Michael N. Diringer

Guidelines for the Management of Aneurysmal Subarachnoid Hemorrhage A Statement for Healthcare Professionals From a Special Writing Group of the Stroke Council, American Heart Association

Subarachnoid hemorrhage (SAH) is a common and frequently devastating condition, accounting for ≈5% of all strokes and affecting as many as 30 000 Americans each year.1,2 The American Heart Association (AHA) previously published “Guidelines for the Management of Aneurysmal Subarachnoid Hemorrhage.”3 Since then, considerable advances have been made in endovascular techniques, diagnostic methods, and surgical and perioperative management paradigms. Nevertheless, outcome for patients with SAH remains poor, with population-based mortality rates as high as 45% and significant morbidity among survivors.4–9 Several multicenter, prospective, randomized trials and prospective cohort analyses have influenced treatment protocols for SAH. However, rapid evolution of newer treatment modalities, as well as other practical and ethical considerations, has meant that rigorous clinical scientific assessment of the treatment protocols has not been feasible in several important areas. To address these issues, the Stroke Council of the AHA formed a writing group to reevaluate the recommendations for management of aneurysmal SAH. A consensus committee reviewed existing data in this field and prepared the recommendations in 1994.3 In an effort to update those recommendations, a systematic literature review was conducted based on a search of MEDLINE to identify all relevant randomized clinical trials published between June 30, 1994, and November 1, 2006 (search terms: subarachnoid hemorrhage , cerebral aneurysm , trial ; Table 1). Each identified article was reviewed by at least 2 members of the writing group. Selected articles had to meet one of the following criteria to be included: randomized trial or nonrandomized concurrent cohort study. Case series and nonrandomized historical cohort studies were reviewed if no studies with a higher level of evidence were available for a particular topic covered in the initial guidelines. These were chosen on the basis of sample size and the relevance of the particular studies to subjects that …

Efficacy and safety of recombinant activated factor VII for acute intracerebral hemorrhage

BACKGROUND Intracerebral hemorrhage is the least treatable form of stroke. We performed this phase 3 trial to confirm a previous study in which recombinant activated factor VII (rFVIIa) reduced growth of the hematoma and improved survival and functional outcomes. METHODS We randomly assigned 841 patients with intracerebral hemorrhage to receive placebo (268 patients), 20 microg of rFVIIa per kilogram of body weight (276 patients), or 80 microg of rFVIIa per kilogram (297 patients) within 4 hours after the onset of stroke. The primary end point was poor outcome, defined as severe disability or death according to the modified Rankin scale 90 days after the stroke. RESULTS Treatment with 80 microg of rFVIIa per kilogram resulted in a significant reduction in growth in volume of the hemorrhage. The mean estimated increase in volume of the intracerebral hemorrhage at 24 hours was 26% in the placebo group, as compared with 18% in the group receiving 20 microg of rFVIIa per kilogram (P=0.09) and 11% in the group receiving 80 microg (P<0.001). The growth in volume of intracerebral hemorrhage was reduced by 2.6 ml (95% confidence interval [CI], -0.3 to 5.5; P=0.08) in the group receiving 20 microg of rFVIIa per kilogram and by 3.8 ml (95% CI, 0.9 to 6.7; P=0.009) in the group receiving 80 microg, as compared with the placebo group. Despite this reduction in bleeding, there was no significant difference among the three groups in the proportion of patients with poor clinical outcome (24% in the placebo group, 26% in the group receiving 20 microg of rFVIIa per kilogram, and 29% in the group receiving 80 microg). The overall frequency of thromboembolic serious adverse events was similar in the three groups; however, arterial events were more frequent in the group receiving 80 microg of rFVIIa than in the placebo group (9% vs. 4%, P=0.04). CONCLUSIONS Hemostatic therapy with rFVIIa reduced growth of the hematoma but did not improve survival or functional outcome after intracerebral hemorrhage. (ClinicalTrials.gov number, NCT00127283 [ClinicalTrials.gov].).

Critical Care Management of Patients Following Aneurysmal Subarachnoid Hemorrhage: Recommendations from the Neurocritical Care Society’s Multidisciplinary Consensus Conference

Subarachnoid hemorrhage (SAH) is an acute cerebrovascular event which can have devastating effects on the central nervous system as well as a profound impact on several other organs. SAH patients are routinely admitted to an intensive care unit and are cared for by a multidisciplinary team. A lack of high quality data has led to numerous approaches to management and limited guidance on choosing among them. Existing guidelines emphasize risk factors, prevention, natural history, and prevention of rebleeding, but provide limited discussion of the complex critical care issues involved in the care of SAH patients. The Neurocritical Care Society organized an international, multidisciplinary consensus conference on the critical care management of SAH to address this need. Experts from neurocritical care, neurosurgery, neurology, interventional neuroradiology, and neuroanesthesiology from Europe and North America were recruited based on their publications and expertise. A jury of four experienced neurointensivists was selected for their experience in clinical investigations and development of practice guidelines. Recommendations were developed based on literature review using the GRADE system, discussion integrating the literature with the collective experience of the participants and critical review by an impartial jury. Recommendations were developed using the GRADE system. Emphasis was placed on the principle that recommendations should be based not only on the quality of the data but also tradeoffs and translation into practice. Strong consideration was given to providing guidance and recommendations for all issues faced in the daily management of SAH patients, even in the absence of high quality data.

Definition of Delayed Cerebral Ischemia After Aneurysmal Subarachnoid Hemorrhage as an Outcome Event in Clinical Trials and Observational Studies Proposal of a Multidisciplinary Research Group

Background and Purpose— In clinical trials and observational studies there is considerable inconsistency in the use of definitions to describe delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage. A major cause for this inconsistency is the combining of radiographic evidence of vasospasm with clinical features of cerebral ischemia, although multiple factors may contribute to DCI. The second issue is the variability and overlap of terms used to describe each phenomenon. This makes comparisons among studies difficult. Methods— An international ad hoc panel of experts involved in subarachnoid hemorrhage research developed and proposed a definition of DCI to be used as an outcome measure in clinical trials and observational studies. We used a consensus-building approach. Results— It is proposed that in observational studies and clinical trials aiming to investigate strategies to prevent DCI, the 2 main outcome measures should be: (1) cerebral infarction identified on CT or MRI or proven at autopsy, after exclusion of procedure-related infarctions; and (2) functional outcome. Secondary outcome measure should be clinical deterioration caused by DCI, after exclusion of other potential causes of clinical deterioration. Vasospasm on angiography or transcranial Doppler can also be used as an outcome measure to investigate proof of concept but should be interpreted in conjunction with DCI or functional outcome. Conclusion— The proposed measures reflect the most relevant morphological and clinical features of DCI without regard to pathogenesis to be used as an outcome measure in clinical trials and observational studies.

Admission to a neurologic/neurosurgical intensive care unit is associated with reduced mortality rate after intracerebral hemorrhage.

ObjectiveTo determine whether mortality rate after intracerebral hemorrhage (ICH) is lower in patients admitted to a neurologic or neurosurgical (neuro) intensive care unit (ICU) compared to those admitted to general ICUs. BackgroundThe utility of specialty ICUs is debated. From a cost perspective, having fewer larger ICUs is preferred. Alternatively, the impact of specialty ICUs on patient outcome is unknown. Patients with ICH are admitted routinely to both general and neuro ICUs and provide an opportunity to address this question. SettingForty-two neuro, medical, surgical, and medical-surgical ICUs. Measurements and Main Results The study was an analysis of data prospectively collected by Project Impact over 3 yrs from 42 participating ICUs (including one neuro ICU) across the country. The records of 36,986 patients were merged with records of 3,298 patients from a second neuro ICU that collected the same data over the same period. The impact of clinical (age, race, gender, Glasgow Coma Scale score, reason for admission, insurance), ICU (size, number of ICH patients, full-time intensivist, clinical service, American College for Graduate Medical Education or Critical Care Medicine fellowship), and institutional (size, location, medical school affiliation) characteristics on hospital mortality rate of ICH patients was assessed by using a forward-enter multivariate analysis. Data from 1,038 patients were included. The 13 ICUs that admitted >20 patients accounted for 83% of the admissions with a mortality rate that ranged from 25% to 64%. Multivariate analysis adjusted for patient demographics, severity of ICH, and ICU and institutional characteristics indicated that not being in a neuro ICU was associated with an increase in hospital mortality rate (odds ratio [OR], 3.4; 95% confidence interval [CI], 1.65–7.6). Other factors associated with higher mortality rate were greater age (OR, 1.03/year; 95% CI, 1.01–1.04), lower Glasgow Coma Scale score (OR, 0.6/point; 95% CI, 0.58–0.65), fewer ICH patients (OR, 1.01/patient; 95% CI, 1.00–1.01), and smaller ICU (OR, 1.1/bed; 95% CI, 1.02–1.13). Having a full time intensivist was associated with lower mortality rate (OR, 0.388; 95% CI, 0.22–0.67). ConclusionsFor patients with acute ICH, admission to a neuro vs. general ICU is associated with reduced mortality rate.

Hypoperfusion Without Ischemia Surrounding Acute Intracerebral Hemorrhage

A zone of hypoperfusion surrounding acute intracerebral hemorrhage (ICH) has been interpreted as regional ischemia. To determine if ischemia is present in the periclot area, the authors measured cerebral blood flow (CBF), cerebral metabolic rate of oxygen (CMRO2), and oxygen extraction fraction (OEF) with positron emission tomography (PET) in 19 patients 5 to 22 hours after hemorrhage onset. Periclot CBF, CMRO2, and OEF were determined in a 1-cm-wide area around the clot. In the 16 patients without midline shift, periclot data were compared with mirror contralateral regions. All PET images were masked to exclude noncerebral structures, and all PET measurements were corrected for partial volume effect due to clot and ventricles. Both periclot CBF and CMRO2 were significantly reduced compared with contralateral values (CBF: 20.9 ± 7.6 vs. 37.0 ± 13.9 mL 100 g−1 min−1, P = 0.0004; CMRO2: 1.4 ± 0.5 vs. 2.9 ± 0.9 mL 100 g−1 min−1, P = 0.00001). Periclot OEF was less than both hemispheric OEF (0.42 ± 0.15 vs. 0.47 ± 0.13, P = 0.05; n = 19) and contralateral regional OEF (0.44 ± 0.16 vs. 0.51 ± 0.13, P = 0.05; n = 16). In conclusion, CMRO2 was reduced to a greater degree than CBF in the periclot region in acute ICH, resulting in reduced OEF rather than the increased OEF that occurs in ischemia. Thus, the authors found no evidence for ischemia in the periclot zone of hypoperfusion in acute ICH patients studied 5 to 22 hours after hemorrhage onset.

Progression of Mass Effect After Intracerebral Hemorrhage

BACKGROUND AND PURPOSE While the evolution of mass effect after cerebral infarction is well characterized, similar data regarding intracerebral hemorrhage (ICH) are scant. Our goal was to determine the time course and cause for progression of mass effect after ICH. METHODS Patients with spontaneous supratentorial ICH who underwent >/=2 CT scans were identified in our prospectively collected database. CT lesion size and midline shift of the pineal and septum pellucidum were retrospectively measured and correlated with clinical and CT characteristics. Causes for increased midline shift were determined by 2 independent observers. RESULTS Seventy-six patients underwent 235 scans (3.1+/-1.3 per patient). Initial CT was obtained within 24 hours of ICH in 66. Twenty-five scans were repeated on day 1, 80 on days 2 through 7, 31 on days 8 through 14, and 24 >14 days after ICH. Midline shift was present on 88% of the initial scans. There were 17 instances of midline shift progression: 10 occurred early (0.2 to 1.7 days) and were associated with hematoma enlargement, and 7 occurred late (9 to 21 days) and were associated with edema progression. Progression of mass effect due to edema occurred with larger hemorrhages (P<0.05). Of 65 scans repeated for clinical deterioration, only 10 were associated with increased mass effect. CONCLUSIONS Progression of mass effect after ICH occurred at 2 distinct time points: within 2 days, associated with hematoma enlargement, and in the second and third weeks, associated with increase in edema. The clinical significance of later-developing edema is unclear.

Autoregulation of cerebral blood flow surrounding acute (6 to 22 hours) intracerebral hemorrhage

Background: Arterial hypertension is common in the first 24 hours after acute intracerebral hemorrhage (ICH). Although increased blood pressure usually declines to baseline values within several days, the appropriate treatment during the acute period has remained controversial. Arguments against treatment of hypertension in patients with acute ICH are based primarily on the concern that reducing arterial blood pressure will reduce cerebral blood flow (CBF). The authors undertook this study to provide further information on the changes in whole-brain and periclot regional CBF that occur with pharmacologic reductions in mean arterial pressure (MAP) in patients with acute ICH. Methods: Fourteen patients with acute supratentorial ICH 1 to 45 mL in size were studied 6 to 22 hours after onset. CBF was measured with PET and 15O-water. After completion of the first CBF measurement, patients were randomized to receive either nicardipine or labetalol to reduce MAP by 15%, and the CBF study was repeated. Results: MAP was lowered by −16.7 ± 5.4% from 143 ± 10 to 119 ± 11 mm Hg. There was no significant change in either global CBF or periclot CBF. Calculation of the 95% CI demonstrated that there is less than a 5% chance that global or periclot CBF fell by more than −2.7 mL 100 g−1 min−1. Conclusion: In patients with small- to medium-sized acute ICH, autoregulation of CBF was preserved with arterial blood pressure reductions in the range studied.

Intracerebral Hemorrhage Associated With Oral Anticoagulant Therapy Current Practices and Unresolved Questions

Background and Purpose— Life-threatening intracranial hemorrhage, predominantly intracerebral hemorrhage (ICH), is the most serious complication of oral anticoagulant therapy (OAT), with mortality in excess of 50%. Early intervention focuses on rapid correction of coagulopathy in order to prevent continued bleeding. Summary of Review— This article reviews the epidemiology of OAT-associated ICH (OAT-ICH), and current treatment options, with the aim of providing a framework for future studies of unresolved questions. A number of acute treatments are available, but all have a significant risk of inducing thrombosis and other side effects, and vary in their rapidity of effect: vitamin K (very slow response time), fresh frozen plasma (slow response time, large volume of fluid required, transfusion-related acute lung injury), prothrombin complex concentrates, and recombinant activated factor VII. Current practice is to administer a combination of vitamin K and either fresh frozen plasma or prothrombin complex concentrates; the occasional use of recombinant activated factor VII has been reported. No prospective study has addressed the efficacy of, or outcomes from, the use of these practices. Conclusions— Current management of OAT-ICH is varied and not based on evidence from randomized controlled trials. Well-designed clinical trials are essential if we are to identify the effective acute treatments for OAT-ICH that are urgently needed.

Hydrocephalus: A Previously Unrecognized Predictor of Poor Outcome From Supratentorial Intracerebral Hemorrhage

BACKGROUND AND PURPOSE Although several factors have been identified that predict outcome after intracerebral hemorrhage (ICH), no previous study has investigated the impact of hydrocephalus. The purpose of this study was to determine whether the presence of hydrocephalus after ICH would predict mortality and functional outcome. METHODS Patients with spontaneous supratentorial ICH were identified in our prospectively collected database to determine the following: age, sex, race, past medical history; Glasgow Coma Scale (GCS) score and blood pressure on admission; use of mechanical ventilation, mannitol, and ventriculostomy; and medical complications. CT scans performed within 24 hours of hemorrhage were retrospectively analyzed to determine lesion size and location, pineal shift, cisternal effacement, intraventricular hemorrhage (IVH), and hydrocephalus. Outcome was determined with use of hospital disposition (dead, nursing home, rehabilitation, home) and functional outcome (Functional Independence Measure [FIM]) at 3 months. Patients with and without hydrocephalus were compared and univariate and multivariate analyses performed to determine whether hydrocephalus was an independent predictor of mortality. Data are presented as mean+/-SD. RESULTS Of the 81 patients studied, 40 had hydrocephalus. Those with hydrocephalus were younger (57+/-15 versus 67+/-15 years), had lower GCS scores (8.2+/-4.2 versus 11+/-2.9), were more likely to have ganglionic or thalamic hemorrhages, and were intubated more frequently (70% versus 27%). Hospital mortality was higher in patients with hydrocephalus (51% versus 2%), and fewer patients went home (21% versus 35%). Those who died had higher hydrocephalus scores (9.67+/-7.1 versus 5.75+/-4.5). Outcome was no different if a ventriculostomy was placed. The final logistic regression model included hydrocephalus score, gender, GCS, and pineal shift, and it correctly predicted 85% of patients as dead or alive. Multivariate analyses indicated that hydrocephalus is an independent predictor of mortality. CONCLUSIONS We conclude that hydrocephalus is an independent predictor of mortality after ICH.