Intracerebral hemorrhage (ICH) is the deadliest type of stroke and up to half of patients die in hospital. Blood pressure management, coagulopathy reversal, and intracranial pressure control are the mainstays of acute ICH treatment. Prevention of hematoma expansion and minimally invasive hematoma evacuation are promising therapeutic strategies under investigation. This article provides an updated review on ICH diagnosis and management in the emergency department.
Key points
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Intracerebral hemorrhage (ICH) is a dynamic disease and up to one-third of the patients experience early clinical deterioration caused by hematoma expansion.
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Intensive blood pressure reduction is safe and might improve neurologic outcome.
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Rapid correction of coagulopathy may minimize the risk of ongoing bleeding.
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Surgical evacuation of the hematoma should be considered for patients with clinical deterioration caused by cerebellar ICH.
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Patients with ICH should be admitted to a neuroscience intensive care unit or stroke unit.
Introduction and epidemiology
Intracerebral hemorrhage (ICH) refers to primary, spontaneous, nontraumatic bleeding occurring in the brain parenchyma. ICH accounts for 10% to 20% of all cerebrovascular events in the United States and is the deadliest type of stroke, with 30-day mortality up to 40% and severe disability in most survivors. Older age, hypertension, cerebral amyloid angiopathy (CAA), and oral anticoagulant treatment (OAT) are the most important risk factors for ICH. Other ICH risk factors are summarized in Box 1 .
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Hypertension is the most important modifiable risk factor for ICH. Poor control of blood pressure values is also associated with increased risk of recurrent ICH.
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CAA accounts for up to 20% of all spontaneous ICH cases. CAA-related bleeding typically arises from corticosubcortical brain regions and frequently affects elderly patients.
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Alcohol intake: this relationship seems to be dose dependent.
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Smoking: current smoking increases the risk of ICH.
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Cholesterol levels and statin use: in contrast with ischemic stroke, hypercholesterolemia has a protective effect against the risk of ICH. The association between statins and ICH risk is still unclear.
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Diabetes: a meta-analysis including almost 70.000 subjects provided evidence in favor of diabetes as a risk factor for ICH.
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Genetics: the gene most strongly associated with ICH is the apolipoprotein E (APOE) gene and its ε2 and ε4 alleles.
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Ethnicity: ICH incidence is higher in Asian populations.
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Drug abuse: illicit drug consumption, such as cocaine and methamphetamine, is an important risk factor for ICH, especially in young adults.
Introduction and epidemiology
Intracerebral hemorrhage (ICH) refers to primary, spontaneous, nontraumatic bleeding occurring in the brain parenchyma. ICH accounts for 10% to 20% of all cerebrovascular events in the United States and is the deadliest type of stroke, with 30-day mortality up to 40% and severe disability in most survivors. Older age, hypertension, cerebral amyloid angiopathy (CAA), and oral anticoagulant treatment (OAT) are the most important risk factors for ICH. Other ICH risk factors are summarized in Box 1 .
- •
Hypertension is the most important modifiable risk factor for ICH. Poor control of blood pressure values is also associated with increased risk of recurrent ICH.
- •
CAA accounts for up to 20% of all spontaneous ICH cases. CAA-related bleeding typically arises from corticosubcortical brain regions and frequently affects elderly patients.
- •
Alcohol intake: this relationship seems to be dose dependent.
- •
Smoking: current smoking increases the risk of ICH.
- •
Cholesterol levels and statin use: in contrast with ischemic stroke, hypercholesterolemia has a protective effect against the risk of ICH. The association between statins and ICH risk is still unclear.
- •
Diabetes: a meta-analysis including almost 70.000 subjects provided evidence in favor of diabetes as a risk factor for ICH.
- •
Genetics: the gene most strongly associated with ICH is the apolipoprotein E (APOE) gene and its ε2 and ε4 alleles.
- •
Ethnicity: ICH incidence is higher in Asian populations.
- •
Drug abuse: illicit drug consumption, such as cocaine and methamphetamine, is an important risk factor for ICH, especially in young adults.
Pathophysiology
ICH represents an acute manifestation of an underlying progressive small vessel disease. Primary brain damage in the acute phase of ICH is caused by mechanical mass effect of the hematoma, leading to increased intracranial pressure (ICP) and consequent reduced cerebral perfusion and possible herniation. Intraventricular extension of the hemorrhage (intraventricular hemorrhage [IVH]) occurs in up to 40% of ICH cases and is another important determinant of clinical deterioration and an independent predictor of mortality.
Clinical presentation and diagnosis
The clinical presentations of ICH and ischemic stroke are similar, typically consisting of abrupt onset of a focal neurologic deficit. Decreased level of consciousness, vomiting, headache, seizures, and very high blood pressure (BP) might suggest the presence of ICH. However, none of these symptoms/signs is specific enough to distinguish hemorrhagic from ischemic stroke and therefore the diagnosis of ICH must always rely on neuroimaging. A significant proportion of patients with ICH manifest a loss of at least 2 points on the Glasgow Coma Scale (GCS) during acute evaluation and coma can be the presenting symptom of posterior fossa hemorrhages.
Clinical Assessment
Vital signs measurement and general physical examination should be performed in all patients. The American Heart Association (AHA) and American Stroke Association (ASA) recommend routine application of a neurologic baseline severity score, and the National Institutes of Health Stroke Scale score seems to be useful in patients with ICH. The GCS is a widely known, rapid, and reproducible tool for consciousness evaluation. The ICH score is a reliable and validated scale for rapid assessment of ICH severity.
Blood Tests
In patients with ICH, complete blood count, electrolytes and creatinine, glucose, and coagulation studies should be obtained.
Neuroimaging
Noncontrast computed tomography
Noncontrast computed tomography (NCCT) is a fast technique with excellent sensitivity for identifying acute ICH, and given its wide availability is considered the gold standard for the diagnosis of ICH in the emergency department (ED). Beyond the diagnosis of ICH, NCCT can provide useful elements such as ICH location, intraventricular extension, hydrocephalus, presence and degree of edema, and midline shift or brainstem compression secondary to the mass effect from the hematoma. Furthermore, ICH volume is a strong predictor of ICH outcome and can be rapidly estimated in the ED with the ABC/2 technique ( Fig. 1 ).
Computed tomography angiography
Computed tomography angiography (CTA) is a useful diagnostic tool in the acute setting of ICH. It is the most widely available noninvasive technique for the detection of vascular abnormalities as secondary causes of ICH. The presence of lobar ICH, significant IVH, young age, and absence of traditional cerebrovascular risk factors should trigger the suspicion of ICH secondary to vascular malformation or other intracranial disorder. Prompt detection of these lesions is crucial and has a significant impact on patient management. Although CTA is an excellent noninvasive screening tool, digital subtraction angiography remains the gold standard investigation for diagnosis, and frequently endovascular treatment, of cerebral vascular malformations.
Presence of contrast extravasation within the hematoma on CTA images, also termed spot sign, is an independent predictor of hematoma expansion and poor outcome in patients with supratentorial ICH ( Fig. 2 ). Furthermore, CTA spot sign is associated with active bleeding during surgical evacuation, and may help indicate which patients may benefit from surgery. The main drawback of CTA is cost and the additional radiation exposure. Although some clinicians are concerned about the risk of contrast-induced nephropathy, there is debate in the literature about whether this entity exists, and there is no evidence that CTA increases the risk of nephropathy in patients with ICH.
MRI
MRI sensitivity for the diagnosis of ICH is equivalent to that of NCCT. MRI can be a useful technique to detect underlying secondary causes of ICH, such as neoplastic lesions or hemorrhagic transformation of ischemic stroke. In addition, in patients with poor kidney function, contrast allergies, or other contraindications to CTA, brain vessel imaging can be achieved without contrast through magnetic resonance angiography. Given the cost, duration of the examination, and poor tolerability for some patients, MRI is rarely used in the ED work-up of ICH.
Natural History and Clinical Evolution
Even though ICH was traditionally viewed as a monophasic disease, growing evidence suggests that ICH is a dynamic disease, characterized by early significant expansion in up to one-third of patients. Early imaging after symptom onset, large baseline hematoma volume, anticoagulant therapy, and presence of CTA spot sign are consistently the most powerful predictors of significant hematoma growth. Other factors associated with clinical deterioration include perihematomal edema, intraventricular extension of the ICH, hydrocephalus, seizures, fever, and infections.
Acute management
Prehospital Care
The main goal of prehospital management of ICH is to provide airway and cardiovascular support to unstable patients, along with careful reconstruction of symptom onset timing, medical history, and current medications. Moreover, early notification reduces the time to NCCT scan in the ED and therefore allows a faster diagnosis of ICH. Mobile stroke units have been developed to reduce the time from symptom onset to intravenous (IV) thrombolysis administration in patients with ischemic stroke. This approach also seems potentially useful for patients with ICH, allowing the possibility of early BP management, reversal of coagulopathy, and delivery of patients to tertiary care centers with neurosurgical and neurocritical care facilities.
Airway Protection
Patients with ICH are often unable to protect the airway because of reduced consciousness. Endotracheal intubation may therefore be necessary, but this decision should be balanced against the risk of losing the neurologic examination. Rapid sequence intubation is typically the preferred approach in the acute setting. Pretreatment with lidocaine may be preferred because it may blunt an increase in ICP associated with intubation.
Blood Pressure Management
Most patients with ICH present with increased BP in the acute phase. BP increase is associated with higher risk of hematoma growth and poor outcome and is therefore an appealing target for ICH treatment. The most robust data on BP management come from the INTERACT2 (Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial 2) study, a large clinical trial randomizing patients to one of 2 different BP control strategies (systolic BP [SBP] <140 mm Hg vs SBP <180 mm Hg for the first 24 hours). The study failed to meet its primary end point, and did not definitively show improved outcome with intensive BP treatment (SBP target <140 mm Hg). However, intensive BP reduction seemed safe, and numerous secondary measures of outcome seemed to be superior with the intensive strategy. As a result, some clinicians argue that the weight of evidence is now in favor of maintaining SBP less than 140 mm Hg in the acute phase. However, this study had numerous limitations, including the disproportionate inclusion of patients with small ICH, difficulty achieving target BP quickly, and the use of a heterogeneous range of pharmacologic agents. The current AHA/ASA guidelines indicate that intensive BP treatment is safe and might be associated with better outcome in patients presenting with SBP between 150 and 220 mm Hg. Increased BP should be treated with agents with short half-lives, such as labetalol or nicardipine, to avoid overshoot hypotension. Hydralazine and nitroprusside should be avoided given their possible association with increased ICP.
Hemostatic Treatment
Platelet function
The utility and safety of platelet transfusion in patients with ICH taking antiplatelet medications remains unclarified and there is not enough evidence to support routine application of a reversal strategy to improve platelet function. Platelet transfusion is indicated in patients with severe thrombocytopenia, with suggested thresholds between 50,000 and 100,000 platelets per microliter.
Warfarin-associated coagulopathy
OAT is associated with higher baseline ICH volume, increased risk of hematoma expansion, and poor outcome. Coagulopathy correction is designed to prevent continued bleeding. Warfarin discontinuation and IV administration of vitamin K are the first therapeutic steps. Vitamin K should be infused slowly (over 10 minutes), at a dose of 10 mg with close monitoring of vital signs given the rare but not negligible risk of anaphylaxis (1 in 10,000). Given its slow onset of action (6–24 hours), emergent factor repletion is typically also provided. Fresh frozen plasma (FFP) and prothrombin complex concentrates (PCCs) are commonly used. According to the AHA/ASA guidelines, PCCs may be preferred to FFP because of more rapid action. Two randomized controlled trials of PCC versus FFP showed that PCCs restore coagulation factors and reverse the International Normalized Ratio (INR) more rapidly than FFP, with no clear difference in thromboembolic risk. Although these trials failed to show improved clinical outcome in patients with ICH, some observational studies have suggested improved outcome from more rapid INR reversal. The optimal INR target is still debated and proposed target values range from 1.3 to 1.5. Although it is not clear whether INR values less than 1.7 represent clinically relevant coagulation abnormalities, 1 observational study found that achievement of an INR value less than 1.3 within 4 hours from admission was associated with reduced risk of hematoma expansion. The European Stroke Organization guidelines do not provide a specific recommendation about the warfarin reversal strategy, whereas the Neurocritical Care Society recommends warfarin reversal with either PCCs or FFP with a target INR less than 1.5. Characteristics of FFP and PCCs and 1 reasonable reversal strategy for warfarin-associated ICH are shown in Table 1 and Box 2 .
| FFP | PCCs |
|---|---|
|
|
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Discontinue warfarin treatment
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Obtain complete blood count and INR
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Administer 10 mg of vitamin K intravenously (infuse over 10 minutes)
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Administer 4-factor PCC in weight-based and INR-based dosing:
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PCC: 20 IU/kg if INR less than 2.0
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PCC: 30 IU/kg if INR 2.0 to 3.0
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PCC: 50 IU/kg if INR greater than 3.0
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If PCCs are not available or desired, administer FFP 10 to 20 mL/kg
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Repeat INR after infusion
Heparin-associated coagulopathy
If ICH occurs during IV heparin or low-molecular-weight heparin treatment, protamine sulfate administration can be used for coagulopathy reversal, at the dose of 1 mg per 100 units of heparin. The maximum dose should be 50 mg and the infusion must be slow (maximum infusion speed: 5 mg/min) with vital signs monitoring given the significant risk of hypotension.
Direct oral anticoagulants
Alternatives to warfarin are now available, and the most commonly used are the factor Xa inhibitors apixaban, rivaroxaban, and edoxaban, and the direct thrombin inhibitor dabigatran. These agents were traditionally termed novel oral anticoagulants but the International Society of Thrombosis and Hemostasis has recommended the term direct oral anticoagulants (DOACs); this article uses this new terminology. Unlike warfarin, there is no specific commercially available laboratory test to assess level of DOAC function; however, some traditional and novel blood tests may assist clinical providers in estimation of anticoagulant effect. These tests are listed in Table 2 . Compared with warfarin, DOACs have shorter half-lives and their blood concentrations typically follow a peak-trough format. Therefore, timing of last intake and renal function should always take into consideration whether the patient is still, at the time of presentation, coagulopathic. Current evidence for DOACs reversal is limited and comes from in-vitro and animal models or studies on healthy volunteers. For dabigatran reversal, a specific antagonist is now available that addresses coagulopathy but has not yet been shown to reduce expansion. For reversal of other agents, it may be that no currently available product is effective for this purpose, although more specific reversal agents are under investigation ( ClinicalTrials.gov identifiers NCT02329327 and NCT02220725 ). Patients taking DOACs are not deficient in vitamin K–dependent factors, so vitamin K administration is not likely to be of value. Some authorities use activated PCCs for this purpose, to provide excess coagulation factor activity. Activated charcoal can be considered if administered within 2 to 3 hours from the last drug intake.
| Dabigatran | Rivaroxaban | Apixaban | Edoxaban | |
|---|---|---|---|---|
| aPTT |
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| PT/INR |
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| dTT |
| — | — | — |
| ECT |
| — | — | — |
| Anti-Xa activity | — |
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| Specific test system | Hemoclot: dabigatran-calibrated dTT | Rivaroxaban-calibrated anti-Xa activity | Apixaban-calibrated anti-Xa activity | Edoxaban-calibrated anti-Xa activity |
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