4rd Congress of the European Academy of Neurology

Lisbon, Portugal, June 16 - 19, 2018

Teaching Course 13

New concepts in critical care of stroke patients - Level 3

Subarachnoid hemorrhage (SAH): how do we

treat delayed ischemic neruological deficit
(DIND)
Erich Schmutzhard
Innsbruck, Austria

Email: [email protected]
Conflict of interest: The author received research grants and speaker's
honoraria from Actelion and Edge.

Introduction

SAH (bleeding into the subarachnoid space) is a neurologic emergency,

with an overall mortality of up to 50% and 25% dying within the first 24

hours, often pre-admission. It often presents with maximal at onset and

worst of life headache. Patients may demonstrate neck stiffness, nausea/

vomiting, and impaired level of consciousness. Approximately 80% of

nontraumatic SAH are due to aneurysmal rupture. Non-contrast head CT

(at the best within 6 hours) is highly reliable for diagnosis. Management of

SAH includes initial resuscitation with intubation if needed, continuous

cardiopulmonary and neurologic monitoring, earliest possible analgesia

and, if applicable, sedation, blood pressure management, coagulopathy

correction, and seizure treatment. Complications are common, including

seizure including status epilepticus, hydrocephalus, vasospasm,

cardiopulmonary, endocrine and metabolic derangements, aspiration- and

ventilator-associated pneumonia and other nosocomial infections, and,

nowadays rarely, rebleeding, the latter only, if securing the aneurysm is

delayed.

Admission to a neurocritical care unit is recommended and improves

outcome.

Epidemiology

Headache accounts for approximately 2% of emergency department (ED)

visits, with SAH occurring in 1% to 3% of these patients. The incidence of

aneurysmatic SAH is approximately 7 to 10 per 100,000 per year.

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Pathophysiology and Etiology of (SAH and) Vasospasm/DIND/DCI

Risk factors for aneurysm rupture, i.e. aSAH, include a family history of

SAH or aneurysm (2 first degree relatives), smoking, hypertension, and

alcohol abuse.

The so-called vasospasm of intracranial vessels is a delayed and frequently

reversible vasculopathy or SAH complication that occurs within the first 2

weeks, most commonly not before day 3 and rarely after day14 after the

initial hemorrhage. The pathogenesis is still far from being fully

understood. The upregulation of “spasmogenic” substances released

during RBC lysis, like endothelin or endoglin is one of the pathophysiologic

mechanisms for vasospasm and delayed ischemic complications (DIC) or

delayed ischemic neurologic deficits (DIND), respectively. Recently, the

scientific discussion on the pathophysiology of “vasospasm/DIND/DIC” has

concentrated on the role of the vascular endothelium, e.g. cellular

microparticles (derived from endothelial cells), angiopoietin 1 and

inflammatory responses by endothelial cells etc., all of them contributing

to an imbalance of endogenous vasodilating and vasoconstricting

molecular mechanisms. The impaired capacity of autoregulation may add

to reduction in cerebral blood flow (CBF) as does (unintentional)

hypovolemia which may aggravate decrease in regional CPP. Very

recently, the role of a locally activated coagulation cascade leading to

intra-arterial micro-thrombus formation and arterio-arterial embolisation

has been accepted as a major cause of DIND and DCI.

Initial Treatment / Management of SAH

SAH patients must be provided best cardiopulmonary and neurologic

monitoring, adequate analgesia, antiemetics, and sedation, whenever

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deemed necessary. Continuing cardiac monitoring is vital to evaluate for

dysrhythmia, e.g. stress-associated (cave: catecholamine surge!) atrial or

even, ventricular fibrillation, Takotsubo cardiomyopathy, or neurogenic

lung-edema. Head of bed elevation to 30 can decrease elevated ICP.

Continuous and regular reevaluation of neurologic status, incl pupillary

size and reactivity and motor function is warranted. IV fluid

administration targets euvolemia, normal glucose and electrolytes.

Blood pressure control may be required, though the optimal target is not

yet clear. Permissive hypotension (systolic blood pressure (SBP)

<100mmHg) may decrease the initial rebleeding rate but increases

cerebral infarction rate. The American Stroke Association’s 2012

guidelines as well as the DGN guidelines recommend maintaining the

initial SBP at less than 160 mm Hg. Cerebral perfusion pressure (CPP =

MAP-ICP) should be maintained at > 60 mm Hg. Arterial catheter

placement is to be done as soon as continuous blood pressure monitoring

is considered necessary (e.g. during IV administration of vasoactive

medications).

Antifibrinolytic agents, such as tranexamic acid and aminocaproic acid,

may have potential in preventing rebleeding, they should not be

administered indiscriminately as they enhance the risk of vasospasm

associated cerebral infarction. The American Stroke Association

recommends use of these agents for less than 72 hours only if definitive

aneurysm treatment (i.e. securing the aneurysm) is delayed and there are

no contraindications. Again, these agents may reduce rebleeding, though

no benefit in mortality or neurologic outcome has been demonstrated.

Therefore, the now widely employed option to secure the aneurysm as

early as possible (at the best within <24 hours after the bleeding) has

rendered these agents largely obsolet.

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The two primary approaches for aneurysm repair include microvascular

neurosurgical clipping or endovascular coiling, they must be employed in

all (most) SAH patients at the earliest possible point of time (ideally < 6,

max 24 hours). Endovascular coiling has demonstrated better outcomes

when compared with clipping, though not all patients and/or aneurysms

are suitable for coiling. The approach is determined by the aneurysm

anatomy, clinician experience, timely availability, age and comorbidities.

Signs and Symptoms of Vasospasm/DIND/DCI and other

complications of SAH

The incidence of vasospasm/DIND/DCI is related to the amount of blood in

the CSF. Vasospasm may be present without any signs and symptoms (in

30% to 70%) but may lead to severe focal neurologic deficits, as

hemiplegia or impaired level of consciousness. Whenever vasospasm leads

to signs and symptoms, it is associated with significant morbidity.

Hydrocephalus may occur in up to 30% of patients within the first 3 days,

most commonly in those with severe bleeds, and may be asymptomatic. It

should be considered if the SAH patient develops (sudden) neurologic

worsening, including impairment of consciousness. Placement of an

external ventricular drain, allowing for CSF drainage and precise

monitoring of ICP is mandatory.

Increased Intracranial Pressure (ICP) in SAH is usually due to

hydrocephalus, diffuse brain edema and hyperemia after hemorrhage. For

intubated patients with concern of elevated ICP, deepening of

analgosedation might reduce ICP, however careful attention is required to

maintain CPP. Hyperventilation should be used with utmost caution, since

this reduces definitely cerebral perfusion. Decompressive craniectomy

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may be needed for ICP control with cerebral edema, if other measures,

including targeted temperature management or moderate therapeutic

hypothermia, are not effective.

Evaluation of Vasospasm/DIND/DCI

In awake patients the diagnosis of a vasospasm/DIND/DCI is clinical: the

patient complains of increasing headache and shows “neuro-worsening”,

i.e. develops new focal neurological deficits and/or qualitative or

quantitative impairment of consciousness.

Since in the majority of poor grade SAH patients, who are admitted to a

Neurocritical Care Unit and – after securing the aneurysm – are deeply

analgosedated, the neurological examination is virtually impossible,

technical monitoring means and methods are indispensable.

The formerly recommended daily or twice daily transcranial Doppler

sonography did not fulfill its promises in recognizing early and potentially

cerebral-ischemia-relevant “vasospasm”. However, we still recommend its

daily use, if the examiner is always the same neuro-intensivist and well

familiar with this technique, the critical values being an increase in the

mean flow velocity by > 50% and/or an MCA/ICA (Lindegaard)-Index > 3 .

The golden standard technique in diagnosing the „vasospasm“ is the

digital subtraction angiography; however less invasive techniques, as CT-

or MR- angiography, including perfusion techniques, may be preferable.

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In comatose, deeply analgosedated poor grade SAH patients the following

invasive neuro-monitoring techniques are employed in high volume

neurocritical care centers:

- brain oxygen monitoring,

- cerebral microdialysis for brain metabolic monitoring (brain tissue

lactate, pyruvate, glucose, glycerol),

- cerebral blood flow,

- brain tissue temperature monitoring,

- continuous EEG for detection of suclinical seizures or status

epilepticus,

- continuous invasive electrocorticography (COSBID) to detect the

occurence of (clusters of) cortical spreading depolarisations which are

assumed toherald very early the increased danger and risk of brain

tissue ischemia

Management and Prevention of Vasospasm/DIND/DCI

Nimodipine is an oral calcium channel blocker that may reduce vasospasm

and reduces the risk of secondary cerebral ischemia. Multiple studies

support its use; a Cochrane review demonstrated a risk ratio of 0.67 (95%

CI 0.55–0.81) for reducing secondary ischemia, with a trend toward

reducing mortality. The dose is 60 mg orally every 4 hours. Patients

unable to take medications by mouth can be given nimodipine through a

nasogastric tube. Nimodipine is available in its intravenous formulation,

i.e. thereby allowing for most precise dosing and modulating its major

side effect, arterial hypotension. It needs to be stressed that IV

nimodipine requires invasive blood pressure monitoring, CPP monitoring

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and, thus, ICU management. Magnesium sulfate IV has not demonstrated

efficacy in preventing vasospasm neither did statins, NMDA receptor

antagonists, free radical scavengers, chelating agents and endothelin A

receptor antagonists. Locally (intraventricularly) applied "prolonged-

release" Nimodipine is currently subject of a phase 3 trial.

If symptoms of vasospasm occur, often with focal deficit or change in the

level of qualitative and/or quantitative consciousness (3 to 14 days after

the initial hemorrhage) or indicated by the above detailed invasive

monitoring techniques, aggressive therapy is warranted. Immediate CTA is

needed for definitive diagnosis, in particular for objectivizing the

presence of vessel luminal narrowing and cerebral hypodensities and – in

addition - differentiation from rebleeding or hydrocephalus. Formerly

hemodynamic augmentation was recommended, aiming at MAP and

cerebral perfusion, i.e. CPP. However, it has been shown that in the

absence of the vital invasive cardiopulmonary and neuro-monitoring this

hemodynamic augmentation worsens outcome.

Transluminal balloon angioplasty has been proposed to be the mainstay of

treatment, however it is applicable only in large-diameter blood vessels

with an unaccepably high rate of arterio-arterial embolism leading to

exact what it was meant to prevent, namely cerebral ischemia. Therefore,

this purely mechanical transluminal balloon angioplasty has been largely

abandoned.

Intraarterial pharmacological vasodilator therapy can be used both for

localized and diffuse vasospasm, papaverine, nimodipine, verapamil,

milrinone and fasudil have been administered. One of the shortcomings of

these intraarterial vasodilator therapy is its limited, i.e. transient time of

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efficacy, case reports suggest a prolonged intraarterial application of,

e.g., nimodipine achieving sustained effect.

If invasive cardiopulmonary and neuromonitoring is available a cautious

trial to improve / augment the cerebral hemodynamics is warranted and

may even include invasive therapeutic hypothermia or targeted

temperature management

Prognosis of SAH

Mortality/Morbidity:

Close to 15% of patients will die before they reach the hospital, with 25%

dying within 24 hours and 45% of patients dying within 30 days. Morbidity

is also severe, with only one-third of patients demonstrating full recovery

after treatment. Prognosis is predicted by level of consciousness and

neurologic examination on initial evaluation, amount of hemorrhage on

initial imaging (increased hemorrhage associated with worse outcome),

patient’s age (younger patients experience better outcome), timely

aneurysm repair, quality/experience of the intervening neuro-radiologist

or neurosurgeon, admission to a high volume center and post-

interventional care in a specialized neurocritical care unit.

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 Further Reading and References:

• Blok KM, Rinkel GJ, Majoie CB, et al. CT within 6 hours of headache onset
to rule out subarachnoid hemorrhage in nonacademic hospitals. Neurology
2015;84: 1927–32.
• Diringer MN, Bleck TP, Claude Hemphill J 3rd, et al. Critical care
management of patients following aneurysmal subarachnoid hemorrhage:
recommendations from the Neurocritical Care Society’s Multidisciplinary
Consensus Conference. Neurocrit Care 2011;15(2):211–40.
• Dorhout Mees SM, Rinkel GJ, Feigin VL, et al. Calcium antagonists for
aneurysmal subarachnoid haemorrhage. Cochrane Database Syst Rev
2007;(3):CD000277. 124. Pickard JD, Murray GD, Illingworth R, et al.
Effect of oral nimodipine on cerebral infarction and outcome after
subarachnoid haemorrhage: British aneurysm nimodipine trial. BMJ
1989;298(6674):636–42.
• Dubosh NM, Bellolio MF, Rabinstein AA, et al. Sensitivity of early brain
computed tomography to exclude aneurysmal subarachnoid hemorrhage: a
systematic review and meta-analysis. Stroke 2016 Mar;47(3):750–5.
• Guo J, Shi Z, Yang K, et al. Endothelin receptor antagonists for
subarachnoid hemorrhage. Cochrane Database Syst Rev
2012;(9):CD008354.

• Helbok R, Beer R. Cerebrospinal fluid and brain extracellular fluid in

severe brain trauma. Handb Clin Neurol. 2017; 146: 237-258.
• Helbok R, Kofler M, Schiefecker AJ, Gaasch M, Rass V, Pfausler B,
Beer R, Schmutzhard E.Clinical Use of Cerebral Microdialysis in
Patients with Aneurysmal Subarachnoid Hemorrhage-State of the
Art. Front Neurol. 2017 Nov 3; 8: 565. doi: 10.3389/fneur.2017.00565.
eCollection 2017. Review.
• Hemphill JC, Greenberg SM, Anderson CS, et al. Guidelines for the
management of spontaneous intracerebral hemorrhage: a guideline for
healthcare professionals from the American Heart Association/American
Stroke Association. Stroke 2015;46(7):2032–60.Kramer AH, Fletcher JJ.
Locally-administered intrathecal thrombolytics following aneurysmal
subarachnoid hemorrhage: a systematic review and meta-analysis.
Neurocrit Care 2011;14:489. 1
• Larsen CC, Astrup J. Rebleeding after aneurysmal sub- arachnoid
hemorrhage: a literature review. World Neurosurg 2013;79(2):307–12. 120.

• Long B, Koyfman A, Runyon MS. Subarachnoid Hemorrhage: Updates in

Diagnosis and Management.Emerg Med Clin North Am. 2017 Nov; 35(4):
803-824.

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• Macdonald RL, Higashida RT, Keller E, et al. Clazosentan, an endothelin
receptor antagonist, in patients with aneurysmal subarachnoid
haemorrhage undergoing surgical clipping: a randomised, double-blind,
placebo-controlled phase 3 trial (CONSCIOUS-2). Lancet Neurol
2011;10:618.
• Rabinstein AA, Friedman JA, Weigand SD, et al. Predictors of cerebral
infarction in aneurysmal subarachnoid hemorrhage. Stroke
2004;35(8):1862–6.
• Roos Y. Antifibrinolytic treatment in subarachnoid hemorrhage: a
randomized placebo-controlled trial. STAR Study Group. Neurology
2000;54:77.
• Schiefecker AJ, Dietmann A, Beer R, Pfausler B, Lackner P, Kofler M,
Fischer M, Broessner G, Sohm F, Mulino M, Thomé C, Humpel C,
Schmutzhard E, Helbok R. Neuroinflammation is Associated with Brain
Extracellular TAU-Protein Release After Spontaneous Subarachnoid
Hemorrhage. Curr Drug Targets. 2017;18(12):1408-1416.
• Veldeman M, Hollig A, Stevanovic A, et al. Delayed cerebral ischaemia
prevention and treatment after aneurysmal subarachnoid haemorrhage. Br
J Anaesth 2016;117(1):17–40.

• Zwienenberg-Lee M, Hartman J, Rudisill N, et al. Effect of prophylactic

transluminal balloon angioplasty on cerebral vasospasm and outcome in
patients with fisher grade III subarachnoid hemorrhage: results of a phase
II multicenter, randomized, clinical trial. Stroke 2008; 39:1759.

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