Medical Therapy of Intracerebral and Intraventricular Hemorrhage

Key Points

Patients with intracerebral hemorrhage (ICH) should be cared for in specialized units with a focus on monitoring for deterioration and avoiding medical complications such as fever, hyper- or hypoglycemia, and deep vein thrombosis.
Blood pressure lowering after ICH to a target systolic blood pressure less than 140 mm Hg is probably safe but has not been definitively shown to reduce the outcome of death or disability.
Indications for craniotomy and hematoma removal remain uncertain for most cases of supratentorial ICH. For cerebellar hemorrhage with mass effect or hydrocephalus, surgical hematoma evacuation can be lifesaving.
Outcome prediction after ICH may be confounded by very frequent limitations in life-sustaining treatments. Clinicians should be cautious of early limitations in the supportive treatment provided, and work to ensure that the goals of treatment are in line with patient and family values and treatment preferences.

Blood frightens people. Although acute hemorrhage is white rather than red on a CT scan, it usually prompts a community emergency department physician to rapidly call a tertiary referral center to transfer the patient. The physician accepting the call at the referral center is frequently left wondering what the referral center can do for the patient that the local community hospital cannot. The good news is that although we still have no “magic bullet” to treat intracerebral (ICH) and intraventricular hemorrhage (IVH), intensive therapy is likely to reduce mortality and improve outcome. Surgery remains controversial, and many therapies can be provided at any hospital with a good intensive care unit (ICU) and neurologic and/or neurosurgical expertise.

In this chapter, we discuss medical therapy of spontaneous ICH and IVH in adults. Epidemiology, clinical presentation, imaging, and surgical treatment are covered elsewhere in this book. Care for ICH or IVH begins in the community with prompt recognition, transport, and triage of the patient with acute stroke. In the emergency department, after a stat head CT scan determines that a spontaneous cerebral hemorrhage has occurred and a search for the cause begins, therapy commences with gentle blood pressure control and assessment of cerebral edema. A watchful eye for hydrocephalus and complications are critical. Rehabilitation therapies and avoiding malnutrition are important.

We begin with emergency department management of the patient with acute ICH or IVH and follow it with a discussion of the utility of specialized wards for patients with ICH or IVH and the importance of intensive medical therapies. We then consider edema, hydrocephalus, and ventricular drainage procedures; use of acute novel medical therapy, instillation of thrombolytic medication, and clot extraction are also discussed in this section. Next, we discuss hematoma expansion and the steps to prevent this serious complication. Consideration then is given to patient selection for surgical interventions. Finally, we deal with circumstances special to anticoagulant associated cerebral hemorrhage and predictors of outcome. Primary IVH is rare. One study found that primary IVH accounted for only 3% of all cases of IVH. We therefore discuss ICH and IVH as one entity. When recommendations in this chapter cite the American Heart Association/American Stroke Association (AHA/ASA) ICH Guidelines, the classification and level of evidence are noted. Full explanations of evidence classifications are listed in the front matter of the text.

Emergency Department Management

Box 59.1 reviews the first steps in the care of patients with ICH or IVH. Initial concerns should focus on the airway, breathing, circulation (ABCs) of emergency therapy. The patient who has brainstem injury or reduced consciousness may have compromise of airway or breathing. These complications are treated with airway management (with adequate cervical spine protection for those in whom trauma is suspected) and intubation, as discussed in Chapter 56 . Patients who have been immobile for long periods before they are brought to the emergency department may have rhabdomyolysis and renal failure; these possibilities should be kept in mind. In addition, a baseline severity score should be performed as part of the initial evaluation of patients with an ICH. Examples include National Institutes of Health Stroke Scale (NIHSS) and ICH scores (Class I, Level B). The ICH score ^, is externally validated and is the most widely used scoring system to determine the risk of 30-day mortality although it may underestimate the potential for recovery in patients where care is not withdrawn.

BOX 59.1

Emergency Department Considerations for Suspected Intracerebral Hemorrhage

1.
Secure airway, breathing, and circulation
2.
Check for history of recent head trauma, hypertension, tumor, arteriovenous malformation (AVM), aneurysm, antithrombotic medication use, clotting disorder, or chemotherapy
3.
Order stat head computed tomography (CT) scan
4.
Collect and send specimens for complete blood count, prothrombin time, partial thromboplastin time, chemistry panel, and urine drug screen
5.
If CT confirms intracerebral hemorrhage and increased intracranial pressure is not suspected: reduce blood pressure to systolic blood pressure of 140–160 mm Hg if initial systolic blood pressure is ≤220 mm Hg; if initial systolic blood pressure is >220 mm Hg, reduce blood pressure by no more than 15%–20%
6.
Obtain neurologic and neurosurgical consultations
7.
Suspect aneurysm or AVM if CT shows subarachnoid hemorrhage or hemorrhage in an atypical location or if the patient is not known to have hypertension
8.
Watch the patient closely for signs of deterioration; repeat CT if deterioration occurs
9.
Treat fever and hyperglycemia or hypoglycemia

The Importance of Intensive Medical Therapies

Stroke Units and Intensive Care Units

Patients with ICH or IVH should be cared for in specialized units where personnel are familiar with both intensive care procedures and neurologic injury. This should include neuroscience nurses performing frequent neurologic examinations and to promptly recognize deterioration so that rescue therapies can be instituted to halt worsening (Class I, Level B). At many institutions, this implies that ICH patients should be in an ICU, though some ICH patients without respiratory compromise or elevated intracranial pressure (ICP) may be able to be cared for in specialized stroke units as long as access to higher levels of care is immediately available. Support for providing care in specialized hospital areas comes from the data on stroke units, and some evidence suggests stroke units may be more beneficial for ICH compared with other stroke types. Considering studies specific to ICH, Ronning et al. randomly assigned 121 patients with ICH to care in an acute stroke unit or a general medical ward, demonstrating a reduction in 30-day mortality (39% in stroke unit compared with 63% in the general medical ward group). The decision to assign patients to a neurologic ICU rather than a general ICU is also supported by an observational study demonstrating that patients who were not in a neurologic ICU had a higher odds ratio (OR) for mortality, of 3.4 (95% confidence interval [CI], 1.7–7.6). Patients in ICUs that had a full-time intensivist on staff had lower odds of death (OR 0.39; 95% CI, 0.2–0.7). Specialized units not only provide rescue treatment for patients with worsening neurologic signs but also can help prevent complications and avoid conditions that are toxic to damaged neurons.

The decision to transfer a patient with ICH to a tertiary care center versus keep them at a local presenting hospital is complex. Despite the expected benefits of care in specialized units, some studies have suggested a worse outcome in patients transferred to tertiary centers, though this finding is not consistent across studies, ^, and these analyses are almost certainly confounded by unmeasured severity of illness. Some of these transfers may occur through the use of telemedicine for an initial clinical evaluation of ICH patients. Hospitals that lack the capability to provide all available diagnostic and surgical procedures for ICH patients should work with their regional tertiary centers to develop protocols to determine which patients may be cared for locally and which should be transferred, taking into consideration patient factors, local hospital capabilities, geography, and family preferences.

Fever

Fever is an independent predictor of poor outcome in ICH. Routine prophylactic administration of acetaminophen to all stroke patients has not been found to improve outcome, but there is good evidence that patients with stroke do worse if they have fever ^, ^, ; in patients with elevated temperatures, an infectious source should be sought assiduously. Prompt use of acetaminophen and of external cooling devices (blankets) is advocated with a goal of normothermia. However, this therapy has not been shown to improve outcome to date. Nevertheless, the current guidelines suggest that treatment of fever after ICH may be reasonable (Class IIb, Level C).

Hyperglycemia

Elevated serum glucose concentration is associated with poor outcome in ICH, though it remains uncertain to what degree hyperglycemia is a cause of poor outcome versus a marker of severity of brain injury. Elevated serum glucose level may also predispose to secondary ICH after intravenous (IV) recombinant tissue plasminogen activator (rtPA) for ischemic stroke. The injured brain is particularly sensitive to deleterious effect from hypoglycemia, and intensive insulin protocols targeting normoglycemia (e.g., <∼110 mg/dL) have been found to increase the risk of hypoglycemia in neurocritical patients. Efforts to control glucose in ischemic stroke has been an active area of investigation, though results have not proven useful to date. The Stroke in Hyperglycemia Insulin Network Effort (SHINE) was a prospective, randomized, adaptive design clinical trial that investigated the use of intensive versus standard glucose control on the outcomes of acute ischemic stroke patients. Although the SHINE trial did not include ICH cases, it was stopped early for futility after an interim analysis demonstrated harm within the intensive treatment group and no difference in functional outcomes after 90 days. As a result, no specific targets for glucose can be recommended based on existing evidence, though frequent monitoring of blood glucose is recommended to avoid extremes of both hyper- and hypoglycemia (Class I, Level C).

Hypertension

Although lowering the blood pressure in acute hemorrhage holds the theoretical promise of preventing enlargement of the hematoma, some have worried that perihematomal ischemia may be worsened. Experimental laboratory data in dogs first showed that lowering mean arterial pressure (MAP) within normal limits of cerebral autoregulation did not detrimentally affect regional cerebral blood flow or ICP. Positron emission tomography (PET) also fails to demonstrate tissue hypoxia surrounding cerebral hematomas in humans. Powers et al. performed a controlled trial of blood pressure reduction in acute patients with ICH and measured perihematomal and global cerebral blood flow; neither declined. Based in part on these data suggesting probable safety of blood pressure lowering, several large-scale clinical trials have followed.

The INTERACT2 trial demonstrated safety of blood pressure lowering and a trend toward improved outcome. The study randomized 2839 patients, 68% from China, who had a primary ICH within 6 hours of randomization. The intensive treatment arm (goal systolic blood pressure [SBP] <140 mm Hg) had a 3.6% absolute decreased chance of death or disability (52% vs. 55.6%) compared with the guideline concordant treatment arm (goal SBP <180 mm Hg; OR 0.87; 95% CI, 0.75–1.01; P = .06). Treating physicians chose the blood-pressure-lowering agent to use. Mortality and safety did not differ between the treatment groups. The intervention group achieved a mean SBP of 150 mm Hg (139–150 mm Hg), and the control group achieved a mean SBP of 164 mm Hg (155–164 mm Hg). However, a post hoc analysis demonstrated a lower rate of disability and death at 90 days among patients with a larger SBP reduction ≥20 mm Hg within 1 hour and maintained for 7 days. The Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH-II) study was a large multinational randomized control trial designed to determine the efficacy of intensive blood pressure reduction (SBP goal 119–139) versus standard blood pressure reduction (SBP goal 140–179). Unfortunately, this study was terminated early for futility after an interim analysis found no difference in functional outcome between the two treatment groups. The intervention group achieved a mean SBP of 129 mm Hg (113–145 mm Hg), and the control group achieved a mean SBP of 141 mm Hg (126–156 mm Hg). In addition, there were adverse renal events within the intensive reduction group after 7 days of treatment. Over 50% of patients presented with an admission Glasgow Coma Scale (GCS) score of 15 and less than 10% with a greater than 30 mL hemorrhage size. As a result, we do not know if the subgroup of patients with unfavorable clinical and imaging characteristics would receive benefit from intensive blood pressure reduction. It is worth noting that the blood pressure levels in the ATACH-II control group were similar to those seen in the INTERACT2 intervention group, which may account for some of the differences seen between these studies.

Of some concern is the observation that many patients with ICH have positive diffusion signal on brain MRI in locations away from the hemorrhage. One study of 118 ICH patients found that 22.9% had positive diffusion signal reflecting acute ischemia during the first month after ICH. The overwhelming majority of these diffusion changes were small and asymptomatic, though blood pressure lowering was associated with these abnormalities. The 2015 AHA/ASA Guidelines recommend a target systolic blood pressure of less than 140 mm Hg for ICH patients presenting with SBP between 150 mm Hg and 220 mm Hg without contraindications to acute treatment (Class I, Level A), though it is worth noting that this recommendation was made after INTERACT2 and before ATACH-II.

When ICP is elevated, it takes higher MAPs to drive cerebral perfusion pressure. Choice of antihypertensive agent may be important. IV labetalol or nicardipine may provide smooth onset of action and allow physicians to control blood pressure in patients without cardiac contraindications to these agents. Labetalol is begun as 10–20 mg IV push over 1–2 minutes. Doses can be increased up to 20–80 mg every 10-15 minutes, or a continuous infusion starting at 0.5–2 mg/minute can be used if needed. The maximum dose is 300 mg/day. Nicardipine infusions are begun at 5 mg/h. The dose can be increased by 2.5 mg/h at 5–15 minute intervals. The maximum dose is 15 mg/h. Nitrates theoretically may worsen cerebral edema owing to their vasodilatory properties and have traditionally been avoided, given the other available agents. However, this concern may need to be reconsidered based on more recent clinical trial data. The Efficacy of Nitric Oxide in Stroke (ENOS) trial investigated the safety and efficacy of reducing blood pressure using transdermal glyceryl trinitrate given within 48 hours of an ischemic stroke or ICH. In a subgroup analysis restricted to ICH, glyceryl trinitrate was safe in the overall population but did not improve functional outcomes at 90 days. There was a possible functional outcome benefit among the 61 patients randomized to treatment within 6 hours, although this result requires confirmation given the small sample and limitations of subgroup analyses.

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