British Journal of Anaesthesia, 121 (4): 768e775 (2018)

doi: 10.1016/j.bja.2018.06.018
Advance Access Publication Date: 25 July 2018
Special Article

NEUROSCIENCE AND NEUROANAESTHESIA

Targeted temperature management in patients with

intracerebral haemorrhage, subarachnoid
haemorrhage, or acute ischaemic stroke: consensus
recommendations
P. J. D. Andrews1,*, V. Verma2, M. Healy2, A. Lavinio3, C. Curtis4, U. Reddy5,
J. Andrzejowski6, A. Foulkes7 and S. Canestrini8
1
Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK, 2Royal London Hospital,
London, UK, 3Neurosciences and Trauma Critical Care Unit, Addenbrooke’s Hospital, Cambridge,
UK, 4University College London Hospital, London, UK, 5National Hospital for Neurology and Neurosurgery,
University College London Hospitals NHS Foundation Trust, London, UK, 6Sheffield Teaching Hospitals NHS
Foundation Trust, Sheffield, UK, 7The Walton Centre for Neurology and Neurosurgery, Liverpool, UK and
8
King’s College Hospital NHS Foundation Trust, London, UK

*Corresponding author. E-mail: [email protected]

Abstract
Background: A modified Delphi approach was used to identify a consensus on practical recommendations for the use of
non-pharmacological targeted temperature management in patients with intracerebral haemorrhage, subarachnoid
haemorrhage, or acute ischaemic stroke with non-infectious fever (assumed neurogenic fever).
Methods: Nine experts in the management of neurogenic fever participated in the process, involving the completion of
online questionnaires, face-to-face discussions, and summary reviews, to consolidate a consensus on targeted tem-
perature management.
Results: The panel’s recommendations are based on a balance of existing evidence and practical considerations. With
this in mind, they highlight the importance of managing neurogenic fever using a single protocol for targeted temper-
ature management. Targeted temperature management should be initiated if the patient temperature increases above
37.5
C, once an appropriate workup for infection has been undertaken. This helps prevent prophylactic targeted tem-
perature management use and ensures infection is addressed appropriately. When neurogenic fever is detected, targeted
temperature management should be initiated rapidly if antipyretic agents fail to control the temperature within 1 h, and
should then be maintained for as long as there is potential for secondary brain damage. The recommended target
temperature for targeted temperature management is 36.5e37.5
C. The use of advanced targeted temperature man-
agement methods that enable continuous, or near continuous, temperature measurement and precise temperature
control is recommended.
Conclusions: Given the limited heterogeneous evidence currently available on targeted temperature management use in
patients with neurogenic fever and intracerebral haemorrhage, subarachnoid haemorrhage, or acute ischaemic stroke, a

Editorial decision: 2 July 2018; Accepted: 2 July 2018

© 2018 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.
For Permissions, please email: [email protected]

768
 Targeted temperature management in neurogenic fever - 769

Delphi approach was appropriate to gather an expert consensus. To aid in the development of future investigations, the
panel provides recommendations for data gathering.

Keywords: stroke; subarachnoid hemorrhage; intracerebral hemorrhage; Delphi technique

Targeted temperature management (TTM) is the process of Methods

controlling the core body temperature at a specific level. It can
A modified Delphi consensus approach was used, which
be used to achieve hypothermia (TTMhypo) or maintain normal
involved a combination of online questionnaires, a face-to-
body temperature (TTMnorm). TTM has been used in several
face meeting, and post-meeting reviews. The process con-
clinical situations, such as out-of-hospital cardiac arrest,
sisted of two rounds of a Delphi questionnaire (questions are
traumatic brain injury (TBI), and cerebral vascular accidents,
in supplementary data) plus a final validation stage, as shown
in an attempt to reduce neurological damage and enhance
in Table 1. Rounds 1 and 2 were conducted at a face-to-face
functional outcomes.1 The evidence base for TTM use in pa-
meeting held at the De Vere Grand Connaught Rooms in
tients with intracerebral haemorrhage (ICH), subarachnoid
London on July 5, 2017. P.J.D.A. acted as Chair, with an inde-
haemorrhage (SAH), or acute ischaemic stroke (AIS) is limited
pendent Delphi facilitator moderating the meeting. After the
and difficult to interpret given the range of TTM methods used,
initial meeting, the outcomes report (Round 3) and manuscript
the different target temperatures used, the heterogeneity of
validations were conducted asynchronously, with documents
the patient groups, and the presence or absence of neurogenic
shared by e-mail and feedback collected from each participant
or infectious fever. A similar amount of heterogeneity exists in
independently by the facilitator. The agreed cut-off of for the
the limited number of clinical guidelines published in France
consensus was 70% of experts in agreement; this was in
and the USA.
keeping with recent consensus initiatives in this field.12
Fever is common in critically ill patients with neurological
conditions.2,3 In those with AIS or TBI, fever can contribute to
secondary brain injury, and is associated with poorer func- Participants
tional outcomes and higher morbidity and mortality.4e6 Fever
A total of nine experts in the management of neurogenic fever
has an infectious cause in about half of all cases.2,3,7,8 It has
participated in the consensus process. The participants were
also been shown to have a strong independent association
selected on the basis of their clinical role, and their experience
with poor outcomes.7,9,10 Most evidence on fever prevention in
of managing patients with ICH, SAH, and AIS; managing fever
patients in critical care is observational in nature, so the spe-
in these patients; and using TTM. The nine participants were
cific role fever plays in causing secondary brain injury is un-
drawn from leading intensive and neurocritical care groups in
clear. The Impact of Fever Prevention in Brain Injured Patients
the UK. Five participants attended Rounds 1 and 2. Of these
study (NCT02996266) is a US study that may provide some
five participants, one felt that they had insufficient breadth of
answers to this question, as it is designed to assess the impact
relevant expertise to respond to the questions, and therefore,
of fever prevention on fever burden and short- and long-term
withdrew from voting to avoid bias. This participant did,
neurological outcomes in brain-injured patients.11
however, engage in the discussions and provided insight into
The goal of this modified Delphi consensusd‘establishing
infection-related issues. Nine participants were involved in
consensus in health outcomes (ECHO) for TTM in patients with
the final manuscript validation.
neurogenic fever’dwas to identify common expert practice
recommendations for the use of non-pharmacological TTM in
patients with ICH, SAH, or AIS who develop fever. The panel of Rounds 1 and 2 questions
experts were drawn from UK centres and reflect UK-specific
Statements and questions for each round were prepared by
practice, although their recommendations may be extrapo-
the facilitator in consultation with P.J.D.A. and delivered by
lated to other high-income countries with similar healthcare
SurveyMonkey® to each attendee’s e-mail address for them to
systems.
complete anonymously online and without collaboration

Table 1 Delphi process

Step Format Description n

Round 1 Face-to-face meeting; SurveyMonkey Questionnaire completed anonymously; 4

questionnaire 25 statements/questions
Round 2 Face-to-face meeting; SurveyMonkey Revised questionnaire completed anonymously; 4
questionnaire 14 revised/new consensus statements
Round 3 Independent, asynchronous review Consensus summary document for review 9
via e-mail and comment
Manuscript Independent, asynchronous review Final manuscript review and validation 9
validation via e-mail
 770 - Andrews et al.

whilst at the meeting. Statements and questions were meeting. For Round 3, this summary was distributed to all
informed by a literature search; the search yielded very few participants via e-mail, with meeting attendees asked to
publications relevant to the specific topics under discussion, confirm the accuracy of the discussion and non-attendees
and these were not shared with the expert panel. asked to add their opinions to the document. The additional
Round 1 comprised 25 statements and questions related to comments from non-attendees were collated and reviewed.
the clinical use of TTM for neurogenic fever in patients with Areas requiring additional discussion were identified, and the
ICH, SAH, or AIS. These had been created in consultation with process for addressing these was guided by P.J.D.A. A manu-
the meeting Chair. The majority of Round 1 questions were in script was created, structuring the recommendations, adding
a multiple-choice format, with two free-text questions additional narrative, and providing context. This manuscript
designed to elicit information and one ranking question. All was distributed to all participants for review and final
questions were mandatory, and included a comment box validation.
where participants could provide additional comments or
insights.
Pooled responses to the Round 1 questions were displayed Results
on screen to the whole group, and the results and comments The results of the final consensus agreements are presented in
were discussed. All responses were reviewed and discussed Table 2. The debate and considerations behind these agree-
regardless of the level of consensus. Where consensus (70% ments are captured in the discussion section to provide a
agreement) was achieved, the discussion focused on im- broader context, in which they can be properly reviewed.
provements in the phrasing or scope of the initial statement to A detailed debate on the definition of neurogenic fever was
arrive at a final statement that clearly captured the consensus not undertaken; however, the group established that, for the
views of all experts. Where consensus was not reached, a purposes of this Delphi consensus, neurogenic fever equated
detailed facilitated discussion was undertaken to identify the with non-infectious fever.
reasons for the lack of agreement. From these discussions, 14
revised or new statements or questions were identified, which
the participants addressed and voted on in Round 2. Discussion
This consensus discussion approach was necessary because of
the scant and heterogeneous nature of existing published ev-
Round 3 and final validation
idence. The modified Delphi approach sought to combine the
The responses from the meeting were captured in a summary advantages of a traditional Delphi process (specifically, the
document that showed how the consensus evolved at the structured information flow and anonymous submission of

Table 2 Summary of recommendations. AIS, acute ischaemic stroke; ICH, intracerebral haemorrhage; MOHS, modified Oxford
handicap scale; SAH, subarachnoid haemorrhage; TTM, targeted temperature management

Topic Level of consensus

Core-temperature measurement 100% Round 2

Core-temperature measurement is important to enable the effective identification, treatment, and
monitoring of neurogenic fever.
Core temperature should be measured continuously, or at a minimum hourly, in patients with ICH, 100% Round 1
SAH, or AIS.
Neurogenic fever and TTM 100% Round 1
As neurogenic fever is associated with poor patient outcomes amongst patients with ICH, SAH, or AIS,
treating it is important.
TTMnorm is appropriate for the treatment of neurogenic fever in adult patients with ICH, SAH, and AIS. 75% ICH; 100% SAH,
AIS Round 1
From a practical perspective, it is appropriate to have a single protocol for TTM of neurogenic fever in 100% Round 2
ICH, SAH, and AIS.
When to use TTM 100% Round 1
TTM should be used reactively in patients with ICH, SAH, or AIS in response to neurogenic fever.
TTM should be initiated if the patient’s temperature increases to 37.5
C and infection is excluded. >75% Round 3
TTM should be initiated as rapidly as possibly once fever is detected and if pharmacological treatment 100% Round 2
has not controlled the temperature within 1 h of administration.
How to use TTM 100% Round 2
The target temperature for patients with ICH, SAH, or AIS who develop neurogenic fever is
37.0
C±0.5
C.
TTM should be maintained for as long as there is potential for secondary brain damage. 100% Round 2
The use of an advanced TTM method, enabling precise temperature control, is required to maintain 100% Round 1
the temperature effectively.
Shivering 100% Round 1
Shivering should be managed during TTM.
Outcomes assessment 100% Round 2
Data on outcomes should be collected for patients with ICH, SAH, or AIS
(i) MOHS assessment is recommended at 1 month.
(ii) MOHS and modified Rankin scale assessment should be attempted at 6 months.
 Targeted temperature management in neurogenic fever - 771

opinion) with those of the nominal group technique (specif- to discern the evidence for reactive TTMnorm to manage neuro-
ically, the ability to actively discuss the responses to the genic fever from the data published on the use of prophylactic
questions, leading to further voting). The focus was on gaining TTMnorm or TTMhypo for neuroprotection in TBI and
a consensus and expert insight into the usual practice in the stroke.5,12,14,15 Overall, the panel felt that the evidence for
UK regarding TTM, which, in this case, relates to TTMnorm, TTMhypo in patients with neurogenic fever in ICH, SAH, and AIS
with the recommendations focusing on non-pharmacological was poor, and that, on balance, hypothermia could be associated
TTM approaches. with negative outcomes. The panel, therefore, recommended
TTMnorm for these patients, and hence, the focus of this paper.
There was no detailed discussion of the criteria for TTMhypo.
Core-temperature measurement
(iii) From a practical perspective, it is appropriate to have a
(i) Core-temperature measurement is important to enable
single protocol for TTM of neurogenic fever in ICH, SAH,
effective identification, treatment, and monitoring of
and AIS.
neurogenic fever.
(ii) Core temperature should be measured continuously, or at Although the panel acknowledged the existence of some
a minimum hourly, in patients with ICH, SAH, or AIS. differences between the three conditions, they felt that there
was enough similarity to allow recommendations to be
There was no clear agreement amongst the participants on
grouped in a single protocol, especially as it was felt imprac-
the best site at which to measure core temperature. The lack of
tical to have more than one. The panel did not consider loca-
a final consensus related to the practical challenges that can
tion of care (ICU or ward) for these patients important,
exist locally, if the patient was awake or comatose, or how the
appreciating that such decisions would be dictated by local
core-temperature measurements were interpreted at specific
practice, service availability, and patient needs.
sites, especially if these sites are not standard practice.
Guidelines from a French expert panel, whilst recom-
mending a core-temperature measurement for TTM in ICUs,
When to use targeted temperature management
failed to indicate specific sites.12 Oesophageal or bladder
probes are recommended for temperature measurement (i) TTM should be used reactively in patients with ICH, SAH, or
during TTM after a neurological injury by recent guidelines AIS in response to neurogenic fever.
from the US Neurocritical Care Society (NCS), which also
The panel felt that TTM should only be used once a patient
suggest a preference for continuous monitoring.5
develops fever, as there is limited evidence to support the use
The Delphi participants’ recommendations for sites of
of prophylactic TTM after ICH, SAH, or AIS regardless of core
temperature measurement were split between two non-gold
temperature. Prophylactic TTM also carries additional risks,
standard sites: the oesophagus and the rectum. The panel
such as masking fever associated with infection, and should
felt that whatever site is selected, it should enable continuous,
therefore be avoided.
or near continuous, monitoring. However, specific clinical
situations may make continuous monitoring impractical and, (ii) TTM should be initiated if the patient temperature in-
in such cases, a minimum of hourly measurements is advised. creases to 37.5
C and infection is excluded.

The temperature threshold for TTM was discussed in detail

Neurogenic fever and targeted temperature at the meeting and in subsequent review rounds. The
management threshold debate centred on balancing the need to act as soon
as temperature increase is detected, against mitigating the
(i) As neurogenic fever is associated with poor patient out-
risk of prophylactic TTM use.
comes amongst patients with ICH, SAH, or AIS, treating it is
In healthy individuals, core temperature is not constant but
important.
fluctuates by up to 0.5
C around the ‘normal’ 37
C average
(ii) TTMnorm is appropriate for the management of neurogenic
temperature.16 Although the term fever is commonly under-
fever in adult patients with ICH, SAH, or AIS.
stood, no universally accepted definition exists, and it is often
Fever is commonly reported in ICH, SAH, and AIS, although used interchangeably with the terms pyrexia or hyperthermia.2,17
incidence rates vary between studies and the cause of fever is Similarly, there is no accepted temperature threshold that de-
often not clearly defined. In a large retrospective US study of fines the occurrence of fever, with between 5 and 14 different
fever in patients with brain injuries, 51% were classified as thresholds reported in various studies identified by a literature
having fever, with fever incidences of 60% for TBI, 54% for review.2 A threshold of 38.3
C is often cited. This equates to
aneurysmal SAH, 50% for ICH, and 37% for AIS.3 101
F and is based on US recommendations on fever control.17
All panel members accepted that poor outcomes are associ- The majority of the panel felt that >37.5
C was appropriate
ated with neurogenic fever in these patients, given the weight of and in line with the range agreed for normothermia (see later),
published evidence, for example, by Scaravilli and colleagues6 although a minority preferred 38
C. The panel also recog-
and Kramer and colleagues9 on SAH, Leira and colleagues10 on nised the urgency of expediting the identification and treat-
ICH, and Rincon and colleagues3 and Greer and colleagues4 on all ment of potentially life-threatening infection as an important
strokes and TBI. Fever can increase the brain’s metabolic de- step before the use of TTM. Fever should be treated early,
mand, exacerbating ischaemic injury and leading to cerebral regardless of its cause.
vessel vasodilation, ultimately worsening the intracranial
(iii) TTM should be initiated as rapidly as possible once fever is
pressure (ICP)13; therefore, it should be avoided or treated.
detected if pharmacological treatment has not controlled
A major question regarding the use of TTM in febrile patients
temperature within 1 h of administration.
with brain injury is the type of TTM that should be used: TTMhypo
(maintenance of temperature below 37
C) or TTMnorm (mainte- The panel thought that the evidence for the effectiveness of
nance of temperature at 37
C). From the literature, it is difficult antipyretic agents, such as paracetamol, in controlling fever in
 772 - Andrews et al.

patients with ICH, SAH, or AIS was limited. However, they with TBI. Their conditional recommendation, based on low-
accepted that, as these agents are widely used as the first quality evidence, was to suggest longer duration of TTM for
option for fever control, it was appropriate to try them, but act severe TBI patients should ICP control be the goal.5
swiftly if they yield no benefit within 1 h. The panel advised a
(iii) The use of an advanced TTM method enabling precise
more aggressive treatment of temperature if the fever was
temperature control is required to maintain temperature
associated with seizures.
effectively.
Paracetamol is widely used in ICU patients to treat both
fever and pain. A 4 g day1 dose is often administered as The panel felt that accurate and consistent temperature
standard, but reports suggest this is frequently ineffective for control required advanced TTM methods, although there was
fever control in patients with brain injury.1 Other studies using no detailed debate on what specific advanced methods were
a higher dose (6 g day1) have shown small but important re- preferred.
ductions in temperature.1,18,19 Many of these studies admin- The two main non-pharmacological advanced TTM
istered paracetamol to all patients, not only those with fever, methods currently in use are surface cooling and endovascular
so it is difficult to draw firm conclusions on its use in fever. cooling. Surface-cooling methods include air-circulating
There is little evidence on functional outcomes in the use of blankets, water-circulating blankets, and hydrogel-coated
paracetamol in patients with acute stroke.20e22 However, one water-circulating pads, whilst endovascular cooling uses i.v.
study suggested that stroke patients with fever on admission heat exchange catheters. Endovascular cooling can be asso-
experience functional outcome benefits from paracetamol ciated with additional risks similar to those found with inva-
use.23 sive central vascular access.1 The recent NCS guidelines made
The alternative antipyretic agent, ibuprofen, shows no a strong recommendation for the use of intravascular cathe-
greater efficacy than paracetamol, and can be associated with ters or gel pads if such catheters are not available to maintain
an increased bleeding risk.18,24 When NSAIDs are used, one constant temperature.5
small randomised study on neurosurgical ICU patients sug- The panel also considered inadvertent overcooling, when the
gested that temperature control is significantly better with a core temperature decreases below the normothermic range of
low-dose continuous infusion of diclofenac than with inter- 37.0
C±0.5
C. This can occur when less advanced TTM methods
mittent bolus doses of NSAIDs.25 are used. In such a situation, rewarming to normothermia
The panel debated the relative benefit of high-dose para- should be slow and controlled at a rate of 0.25
C per hour.
cetamol compared with the risk of possible side-effects. The
panel also discussed the possibility of augmented fever control
Shivering
by combing paracetamol with external cooling via fans. No
specific recommendations emerged from these discussions. (i) Shivering should be managed during TTM.

All panellists recommended that shivering should be

How to use TTM managed, as it can cause cerebral and metabolic stress, and
negate the beneficial effects of TTM. However, there was no
(i) The target temperature for patients with ICH, SAH, or AIS
clear agreement on the method(s) that should be used to
who develop neurogenic fever is 37.0
C±0.5
C.
manage shivering. The approaches to shivering control sug-
The specific definition of normothermia recommended by gested by the panel included pharmacological and non-
the panel is 37.0
C±0.5
C, with a target temperature plus range pharmacological methods, either alone or in combination:
believed to offer clear parameters within which to control sedation, counter-warming (not all members of the panel were
temperature. Strict control of core temperature to avoid fluc- aware of counter-warming, so felt unable to comment on its
tuations may be beneficial. Evidence from a post hoc analysis of value), neuromuscular block, and a combination of the above.
the Eurotherm3235 Trial on TTM to 32e35
C in patients with Shivering is a physiological heat-generating mechanism
TBI showed that temperature fluctuations during the first 48 h that occurs to maintain core temperature at the set-point
cooling period was associated with worse neurological out- temperature of the hypothalamus.24 As about 20% of the
comes only in the control group. Patients in the control group thermoregulatory drive for shivering comes from the skin,
were managed to normothermia and had more episodes of counter-warming of the skin on the head, hands, arms, or face
temperature in excess of 38
C than those in the hypothermia (use of gloves, hats, socks, and blankets) can reduce shivering
group.26 without pharmacological intervention, whilst allowing the
core temperature to be controlled.27
(ii) TTM should be maintained for as long as there is potential
Paracetamol, magnesium, sedatives (such as dexmedeto-
for secondary brain damage.
midine or buspirone), opioids (such as pethidine, tramadol,
The panel debated various durations of TTM in an attempt and naloxone), neuromuscular blocking agents, and alpha-2
to provide specific guidance, but no consensus was achieved. adrenergic agonists (such as clonidine and dexmedetomi-
The suggested durations included 48 h, 72 h, 3e5 days, or dine) have all been used to treat shivering pharmacologi-
based on need. Overall, the group felt that it was difficult to cally.5,27 Decisions may be guided by the level of
provide categorical recommendations, especially as clinical consciousness of the patient (e.g. paracetamol and clonidine
situations, such as whether the patient is awake or comatose, may be more appropriate in patients who are awake) or the
could impact the decision. The panel also recognised that risks of pharmacological interventions (e.g. clonidine can
clinicians must be vigilant for the possibility of infection cause bradycardia and hypotension).
occurring during the period of TTM. Shivering is well recognised as a problem with TTM. Like
The NCS TTM guidelines also addressed the question of the Delphi panel, the NCS also suggested the prompt treat-
TTM duration by comparing the benefits of a pre-specified ment of shivering during TTM in brain-injury patients, but
duration of TTM with a goal-based approach for patients specifically suggested a stepwise approach, starting with non-
 Targeted temperature management in neurogenic fever - 773

Table 3 Summary of recommendations and guidelines on the use of TTM. Shading shows recommendations in line with this paper.
AHA, American Heart Association; AIS, acute ischaemic stroke; ASA, American Stroke Association; aSAH, aneurysmal subarachnoid
haemorrhage; DCI, delayed cerebral ischaemia; ESO, European Stroke Organisation; GCP, good clinical practice; ICH, intracerebral
haemorrhage; ICP, intracranial pressure; NCS, Neurocritical Care Society; RCT, randomised controlled trial; SAH, subarachnoid hae-
morrhage; SFAR, Socie  te
 Française d’Anesthe
sie Re
animation (French Society of Anaesthesia and Intensive Care Medicine); SRLF,
 te
Socie  de Re
animation de Langue Française (French Intensive Care Society); TTM, targeted temperature management

Paper and Condition or situation

guideline
Intracerebral Subarachnoid haemorrhage Acute ischaemic stroke Patients in
haemorrhage neurocritical care

Cariou and Consider hypothermia Consider TTM (to an unspecified Consider prophylactic
colleagues12 (35e37
C) in temperature) in comatose normothermia during
(2017); comatose patients patients with aneurysmal SAH the early phase of severe
SRLF/SFAR with spontaneous to lower the ICP or to improve ischaemic stroke.
ICH. the neurological outcome.
Madden and Recommend using
collleagues5 controlled
(2017); NCS normothermia to
reduce fever
burden in patients
with fever
refractory to
conventional
therapy.
Steiner and Increased temperature should be
collleagues32 treated medically and
(2013); ESO physically (GCP).
Steiner and There is insufficient
collleagues33 evidence from RCTs
(2014); ESO to make strong
recommendations on
whether, when, and
for whom preventive
or early fever
treatment should be
given after acute ICH.
Ntaios and In patients with AIS and
colleagues22 hyperthermia, we
(2015); ESO cannot make any
recommendation for
treating hyperthermia to
improve the functional
outcome or survival.
Connolly and Aggressive control of fever to
collleagues28 normothermia using standard
(2012); AHA/ASA or advanced temperature-
modulating systems is
reasonable in the acute phase of
aSAH.
Diringer and During the period of risk for DCI,
Bleck29 (2011); control of fever is desirable; the
NCS intensity should reflect the
individual patient’s relative risk
of ischaemia; surface cooling or
intravascular devices are more
effective, and should be used
when antipyretics fail in cases
where fever control is highly
desirable.
Hemphill and Treatment of fever
collleagues30 after ICH may be
(2015); AHA/ASA reasonable.
Jauch and Sources of hyperthermia
collleagues31 (temperature >38
C)
(2013) AHA/ASA should be identified and
treated, and antipyretic
medications should be
administered to lower
the temperature in
hyperthermic patients
with stroke.
 774 - Andrews et al.

sedating interventions, such as counter-warming, before the and practice, and the panel was keen to ensure that the rec-
use of sedatives or neuromuscular block.5 The NCS also rec- ommendations could be used in any care setting, yet not be so
ommends the use of a scale, such as the bedside shivering complex or prescriptive as to deter adoption.
assessment scale, to help characterise shivering and support The Delphi process has some drawbacks. Although the
decision-making.5 online questionnaire was completed anonymously and inde-
pendently, the subsequent group discussion could allow social
Outcomes assessment bias in responses. Several panellists could not attend the
meeting, so their input was gathered on the meeting summary
(i) Data on outcomes should be collected for patients with ICH, document. This approach may have led to an unequal
SAH, or AIS: weighting of opinions, with greater weight given to those who
(a) The modified Oxford handicap scale (MOHS) assess- attended in person.
ment is recommended at 1 month. Given the heterogeneity of published evidence and clinical
(b) The MOHS and modified Rankin scale assessment guidelines on the use of targeted temperature management to
should be attempted at 6 months. treat fever in patients with intracerebral haemorrhage, sub-
arachnoid haemorrhage, or acute ischaemic stroke, all at-
Given the lack of consistent evidence on TTM use in pa-
tendees felt that the agreed recommendations would provide
tients with ICH, SAH, or AIS, the collection of outcome data at
clinical guidance for the development of local protocols for the
specific time points could support better audit and guide
benefit of clinicians and patients. The next challenge will be to
further recommendations on TTM use. These recommenda-
assess their use and the impact on patient outcomes.
tions should, however, balance the value of the data against
the practicality of data collection.
Authors’ contributions
Conclusions Meeting participation: P.J.D.A., V.V., M.H., A.L., C.C.
This consensus project was based on the shared desire to Delphi participation: P.J.D.A., V.V., M.H., A.L.
develop a series of practical recommendations based on Review of meeting report: all authors.
expert opinion to support clinicians less experienced in using Review of manuscript: all authors.
TTM to manage neurogenic fever in ICH, SAH, and AIS pa-
tients. The modified Delphi approach utilised was designed to Acknowledgements
overcome some of the gaps in published evidence on TTM in
these specific situations and to allow the recommendations to The authors would like to acknowledge the support of K.
be practically focused. McKillen in facilitating the Delphi meeting and Hayward
Other expert panels have considered similar, although not Medical Communications in preparing the manuscript.
identical, questions using population, intervention, compari-
son, outcomes and grades of recommendation, assessment, Declaration of interest
development, and evaluation methodologies, and have come
up with differing opinions. A range of guidelines for the P.J.D.A. receives consultancy and speaker fees from C. R. Bard,
management of patients with ICH, SAH, or AIS, or the use of Inc. and Bard Medical Division, and speaker fees and Centre of
TTM in neurological patients, exists, but these provide no, or Excellence payment from Integra Neurosciences. The views
conflicting, recommendations for TTM because of limitations and opinions reported are those of the authors and not
of currently available data. Table 3 summarises the key necessarily those of C. R. Bard, Inc. and Bard Medical Division.
statements on control of fever or use of TTM from these
guidelines.5,12,22,28e33 The 2017 NCS guidelines on the use of
Funding
TTM in patients in neurocritical care, for example, recom-
mend using controlled normothermia to reduce fever in those C. R. Bard, Inc. and Bard Medical Division. Bard is now a
whose fever is refractory to conventional therapy,5 whilst the wholly-owned subsidary of BD (Becton, Dickinson and
French 2017 guidelines on TTM recommend prophylactic Company).
normothermia during the early phase of severe ischaemic
stroke, hypothermia (35e37
C) in comatose patients with
Appendix A. Supplementary data
spontaneous ICH to lower ICP, and TTM (to an unspecified
temperature) in comatose patients with aneurysmal SAH to Supplementary data related to this article can be found at
lower ICP or improve the neurological outcome.12 This un- https://doi.org/10.1016/j.bja.2018.06.018.
derscores the challenge of interpreting and extrapolating data
to specific clinical situations. Looking more widely at general
References
guidelines on the management of ICH, SAH, and AIS, a simi-
larly mixed picture emerges (Table 3). On balance, reactive 1. Doyle JF, Schortgen F. Should we treat pyrexia? And how
TTMnorm appears a rational and consistent recommendation do we do it? Crit Care 2016; 20: 303
for the management of neurogenic fever in patients with ICH, 2. Niven DJ, Laupland KB. Pyrexia: aetiology in the ICU. Crit
SAH, or AIS given the range of views. Care 2016; 20: 247
The consensus statements presented here focus on rec- 3. Rincon F, Hunter K, Schorr C, Dellinger RP, Zanotti-
ommendations for a specific group of patients. They do not Cavazzoni S. The epidemiology of spontaneous fever and
contain detailed recommendations on the level of care or the hypothermia on admission of brain injury patients to
situation for comatose vs non-comatose patients. Many of intensive care units: a multicenter cohort study.
these statements may be influenced by local service structure J Neurosurg 2014; 121: 950e60
 Targeted temperature management in neurogenic fever - 775

4. Greer DM, Funk SE, Reaven NL, Ouzounelli M, Uman GC. 20. de Ridder IR, den Hertog HM, van Gemert HMA, et al. PAIS
Neurologic injury: a comprehensive meta-analysis. Stroke 2 (Paracetamol Acetaminophen in Stroke 2): results of a
2008; 39: 3029e36 randomized, double-blind placebo-controlled clinical
5. Madden LK, Hill M, May TL, et al. The implementation of trial. Stroke 2017; 48: 977e82
targeted temperature management: an evidence-based 21. Fang J, Chen C, Cheng H, Wang R, Ma L. Effect of
guideline from the Neurocritical Care Society. Neurocrit paracetamol (acetaminophen) on body temperature in
Care 2017; 27: 468e87 acute stroke: a meta-analysis. Am J Emerg Med 2017; 35:
6. Scaravilli V, Tinchero G, Citerio G. Fever management in 1530e5
SAH. Neurocrit Care 2011; 15: 287e94 22. Ntaios G, Dziedzic T, Michel P, et al. European Stroke
7. Douds GL, Tadzong B, Agarwal AD, Krishnamurthy S, Organisation (ESO) guidelines for the management of
Lehman EB, Cockroft KM. Influence of fever and hospital- temperature in patients with acute ischemic stroke. Int J
acquired infection on the incidence of delayed neurolog- Stroke 2015; 10: 941e9
ical deficit and poor outcome after aneurysmal sub- 23. den Hertog HM, van der Worp HB, van Gemert HM, et al.
arachnoid hemorrhage. Neurol Res Int 2012; 2012, 479865. The Paracetamol (Acetaminophen) in Stroke (PAIS) trial: a
https://doi.org/10.1155/2012/479865 multicentre, randomised, placebo-controlled, phase III
8. Meier K, Lee K. Neurogenic fever. J Intensive Care Med 2017; trial. Lancet Neurol 2009; 8: 434e40
32: 124e9 24. Thompson HJ. Evidence-base for fever interventions
9. Kramer CL, Pegoli M, Mandrekar J, Lanzino G, following stroke. Stroke 2015; 46: e98e100
Rabinstein AA. Refining the association of fever with 25. Cormio M, Citerio G. Continuous low dose diclofenac so-
functional outcome in aneurysmal subarachnoid hemor- dium infusion to control fever in neurosurgical critical
rhage. Neurocrit Care 2017; 26: 41e7 care. Neurocrit Care 2007; 6: 82e9
10. Leira R, Davalos A, Silva Y, et al. Early neurologic deteri- 26. Abu-Arafeh A, Rodriguez A, Paterson RL, Andrews PJ.
oration in intracerebral hemorrhage: predictors and Temperature variability in a modern targeted tempera-
associated factors. Neurology 2004; 63: 461e7 ture management trial. Crit Care Med 2018 Feb; 46(2):
11. ClinicalTrials.gov. Impact of Fever Prevention in Brain 223e8. https://doi.org/10.1097/CCM.0000000000002832
Injured Patients (INTREPID): NCT02996266. Available from: [Epub ahead of print]
https://clinicaltrials.gov/ct2/show/record/NCT02996266? 27. van der Worp HB, Macleod MR, Bath PM, et al. EuroHYP-1:
view¼record [accessed 30 April 2018]. European multicenter, randomized, phase III clinical trial
12. Cariou A, Payen J-F, Asehnoune K, et al. Targeted tem- of therapeutic hypothermia plus best medical treatment
perature management in the ICU: guidelines from a vs. best medical treatment alone for acute ischemic
French expert panel. Ann Intensive Care 2017; 7: 70 stroke. Int J Stroke 2014; 9: 642e5
13. Zoerle T, Carbonara M, Zanier ER, et al. Rethinking neu- 28. Connolly ES, Rabinstein AA, Carhuapoma JR, et al.
roprotection in severe traumatic brain injury: toward Guidelines for the management of aneurysmal sub-
bedside neuroprotection. Front Neurol 2017; 8: 354 arachnoid hemorrhage. Stroke 2012; 43: 1711e37
14. Lewis SR, Evans DJ, Butler AR, Schofield-Robinson OJ, 29. Diringer MN, Bleck TP. Critical care management of pa-
Alderson P. Hypothermia for traumatic brain injury. tients following aneurysmal subarachnoid hemorrhage:
Cochrane Database Syst Rev 2017; 9: CD001048 recommendations from the Neurocritical Care Society’s
15. Madden LK, DeVon HA. A systematic review of the effects multidisciplinary consensus conference. Neurocrit Care
of body temperature on outcome after adult traumatic 2011; 15: 211e40
brain injury. J Neurosci Nurs 2015; 47: 190e203 30. Hemphill JC, Greenberg SM, Anderson CS, et al. Guidelines
16. Kelly G. Body temperature variability (part 1): a review of for the management of spontaneous intracerebral hem-
the history of body temperature and its variability due to orrhage. Stroke 2015; 46: 2032e60
site selection, biological rhythms, fitness, and aging. 31. Jauch EC, Saver JL, Adams HP, et al. Guidelines for the
Altern Med Rev 2006; 11: 278e93 early management of patients with acute ischemic stroke:
17. Walter EJ, Hanna-Jumma S, Carraretto M, Forni L. The a guideline for healthcare professionals from the Amer-
pathophysiological basis and consequences of fever. Crit ican Heart Association/American Stroke Association.
Care 2016; 20: 200 Stroke 2013; 44: 870e947
18. Dippel DWJ, van Breda EJ, van der Worp HB, et al. Effect of 32. Steiner T, Juvela S, Unterberg A, Jung C, Forsting M,
paracetamol (acetaminophen) and ibuprofen on body Rinkel G. European Stroke Organization guidelines for the
temperature in acute ischemic stroke PISA, a phase II management of intracranial aneurysms and subarach-
double-blind, randomized, placebo-controlled trial noid haemorrhage. Cerebrovasc Dis 2013; 35: 93e112
ISRCTN98608690. BMC Cardiovasc Disord 2003; 3: 2 33. Steiner T, Al-Shahi Salman R, Beer R, et al. European
19. Saxena MK, Taylor C, Billot L, et al. The effect of para- Stroke Organisation (ESO) guidelines for the management
cetamol on core body temperature in acute traumatic of spontaneous intracerebral hemorrhage. Int J Stroke
brain injury: a randomised, controlled clinical trial. PloS 2014; 9: 840e55
One 2015; 10. e0144740

Handling editor: H.C. Hemmings Jr