- 1. Emergency Management of Intracerebral Hemorrhage
- 2. Inpatient Care Following Intracerebral Hemorrhage
- 3. Secondary Stroke Prevention in an Individual with Intracerebral Hemorrhage
- These recommendations provide guidance in the management of spontaneous intracerebral hemorrhage (ICH), not hemorrhagic conversion of an ischemic infarction.
- These recommendations may not be applicable to ICH of secondary causes.
- These recommendations should be referred to once a confirmed diagnosis of ICH has been established following brain imaging.
- Prior to diagnosis of ICH, follow the Initial assessments and imaging guidelines defined in the CSBPR Acute Stroke Management module 2018 (Sections 2, 3, 4) for all patients who arrive at hospital with a suspected stroke and during prehospital management.
1.0 Emergency Management of Intracerebral Hemorrhage
Note: For patients presenting in community or rural hospitals, Telestroke modalities could facilitate rapid access to stroke expertise for consultation and decision-making regarding transfer to a higher level of care.
1.1 Initial Clinical Assessment of Intracerebral Hemorrhage
- A severity score based on neurological exam findings should be conducted as part of the initial assessment [Evidence Level B]. The National Institute of Health Stroke Score (NIHSS) is preferred for awake or drowsy patients, or a Glasgow Coma Scale (GCS) in patients who are obtunded, semi or fully comatose [Evidence Level C].
Note: The GCS has been found to be a strong predictor of outcomes following ICH.
- Patients with declining GCS and/or equal to less than 8 should be rapidly assessed for airway support by endotracheal intubation [Evidence Level B].
- Patients with reduced level of consciousness, pupillary changes and/or other signs of herniation should have temporizing maneuvers to manage presumed elevation in intracranial pressure (ICP), such as temporary hyperventilation and hyperosmotics (e.g. mannitol or 3% saline) [Evidence Level C].
- Patients with suspected ICH should undergo computerized tomography (CT) immediately following stabilization to confirm diagnosis, location and extent of hemorrhage [Evidence Level A]. Refer to CSBPR Acute Stroke Management module for additional information on initial brain imaging.
- In patients with confirmed acute ICH, intracranial vascular imaging is recommended for most patients to exclude an underlying lesion such as an aneurysm or arteriovenous malformation or cerebral sinus venous thrombosis [Evidence Level B].
- Evaluation of patients with acute ICH should include questions about medication history [Evidence Level C], and antithrombotic therapy, measurement of platelet count, partial thromboplastin time (PTT) and International Normalized Ratio (INR) [Evidence Level A].
- Patients should be assessed for clinical signs of increased ICP such as pupil reaction and level of consciousness [Evidence Level B].
- A GCS score and neurovital signs should be conducted at baseline and repeated at least hourly for the first 24 hours, depending on stability of patient. [Evidence Level C].
- If physicians with expertise in acute stroke management are not available onsite, protocols should be in place to contact appropriate experts through virtual telestroke technology [Evidence Level B] to expedite patient assessment and decisions regarding transport to a higher level of care [Evidence Level C].
Clinical considerations for Section 1.1
- The resolution of CT angiography is preferred over MR angiography when screening for underlying vascular anomalies.
- Clinical signs of increased ICP include reduced level of consciousness, dilated unresponsive pupils, new cranial nerve VI palsies or other false localizing neurological signs, worsening headache and/or nausea/vomiting, and elevated blood pressure with reduced heart rate and irregular/ decreased respirations (Cushing’s reflex).
- Potential unstable patients requiring greater monitoring frequency (i.e. neurovital signs hourly for first 24 hours) include patients with large (>30 cc) ICH volume, depressed or declining GCS (<12), worsening neurological disability, infratentorial location, associated intraventricular hemorrhage or hydrocephalus, refractory hypertension, and/or neuroimaging markers of ICH expansion (see section 1.5).
- The use of tranexamic acid has been shown to be safe in a large phase 3 trial (TICH-2) but there was no effect on the primary outcome of functional status at 90 days. Post-hoc pre-specified subgroup analyses showed better functional status in patients with baseline systolic blood pressure less than 170 mm Hg. However, this post-hoc finding has yet to be confirmed. Overall, the clinical role of tranexamic acid for spontaneous ICH remains unclear and there is no evidence for its use in the setting of anticoagulant-related ICH.
1.2 Blood Pressure Management
- Blood pressure should be assessed on initial arrival to the Emergency Department and every 15 minutes thereafter until desired blood pressure target is achieved and maintained for the first 24 hours [Evidence Level C].
- Systolic blood pressure lowering to a target of < 140 mmHg systolic does not worsen neurological outcomes (relative to a target of 180 mmHg systolic) [Evidence level A]; however, clinical benefit has yet to be established [Evidence level A].
- Subsequent blood pressure monitoring should be tailored to the individual patients according to stability of the vital signs and intracranial pressure (ICP) [Evidence Level C].
- There is a lack of strong evidence to guide choice of initial blood pressure lowering agents.
Clinical Consideration for Section 1.2
- A systolic blood pressure threshold at an individual target of less than 140-160 mm Hg for the first 24-48 hours post ICH may be reasonable.
- Factors that may favour a lower target within this range (i.e., < 140 mm HG) may include: presentation within 6 hours of symptom onset; presenting systolic blood pressure no greater than 220 mmHg; anticoagulation therapy; presence of neuroimaging markers of expansion (see section 1.5) and/or normal renal function.
- Parenteral labetalol, hydralazine, nicardapine and/or enalapril (oral or intravenous) may be considered for acute blood pressure reduction.
1.3 Management of Anticoagulation
- Patients presenting with anticoagulant-related ICH should have their anticoagulation withheld and should be considered for immediate reversal, irrespective of the underlying indication for anticoagulation [Evidence Level B].
- Beyond initial investigations, further management should be tailored to the specific antithrombotic agent used [Evidence Level C].
- Warfarin should be reversed immediately with prothrombin complex concentrate (PCC) dosed as per local protocols and in conjunction with intravenous Vitamin K 10 mg [Evidence Level B].
- For patients on Direct oral anticoagulants (DOACs), most information about anticoagulation activity would come from establishing time of last dose, creatinine clearance, anti- Factor Xa level if available [Evidence Level C].
- Factor Xa inhibitors (apixaban, edoxaban, rivaroxaban) should be stopped immediately and PCC administered at a dose of 50 units per Kg with a maximum dose of 3000 u [Evidence Level C].
- Dabigatran should be stopped immediately and reversed with idarucizumab; patients should be given a total dose of 5 g, in 2 intravenous bolus doses of 2.5 g each, given no more than 15 minutes apart [Evidence Level B].
- If the patient has received therapeutic low molecular weight heparin (LMWH) within the past 12 hours, consider administering protamine [Evidence Level C].
- If the patient is receiving intravenous heparin infusion at the time of ICH, infusion should be immediately discontinued, and consider administering protamine [Evidence Level C].
- Antiplatelet agents (e.g. acetylsalicylic acid (ASA), clopidogrel, dipyridamole/ASA, ticagrelor) should be stopped immediately [Evidence Level C].
- Platelet transfusions are not recommended (in the absence of significant thrombocytopenia) and may be harmful [Evidence Level B].
Note: Reversal should not be delayed while waiting for laboratory results, rather it should be based on clinical history.
Note: There are no targeted anti-Factor Xa reversal agents available in Canada at this time.
Note: The doses should be given successively. There is no requirement for time delay between doses.
Clinical Considerations for Section 1.3
- Dilute thrombin time can be used as a surrogate measure of anticoagulation in patients on dabigatran; however, we advise against delaying reversal to obtain these results.
- Andexanet alfa is not yet commercially available in Canada but has been shown to reverse the anticoagulant effect of Factor Xa inhibitors in a non-randomized single-arm clinical trial. It could be considered once commercially available.
1.4 Consultation with Neurosurgery
- Neurosurgical consultation can be considered as a life-saving intervention for large ICH that is surgical accessible or causing obstructive hydrocephalus. Smaller non-life-threatening ICH require stroke unit care and do not necessarily require neurosurgical consultation [Evidence Level C].
Note: If neurosurgical services not available onsite, initial consultation should be initiated with nearest neurosurgical services without delay, using telephone or Telemedicine technology
Clinical Consideration for Section 1.4
- Participation and enrollment in randomized trials should be considered where possible.
Note: For recommendations on initial neuro-imaging of all suspected acute stroke patients upon initial arrival to hospital refer to CSBPR Acute Stroke Management module, Section 3 and this module Section 1.1 (ii – iii). And Acute Stroke Management during Pregnancy module.
1.5.1 Recommended additional urgent neuroimaging to confirm ICH diagnosis
- In cases where CTA is not obtained as part of the initial acute stroke protocol, non-invasive angiography (CTA or gadolinium enhanced MRA) of the intracranial circulation should be considered and, if proceeding, be performed promptly on most patients presenting with ICH to identify potential underlying vascular lesions or spot sign/extravasation [Evidence Level B].
- If suspected, CT venography can be performed to evaluate for cerebral venous sinus thrombosis [Evidence Level B].
Clinical Considerations for Section 1.5.1
- Hemorrhage volume (cc) can be quickly estimated using the formula ABC/2 where A is the greatest hemorrhage diameter in cm on an axial slice, B is the largest diameter perpendicular to A, and C is the approximate number of CT slices with hemorrhage multiplied by the slice thickness in cm (i.e. 5 mm slice thickness = 0.5).
- Urgent repeat CT should be performed in patients when there is clinical deterioration or worsening level of consciousness. A repeat CT at 24 hours may be considered even in the absence of clinical deterioration to document hematoma expansion (occurring in ~30% of acute ICH) and to identify extent of mass effect, new intraventricular hemorrhage, or evolution of hydrocephalus
- Baseline clinical and imaging factors that are predictive of hematoma expansion and ensuing worse outcomes include short time from symptom onset to baseline imaging (i.e. 6 hours), larger hematoma volume and antithrombotic therapy. Additional imaging predictors of hematoma expansion including heterogeneous hematoma density or regions of intra-hematomal hypodensity, irregular hematoma shape and satellite hematomas, amongst others, on non-contrast CT, as well as intra-hematomal contrast extravasation (Spot Sign) on CTA. However, these markers have yet to be proven useful for clinical interventions.
- Early marked vasogenic edema that is out of proportion to presumed timing of ICH may be suggestive of underlying hemorrhagic infarction, hemorrhagic tumor or cerebral venous sinus thrombosis. CT hyper-attenuation within a major dural venous sinus or cortical vein draining region of ICH is suggestive of cerebral venous sinus thrombosis
1.5.2 Recommended additional etiological neuroimaging
- MRI should be considered to evaluate potential underlying mass lesions, hemorrhagic transformation of an ischemic infarct, and cavernous malformations [Evidence Level B].
- MRI can additionally provide information on microangiopathic changes to support the diagnosis of spontaneous ICH from underlying cerebral small vessel disease due to chronic hypertension and/or cerebral amyloid angiopathy [Evidence Level B].
- The optimal timing of initial MRI is uncertain [Evidence Level C].
- MRI with MR venogram and GRE/SWI may be considered to exclude cerebral venous thrombosis [Evidence Level B].
- Digital subtraction angiography (DSA) should be considered in select cases where there exists continued high suspicion of underlying vascular anomaly despite normal CTA and MRI, or non-invasive studies are suggestive of an underlying lesion [Evidence Level B].
- The yield of angiography is higher in the presence of the following clinical and radiologic predictors: younger age < 50 years, female sex, lobar/superficial or infratentorial location of ICH, associated intraventricular hemorrhage or subarachnoid hemorrhage, absence of prior history of hypertension or impaired coagulation, associated enlarged vessels or calcifications along the margin of the ICH, and absence of neuroimaging markers of cerebral small vessel disease [Evidence Level B].
- Where sufficient suspicion persists for an underlying lesion responsible for the index ICH, delayed repeat imaging with MRI and DSA following hematoma resolution (usually 3 months post ICH) can be used to detect an underlying lesion that may have initially been unidentified, such as tumors, cavernous malformations or small vascular anomalies initially compressed or obscured by the hematoma [Evidence Level B].
Clinical Considerations for Section 1.5
- The most prevalent cerebral small vessel diseases that contribute to spontaneous ICH are hypertensive arteriopathy and/or cerebral amyloid angiopathy (CAA). CT markers associated with these underlying microangiopathies include multiple chronic lacunes and brainstem, deep grey, periventricular and subcortical white matter disease. Similar findings can be seen on MRI, with addition of enlarged perivascular spaces on T2-weighted imaging, and cerebral microbleeds or cortical superficial siderosis on blood sensitive sequences (T2*-GRE and/or SWI). A strictly cortical/subcortical white matter distribution of these lesions, but with sparing of the brainstem and deep grey matter in older (≥55 years) patients with lobar or cerebellar ICH would favor CAA over hypertensive arteriopathy.
- The increased use of acute/subacute MRI has identified remote punctate DWI hyperintense lesions in up to 25% of spontaneous ICH patients. The underlying etiology of such lesions is currently under investigation, but seems to be strongly associated with the degree of underlying microangiopathy. An embolic workup could however still be considered in such cases, until their clinical significance becomes further elucidated.
1.6 Surgical management of Intracerebral Hemorrhage
- External ventricular drainage (EVD) should be considered in patients with a reduced level of consciousness and hydrocephalus due to either intraventricular hemorrhage or mass effect [Evidence Level B].
- Surgical evacuation is not recommended if symptoms are stable and there are no signs of herniation [Evidence Level B]
- Intraventricular thrombolysis to treat spontaneous intraventricular hemorrhage with or without associated ICH is generally not recommended [Evidence Level B]. Treatment may reduce the risk of death but does not increase the chances of survival without major disability [Evidence Level B].
- Acute surgical intervention may be considered in patients with surgically accessible supratentorial hemorrhages and clinical signs of herniation (e.g., decreasing levels of consciousness (LOC), pupillary changes) [Evidence Level C], particularly in the following subgroups:
- Young patients (<65 years of age)
- Superficial ICH location (less than or equal to 1 cm from the cortical surface)
- Associated vascular or neoplastic lesion
- Patients with cerebellar hemorrhage may be considered for neurosurgical consultation, particularly in the setting of altered level of consciousness (LOC), new brainstem symptoms, or diameter of 3 or more cm [Evidence Level C].
- EVD placement should occur in conjunction with hematoma evacuation in the setting of concurrent hydrocephalus [Evidence Level C].
- The clinical benefit of minimally invasive clot evacuation is yet to be established.
- Routine use of stereotactic thrombolysis and drainage (MISTIE technique (tPA)) is not recommended based on current evidence [Evidence Level B].
Clinical Considerations for Section 1.6
- Patients with significant hydrocephalus and normal level of consciousness should be monitored closely and could be considered for EVD at earliest signs of decreasing LOC.
- Intraventricular thrombolysis to treat spontaneous intraventricular hemorrhage with or without associated ICH may reduce the risk of death, but seems to increase the chances of survival with major disability.
- Based on the findings of one RCT (MISTIE III), stereotactic thrombolysis appears to be safe and reduces mortality compared to medical management alone, but does not improve functional outcomes. Successful hematoma volume reduction to < 15mL may be associated with functional outcome benefit.
- Endoscopic evacuation of deep and superficial ICH also decreases hematoma volume. Small randomized and non-randomized series have suggested benefit. The impact on functional outcomes is currently under assessment in larger randomized clinical trials.
- Endoscopic evacuation without the use of thrombolysis is under ongoing investigations. Its routine use is not recommended outside the framework of a clinical trial.
- Confirmation of anticoagulation reversal should be obtained intraoperatively.
- Pneumatic compression devices (PCDs) should be placed preoperatively and maintained post operatively until pharmacologic DVT prophylaxis can be initiated.
Clinical assessment cannot reliably distinguish intracerebral hemorrhage from ischemic stroke; brain imaging is required. More frequent symptoms of ICH may include:
- Alteration in level of consciousness (present in approximately 50% of patients)
- Nausea and vomiting (approximately 40-50%)
- Sudden, severe headache (approximately 40%)
- Seizures (approximately 6-7%)
- Sudden weakness or paralysis of the face, arm or leg, or numbness, particularly on one side of the body
- Sudden vision changes
- Loss of balance or coordination
- Difficulty understanding, speaking (slurring, confusion), reading, or writing
- The classic presentation of ICH is sudden onset of a focal neurological deficit that progresses over minutes to hours with accompanying headache, nausea, vomiting, decreased consciousness, and elevated blood pressure.
- Patients may present with symptoms upon awakening from sleep. Neurologic deficits are related to the site of parenchymal hemorrhage.
- Thus, ataxia is the initial deficit noted in cerebellar hemorrhage, whereas weakness may be the initial symptom with a basal ganglia hemorrhage.
- Early progression of neurologic deficits and decreased level of consciousness can be expected in 50% of patients with ICH. (Ramandeep Sahni and Jesse Weinberger; Vasc Health Risk Manag. 2007 October; 3(5): 701–709.)
Box Two: Modified Boston Criteria (Linn 2010)*
* J. Linn, MD, A. Halpin, MD, P. Demaerel, PhD, J. Ruhland, A.D. Giese, PhD, M. Dichgans, PhD, M.A. van Buchem, PhD, H. Bruckmann, PhD, and S.M. Greenberg, PhD. Prevalence of superficial siderosis in patients with cerebral amyloid angiopathy. Neurology. 2010 Apr 27; 74(17): 1346–1350. Doi: 10.1212/WNL.0b013e3181dad605
The incidence of ICH is approximately 20/100,000 in the western populations (van Asch et al. 2010), with a cumulative risk of recurrence of 1% to 7% per year (Poon et al. 2014). The patients who present to hospital with suspected ICH often also have significant physiological abnormalities and comorbidities, which can complicate management. Medical conditions such as hypertension or the presence of a coagulopathy, may have an impact on treatment decisions. An efficient and focused assessment is required to understand the needs of each patient. Rapid identification, diagnosis and management by an expert stroke team are essential to reduce mortality, prevent complications and promote optimal recovery. Specialized care for people with ICH, especially neurosurgical care, is available at a limited number of larger community hospitals and tertiary centres, and people experiencing ICH outside of urban centres encounter longer delays in access to emergent assessment and intervention.
- Establishing multidisciplinary pathways for risk-benefit assessment of urgent management decisions in ICH patients.
- Agreements to ensure patients initially managed in rural hospitals without neurovascular imaging capability have timely access to receive imaging.
- Education for Emergency Medical Services, Emergency Department, and hospital staff on the characteristics and urgency for management of ICH patients.
- Considerations should be given to northern, rural, remote and Indigenous residents to ensure immediate access to appropriate diagnostics and treatment is not delayed.
- Protocols and standing orders to guide initial blood work and other clinical investigations.
- Local protocols, especially in rural and remote locations, for rapid access to clinicians experienced in interpretation of diagnostic imaging, including access through telemedicine technology.
- Provinces and regions should ensure availability of physicians and other healthcare professionals with stroke expertise, including recruitment and retention strategies to increase accessibility of acute stroke services for all Canadians.
- Proportion of ICH patients treated in a primary or comprehensive stroke centre (H&S Level 4 or 5 stroke centre).
- Proportion of ICH patients who bypass a smaller stroke-enabled hospital for direct transfer to a comprehensive stroke centre (H&S Level 4 or 5 stroke centre).
- Proportion of ICH patients who arrive by ambulance.
- Proportion of intracerebral hemorrhage patients who receive a CT or MRI within 25 minutes and one hour of hospital arrival.
- Proportion of intracerebral hemorrhage patients who require surgical intervention.
- Proportion of intracerebral hemorrhage patients who experience intraoperative complications and mortality during surgery for intracerebral hemorrhage.
- Risk-adjusted mortality rates for intracerebral hemorrhage in-hospital, 30-day and one year.
- Distribution of functional ability measured by standardized functional outcome tools at time of discharge from hospital.
- Self-reported quality of life following ICH at time of discharge from hospital, measured by a validated tool.
- Family and caregiver ratings on the palliative care experience following the death in hospital of a patient with ICH.
- Mortality rates should be risk-adjusted for age, gender, stroke severity and comorbidities.
- Time interval measurements should start from symptom onset of known or from triage time in the emergency department as appropriate.
Health Care Provider Information
- Stroke Engine
- CSBPR Virtual Healthcare Toolkit
- American College of Chest Physicians (ACCP) Anticoagulation Guidelines
- Hypertension Canada Treatment Guidelines
- Canadian Stroke Best Practices Acute Stroke Management Table 2B: Recommended Laboratory Investigations for Acute Stroke and Transient Ischemic Attack
- Canadian Stroke Best Practices Acute Stroke Management Appendix Three: Screening and Assessment Tools for Acute Stroke Severity
Information for People with Stroke, their Families and Caregivers
Evidence Table and Reference List
Patients with suspected intracerebral hemorrhage (ICH) should undergo a non-contrast CT or MRI immediately to confirm the diagnosis. Both forms of imaging have been shown to accurately detect acute intracranial hemorrhage (Chalela et al. 2007, Fiebach et al. 2004). Given that an underlying macrovascular cause is responsible for 15%-25% of non-traumatic ICHs, further imaging studies should be conducted using CT angiography, MR angiography or digital subtraction angiography to detect possible arteriovenous malformations, aneurysms or cases of cerebral venous sinus thrombosis. In the DIAGRAM study, Van Ash et al. (2015) estimated the diagnostic yield and accuracy of CTA performed in the acute phase after non-contrast CT, and with the addition of MRI/MRA and then digital subtraction angiography combined (DSA), if the results of the CTA scans were negative. In a cohort of 298 patients, an underlying vascular cause was identified in 69 patients (23%), using the reference standard of best available evidence from all diagnostic procedures. The diagnostic yield of CTA was 17%, 18% with the addition of MRI/MRA and 23% with the addition of DSA. The positive predictive value (PPV) of CTA was 72% (95% CI 60% to 82%). The addition of MRI/MRA increased PPV to 77%, (95% CI 65% to 86%), while addition of DSA increased it to 100% (95% CI 80%-100%). A single cavernoma was not identified using any of the imaging techniques. The accuracy of CTA to identify vascular lesions compared with DSA reported in other studies has been higher. In another DIAGRAM publication, younger age, lobar or posterior fossa location of ICH, absence of neuroimaging markers of cerebral small vessel disease, and a positive or inconclusive CTA were independent predictors for an ultimate macrovascular cause for the ICH being identified within 1 year of follow-up (Hilkens et al. 2017). Josephson et al. (2014) examined the diagnostic test accuracy of CTA and MRA versus intra-arterial digital subtraction angiography (IADSA) for the detection of intracranial vascular malformations. Eight studies compared CTA with IADSA and 3 studies compared MRA with IADSA. The sensitivity and specificity of both strategies was excellent (CTA: sensitivity 0.95, specificity 0.99; MRA: 0.98 and 0.99). Wong et al. (2011) reported the sensitivity, specificity and accuracy of CTA to be 100%, 98.6% and 99.1%, respectively, in a prospective sample of 109 patients, while Delgado Almandoz et al. (2009) reported the respective sensitivity and specificity as 96.1% and 98.5%.
Blood Pressure Management
While the optimum blood pressure targets for patients who have experienced a spontaneous ICH are not known, systolic blood pressure (SBP) greater than 180 mm Hg is thought to increase the risks of rebleeding and hematoma expansion. While this finding suggests that steps to lower blood pressure aggressively would be beneficial, the results from several large controlled trials on the topic are not conclusive. Qureshi et al. (2016) reported in the ATACH-2 trial that intensive blood pressure management, with an SBP target of 110-139 mm Hg did not reduce the risk of death or disability at 90 days (adjusted OR=1.04, 95% CI 0.85-1.27, p=0.72), or hematoma expansion within 24 hours (adj OR=0.78, 95% CI 0.58-1.03, p=0.08), compared with standard treatment (target of 140-179 mm Hg) in 1,000 patients admitted acutely with an ICH, while recent results from a subgroup analysis of the trial (Leasure et al. 2019) suggested that patients with deep intracranial hemorrhage may benefit from intensive treatment. Within this subgroup, the risk of hematoma expansion (defined as an increase of ≥33%) was significantly lower for patients in the intensive group (adj OR=0.61, 95% CI 0.42-0.88, p=0.009. The effect of treatment was modified by deep ICH location (p for interaction=0.02), whereby patients with a basal ganglia hemorrhage benefited from intensive BP reduction and those with thalamic hemorrhages did not. In the INTERACT-2 trial, (Anderson et al. 2013), patients in the intensive treatment arm also had SBP target of <140 mm Hg. At 90 days, 52.0% of patients in the intensive group had experienced a poor outcome (mRS score 3-5) compared with 55.6% of patients in the standard treatment group (OR=0.87, 95% CI 0.75-1.01, p=0.06). There was no significant difference between groups in 90-day mortality (11.9% vs. 12.0%, OR=0.99, 95% CI 0.79-1.25, p=0.96). There was, however, a significant shift towards the distribution of mRS scores favouring less disability among patients in the intensive group (OR=0.87, 95% CI 0.77-1.00, p=0.04). In contrast, data from the INTERACT 1 study showed that early intensive blood pressure lowering reduced hematoma growth (Anderson et al. 2008). Recent evidence from the EnRICH trial (Meeks et al. 2019) indicates blood pressure variability in the hyperacute and acute periods may play a more important role in outcome, whereby high variability was associated with poorer outcomes.
Although not currently recommended for use in spontaneous ICH, another potential treatment that may help to optimize hemostasis and minimize hematoma expansion is recombinant activated factor VII (rFVIIa). In a recent trial that included 69 patients with primary spontaneous acute ICH who were spot-sign positive and randomized to receive rFVIIa (80 μg/kg or placebo), there were no significant differences between groups in the change (increase) in median parenchymal ICH volume from baseline to 24 hours (2.5 vs. 2.6 mL, p=0.89), or in median total hemorrhagic volume (3.2 mL vs. 4.8 mL, p=0.91) (Gladstone et al. 2019). Results of the FAST II (Mayer et al. 2005) and FAST III (Mayer et al. 2008) trials, suggested that treatment with rFVIIa could help to blunt the increase in ICH volume at 24 hours post treatment; however, the trials conflicted with respect to functional outcome. The FAST III trial did not report a significant difference in the proportion of patients with death or severe disability at 90 days, while FAST II reported a lower proportion in active treatment group patients. The authors of a recent Cochrane review (Al-Shahi Salman et al. 2018) stated that they could not draw firm conclusions of the benefit of blood clotting factors in the treatment of ICH, but noted ongoing research in subgroups (e.g. younger patients, earlier time windows). Other hemostatic therapies are under investigation. The benefits of the antifibrinolytic agent tranexamic acid in major trauma have increased interest in its potential benefits in spontaneous ICH. In the TICH-2 trial, the use of tranexamic acid (1 g bolus, followed by 1 g infused over 8 hours) was shown to be safe, seemed to reduce hematoma expansion and reduced early deaths, but ultimately did not improve functional outcomes at 90 days in spontaneous ICH patients treated within 8 hours of symptom onset (Sprigg et al. 2018).
Management of Anticoagulation
For patients who had been managed with warfarin prior to ICH, the results of the INCH trial (Steiner et al. 2016) indicate that treatment with prothrombin complex concentrate (PCC) is superior to intravenous fresh frozen plasma (FFP). The trial was halted early due to safety concerns, after significantly more patients in the PCC group achieved anticoagulation reversal (INR ≤1.2) within 3 hours after treatment (67% vs. 9%, OR=30.6, 95% CI 4.7-197.9, p=0.0003). There are other options when treating patients taking non-vitamin K oral anticoagulants. Treatment with idarucizumab, has been shown to be effective in reversing anticoagulation for patients requiring surgery or other invasive procedures, who had been previously receiving treatment with the direct oral anticoagulation agent, dabigatran (Pollack et al. 2015). The ANNEXA-4 trial (Connolly et al. 2019) included patients who had sustained acute major bleeding occurring while taking a factor Xa inhibitor. The primary site of bleeding was intracranial in 64% of 352 patients enrolled. Following treatment with andexanet, there was a median reduction of 92% in anti–factor Xa activity among the patients who had been taking apixaban or rivaroxaban, while 82% of all patients who could be evaluated had excellent or good hemostasis 12 hours after infusion. The ongoing ANNEXA-I trial is assessing the clinical efficacy of random assignment to andexanet alfa compared with standard treatment (including PCC) in factor Xa inhibitor-related ICH.
The role of surgical intervention for the evacuation of supratentorial ICH remains uncertain. While these procedures can stop bleeding, prevent rebleeding, and prevent secondary brain damage by removing the mass effect, trial results have been disappointing. In the Surgical Trial in Intracerebral Hemorrhage (STICH) trial, 1,033 patients with CT evidence of a spontaneous ICH that had occurred within 72 hours were randomized to early (within 24 hours) surgery for evacuation of the hematoma or to initial conservative treatment (Mendelow et al. 2005). There was no difference in the percentage of patients with a favourable outcome, which was defined based on initial prognosis. 26% of patient in the early surgical group vs. 24% of patients in the medical management group had a favourable outcome (OR=0.89, 95% CI 0.66-1.19, p=0.414, absolute benefit=2.3, 95% CI -3.2 to 7.7). There was speculation that the null findings may have been attributed, in part, to the inclusion of patients with intraventricular hemorrhages with poorer prognosis and the late timing of intervention. Therefore, in the Surgical Trial in Lobar Intracerebral Haemorrhage (STICH II) trial (Mendelow et al. 2013), 601 patients were randomized to early craniotomy (within 12 hours) to evacuate hematoma or treated conservatively, following spontaneous superficial ICH affecting the lobar region, within 1 cm of the cortex and without ventricular extension, the subgroup of patients thought to be most likely to benefit. While there were no differences between groups in the proportion of patients who experienced a good outcome at 6 months (41% surgical group vs. 38% medical management group; OR=0.86, 95% CI 0.62-1.20, p=0.367) or who had died (18%. surgical vs. 24% medical management, OR=0.71, 95% CI 0.48-1.06, p=0.095), patients with poor prognosis were more likely to have a favourable outcome (OR=0.49, 95% CI 0.26-0.92, p=0.04). In contrast, patients with a good prognosis were no more likely to benefit from early surgery (OR=1.12, 95% 0.75-1.68, p=0.57). The results of a patient-level meta-analysis, which included the results from 8 RCTs indicated that the odds of unfavourable outcome at 3-6 months were significantly reduced among persons aged 50-69 years, in those who received surgery within 8 hours of the event, in those with baseline hematoma volumes of 20-50 mLs and with baseline Glasgow Coma Scale (GCS) score was between 9 and 12 (Gregson et al. 2012).
Minimally invasive surgery with the addition of thrombolysis has been used to treat patients with ICH and intraventricular hemorrhages, with mixed results. In the CLEAR III trial (Hanley et al. 2017), 500 patients, with spontaneous ICH ≤30 cc and an intraventricular hemorrhage (IVH) obstructing third and/or fourth ventricles, were included. Patients were randomized to irrigation of the ventricles with a maximum dose of 12.0 mg alteplase or saline placebo via a routine extraventricular drain. Treatment with alteplase did not improve the likelihood of a good functional outcome. The proportion of patients achieving an mRS score of ≤3 at 6 months was non-significantly higher in the alteplase group (48% vs. 45%, RR=1.06, 95% CI 0.88-1.28, p=0.554), although the odds of death at 6 months were significantly reduced in the alteplase group (OR=0.50, 95% CI 0.31-0.80, p=0.004). Treatment with alteplase via the MISTIE technique significantly reduced hematoma size compared with standard care in 506 patients with supratentorial ICH of ≥30 mL, although there was no significant difference between groups in the proportion of patients who achieved a good functional outcome (mRS 0-3) at one year (45% vs. 41%)(MISTIE III,Hanley et al. 2019). One-year and 180-day mortality were both significantly lower in the MISTIE group, but not 30-day mortality.
Sex and Gender considerations
Data on sex specific differences in ICH is limited. Future research directions should include sex or gender specific analysis, regardless of ICH cause and should consider biological age (specifically across the women’s lifespan), clinical presentations, hematoma location/volume, expansion/risk for expansion, imaging, therapy, functional outcomes and patient-reported outcome measures.
Prior studies have demonstrated sex-disparities in ischemic stroke, but there is still a knowledge-gap regarding the role of sex or gender on the ICH risk, clinical presentation, management and /or outcomes.
Large studies, such as the ERICH study and the MGH hospital-based ICH cohort study have observed sex-related differences in primary ICH location. Lobar ICH is more common in females, while deep ICH was more frequent in males.
In the acute setting, women do not receive less aggressive care, including surgery or palliative care, than men after controlling for the substantial comorbidity differences. However, some studies found that women are more likely to receive early DNR orders after ICH than men.