EARLY CLINICAL DETERIORATION IS ASSOCIATED WITH INCREASED MORTALITY AND MORBIDITY IN INTRACEREBRAL HEMORRHAGE

Spontaneous intracerebral hemorrhage (ICH) remains the most lethal and disabling form of stroke. Overall mortality is close to 50% and, unlike in patients with ischemic stroke, most mortality occurs early, often within the first 48 hours.¹ Patients fortunate enough to survive are often left with significant neurologic deficits, and few ever regain independence. Nearly 50% of all survivors of ICH remain dependent months after the hemorrhage, most are institutionalized in skilled nursing settings, and only 10% return to independence.²

Clinical deterioration may occur throughout the first week after the hemorrhage occurs. While early neurologic deterioration (END) occurs in patients with ischemic stroke, it is far more common in patients with ICH; up to 40% of all patients with ICH clinically deteriorate in the first 24-48 hours.^3,4 Although patients may gradually improve clinically over the days and weeks that follow hemorrhage onset, most are left permanently impaired, and the occurrence of END is associated with worse long-term mortality and disability.⁴ In the study by Leira et al, END was associated with a nearly 8-fold increase in the likelihood of poor outcome.⁴ Therefore, attempting to stop or limit the development of END in patients with ICH is desirable, with the hope and goal of mitigating permanent impairment and, even, death.

END and worse clinical outcomes have been associated with several factors. Hematoma expansion, rebleeding, intraventricular hemorrhage extension, hyperthermia, increased inflammatory response, subsequent hydrocephalus, and hemostatic abnormalities that cause larger and more prolonged hemorrhages have all been hypothesized to contribute to END.⁴ Later clinical deterioration is often associated with resulting perihematomal edema and perilesional inflammation formation, and, again, secondary medical complications precipitated by the ICH. All potential causes of END represent targets for therapeutic intervention; intuitively, decreasing END would decrease subacute decline and, therefore, decrease permanent disability.

In order to limit END, a better understanding of the hematoma development is critical. Brott and colleagues first began to study ultra-early hematoma growth and clinical deterioration only a decade ago.⁵ Their landmark study dismissed the idea that spontaneous ICH is a monophasic event (that hematoma volume is stable and no further growth occurs). In their conservative estimate, nearly one third of hemorrhages increased in size over the first 24 hours, and most growth occurred within the first hour after presentation. In these early studies, END often paralleled increasing hematoma volume and edema formation.³ More recent studies estimate that hematoma growth of some degree occurs in up to 72% of patients over the first 24 hours.⁶ After demonstrating that a significant number of patients experience hematoma growth and establishing the temporal association of END with hematoma growth, the obvious challenge was to develop strategies to limit hematoma expansion.

Therapeutic strategies to limit hematoma growth remain elusive. Physicians must first better understand what potentiates hematoma growth. Intuitively, ICH growth is associated with anticoagulation use (both heparin and warfarin). However, most patients with ICH are not taking anticoagulants but still experience hematoma expansion. Early studies attempted to link ICH growth with seemingly obvious clinical features: elevated blood pressure, antiplatelet use, and initial CT findings.^4,7,8 However, what seemed obvious has not been conclusively associated with continued hemorrhage.⁸ Numerous studies have failed to link elevated blood pressure or hemodynamic variables with hematoma growth.^5,8 However, while elevations in blood pressure may not produce hematoma expansion, they may still be associated with END and worse outcomes.⁹ Similarly, the association of antiplatelet use and hematoma expansion has not been confirmed. Without obvious therapeutic targets for limiting hematoma expansion, optimizing and manipulating hemostatic conditions both in patients who are taking anticoagulants and in those who are not has become an intense area of research interest.

Recognizing that END is associated with increased mortality and morbidity, and that clinical decline closely follows hematoma expansion and edema formation, limiting these pathophysiological processes are likely essential to improving the typical devastating clinical outcome in ICH. Ongoing research aims to stop hematoma growth and its associated edema formation.

As other issues in this series discuss, until this past decade, few studies have investigated altering the normal coagulation pathways in an attempt to limit hematoma growth. Small, largely convenience studies of both spontaneous hemorrhages and those associated with anticoagulation have investigated the capabilities of fresh frozen plasma, prothrombin complex concentrates, vitamin K, and tranexamic acid to limit ICH expansion.¹⁰ These studies have not demonstrated a strong rationale to move forward with larger studies of these agents, although, in fairness, few have been studied in the hyperacute phase, which is when most hematoma expansion occurs and when limiting hematoma growth would produce maximal clinical benefit.

Recently, stroke researchers have studied the use of recombinant activated factor VII (rFVIIa) in the hyperacute phase (<4 h from hemorrhage onset).¹¹ Pilot data and a phase II study demonstrated encouraging safety and efficacy and were the basis for the phase III clinical trial that is now near completion.^12,13 Perhaps, in the coming year, the first targeted therapeutic intervention for ICH may be available.

Recognizing that hematoma expansion and associated clinical deterioration occur early and rapidly, the responsibility of preventing growth and END places the emergency medicine physician at the forefront of care for patients with ICH. Rapid presentation to the emergency department, early identification and diagnosis, physiologic optimization, emergent hemostatic therapy (possibly), and admission to stroke units may finally make inroads into what has been a largely lethal and disabling disease.

REFERENCES

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