intracranial hemorrhage

Intracranial Hemorrhage

J. Alfredo Caceres, MDa, Joshua N. Goldstein, MD, PhDb,c,*

KEYWORDS

� Intracranial hemorrhage � Acute stroke � Intracerebral hemorrhage� Subarachnoid hemorrhage

KEY POINTS

� Intracerebral hemorrhage is the most devastating form of stroke, with high mortality andsevere disability among survivors.

� While no single therapy has been demonstrated to improve outcome, there is evidencethat high quality supportive care can provide substantial benefit.

� National evidence-based guidelines are available to guide management for both intrace-rebral hemorrhage and subarachnoid hemorrhage.

� Ruptured aneurysms are best managed by teams with experience in both surgical and en-dovascular techniques.

INTRODUCTION

Intracranial hemorrhage refers to any bleeding within the intracranial vault, includingthe brain parenchyma and surrounding meningeal spaces. This article focuses onthe acute diagnosis and management of primary nontraumatic intracerebral hemor-rhage (ICH) and subarachnoid hemorrhage (SAH) in emergency departments (EDs).

INTRACEREBRAL HEMORRHAGE

ICH is a devastating disease. The overall incidence of spontaneous ICH worldwide is24.6 per 100,000 person-years with approximately 40,000 to 67,000 cases per year inthe United States.1–3 The 30-day mortality rate ranges from 35% to 52% with only20% of survivors expected to have full functional recovery at 6 months.3 Approxi-mately half of this mortality occurs within the first 24 hours,4 highlighting the criticalimportance of early and effective treatment in EDs.

Risk Factors

A recent population-basedmeta-analysis showed that risk factors for ICH includemalegender, older age, and Asian ethnicity.1,5 ICH is twice as frequent in low-income to

a Department of Neurology, Massachusetts General Hospital, Suite 3B, Zero Emerson Place,Boston, MA 01940, USA; b Harvard Medical School, 25 Shattuck Street, Boston, MA 02115,USA; c Department of Emergency Medicine, Massachusetts General Hospital, Suite 3B, ZeroEmersion place, Boston, MA 01940, USA* Corresponding author.E-mail address: [email protected]

Emerg Med Clin N Am 30 (2012) 771–794http://dx.doi.org/10.1016/j.emc.2012.06.003 emed.theclinics.com0733-8627/12/$ – see front matter � 2012 Elsevier Inc. All rights reserved.

mailto:[email protected]

http://dx.doi.org/10.1016/j.emc.2012.06.003

http://emed.theclinics.com

Caceres & Goldstein772

middle-income countries compared with high-income countries.5 In the United States,several studies have shown that the incidence of ICH is greater in African Americansand Hispanics than in whites.6–8

The most important risk factors for ICH include hypertension (HTN) and cerebralamyloid angiopathy (CAA). HTN-related ICH is more likely to occur in deep structures,9

and the risk of ICH increases with increasing blood pressure (BP) values.10 CAA tendsto occur in association with advanced age, and CAA-related ICH tends to occur inlobar regions.11

Other risk factors for ICH include

1. Alcohol intake: this risk seems dose-dependent, with a higher risk of ICH amongthose with a higher daily alcohol intake.10 Acute changes in BP during ingestionand withdrawal, effects on platelet function and coagulation, and dysfunction ofthe vascular endothelium may account for this risk.12

2. Cholesterol: low levels of total serum cholesterol are risk factors for ICH (in contrastto ischemic stroke, for which high cholesterol levels are a risk).13

3. Genetics: the gene most strongly associated with ICH is the apolipoprotein E geneand its ε2 and ε4 alleles.14 The presence of the ε2 allele was recently also linked tohematoma expansion.15

4. Anticoagulation: oral anticoagulants are widely used as prophylaxis in patients withatrial fibrillation and other cardiovascular and prothrombotic states. The annual riskof ICH in patients taking warfarin ranges from 0.3% to 1.0% per patient-year, witha significantly increased risk when the international normalized ratio (INR) is greaterthan 3.5.16

5. Drug abuse: sympathomimetic drugs, such as cocaine, are risk factors for ICH, andpatients actively using cocaine at the time of their ICH have significantly moresevere presentations and worse outcomes.17

Pathophysiology

Primary ICH is typically a manifestation of underlying small vessel disease. First, long-standing HTN leads to hypertensive vasculopathy, causing microscopic degenerativechanges in the walls of small-to-medium penetrating vessels, which is known as lip-ohyalinosis.18 Second, CAA is characterized by the deposition of amyloid-b peptidein the walls of small leptomeningeal and cortical vessels.19 Although the underlyingmechanism leading to the accumulation of amyloid is still unknown, the final conse-quences are degenerative changes in the vessel wall characterized by the loss ofsmooth muscle cells, wall thickening, luminal narrowing, microaneurysm formation,and microhemorrhages.20

After initial vessel rupture, the hematoma causes direct mechanical injury to the brainparenchyma. Perihematomal edema develops within the first 3 hours from symptomonset and peaks between 10 and 20 days.21 Next, blood and plasma products mediatesecondary injury processes, including an inflammatory response, activation of thecoagulation cascade, and iron deposition from hemoglobin degradation.21 Finally, thehematoma can continue to expand in up to 38% of patients during the first 24 hours.22

Clinical Presentation and Diagnosis

The acute presentation of ICH can be difficult to distinguish from ischemic stroke.Symptoms may include headache, nausea, seizures, and focal or generalized neuro-logic symptoms. Findings, such as coma, headache, vomiting, seizures, neck stiff-ness, and raised diastolic BP, increase the likelihood of ICH compared withischemic stroke, but only neuroimaging can provide a definitive diagnosis.23

Intracranial Hemorrhage 773

Neuroimaging

Noncontrast CTNoncontrast CT is the most rapid and readily available tool for the diagnosis of ICH24

and remains the most commonly used technique in the ED. Besides providing thedefinitive diagnosis, CT may also show basic characteristics of the hematoma, suchas hematoma location, extension to the ventricular system, presence of surroundingedema, development of mass effect, and midline shift.A quick estimation of the hematoma volume can be rapidly performed in an ED with

the validated ABC/2 technique (Fig. 1).25 The steps to follow using this technique are

� The CT slice with the largest area of hemorrhage is selected.� A is the largest hemorrhage diameter on the selected slice (in centimeters [cm]).� B is the largest diameter perpendicular to A on the same slice.� C is the approximate number of slices in which the hemorrhage is seen multipliedby the slice thickness (often 0.5-cm slices).

� A, B, and C are multiplied and the product divided by 2.

CT angiographyCT angiography (CTA) is gaining increasing acceptance as a diagnostic tool in theacute setting.26 It is the most widely available, noninvasive technique for ruling outvascular abnormalities as secondary causes of ICH. The risk of acute nephropathy,if any, is likely low.27 Up to 15% of patients with ICH show an underlying vascularetiology on CTA, potentially changing acute management.28 Finally, contrast extrava-sation seen on CTA images, also known as a spot sign (Fig. 2), is thought to representongoing bleeding and seems to mark those patients at highest risk of hematomaexpansion and with poor outcome and mortality.29–32

MRIMRI is equivalent to CT for the detection of acute ICH.33 The imaging characteristics ofICH vary with time as the hemoglobin passes through different stages during the

Fig. 1. ABC/2 technique. (From Li N, Wang Y, Wang W, et al. Contrast extravasation oncomputed tomography angiography predicts clinical outcome in primary intracerebralhemorrhage. Stroke 2011;42:3441–6; with permission.)

Fig. 2. CT and CTA of acute ICH. (A) Noncontrast CT shows a right thalamic ICH (24 mL) withassociated IVH(6mL). (B) CTAdemonstrates3 fociof contrast (spot signs)within the ICH (arrow-heads) (C). Delayed CTA shows increased volume and changed morphology of the spot signs(arrowheads). (D) Noncontrast CT after 8 hours demonstrates expansion of the ICH (94 mL)and IVH (82 mL). (From Kidwell CS, Chalela JA, Saver JL, et al. Comparison of MRI and CT fordetection of acute intracerebral hemorrhage. JAMA 2004;292[15]:1823–30; with permission.)


pathologic process. In the acute phase, gradient-recalled-echo imaging techniqueswith T2* weighting are the best option to detect the presence of ICH.34 MRI canalso detect underlying secondary causes of ICH, such as tumor and hemorrhagictransformation of ischemic stroke. Finally, for patients with poor kidney function orcontrast allergies, the cerebral vasculature can be analyzed without contrast usingtime-of-flight magnetic resonance angiography.35

Acute Management

AirwayPatients with ICH are often unable to protect the airway. Endotracheal intubation maybe necessary but this decision should be balanced against the risk of losing the


neurologic examination. Rapid sequence intubation is typically the preferred approachin the acute setting. Pretreatment with lidocaine may be considered because it mayblunt a rise in intracranial pressure (ICP) associated with intubation. Paralytic agentsinclude succinylcholine, rocuronium, and vecuronium, and, for postintubation seda-tion, propofol is a reasonable choice, given its short half-life.36,37

Blood pressure managementElevated BP is common in the acute setting after an ICH, and higher BP levels areassociated with hematoma expansion and poor prognosis. It is not clear, however,that reducing BP improves outcomes.38 Although lowering BP may reduce the riskof expansion, it may theoretically also reduce cerebral perfusion. One randomizedclinical trial found that lowering systolic BP (SBP) to 140 mm Hg compared with 180mm Hg reduced the risk of hematoma expansion but had no effect on outcomes.39

A second trial found that rapid BP lowering using intravenous nicardipine seemssafe but again showed no difference in outcomes.40 Several clinical trials are currentlyongoing to address this issue.41–43

Until these trials clarify the role of BP management on hematoma expansion,expert guidelines from the American Heart Association/American Stroke Association(AHA/ASA) recommend BP treatment (Box 1).38 The European Stroke Initiative(EUSI) guidelines are similar (Table 1).44

In choosing medications to manage HTN, intravenous antihypertensives with shorthalf-lives should be considered as first-line therapy. The AHA recommends consid-ering IV labetalol, nicardipine, esmolol, enalapril, hydralazine, sodium nitroprusside,or nitroglycerin.38 The EUSI recommends IV labetalol, urapidil, sodium nitroprusside,nitroglycerin, or captopril.44

Hemostatic therapyIt is tempting to consider that in a patient with ICH, acute hemostatic therapy willprovide benefit. One phase III randomized trial in patients with no underlying coagul-opathy found no clinical benefit from this approach.45 As a result, current approachesto hemostasis are focused on correcting any underlying coagulopathies.

Oral anticoagulation Themost common class of agent used for oral anticoagulation iswarfarin. Many investigators believe that early action to rapidly correct the coagulop-athy may prevent continued bleeding.46 Several therapeutic options are available forwarfarin reversal.

Box 1

Recommended guidelines from the AHA/ASA for treating elevated BP in spontaneous ICH

1. If SBP is >200 mm Hg or mean arterial pressure (MAP) is >150 mm Hg, then consideraggressive reduction of BP with continuous intravenous infusion, with frequent BPmonitoring every 5 minutes.

2. If SBP is >180 mm Hg or MAP is >130 mm Hg and there is the possibility of elevated ICP, thenconsider monitoring ICP and reducing BP using intermittent or continuous intravenousmedications while maintaining a cerebral perfusion pressure (CPP) �60 mm Hg.

3. If SBP is >180 mm Hg or MAP is >130 mm Hg and there is no evidence of elevated ICP, thenconsider a modest reduction of BP (eg, MAP of 110 mm Hg or target BP of 160/90 mm Hg)using intermittent or continuous intravenous medications to control BP and clinically re-examine the patient every 15 minutes.

Adapted from Morgenstern LB, Hemphill JC III, Anderson C, et al. Guidelines for the manage-ment of spontaneous intracerebral hemorrhage. Stroke 2010;41(9):2108–29; with permission.

Table 1Recommendations from EUSI for BP management in ICH

Previous history of HTN Gradually reduce MAP to <120 but >84 mm Hg; avoida reduction of >20%.

BP limit is <180/105 mm Hg; target shouldbe <170/100 mm Hg. Avoid a reduction of >20%.

No history of HTN Reduce MAP to 110 mm Hg.BP limit is <160/95 mm Hg; target should be

<150/90 mm Hg. Avoid a reduction of >20%.

When increased ICP is present Adapt MAP and BP limits to target a CPP of 60–70 mm Hg.

Data from Steiner T, Kaste M, ForstingM, et al. Recommendations for the management of intracra-nial haemorrhage—part I: spontaneous intracerebral haemorrhage. The European Stroke InitiativeWriting Committee and theWriting Committee for the EUSI Executive Committee. Cerebrovasc Dis2006;22(4):294–316.


Because warfarin inhibits the vitamin K–dependent carboxylation of factors II, VII,IX, and X, vitamin K is a first-line agent to restore these factors. Vitamin K given intra-venously lowers the INR as early as 4 hours but requires more than 24 hours for fulleffect when used as monotherapy.47 Vitamin K infusion at a dose of 5 mg to 10 mgshould be started promptly and given slowly over 30 minutes.48,49

While awaiting the effect of intravenous vitamin K, coagulation factors should beinfused emergently. Fresh frozen plasma (FFP) contains all coagulation factors and isthemost widely available and commonly used agent in the United States.50 Limitationsinclude adverse events, such as allergic reactions, potential transmission of infectiousagents, and transfusion-related acute lung injury.51 There is also significant timeneeded for its administration in actual practice, including time spent ordering, match-ing, thawing, and delivering to an ED.50 The dose of FFP ranges from 10 mL/kg to 20mL/kg of body weight. On average, the volume needed to correct the INR varies from800mL to 3500mL,whichmay impose a significant volume load.52 Early administrationof coagulation factors maximizes the opportunity for early INR correction.53

Prothrombin complex concentrates (PCCs) provide an alternate source of coagula-tion factors. PCCs contain coagulation factors prepared from pooled plasma. All avail-able PCCs contain factors II, IX, and X, and some contain relevant amounts of factorVII and proteins C and S. In the United States there are currently 2 commercially avail-able PCCs, Bebulin VH Factor IX Complex (Baxter, Westlake, California) and ProfilnineSD (Grifols Biologicals, Los Angeles, California).54 Many other products are availablein other countries, including Octaplex (Octapharma) and Beriplex (CSL Behring, Kingof Prussia, PA, USA), which include clinically relevant amounts of all 4 vitamin K–dependent factors, sometimes termed, 4-factor PCCs, to differentiate them fromthe other 3-factor PCCs.55 PCC offers several advantages over FFP, including smallerinfusion volume, faster time to INR correction, and lack of need for blood type match-ing.54 Thromboembolic events are potential complications of the use of PCC, althoughit is not clear that this risk (approximately 1.9%) is any different with FFP.56,57

Heparinoids Heparin-related ICH is rare and data are sparse regarding appropriatetreatment. One reasonable approach would be to reverse heparin with IV protaminesulfate at a dose of 1 mg to 1.5 mg per 100 units of heparin with a maximum doseof 50 mg.58

Platelet function The 2 major causes of platelet dysfunction are antiplatelet therapyand thrombocytopenia.


Antiplatelet agents use before an ICH is associatedwith a small increase inmortality,suggesting anopportunity for intervention.59 Theutility andsafety of platelet transfusionin such patients is unknown, although some laboratory data suggest that such transfu-sions may improve platelet activity.60 Platelet transfusion is, therefore, consideredinvestigational by the AHA and is not recommended by the EUSI. The ongoing PATCHclinical trial will investigate whether platelet transfusions can improve outcome.61

Additionally, it is not clear whether low platelets contribute to ongoing bleeding orworse outcome. Pending further data, current AHA recommendations are that patientswith severe thrombocytopenia should receive platelet transfusion.38 A specific cutoffis not clarified; different groups use thresholds between 10,000 and 50,000 per mL.

Novel antithrombotics Recently, several new agents, such as factor Xa inhibitors,apixaban and rivaroxaban, and the direct thrombin inhibitor, dabigatran, have becomeavailable for stroke prevention.62–64 There is no currently known antidote for reversal ofthese agents. Specific hemostatic agents, such as recombinant activated factor VIIand PCCs, may be considered, although there are limited data on their use.65,66 Forthose cases related to dabigatran use, a recently published expert recommendationstates that the drug should be stopped immediately, supportive and symptomatictreatment should be initiated, and, due to its renal excretion, aggressive diuresisand potential dialysis could be considered.67

Intracranial pressure managementAn increase in the ICP may arise from the presence of intraventricular hemorrhage(IVH) and subsequent hydrocephalus or from mass effect from a large hematoma orperihematomal edema. Currently, there are limited data regarding indications forICP monitoring. Current guidelines from the AHA/ASA suggest that patients witha Glasgow Coma Scale (GCS) score of less than or equal to 8, those with clinicalevidence of transtentorial herniation, and those with significant IVH or hydrocephalusshould be considered for ICPmonitoring and treatment.38 CPP can then bemonitored,and recommendations are to maintain CPP between 50 mm Hg to 70 mm Hg.28

The initial management of elevated ICP should comprise simple measures, such aselevation of the head of the bed, analgesia, and sedation. Medical options for ICPtreatment include mannitol, hypertonic saline (ranging from 3% to 23.4%), and neuro-muscular paralysis.3,68,69 Barbiturates can be considered in refractory intracranialHTN.36 Although hyperventilation can produce a rapid decrease in the ICP, its effectsare temporary, and its use should be reserved for impending herniation while awaitingsurgical decompression.

Hyperglycemia managementHyperglycemia measured at arrival in the ED is associated with worse outcome in bothnondiabetic and diabetic patients.70,71 Declining glucose values after ICH are associ-ated with a decreased risk of hematoma expansion and poor outcome, suggestingthat early glucose control may improve outcomes.46 Early evidence for this interven-tion comes from the Quality in Acute Stroke Care (QASC) trial, in which patients withICH and ischemic stroke were randomized to receive standard care, or a set of inter-ventions aimed at treating fever, hyperglycemia, and performing swallow screens.72

The intervention (including glucose management) lowered mortality, and improvedoutcome, highlighting the need for careful glycemic control in the early phase.38

TemperatureThe presence of fever is a common finding in patients with ICH, especially in those withIVH. Again, data from the QASC trial suggest lower mortality and improved outcome in


those patients receiving fever control as part of a multidisciplinary approach.72 Thosewith fever should undergo a thorough investigation to find a fever source if possible.38

AnemiaThe presence of anemia is common in patients with ICH. It is present in up to 25% ofcases at admission and is associated with larger hematoma volumes.73 It alsofrequently develops during hospital stay.74 Although current guidelines do not addressthis issue, a recent study found that packed red blood cell transfusion in these patientswas associated with improved survival at 30 days.74 Therefore, transfusion can beconsidered in such patients, although the ideal target hemoglobin level has notbeen determined.

AntiepilepticsPatients with ICH are at an increased risk of developing seizures; however, most ofthese events are subclinical electroencephalographic findings. Seizures are morecommon in lobar ICH and during the first 72 hours after admission.75–77 The majorityof patients develop a single episode of seizure during hospitalization, suggesting thatthose episodes are related to the pathophysiologic processes that occur early after anICH.77 The use of prophylactic antiepileptic drugs (AEDs) in patients with ICH isa common practice, although it is not clear that the presence of seizures and/or theuse of prophylactic AEDs affects short-term or long-term outcome.78,79 Some studieshave reported an association between AEDs and worse outcome, although thesepatients were disproportionately exposed to phenytoin as the AED of choice.80,81

Currently, the AHA/ASA recommends that AEDs should not be used routinely inpatients with ICH. The only clear indications are the presence of clinical seizures orelectrographic seizures in patients with a change in mental status. They also suggestthat the use of continuous electroencephalography monitoring should be consideredin those patients with depressed mental status out of proportion to the degree of braininjury.38

Surgical Interventions

External ventricular drain placementAs described previously, some patients may benefit from ICP monitoring. Externalventricular drain placement not only provides the ability to monitor ICP but also hasthe advantage of allowing therapeutic drainage of the cerebrospinal fluid (CSF), whichis valuable in patients with hydrocephalus.82 The AHA recommends that ICP moni-toring and treatment be considered in patients with a GCS score less than or equalto 8, those with clinical evidence of transtentorial herniation, or those with significantIVH or hydrocephalus.38 The EUSI recommends considering continuous ICP moni-toring in patients who need mechanical ventilation and recommends medical treat-ment of elevated ICP if clinical deterioration is related to increasing edema.44

Intraventricular thrombolysisIVH occurs when ICH extends into the ventricles. It occurs in approximately 45% ofICH, more frequently in large and deeply located (caudate nucleus and thalamus)hemorrhages.83 The presence and the volume of IVH are correlated with poor prog-nosis in patients with ICH.84 Although evacuation of an intraventricular clot is currentlynot routinely recommended, a recent study comparing the use of intraventricularrecombinant tissue plasminogen activator (rtPA) to placebo not only showed thatthe use of rtPA was feasible and safe but also showed a significantly greater rate ofblood clot resolution.85 In addition, a recent meta-analysis found that adding intraven-tricular fibrinolysis to external ventricular drain placement is associated with better


functional outcome,86 although no prospective randomized trial has evaluated this.The Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage(CLEAR III) study, an ongoing phase III randomized clinical trial, was designed tocompare the effect on clinical outcome of the intraventricular use of rtPA comparedwith placebo (ClinicalTrials.gov [NCT00784134]).

Hematoma evacuationThe role of surgical evacuation is to decrease mass effect related to the presence ofblood as well as to minimize secondary injury. The only clear recommendation forimmediate surgical intervention is in patients with cerebellar hemorrhages with neuro-logic deterioration, brainstem compression, and/or hydrocephalus from ventricularobstruction.38 For these patients, emergency neurosurgical consultation should beobtained. It is less clear, however, whether patients with supratentorial ICH willbenefit. One large phase III clinical trial, Surgical Treatment for Intracerebral Hemor-rhage (STICH), compared early hematoma evacuation with initial conservative treat-ment of patients with spontaneous supratentorial ICH.87 This study showed nodifference in outcome, suggesting that surgical evacuation provided no benefit. Asubsequent subgroup analysis, however, raised the possibility that those with hema-tomas less than or equal to 1 cm from the cortical surface (which are more easilyaccessible) might receive benefit.87 This possibility is being evaluated in the ongoingSTICH II trial.88 The theoretic idea that hyperacute evacuation of the hematoma wouldbe beneficial was not borne out when a study evaluating the effect of surgery within 4hours was stopped due to a high rate of rebleeding.89

Minimally invasive surgeryThe development of less-invasive surgical techniques may decrease the risk ofsurgical complications. These techniques are showing promising results, particularlyin deep hemorrhages where conventional surgery showed no benefit in the past.90

Minimally invasive stereotactic puncture is reported safe and feasible and may leadto better long-term outcome and fewer complications when compared with conven-tional craniotomy91 and conventional medical treatment.92,93

Prognosis

Multiple grading scoresexist that allow forevidence-based riskstratification in theacutephase. First, the ICH score predicts 30-day mortality using features, such as age, ICHvolume, and the presence of IVH, with higher score associated with worse outcome(Table 2).94 Second, the FUNC (functional outcome risk stratification) score predictsfunctional independence rather than mortality at 90 days (Table 3).95 The higher theFUNC score, the greater the chance of the patient recovering functional independence.There are some data that poor prognosis can lead to self-fulfilling prophecies of

early death. Limiting care via early do-not-resuscitate (DNR) orders, withdrawal ofcare, or deferral of other life-sustaining interventions is independently associatedwith both short-term and long-term mortality after ICH, after controlling for clinicalmarkers of disease severity, even in patients who do not specifically require defibrilla-tion.96 As such, new DNR orders or withdrawal of care is generally not recommendedin the ED. The AHA recommends aggressive full care early after ICH onset with post-ponement of new DNR orders until at least the second full day of hospitalization.38

SUBARACHNOID HEMORRHAGE

SAH is defined by the extravasation of blood into the subarachnoid space. The mostcommon cause of SAH is trauma; among nontraumatic cases, rupture of an

http://ClinicalTrials.gov

Table 2The ICH Score

Component ICH Score Points

GCS score

3–4 2

5–12 1

13–15 0

ICH volume (cm3)

�30 1

<30 0

IVH

Yes 1

No 0

Infratentorial origin of ICH

Yes 1

No 0

Age (y)

�80 1

<80 0

Data from Hemphill JC III, Bonovich DC, Besmertis L, et al. The ICH score: a simple, reliable gradingscale for intracerebral hemorrhage. Stroke 2001;32(4):891–7.

Table 3The FUNC Score

Component FUNC Score Points

ICH volume (cm3)

<30 4

30–60 2

>60 0

Age (y)

<70 2

70–79 1

�80 0

ICH location

Lobar 2

Deep 1

Infratentorial 0

GCS score

�9 2

�8 0

Pre-ICH cognitive impairment

No 1

Yes 0

Total FUNC score 0–11

Data from Rost NS, Smith EE, Chang Y, et al. Prediction of functional outcome in patients withprimary intracerebral hemorrhage: the FUNC score. Stroke 2008;39(8):2304–9.



intracranial aneurysm is the leading cause, representing up to 85% of cases. Thisreview focuses on aneurysmal SAH.

Epidemiology

The overall incidence of SAH is between 9 and 20 per 100,000 person-years. SAH ismore frequent in women, and the mean age of presentation is 55 years.97,98 In theUnited States, the number of cases of SAH is 30,000 per year.99

Risk Factors and Prognosis

Major risk factors associated with SAH are current and former history of smoking,HTN, and excessive alcohol intake.100 Although one-third of cases can be attributedto a current smoking status, this risk seems to rapidly disappear after a few years ofsmoking cessation.101 Cocaine use is also associated with SAH, and patients takingcocaine tend to be younger and have a worse outcome.102,103 First-degree familyhistory as well as some genetic conditions, including autosomal dominant polycystickidney disease, Marfan syndrome, and Ehlers-Danlos syndrome, are also associatedwith an increased risk of SAH.104

A recent meta-analysis reported that in a population without comorbidities, theprevalence of unruptured intracranial aneurysms is 3.2%.105 Only a small percentageof these unruptured intracranial aneurysms rupture and cause an SAH. The risk ofrupture is increased in cases of previous history of SAH, age older than 60, femalegender, and Japanese or Finnish descent. In addition, the risk is greater for aneurysmsgreater than 10 mm and those located in the posterior circulation.106–108

The introduction of surgical treatment options improved the prognosis of patientswith SAH.109 In a retrospective analysis before the introduction of endovascular treat-ment of SAH, the most important factors predicting poor outcome at 3 months wereincreasing age, worse admission grade on the World Federation of NeurologicalSurgeons (WFNS) grading scale (Table 4), the development of cerebral infarction,and symptomatic vasospasm. Other factors included greater clot thickness on admis-sion CT scan, aneurysm rupture within the posterior circulation, intraventricular andintracerebral extension of the hematoma, and higher SBP on admission.110 Analysisfrom the large International Subarachnoid Aneurysm Trial (ISAT) comparing neurosur-gical clipping with endovascular coiling showed similar results.111

Pathophysiology

Aneurysms are more common at the bifurcation of the arteries located on the base ofthe brain, especially the large arteries that form the circle of Willis.112 Hemodynamicfactors that contribute to the formation and growth of aneurysms are wall shear stress

Table 4World Federation of Neurological Surgeons grading scale

WFNS Grade GCS Motor Deficit

1 15 Absent

2 13 to 14 Absent

3 13 to 14 Present

4 7 to 12 Present or absent

5 3 to 6 Present or absent

Data from Report of World Federation of Neurological Surgeons committee on a universalsubarachnoid hemorrhage grading scale. J Neurosurg 1988;68(6):985–6.


and hydrostatic and transmural pressures. High wall shear stress is encountered at thebranch points of cerebral arteries, and long-term exposure to this could trigger vesselwall remodeling through interaction with the endothelium and the secretion of factors,such as nitric oxide and endothelial growth factors. Hydrostatic and transmural pres-sures produce a mechanical stretch of the wall that induces upregulation of certainmolecules, such as endothelin-1B receptors, that further affect vascular smoothmuscle cells by promoting apoptosis.113 Although the mechanism of formation andgrowth of aneurysms is partially understood, it is still unclear what leads to aneurysmalrupture.

Clinical Presentation

The characteristic complaint of patients with SAH is a severe headache of acute onset.This headache is commonly described as “the worst headache of my life,” with thehighest intensity at onset. Although it is frequently accompanied by other symptoms,headache may be the only complaint in up to 40% of patients.114 Recently, a prospec-tive study found that the following clinical characteristics represent the highest risk ofbelonging to a case of SAH: age greater than 40 years, associated neck pain or stiff-ness, witnessed loss of consciousness, onset with exertion, vomiting, arrival by ambu-lance, and BP above 160/100.115

A subgroup of patients develops warning signs before the index SAH. The mostcommon warning sign is again headache, which is of moderate intensity and lesssevere than that described in SAH. This is commonly referred to as sentinel headacheor warning leak and may be associated with a small leakage of blood into thesubarachnoid space or a small bleed into the aneurysmal wall. A thorough evaluationis warranted in these cases, because SAH can develop up to 110 days later.116,117

Physical examination may demonstrate neck stiffness and meningismus.118

Although not specific, funduscopic evaluation may reveal subhyaloid, vitreous, orintraretinal hemorrhage (known as Terson syndrome), which is associated with highermortality.119 These eye findings may be found with any intracranial bleeding and arebelieved associated with sudden increase in ICP. Focal neurologic deficits may alsobe found and can be related to nerve compression by the aneurysm, intraparenchymalextension of the bleeding, or vasospasm (which typically occurs later in the course).

Diagnosis

Up to 1 in 20 SAH patients are missed during initial evaluation.120 A high index ofsuspicion and a low threshold for performing diagnostic studies are key factors inmaking the diagnosis of SAH.The gold standard diagnostic approach has been to initially perform a noncontrast

CT scan of the brain followed by a lumbar puncture (LP) and analysis of the CSF whenthe CT is negative. Recently, however, some groups have suggested that current-generation multislice CT scanners as well as the availability of CTA in the acute settingmay offer opportunities to selectively defer LP.121,122

CTWhen there is clinical suspicion of SAH, the initial test of choice is a noncontrast CTscan. The sensitivity of the CT scan to detect SAH is maximal within the first 24 hoursafter the bleed and then decreases with time. The volume of blood in thesubarachnoid space and the resolution of the scanner also influence the CT detectionrate.123 A recent multicenter prospective study of 3132 patients found that of thoseundergoing current-generation CT within 6 hours of symptom onset, the sensitivitywas 100% (95% CI, 97%–100%) with a negative predictive value of 100% (95% CI,


99.5%–100%).122 Noncontrast CT also provides information regarding the volume ofblood, extension to the cerebral parenchyma, the presence of hydrocephalus, and thepotential location of the aneurysm. Blood located in the interhemispheric fissure andthe surrounding sulci has a high probability of coming from an anterior cerebral oranterior communicating artery aneurysm, whereas blood in the posterior aspect ofthe sylvian fissure is probably related to a middle cerebral artery aneurysm(Fig. 3).123–125

CT angiographyCTA is a fast, noninvasive, and readily available method to screen for the presence ofaneurysm.126 A recent meta-analysis showed that CTA has a pooled sensitivity ofapproximately 98% to detect aneurysm, with sensitivities ranging from 86% to100%.127 Aneurysm detection rates are related to the experience of the reviewerand aneurysmal size. Pooled specificity of CTA in this analysis reached 100% witha range of 50% to 100%.127 Also, 3-D CTA may be as sensitive and specific as digitalsubtraction angiography for the detection of aneurysms (Fig. 4).128 As a result,patients with negative CT/CTA have a less than 1% likelihood of aneurysmalSAH.121 The Neurocritical Care Society recommends preferential use of CTA as anexploratory approach when it is readily available and of high technical quality overdigital subtraction angiography if an immediate intervention is not planned.129

Lumbar punctureLP is considered effectively 100% sensitive for detection of blood in the subarachnoidspace, and it is recommended in all patients undergoing aworkup for SAHwith a nega-tive CT.130–132 CSF characteristics of SAH include an elevated opening pressure,presence of erythrocytes or red blood cells, and xanthochromia. CSF should be visu-ally inspected for the presence of xanthochromia, a term that refers to the yellowaspect of the CSF attributable to the formation of bilirubin from the breakdown ofhemoglobin in the CSF.133

Special consideration should be given to the use of spectrophotometry in CSF anal-ysis for the detection of bilirubin. The use of this technique is strongly advocated in theUnited Kingdom, where the rate of visual assessment of the cerebrospinal fluid fell to

Fig. 3. SAH in the left sylvian fissure, sulci of the left hemisphere and along the left andcentral aspect of the suprasellar cistern, left ambient cistern, and interpenduncular cistern.

Fig. 4. 3-D reconstruction CTA on the same patient as in Fig. 3. An aneurysmal sac is appre-ciated at the distal M1 segment of the left middle cerebral artery.


6%, whereas the use of spectrophotometry rose to 94% in recent years.134 Thismethod has been shown to have approximately 100% sensitivity for the detectionof bilirubin in patients with SAH but with low specificity.135,136 In the United States,however, the majority of centers use visual inspection instead.137 Some investigatorsrecommend spectrophotometry, if available, in those cases where visual inspectionyields doubtful results.138

Digital subtraction angiographyDigital subtraction angiography allows for direct visualization of the cerebral vascula-ture and remains the gold standard for detecting aneurysms. This diagnostic toolrequires a dedicated neurointerventional team and provides an opportunity for thera-peutic interventions as well as diagnosis.

MRIMRI is rarely used to diagnose SAH in the ED because availability is limited, and logis-tical barriers to its use are much higher than with CT. Blood is not easily detectable inT1-weighted and T2-weighted MRI sequences in the acute setting, likely because thegeneration of deoxyhemoglobin with paramagnetic properties is delayed in thesubarachnoid space.139 The sensitivity of fluid-attenuated inversion recoverysequences, however, is comparable to that of the CT in the acute phase of an SAHand potentially superior in the subacute phase.140,141

Emergency Management

Airway managementThe initial management of an SAH does not differ from other medical emergencies,and airway management is similar to that described previously for ICH.

Neurologic examinationDuring the initial evaluation, a neurologic examination should be performed and docu-mented. Clinical grading scales that mark the severity of SAH include the Hunt and


Hess scale (Table 5) and the WFNS grading scale (see Table 4). The Hunt and Hessscale was originally designed to evaluate the operative risk of patients and to aid atdeciding the best timing for neurosurgical intervention,142 but it is now widely knownand accepted as a predictor of outcome. It is based on the level of severity of clinicalsigns with a correlation with poor outcome with a higher grade. The WFNS gradingscale uses the GCS score and groups them into 5 grades and also takes into accountthe presence of a motor neurologic deficit.143

Medical Management

Blood pressure managementWhen considering an optimal BP goal, an appropriate balance should be maintained.Hypotension may theoretically increase the risk of ischemia, whereas elevated BP rai-ses the concern for aneurysmal rupture and rebleeding. Current guidelines recom-mend that hypotension should be avoided and that treatment of HTN should beinitiated until the aneurysm is secure only with extreme BP values when the MAP isgreater than 110 mm Hg, aiming at maintaining a good CPP. The recommendedagents to lower BP are nicardipine, labetalol, and esmolol.129,144

Seizure prophylaxisTo date, no randomized controlled trial has evaluated the benefits of the prophylacticuse of AEDs in patients with SAH. The incidence of seizure varies extensively in theliterature.145 Risk factors for the development of onset seizures include poor Huntand Hess score, acute hydrocephalus, cerebral ischemia, and large volume ofsubarachnoid blood.129,146,147

Nonconvulsive seizures and nonconvulsive status epilepticus may occur after SAH,leading clinicians to recommend continuous electroencephalography monitoring inpatients with poor Hunt and Hess scores.148 Current guidelines recommend consid-ering the use of routine AEDs, especially in patients at higher risk, and using an alter-native to phenytoin, which has been linked to a poor prognosis.129 Commonly usedagents include levetiracetam, valproate, and fosphenytoin (it is unclear whether thisshares the same possible negative effects as phenytoin).

Glycemic controlBoth elevated and low glucose levels are associated with worse outcome after SAH.Hypoglycemia is associated with vasospasm, infarction, and more disability at 3months. Hyperglycemia on admission and during hospitalization is also associatedwith poor outcome and short-term mortality.149–151 Although a specific target glucoselevel has not been established, it is currently recommended to avoid hypoglycemia(serum glucose <80 mg/dL) and maintain maximum values below 200 mg/dL.129

Table 5Hunt and Hess grading scale

Grade Criteria

1 Asymptomatic or minimal headache and slight nuchal rigidity

2 Moderate to severe headache, nuchalrigidity, no neurologic deficit other thancranial nerve palsy

3 Drowsiness, confusion, or mild focal neurologic deficit

4 Stupor, moderate to severe hemiparesis, possibly early decerebrate rigidity

5 Deep coma, decerebrate rigidity

Data from Hunt WE, Hess RM. Surgical risk as related to time of intervention in the repair of intra-cranial aneurysms. J Neurosurg 1968;28(1):14–20.


TemperatureFever is common after SAH. Fever at admission and its presence during hospitaliza-tion are associated with poor outcome.152 A possible infectious etiology should alwaysbe investigated, although this is uncommon during initial presentation. Medical andphysical interventions can be used as therapeutic measures to reduce fever.Currently, it is recommended to initiate therapy with antipyretic agents, such as acet-aminophen, when fever is present.129 Physical surface or intravascular coolingdevices should be used only when antipyretics fail, and close monitoring and treat-ment of shivering should be started.129

Vasospasm and Delayed Cerebral Ischemia

Vasospasm and delayed cerebral ischemia are deadly complications of SAH associ-ated with poor outcome. Angiographic vasospasm occurs in up to 70% of cases.153

Symptomatic vasospasm, associated with new focal neurologic findings and/or dete-rioration in the level of consciousness, occurs in approximately 30% of cases.154

Delayed cerebral ischemia can occur days after the index SAH and can lead to neuro-logic deterioration and focal neurologic deficits.155 One preventive measure is the useof oral nimodipine (60 mg by mouth or nasogastric tube every 4 hours for 21 days) andshould be initiated soon after diagnosis of SAH.156 Once vasospasm occurs, a rangeof medical and interventional therapies is available to maintain adequate cerebralperfusion.129 One recognized therapy is the triple-H therapy, characterized by hyper-volemia through volume expansion, HTN with BP augmentation, and hemodilutionaimed at reducing blood viscosity.157 Currently, the Neurocritical Care Society recom-mends that euvolemia be pursued and that the routine use of hemodilution should bereserved for cases of erythrocythemia.129 For BP augmentation, a stepwise approachis recommended and an SBP goal of greater than 160 mm Hg or an MAP greater than120 mm Hg is a reasonable approach.129,158

Aneurysm Repair

Patients with SAH require emergency neurosurgical and/or endovascular consulta-tion. There are currently at least 2 options for the acute treatment of a ruptured aneu-rysm: endovascular coiling or surgical clipping. Treatment of a recently rupturedaneurysm reduces the rate of rebleeding, and the benefit is related to the time to treat-ment initiation.159 Current guidelines recommend that surgical clipping or endovascu-lar coiling should be performed to reduce the rate of rebleeding after aneurysmal SAH,and these procedures should be performed early in the disease course.129,144

The selection of the most appropriate intervention depends on a range of character-istics, including age, clinical status, and medical comorbidities. Aneurysm character-istics, such as location, shape, and size, are taken into consideration as well,highlighting the value of a specialized multidisciplinary group to provide care and deci-sion making. Some expert consensus groups recommend that SAH be preferentiallymanaged at high-volume centers (defined as those centers with greater than 60 casesof SAH per year).129

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