Bovill, J. Surgery for cancer: does anesthesia matter? Anesth Analg (2010) vol. 110 (6) p. 1524-6.
11. Kurata, J. Deep hypnosis as a sign of imbalance in balanced anesthesia. Anesthesia and Analgesia (2010)
vol. 110 (3) p. 663-5.
12. Australia to 2050: Future Challenges. The Treasury, Australian Government (2010) p. 1-26. Canberra.
13. Kelley, AS. Treatment intensity at end of life time to act on the evidence. Online. October 6. Lancet (2011)
378, Issue 9800, 1364-1365.
14. Singer, P. Why we must ration health care. 15/07/2009. http://www.nytimes.com/2009/07/19/
magazine/19healthcare-t.html (accessed 31/10/2010).
15. Brody, H. Medicines ethical responsibility for health care reform The Top Five list. N Engl J Med (2010) vol.
362 (4) p. 283-5.
16. Heath, I. What do we want to die from? BMJ (2010) vol. 341 pp. 181.
17. Story, DA et al. Complications and mortality in older surgical patients in Australia and New Zealand (the REASON
study): a multicentre, prospective, observational study. Anaesthesia (2010) vol. 65 (10) p. 1022-1030.
18. Editorial. Towards risk reduction in non-cardiac surgery. Lancet (2011) online, October 6.
19. Lee, TH et al. Derivation and prospective validation of a simple index for prediction of cardiac risk of major
noncardiac surgery. Circulation (1999) vol. 100 (10) p. 1043-1049.
20. Kehlet, H and Mythen, M. Why is the surgical high-risk patient still at risk? British Journal of Anaesthesia (2011)
vol. 106 (3) p. 289-91.
21. Royal College of Physicians and Surgeons of Canada. CanMEDS. http://rcpsc.medical.org/canmeds/ 2005.
(accessed 31/10/2010).
22. FDA advisory committee approval of SEDASYS sedation system. http://www.fda.gov/AdvisoryCommittees/
CommitteesMeetingMaterials/MedicalDevices/MedicalDevicesAdvisoryCommittee/AnesthesiologyandRespir
atoryTherapyDevicesPanel/ucm163851.htm. (accessed 31/10/2010).
23. Pambianco, DJ et al. Computer-assisted personalized sedation for upper endoscopy and colonoscopy:
A comparative, multicenter randomized study. Gastrointest Endosc (2011) vol. 73 (4) p. 765-772.
24. McGill University news. World first: researchers develop completely automated anesthesia system.
http://www.mcgill.ca/newsroom/news/item/?item_id=100263. (accessed 31/10/2010.
25. McSleepy meets Da Vinci - McGill University Health Centre specialists conduct first-ever all-robotic surgery and
anesthesia. October 18, 2010. http://muhc.ca/newsroom/news/mcsleepy-meets-davinci (accessed 6/6/2011).
26. Quoted in The Definitive Drucker. Elizabeth Edersheim & Peter Drucker. McGraw-Hill. 2007. p. 83.
207
209
210
CHANGES IN HEALTHCARE
The growth of the centralised bureaucracy in health, in my view, is a major cause of a disenfranchised medical
profession and has been a large deterrent to doctors engaging and volunteering for service roles in their hospitals.
It is worthwhile considering the changes in governance of our public hospitals and the health system in Australia.
Prior to 1972 and the advent of the Whitlam government, public teaching hospitals in Australia were the predominant
place for surgical intervention and hospitalised medical treatment. Over the ensuing years this preeminent position
has shifted. In a report in 2008, the Federal Department notes that of the 2.1million surgical procedures performed
in Australia only 908,000 were in public hospitals.3 The public hospitals, where the largest departments of anaesthesia
are found, have been eroded over the last two decades in more important ways than can be measured numerically.
An important and fundamental shift away from traditional allegiance to public hospitals by specialists occurred as
a result of the doctors strike of 1985, at the introduction of Medicare during the Hawke government. This era also
coincided with the rise of centralised bureaucracy.
The rise of centralised bureaucracy has created a divide between clinical departments and hospital administration;
the latter now looks centrally to the state bureaucracy, rather than being accountable to local clinician power. The
report into the state of hospitals in NSW by Peter Garling SC perhaps summarised the basic issue most succinctly:
During the course of this inquiry, I have identified one impediment to good, safe care which infects the whole
public hospital system. I liken it to the Great Schism of 1054. It is the breakdown of good working relations
between clinicians and management which is very detrimental to patients. It is alienating the most skilled in the
medical workforce from service in the public system. If it continues, NSW will risk losing one of the crown jewels
of the public hospital system: the engagement of the best and brightest from the professionals who are able to
provide world-class care.4
The Workplace Research Centre at the University of Sydney in its submission to the Garling Report in 2008
found that only 17% of doctors and 33% of nurses in public hospitals trusted their managers. The national workplace
average is 70%.5
In his submission to the Garling Report, Professor Michael Cousins, previous President of the Australian and
New Zealand College of Anaesthetists said6:
After 50 years of observing this hospital, Im sad to say that over the last 10 to 12 years there has been a
progressive and, I would have to say, increasing erosion of morale, commitment and loyalty to the institution.
I, like many others, are on a knife edge, of feeling that weve just about tolerated as much as we can and we are
considering leavingI would feel an enormous sense of loss not loss for myself, but a sense of loss for what
might happen to the service that I have tried so very hard to build...one of the key issues is a lack of delegation
of decision-makingWe still bear the responsibility for the clinical services, quality and the safety...The problem
from my point of view (is) its been very difficult to get a decision.
Partly, the issues outlined by Cousins and others relate to the nature of bureaucracy. According to German
sociologist, Max Weber,7 writing in the late 1800s, bureaucracy has fundamental characteristics:
centrally controlled and hierarchical,
it is policy driven, ie one size fits all,
it is budget driven, even budget obsessed,
rules are implemented by neutral officers, it is highly impersonal,
risk averse.
To these characteristics, Cyril Northcote Parkinson, a British naval historian, added that bureaucracy was self
replicative.8 In fact he created a much quoted law of bureaucracy that All work expands to fill the resources and
time available for its completion. A corollary of this law is that bureaucracy is self perpetuating.
If one compares these characteristics to the practice of medicine, one sees an almost opposite set of characteristics.
These fundamental characteristics of bureaucracy make it unsuitable as a paradigm for the management and
running of health. Consider that medicine runs in an almost opposite milieu:
control is devolved to the point of care. Ultimate control is at the end of an injection of Propofol,
each case is completely different,
spending is emotional,
it is highly personal,
it is risky.
The National Health and Hospitals Reform Commission has tried to address this chasm through the creation of
smaller health governance district boards. This may bring about nothing more than further local accountability with
delegation and decision making being kept central. Time will tell.
211
BAD LEADERSHIP
Regardless, there is a need to interface with the bureaucracy, and the medical profession can no longer sustain a
Ghandi-like non-participation policy. We need to take up the challenge. To steer all clinical departments, including
anaesthetic departments, through these changing and stormy times we need good leaders and leadership. What
does make good leadership? I think the obverse is probably easier to answer. Bad leadership is clear to any who
have struggled under its burden. Each of the bad leaders I have observed in my career thus far tends to exhibit a
fatal flaw, a deadly sin that causes them to be less effective. These sins fit into the seven cardinal sins first outlined
in 590 AD by Pope Gregory the First. He was the first monk to become a pope and is credited with indirectly
converting the pagan English, the Anglo Saxons, to Catholicism. He categorised sins into the venial (everyday
forgivable sins) and the cardinal sins (those that relegate the sinner to eternal hell).
Some bad leaders exhibit the sin of pride which is about a feeling or desire that they are more attractive and
important than others. These are the leaders whose first order of business after being appointed is to design and
print good quality business cards, have the signage in the department changed and order a new computer and, if
the budget allows, new office furniture. Often, coupled with the sin of pride, is a lack of insight into their own
performance and more importantly, a lack of insight into the bemusement in which they are held by their department.
Other leaders I have met exhibit the sin of envy where they believe that another person has something they
perceive themselves as lacking, and wish the other person to be deprived of it. These are the leaders who are
constantly whispering in corridors and hatching Machiavellian games to destroy others in order to self promote.
They are amusing in the short term and tiresome in the medium to long term. These leaders are so busy with the
politics that they fail to achieve tangible advances and benefits in their departments.
Wrath is also a cardinal sin. These leaders display impatience with any of the processes that actually can advance
their departments. They advocate withdrawal of services as a first line strategy when dealing with the hospital
administration and believe business plans are a waste of time. They see cooperation with hospital administration
as weakness and believe that the media is a viable and sustainable forum for their venomous views about their
perceived lack of resources. Meanwhile, their departments and their areas suffer. The bureaucracy is not averse to
using their own strategies to negate the media attention these leaders generate.
Then there are the leaders with avarice as a cardinal sin. Avarice also includes greedy behaviour, disloyalty, and
deliberate betrayal, especially for personal gain. This is the leader who takes the best lists for themselves and uses
their position for their own personal gain. In other words, they are disloyal to their colleagues in order to benefit
themselves. Sometimes this type of leader will enter pacts with the administration on how to control members of
their department. This behaviour engenders distrust among the department which quickly becomes ineffective.
A related sin is that of gluttony. This is about over-indulgence to the point of waste. I have seen this often in
departments that have a leader with a strong subspecialty interest. All other departmental pursuits and priorities
pale into insignificance when the subspecialty of the departmental leader requires more resources. There are the
research nurses, the offices and the laboratories - meanwhile the rest of the department struggles for a meeting
place or lounge.
The next cardinal sin is lust which is exhibited by the leader who uses their current post to achieve the next.
They take on the leadership of the department as a means of achieving a job in administration, state bureaucracy
or even the pharmaceutical industry. Their every action aims to add to their burgeoning curriculum vitae. They are
in it for themselves.
Finally, there is sloth. This is the most common of all the cardinal sins. The appointment is made by looking
around the department to spot the anaesthetist who has not yet had a turn at being head of department. This
reluctance to be appointed is used as an excuse to avoid hospital meetings at which their departmental budget is
being decided. The world is run by those who turn up and these slothful leaders do not turn up, much to the
disadvantage of their department.
GOOD LEADERSHIP
So let us turn now to trying to answer the more difficult question of what makes a good leader. There is much
written about the characteristics of good leaders but all seem to agree on three characteristics. Garry Wills, writing
in the Atlantic Weekly in 1994 outlined these as integrity, the ability to listen and finally the ability to create a shared
goal or vision.9 Hogan found that leadership is a survival tool for an organisation, is vital for its success and
fundamentally is about convincing individuals to give up their selfish goals in order to pursue a common and shared
goal.10
When we consider the characteristics of good leadership it becomes clear that anaesthetists are naturally
selected leaders. They minimise distractions among the staff, registrars, patients and theatre administration to
achieve the shared goal of completing the days work with efficiency and safety. More importantly they are called
upon to coordinate, counsel, arrange, cajole and organise surgeons! No greater test of leadership exists.
212
The modern health system needs anaesthetic leaders to apply their skills to the wider medical community to
help us all meet the challenges of the National Health and Hospital Reforms, the medicolegal milieu and the
complexities of maintaining evidence-based safe practice in an increasingly commoditised operating environment.
It is clear that this battle needs to be fought not just at the macroeconomic and macropolitical level, but even more
importantly, on the micro, every day level. We are all leaders in our own environment. We can choose to take the
mantle or to discard it, but that does not deny nor negate our natural role. Doing the latter simply results in
disappointment and defeat.
To paraphrase Professor Malcolm Fishers definition of anaesthesia, we now need, more than ever, the half
asleep who attempt to keep the half awake from being half killed by the half witted to take a half interest in medical
leadership.
REFERENCES
1. Mets, B et al. Leadership of United States Academic Anesthesiology Programs 2006: Chairperson Characteristics
and Accomplishments. Vol. 105, No. 5, 1338-1245, November 2007.
2. EOWA Australian Census of Women in Leadership (2008-2010), available at http://www.eowa.gov.au/Information_
Centres/Resource_Centre/EOWA_Publications/EOWA_Census/2010_Census/2010_ Census_Report.asp The
Census is conducted every two years.
3. http://www.health.gov.au/internet/main/publishing.nsf/Content/E6CAF670D550F646CA25747700074A51/$Fi
le/Our%20surgery.pdf.
4. Final Report of the Special Commission of Inquiry into Acute Care Services in NSW Public Hospitals,
Commissioner Peter Garling SC, 2008, p11, 1.73.
5. Working Conditions of Doctors and Nurses in NSW Public Hospitals. Survey for submission to the Garling
Inquiry, submitted to Australian Medical Association (NSW), Australian Salaried Medical Officers Federation
(NSW), NSW Nurses Association. 20th March 2008. Centre for Workplace Research, University Of Sydney.
6. Final Report of the Special Commission of Inquiry into Acute Care Services in NSW Public Hospitals,
Commissioner Peter Garling SC, 2008, p1076, 31.200.
7. Weber, Max. The Theory of Social and Economic Organization. Translated by A.M. Henderson and Talcott
Parsons. London: Collier Macmillan Publishers, 1947.
8. Northcote Parkinson, C. Parkinsons Law. The Economist, Nov 19th, 1955.
9. Wills, G. What Makes a Good Leader? The Atlantic Monthly, 1994.
10. Hogan, R and Kaiser, R B. What We Know About Leadership. Review of General Psychology, Vol 9(2),
Jun 2005, 169-180.
AUSTRALASIAN
ANAESTHESIA
2011