Nontraumatic intracerebral and subarachnoid hemorrhage

Hypertension

The most common etiology of ICH is hypertension. Hypertension more than doubles the risk of ICH. Hypertensive ICH predominantly occurs deep in the cerebral hemispheres, most often in the putamen, thalamus, lobar white matter, cerebellum, and pons ( Fig. 47.1 ). The link between these sites is the supply of small penetrating arteries —that is, perpendicular branches directly off major arteries that are subject to high shear stress and have no collaterals.

Intracranial aneurysms and vascular malformations

Although aneurysmal rupture is most commonly associated with hemorrhage in the subarachnoid space, blood may also be directed into the parenchyma of the brain. Aneurysms located at the middle cerebral artery bifurcation can produce hemorrhages into the basal ganglia similar to hypertensive hemorrhage, and anterior communicating artery aneurysms can produce flame-shaped hemorrhages at the base of the frontal lobes. About half of adults with intracranial arteriovenous malformations (AVMs) present with ICH. In 60% of cases, the hemorrhage is parenchymal, involving virtually any location of the brain. Hemorrhage resulting from AVM occurs more frequently in a younger population than that resulting from aneurysms or hypertension.

Cerebral amyloid angiopathy

CAA is an important cause of primarily lobar, often recurrent, ICH in the elderly. The prevalence of amyloid deposition in cerebral vessels increases dramatically with age ^, and may contribute to the exponential rise in the risk of ICH with age. Although CAA is asymptomatic, it is an important cause of ICH. Apolipoprotein E ε2 and ε4 genotypes are associated with an earlier age at onset of first hemorrhage and a higher risk of early recurrence. ^, The presence of multiple or recurrent lobar ICH in individuals 55 years or older without other known causes of hemorrhage strongly suggests this etiology.

Antithrombotic therapy

Antithrombotics include anticoagulants, antiplatelets, and thrombolytic agents, which increase the risk of spontaneous ICH. The incidence of oral anticoagulant–associated ICH has been increasing in parallel with the rising use of the anticoagulants. Warfarin increases the risk of ICH by twofold. Although the risk of ICH is greater with a supratherapeutic international normalized ratio (INR), a significant number of hemorrhages occur when the INR is therapeutic. Hematoma expansion among warfarin users may be more common and occur over a longer time frame, contributing to a higher mortality rate versus spontaneous ICH. The novel anticoagulants (NOACs), which act by inhibition of thrombin or factor Xa, may have a lower risk of ICH than warfarin.

Most studies suggest that antiplatelet use at ICH onset is not associated with larger hematoma size, hematoma growth, or poor clinical outcome. Platelet dysfunction is associated with hematoma expansion and worse outcome, but to date, platelet transfusion has not provided a mortality benefit or improved functional outcome.

Alteplase administered intravenously for the treatment of acute ischemic stroke (presenting within the time window) increases the risk of spontaneous ICH 5%–7%. ^,

Other causes

Hemorrhage from an underlying neoplasm is rare but occasionally occurs with malignant primary central nervous system (CNS) tumors such as glioblastoma multiforme and lymphoma and with metastatic tumors.

ICH may also occur in association with infection, ^, vasculitis, venous sinus occlusion, after head trauma, after reperfusion, and with the use of various drugs, particularly sympathomimetics. Some degree of hemorrhagic transformation of acute cerebral infarcts is common, although symptomatic ICH in this setting is rare in the absence of anticoagulation or thrombolytic therapy.

Systemic diseases (e.g., thrombocytopenia, leukemia, and hepatic and renal failure) and congenital or acquired clotting factor deficiencies also increase the risk for spontaneous ICH.

Initial stabilization

Acute ICH is a medical emergency requiring careful attention to airway, blood pressure, and correction of underlying coagulopathy. Multidisciplinary teams with expertise in emergency medicine, neurology, and neurosurgery should evaluate and manage ICH patients in a dedicated neurocritical care unit. Acute-phase care may require mechanical ventilation, blood pressure control, reversal of coagulopathy, ventriculostomy, treatment of intracranial hypertension and seizures, and surgical evacuation. Blood pressure is often elevated at presentation, sometimes markedly so, and early control is an important component of initial stabilization.

Airway and respiratory management

As many as half of all patients with ICH require mechanical ventilation. With decreased level of consciousness, the pharyngeal and tongue musculature relax and cough and gag reflexes are inhibited, leading to airway compromise. Additionally, if the hemorrhage is in the brainstem or cerebellum, there may be complete loss of pharyngeal tone and early airway obstruction.

Initial airway management includes proper positioning, frequent suctioning, and placement of an oral or nasal airway to maintain patency. If snoring respiration, inability to clear oral secretions, or decreased oxygen saturation does not improve, intubation is warranted. A rapid-sequence intubation is necessary for patients showing signs of herniation, apneic breathing, Glasgow Coma Scale (GCS) score <8, or soiled airway. In the absence of these findings, a semi-elective protective intubation is recommended to avoid the harmful consequences of hypotension, exaggerated sympathetic reflex from stimulation during laryngoscopy, and worsening of intracranial hypertension. Perform a complete neurologic examination if time permits.

Premedication should be administered to produce adequate sedation and jaw relaxation and to prevent elevation of intracranial pressure (ICP). Short-acting intravenous (IV) anesthetic agents (e.g., etomidate or thiopental) block this response and additionally suppress brain metabolic rate. Etomidate is generally preferred over thiopental because it is less likely to lower blood pressure. IV lidocaine (1–1.5 mg/kg) has been recommended to block this response, although data supporting its use are lacking. Paralytic agents are usually unnecessary, but if needed, short-acting agents should be used.

Hemodynamics

Arterial blood pressure is often elevated on admission in the majority of patients with ICH, even in the absence of a history of hypertension. ^, Although this acute increase in blood pressure is often implicated as the cause of the hemorrhage, it more likely reflects the brain’s attempt to maintain cerebral perfusion pressure (CPP) in response to the sudden increase in ICP, pain, anxiety, and sympathetic activation. Even without treatment, blood pressure tends to decline to premorbid levels within a week of ICH.

There has been substantial controversy over if and when to lower elevated blood pressure after acute ICH. Proponents of rapid treatment of acute hypertension argue that high blood pressure may make the hematoma prone to enlargement and exacerbate vasogenic edema. Another compelling reason to lower blood pressure in ICH patients with moderate to severe hypertension is the potential for end-organ damage, including myocardial ischemia, congestive heart failure, and acute renal failure.

The major argument against the treatment of elevated blood pressure is reduction of CBF and exacerbation of ischemia surrounding the hematoma. Because chronic hypertension shifts the cerebral autoregulatory curve to the right, a higher CPP may be required to maintain adequate CBF. ^, Lowering the blood pressure to “normal” levels might thus lead to ischemic damage. Similarly, lowering blood pressure may critically reduce CPP in patients in whom ICP is elevated.

Several studies have addressed this issue in patients with mean arterial pressure (MAP) more than 130–140 mm Hg. These studies demonstrate that regional and global CBF are preserved when MAP is lowered to 110 mm Hg or 80% of the admission MAP.

These observations set the stage for the INTERACT trial, a prospective trial of blood pressure management beginning within 6 hours of symptom onset. Patients were randomized to either an early, intensive blood pressure–lowering group (systolic blood pressure [SBP] <140 mm Hg) or a control group (SBP <180 mm Hg). After adjusting for initial hematoma volume and time from onset to CT, median hematoma growth at 24 hours differed by 1.7 mL. Intensive blood pressure lowering did not increase the risk of adverse events or improve 90-day clinical outcome. This was followed by the much larger INTERACT2, which used the identical protocol and enrolled almost 3000 patients. Again there was a very small, if any, impact on hematoma expansion, although the hematoma sizes of those enrolled were fairly small. Although the study did not reach its primary endpoint, an ordinal analysis of modified Rankin scores (mRS) indicated improved functional outcomes with intensive lowering of blood pressure. Based on this study, many clinicians are now more aggressive in treating early hypertension in these patients. For patients presenting with SBP between 150 and 220 mm Hg, lowering of SBP to 140 mm Hg is generally safe. In patients presenting with SBP >220 mm Hg, the optimal target is unknown, and targeting SBP between 140 and 160 mm Hg is reasonable. In the ATTACH-2 trial, the group with intense lowering of SBP to <140 mm Hg (110–139 mm Hg) was found to have more adverse renal events compared with less intense SBP lowering from 140 to 179 mm Hg.

In the setting of ICH, the ideal antihypertensive agent would be easily titrated, have minimal cerebral hemodynamic effects, and not be prone to sudden, large reductions in blood pressure. Vasodilators, especially venodilators, can raise ICP by increasing cerebral blood volume and should be avoided. Sodium nitroprusside and nitroglycerin increase ICP and lower CBF in patients with reduced intracranial compliance and should not be used. Calcium channel blockers, beta-blockers, and angiotensin-converting enzyme inhibitors have minimal effect on CBF within the autoregulatory range of MAP and do not alter ICP. Therefore popular treatment options in the setting of acute ICH include intermittent boluses of labetalol, ^, enalapril, and/or hydralazine or continuous infusion of nicardipine or clevidipine.

Prevention of hemorrhage extension and reversal of anticoagulation

Abrupt discontinuation of all antithrombotic therapy is imperative. Hemorrhage expansion occurs within the first few hours after symptom onset in about one-third of patients; therefore it is reasonable to correct any existing coagulopathy as rapidly as possible. Patients taking warfarin should receive IV vitamin K and replacement clotting factors. Until recently, fresh frozen plasma (FFP) was used for this purpose, but it can precipitate congestive heart failure, transfusion-related acute lung injury, and transfusion-associated circulatory overload. Four-factor prothrombin complex concentrate (PCC) is an effective alternative that can be administered much more quickly without these risks and is now primarily recommended for reversal.

Management of hemorrhage in patients taking thrombin and factor Xa inhibitors is more difficult. Recently, the Food and Drug Administration (FDA) has approved the antidotes idarucizumab and andexanet alfa for agent-specific reversal.

Symptomatic ICH occurs after thrombolytic treatment of acute ischemic stroke in about 6% of patients. No reliable data are available to guide correction of the thrombolytic effect of tissue plasminogen activator (tPA). Current practice is highly variable and may include administration of FFP, PCC, cryoprecipitate, platelets, and antifibrinolytic agents.

Even in those patients without coagulopathy, promoting early hemostasis might limit ongoing bleeding and decrease hematoma volume. Factor VIIa is a coagulation factor that interacts with tissue factor to initiate platelet aggregation and accelerate formation of a fibrin clot. Although earlier studies suggested a decrease in the hematoma expansion with its use, there was no significant difference in clinical outcomes. Therefore routine use of factor VIIa is not recommended.

Intraventricular hemorrhage and hydrocephalus

Intraventricular hemorrhage (IVH) ( Fig. 47.2 ) complicates about 40%–60% cases of ICH. ^, It is independently associated with death and poor outcome, especially when it occurs late in the course. IVH may present with an abrupt headache, nausea, vomiting, and worsening of neurologic status that may partly be attributed to a sudden rise in ICP. Hydrocephalus may develop because of obstruction of the cerebrospinal fluid (CSF) flow in the ventricles in association with IVH or because of direct mass effect on a ventricle. CT scan is the imaging modality of choice to diagnose IVH. External ventricular drainage (EVD) is often used to treat hydrocephalus and IVH. Ventriculostomy in the setting of IVH is difficult to manage because of catheter obstruction from thrombus, interrupting drainage and raising ICP. Flushing the system helps remove thrombus but increases the risk of ventriculitis. A multicenter randomized study of Clot Lysis Evaluation of Accelerated Resolution (CLEAR-III) of IVH compared the use of ventriculostomy with intraventricular alteplase to ventriculostomy with saline. At 180 days, the treatment group had lower case fatality versus placebo but functional outcomes were no different. Ventriculitis was less in the treatment group, whereas the rate of symptomatic bleeding was similar in both groups.

Intracranial hypertension

Factors contributing to intracranial hypertension in ICH include hematoma size, minimal degree of underlying cerebral atrophy, hydrocephalus, and cytotoxic edema. The true incidence of intracranial hypertension is unclear, as routine ICP monitoring is not performed. Because the hematoma is localized, increases in volume can be compensated for to some degree by reduction in the size of the ventricles and subarachnoid space—a global increase in ICP may not be seen unless the hemorrhage is large or associated with marked hydrocephalus. However, mass effect from the hematoma and local tissue shifts can compress the brainstem and result in herniation in the absence of a global increase in ICP. ^, Thus the utility of ICP monitoring is not clear. In some cases, EVD placement is considered to manage hydrocephalus or IVH.

Acutely elevated ICP, edema, and tissue shifts are often treated with osmotic agents. There are only a few small clinical trials of osmotic agents in ICH, which do not provide sufficient data to support their routine use. Furthermore, corticosteroids in ICH or IVH do not provide benefit. Their use is not routinely recommended, as they increase comorbidities.

Management of seizures

Risk of seizures in patients with acute spontaneous ICH is approximately 15%. They are more common in patients with lobar hemorrhage compared with cerebellar or deep ICH. Seizures may be convulsive or nonconvulsive; thus the true frequency depends at least partly on the extent of monitoring. Although seizures may theoretically exacerbate ICH, they have not been shown to alter outcome. The 2015 American Heart Association/American Society of Anesthesiologists (AHA/ASA) guidelines recommended against antiseizure prophylaxis. A 2019 systematic review and meta-analysis evaluating antiseizure prophylaxis found no reduction in incident seizures, disability, or mortality in patients with spontaneous ICH. Any seizure should be treated to prevent recurrent seizures. Treatment of clinical seizures typically begins with an IV benzodiazepine followed by an IV antiepileptic depending on individual circumstances and contraindications. The use of phenytoin is discouraged based on the poor outcomes associated in observational studies.

Surgical evacuation

The role of surgery in hematoma evacuation is controversial and lacks well-defined indications. The rationale for surgical evacuation is reducing mass effect and removing neurotoxic clot constituents to minimize injury to adjacent brain tissue, decrease the risk for herniation, improve ICP, and hence improve outcome. Early randomized controlled trials of surgery for supratentorial ICH, however, failed to show a benefit. A meta-analysis of three of these trials reported that patients undergoing surgical evacuation via open craniotomy had a higher rate of death or dependency at 6 months compared with those managed medically. Criticisms of these trials are that outdated surgical techniques were used, patient selection was inadequate, and surgery was delayed. Because open craniotomy is complicated by tissue damage sustained during the approach to the hematoma, a variety of new techniques for clot removal have been proposed, including an ultrasonic aspiration and endoscopic approach. However, the recurrence of bleeding because of the loss of tamponade effect on adjacent tissue remains a concern. In addition, because the newer techniques involve limited surgical exposure, concern exists that rebleeding will be more difficult to control than with open craniotomy.

A lack of benefit of surgery in ICH was also shown in the STICH trial, a multicenter study in which 1033 patients were randomized within 72 hours of ICH onset to surgical hematoma evacuation or initial conservative management. Outcome did not differ between groups. Subgroup analysis, however, suggested a possible benefit of surgery in patients with superficial hematomas. Subsequently, the STICH II trial enrolled conscious patients with superficial lobar ICH of 10–100 mL and no intraventricular hemorrhage within 48 hours of ictus. There was a trend toward better survival in the surgical group. In the Minimally Invasive Surgery with Thrombolysis in Intracerebral hemorrhage Evacuation (MISTIE) phase III trial, 516 patients with supratentorial ICH ≥30 mL were randomized to stereotaxic placement of a catheter in the hematoma and instillation of tPA for up to 72 hours or medical management. The number of patients with a good functional outcome, defined by a mRS of 0–3, was similar for both groups at 365 days, although mortality was lower in the surgical group.

Because of the high risk of brainstem compression and hydrocephalus, cerebellar hemorrhages were excluded from the randomized trials of surgery. Case series report good outcomes for surgically treated patients with cerebellar hemorrhages that are large, associated with brainstem compression, or obstruct the fourth ventricle. Recommended criteria for evacuation of a cerebellar hematoma have thus included diminished level of consciousness, large size of the hematoma (>3 cm in diameter), midline location, compression of basal cisterns and/or brainstem, and presence of hydrocephalus. Patient selection is important, as many patients with smaller hemorrhages do well with medical management. A recent 2019 individual participant data meta-analysis of four observational ICH studies concluded that surgical hematoma evacuation in cerebellar hemorrhages compared with conservative medical management did not improve functional outcome.