Joshua B. Bederson

Rat middle cerebral artery occlusion: evaluation of the model and development of a neurologic examination.

We have examined the incidence and size of infarction after occlusion of different portions of the rat middle cerebral artery (MCA) in order to define the reliability and predictability of this model of brain ischemia. We developed a neurologic examination and have correlated changes in neurologic status with the size and location of areas of infarction. The MCA was surgically occluded at different sites in six groups of normal rats. After 24 hr, rats were evaluated for the extent of neurologic deficits and graded as having severe, moderate, or no deficit using a new examination developed for this model. After rats were sacrificed the incidence of infarction was determined at histologic examination. In a subset of rats, the size of the area of infarction was measured as a percent of the area of a standard coronal section. Focal (1-2 mm) occlusion of the MCA at its origin, at the olfactory tract, or lateral to the inferior cerebral vein produced infarction in 13%, 67%, and 0% of rats, respectively (N = 38) and produced variable neurologic deficits. However, more extensive (3 or 6 mm) occlusion of the MCA beginning proximal to the olfactory tract--thus isolating lenticulostriate end-arteries from the proximal and distal supply--produced infarctions of uniform size, location, and with severe neurologic deficit (Grade 2) in 100% of rats (N = 17). Neurologic deficit correlated significantly with the size of the infarcted area (Grade 2, N = 17, 28 +/- 5% infarction; Grade 1, N = 5, 19 +/- 5%; Grade 0, N = 3, 10 +/- 2%; p less than 0.05). We have characterized precise anatomical sites of the MCA that when surgically occluded reliably produce uniform cerebral infarction in rats, and have developed a neurologic grading system that can be used to evaluate the effects of cerebral ischemia rapidly and accurately. The model will be useful for experimental assessment of new therapies for irreversible cerebral ischemia.

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 …

Evaluation of 2,3,5-triphenyltetrazolium chloride as a stain for detection and quantification of experimental cerebral infarction in rats.

We have evaluated the use of 2,3,5-triphenyltetrazolium chloride (TTC) as an histopathologic stain for identification of infarcted rat brain tissue. The middle cerebral artery (MCA) of 35 normal adult rats was occluded surgically. At various times after surgical occlusion, rats were sacrificed and brain slices were obtained and stained with TTC or hematoxolin and eosin (H & E); the size of the area of infarcted tissue stained by each method was quantified. In rats sacrificed 24 hr after occlusion of the MCA, the size of the area of infarction was 21 +/- 2% of the coronal section for TTC, and 21 +/- 2% for H & E (mean +/- S.D., N = 13). The size of areas of infarction determined by either staining method was not significantly different in area by the paired test, and a significant correlation between sizes determined by each method was found by linear regression analysis (r = 0.91, slope = 0.89, and the y intercept = 4.4%). Staining with TTC is a rapid, convenient, inexpensive, and reliable method for the detection and quantification of cerebral infarction in rats 24 hr after the onset of ischemia.

Recommendations for the management of patients with unruptured intracranial aneurysms: A statement for healthcare professionals from the Stroke Council of the American Heart Association.

Aneurysmal subarachnoid hemorrhage (SAH) has a 30-day mortality rate of 45%, with approximately half the survivors sustaining irreversible brain damage.1 On the basis of an annual incidence of 6 per 100 000, ≈15 000 Americans will have an aneurysmal SAH each year. Population-based incidence rates vary considerably from 6 to 16 per 100 000, with the highest rates reported from Japan and Finland.2 3 4 5 Approximately 5% to 15% of stroke cases are secondary to ruptured saccular aneurysms. Although the prevention of hemorrhage has been advocated as the most effective strategy aimed at lowering mortality rates,6 the optimal management of patients with unruptured intracranial aneurysms (UIAs) remains controversial. Management decisions require an accurate assessment of the risks of various treatment options compared with the natural history of the condition. The natural history of UIAs and treatment outcomes are influenced by (1) patient factors, such as previous aneurysmal SAH, age, and coexisting medical conditions; (2) aneurysm characteristics, such as size, location, and morphology; and (3) factors in management, such as the experience of the surgical team and the treating hospital. These many influences have contributed to considerable variability in the reported risks for aneurysmal SAH and the treatment of UIAs. There are no prospective randomized trials of treatment interventions versus conservative management to date, and it is possible that no such studies will be carried out in the future. According to a classification system suggested by Cook et al,7 randomized clinical trials with low likelihoods of false-positive and false-negative errors provide the highest level of evidence (level I) that can be applied to a clinical recommendation. Randomized trials with high likelihoods of false-negative and positive errors provide level II evidence. Level III evidence is generated with nonrandomized concurrent cohort comparisons between contemporaneous patients who did and …

Cortical Blood Flow and Cerebral Perfusion Pressure in a New Noncraniotomy Model of Subarachnoid Hemorrhage in the Rat

BACKGROUND AND PURPOSE Acute cerebral ischemia after subarachnoid hemorrhage (SAH) is a major cause of morbidity whose precise etiology is unclear. The purpose of this study was to examine the relationships between cerebral perfusion pressure (CPP) and cortical blood flow during SAH using a new experimental model in the rat. METHODS CPP (mean arterial pressure minus intracranial pressure), cortical laser-Doppler flowmetry (LDF), and electroencephalogram were continuously recorded during and after SAH in 16 ventilated rats. SAH was produced by advancing an intraluminal suture from the external carotid artery through the internal carotid artery to perforate the vessel near its intracranial bifurcation. RESULTS Eight rats (50%) died within 24 hours of SAH. In all rats, blood was widely distributed throughout the basal, convexity, and interhemispheric subarachnoid spaces and throughout the ventricular system. CPP decreased after SAH at an initial rate of 1.1 +/- 0.2 mm Hg/s, reaching its nadir 59 +/- 9 seconds after the onset of SAH. During the same period, LDF fell at a rate of 1.4 +/- 0.3%/s (P = NS vs CPP). After reaching its nadir, CPP rose at a rate of 0.4 +/- 0.01 mm Hg/s, but LDF continued to fall at 0.2 +/- 0.03%/s (P < .05 vs CPP) reaching a nadir of 21.7 +/- 2.5% significantly later than CPP (189.5 +/- 39 s after SAH, P < .05). No correlation was found between peak changes in CPP and LDF. Electroencephalogram activity followed the changes in LDF, reaching nadir values 289 +/- 55 seconds after SAH. CONCLUSIONS These findings demonstrate that although reduced CPP causes the initial decrease in cortical blood flow after SAH, secondary reductions occurring after CPP has reached its nadir are caused by other factors such as acute vasoconstriction. This noncraniotomy model of SAH in the rat has several advantages over existing models.

Recommendations for the Management of Patients With Unruptured Intracranial Aneurysms A Statement for Healthcare Professionals From the Stroke Council of the American Heart Association

Aneurysmal subarachnoid hemorrhage (SAH) has a 30-day mortality rate of 45%, with approximately half the survivors sustaining irreversible brain damage.1 On the basis of an annual incidence of 6 per 100 000, ≈15 000 Americans will have an aneurysmal SAH each year. Population-based incidence rates vary considerably from 6 to 16 per 100 000, with the highest rates reported from Japan and Finland.2 3 4 5 Approximately 5% to 15% of stroke cases are secondary to ruptured saccular aneurysms. Although the prevention of hemorrhage has been advocated as the most effective strategy aimed at lowering mortality rates,6 the optimal management of patients with unruptured intracranial aneurysms (UIAs) remains controversial. Management decisions require an accurate assessment of the risks of various treatment options compared with the natural history of the condition. The natural history of UIAs and treatment outcomes are influenced by (1) patient factors, such as previous aneurysmal SAH, age, and coexisting medical conditions; (2) aneurysm characteristics, such as size, location, and morphology; and (3) factors in management, such as the experience of the surgical team and the treating hospital. These many influences have contributed to considerable variability in the reported risks for aneurysmal SAH and the treatment of UIAs. There are no prospective randomized trials of treatment interventions versus conservative management to date, and it is possible that no such studies will be carried out in the future. According to a classification system suggested by Cook et al,7 randomized clinical trials with low likelihoods of false-positive and false-negative errors provide the highest level of evidence (level I) that can be applied to a clinical recommendation. Randomized trials with high likelihoods of false-negative and positive errors provide level II evidence. Level III evidence is generated with nonrandomized concurrent cohort comparisons between contemporaneous patients who did and …

Intraventricular thrombolysis speeds blood clot resolution: Results of a pilot, prospective, randomized, double-blind, controlled trial

OBJECTIVEAnimal models and clinical studies suggest that intraventricular thrombolysis improves clot resolution and clinical outcomes among patients with intraventricular hemorrhage. However, this intervention may increase the rates of rebleeding and infection. To assess the safety and efficacy of intraventricular thrombolysis, we conducted a pilot, randomized, double-blind, controlled, multicenter study. METHODSPatients with intraventricular hemorrhage requiring ventriculostomy were randomized to receive intraventricular injections of normal saline solution or urokinase (25,000 international units) at 12-hour intervals. Injections continued until ventricular drainage was discontinued according to prespecified clinical criteria. Head computed tomographic scans were obtained daily, for quantitative determinations of intraventricular hemorrhage volumes. The rate of clot resolution was estimated for each group. RESULTSTwelve subjects were enrolled (urokinase, seven patients; placebo, five patients). Commercial withdrawal of urokinase precluded additional enrollment. The urokinase and placebo groups were similar with respect to age (49.6 versus 55.2 yr, P = 0.43) and presenting Glasgow Coma Scale scores (7.14 versus 8.00, P = 0.72). Randomization to the urokinase treatment arm (P = 0.02) and female sex (P = 0.008) favorably affected the clot resolution rate. The sex-adjusted clot half-life for the urokinase-treated group was reduced 44.6%, compared with the value for the placebo group (4.69 versus 8.48 d). CONCLUSIONIntraventricular thrombolysis with urokinase speeds the resolution of intraventricular blood clots, compared with treatment with ventricular drainage alone.

Treatment of Intraventricular Hemorrhage With Urokinase Effects on 30-Day Survival

BACKGROUND AND PURPOSE Intraventricular hemorrhage (IVH) remains associated with high morbidity and mortality. Therapy with external ventricular drainage alone has not modified outcome in these patients. METHODS Twelve pilot IVH patients who required external ventricular drainage were prospectively treated with intraventricular urokinase followed by the randomized, double-blinded allocation of 8 patients to either treatment or placebo. Observed 30-day mortality was compared with predicted 30-day mortality obtained by use of a previously validated method. RESULTS Twenty patients were enrolled; admission Glasgow Coma Scale score in 11 patients was </=8; 10 patients had pulse pressure <85 mm Hg. Mean+/-SD ICH volume in 16 patients was 6.21+/-7.53 cm(3) (range 0 to 23.88 cm(3)), and mean+/-SD intraventricular hematoma volume was 44.26+/-31.65 cm(3) (range 1.31 to 100.36 cm(3)). Four patients (20%) died within 30 days. Predicted mortality for these 20 patients was 68.42% (range 3% to 100%). Probability of observing </=4 deaths among 20 patients under a 68.42% expected mortality is 0.000012. CONCLUSIONS Intraventricular urokinase may significantly improve 30-day survival in IVH patients. On the basis of current evidence, a double-blinded, placebo-controlled, multicenter study that uses thrombolysis to treat IVH has received funding and began January 1, 2000.

Mechanisms of acute brain injury after subarachnoid hemorrhage

Abstract Brain injury after subarachnoid hemorrhage (SAH) is a biphasic event with an acute ischemic insult at the time of the initial bleed and secondary events such as cerebral vasospasm 3 to 7 days later. Although much has been learned about the delayed effects of SAH, less is known about the mechanisms of acute SAH-induced injury. Distribution of blood in the subarachnoid space, elevation of intracranial pressure, reduced cerebral perfusion and cerebral blood flow (CBF) initiates the acute injury cascade. Together they lead to direct microvascular injury, plugging of vessels and release of vasoactive substances by platelet aggregates, alterations in the nitric oxide (NO)/nitric oxide synthase (NOS) pathways and lipid peroxidation. This review will summarize some of these mechanisms that contribute to acute cerebral injury after SAH.

Use of an acellular dermal allograft for dural replacement: an experimental study.

OBJECTIVE In this study, a nonimmunogenic, acellular, dermal collagen matrix termed XenoDerm (LifeCell Corp., The Woodlands, TX) was examined for use as a dural replacement material in a porcine model. This model was used to investigate whether AlloDerm (LifeCell), an almost identical material made from human dermis, could be safely used in neurological surgery. METHODS Bilateral temporoparietal dural defects were surgically created in 12 Yucatan minipigs. One side was repaired with autologous pericranium, and the other was repaired with XenoDerm. The pigs were killed after 1, 3, or 6 months, and the areas of dural repair were collected and examined macroscopically and histologically. XenoDerm is derived from porcine skin collected in thin sheets. It is processed so that the epidermis and all dermal cells are removed without disruption of the collagen matrix, rendering the material immunogenically inert and resistant to calcification. It is packaged as a freeze-dried sheet and is easily rehydrated at the time of surgery. RESULTS There were no postoperative complications, and all pigs survived. Both grafts performed well as dural replacements in all cases. There was no macroscopic evidence of inflammation or cerebrospinal fluid leakage. The XenoDerm grafts were intact, retained their original dimensions, and resembled the surrounding dura. The autologous pericranial grafts, in contrast, were thicker than when implanted and had bony excrescences firmly adhering to their surfaces. Again, however, there was no evidence of cerebrospinal fluid fistulae. There was no gross adherence to the underlying meninges or brain tissue in any specimen. Repopulation by fibroblasts and neovascularization were evident in the XenoDerm grafts as early as 1 month after surgery; by 3 months, the XenoDerm had been remodeled to assume the connective tissue appearance of the surrounding dura. CONCLUSION In this porcine model, an allograft of acellular dermis is a nearly ideal dural replacement. AlloDerm, the human equivalent of XenoDerm, would be an allograft of acellular dermis after implantation in human subjects. On the basis of this study and previous work with AlloDerm in other reconstructive applications, it is proposed that this material could be similarly used for duraplasty in human subjects.