David E. Levy

Increased damage after ischemic stroke in patients with hyperglycemia with or without established diabetes mellitus

Animal experiments employing controlled degrees of cerebral ischemia have demonstrated that elevated blood-brain glucose concentrations greatly enhance the extent and degree of subsequent brain damage. The question of whether or not a similar relationship applies in man was examined by retrospectively segregating patients admitted with the diagnosis of ischemic stroke into diabetic (n = 35) and nondiabetic (n = 72) groups. A separate nondiabetic population with ischemic stroke was prospectively analyzed by dividing patients into those with an admission blood glucose level above (n = 14) or below (n = 17) 120 mg/dl. The neurologic status at discharge was used to stratify outcome as good, fair, or poor in the retrospective study. The ability or inability to return to work was used to separate good and poor outcomes in the prospective study. Neurologic outcome in diabetic patients with stroke was significantly worse (p less than 0.05) than in nondiabetic patients, and the diabetic patients had a greater (p less than 0.05) number of stroke-related deaths. In the prospective study, neurologic outcome also was worse with high blood sugar levels, only 43 percent of the patients with blood glucose values above 120 mg/dl returned to work, whereas 76 percent of those with lower blood sugar values regained employment (p = 0.061).

Prognosis in Nontraumatic Coma

We conducted serial neurologic examinations on 500 patients in nontraumatic coma to identify factors predicting recovery. Overall, 81 patients (16%) led an independent life at some point within the first year; the remainder either died without recovery from coma (61%), never improved beyond the vegetative state (12%), or regained consciousness but remained dependent on others for daily activities (11%). Functional recovery did not depend on age but was to some degree related to the cause of coma (subarachnoid hemorrhage and other cerebrovascular disease having the worst recovery; hypoxia-ischemia, intermediate; and hepatic and miscellaneous causes, best) and especially to early clinical signs of brain dysfunction. Even within hours of the onset of coma, only one of 120 patients lacking two of corneal, pupillary, and oculovestibular responses ever regained independent function. The study identifies clinical features of comatose patients that appear within the first week and that are important for predicting recovery and designing future therapeutic trials.

Factors related to intracranial hematoma formation in patients receiving tissue-type plasminogen activator for acute ischemic stroke

Background and Purpose Several studies are currently evaluating tissue-type plasminogen activator (TPA) as a potential therapy in acute ischemic stroke. The possibility of inducing intracranial hematomas, however, introduces an important concern into ultimate evaluation of risk and benefit. This retrospective analysis sought to identify factors associated with intracranial hematoma formation in a pilot phase 1 study of TPA for stroke. Methods Ninety-four patients received TPA within 3 hours of the onset of an acute ischemic stroke. Five of these patients developed a symptomatic intracerebral hematoma: 3 of 74 (4%) among patients treated within 90 minutes of stroke onset and 2 of 20 (10%) among those treated at 91 to 180 minutes. Three of the 5 died within 2 weeks. The analysis investigated associations between clinical factors and intracerebral hematomas. Results Factors significantly related to the development of an intracerebral hematoma were TPA dose and diastolic hypertension. Intracerebral hematomas developed in 4 (18%) of 22 patients given a TPA dose of at least 0.90 mg/kg versus only 1 hematoma in the remaining 72 patients (1%; P<<.02, Fishers exact test). Four (18%) of 22 patients who had initial diastolic blood pressures of at least 100 mm Hg suffered an intracerebral hematoma versus only 1 (1%) of 72 patients (P<.02) with lower initial diastolic pressures. Conclusions Since the study was not designed to test specific safety hypotheses, results must not be overinterpreted. Nonetheless, these data emphasize the need for caution in both patient and dose selection for further studies of throm-bolytic agents in stroke. (Stroke. 1994;5:291-297.)

Regional brain blood flow in the conscious gerbil.

Regional brain blood flow was determined in 23 awake, unparalyzed gerbils with a simplified indicator-fractionation technique. The use of intravenous 14C-butanol, an indicator that is freely diffusible into the brain, eliminated the need for repetitive sampling of arterial and cerebral venous blood and reduced the period of indicator circulation to 10 seconds. Gerbils spontaneously breathing room air (Paco2 = 32 ± I (SE) mm Hg) had blood flows in whole cerebrum, cerebellum, and brainstem of 102 ± 4, 93 ± 5, and 114 ± 6 ml/lOOgm/min respectively. Cerebral blood flow increased linearly with elevations in Paco2 (r = 0.969) and averaged 3.14 ± 0.17 ml/lOOgm/min per mm Hg increase in Paco2. Interpolated cerebral blood flow at a Paco2 of 40 mm Hg was 127 ± 2 ml/lOOgm/min. This technique is easy and convenient to use, involves no intracrania! surgery, requires steady state conditions for only 10 seconds, and minimizes blood loss in small animals. In more discrete brain regions a less volatile indicator is needed.

How transient are transient ischemic attacks

Information on 1,343 hospitalized patients in the Cornell Neurology Database with final diagnoses of transient ischemic attacks (TIA), reversible ischemic neurologic deficits (RIND), or ischemic stroke was examined in order to determine the duration of ischemic deficits. Episodes resolved within the first 24 hours (classic definition of TIA) in 382 of the patients (28.4%) and between days 1 and 7 (consistent with RIND) in 34 (2.5%). In 191 of the 382 patients with traditionally-defined TIAs (50.0%), episodes lasted less than 30 minutes, and in another 37 (9.7%), from 30 to 60 minutes. Of 1,115 patients with deficits lasting at least 60 minutes, only 154 (13.8%) resolved within 24 hours and could thus be considered to have had a TIA. Resolution within the next hour occurred in only 39 of 1,152 patients (3.4%) with a deficit at 30 minutes, 21 of 1,115 patients (1.9%) with a deficit at 60 minutes, 19 of 1,113 patients (1.7%) with a deficit at 90 minutes, and 16 of 1,094 patients (1.5%) with a deficit at 120 minutes. The data suggest that as currently managed, patients with a deficit persisting at least 60 minutes have less than a 2% chance of resolving spontaneously during any subsequent 1-hour period. Rapid resolution after instituting a new treatment in relatively few additional patients would suggest a therapeutic effect, even in a nonrandomized trial.

Delayed postischemic hypoperfusion: a potentially damaging consequence of stroke.

Cerebral blood flow (CBF) was assessed with radioactive butanol and antipyrine during and after 1 hour of unilateral carotid artery occlusion in gerbils. Animals with clinical evidence of stroke demonstrated a marked fall in ipsilateral CBF during occlusion “no-reflow” phenomenon did not develop; instead, blood flow returned to normal 5 minutes after the termination of carotid occlusion. Flow subsequently fell to half the control value, however, and remained depressed for several hours despite increased local metabolic demands. This delayed imbalance in energy supply and demand creates a potential for additional brain damage that might be prevented by appropriate therapeutic intervention.

Blood pressure during the first minutes of focal cerebral ischemia

STUDY OBJECTIVE To determine whether blood pressure declines spontaneously during the first minutes and hours of focal cerebral ischemia. DESIGN Multiple blood pressure measurements as part of an urgent stroke therapy trial (treatment within 90 minutes of stroke onset). SETTING Thirteen hospitals in three metropolitan communities. PARTICIPANTS Sixty-nine patients (mean age, 65 +/- 9 years) with acute ischemic stroke who were participants in a phase I urgent stroke therapy trial of recombinant tissue plasminogen activator. MAIN OUTCOME MEASURE Blood pressures recorded at the scene of stroke by life-squad personnel, in the emergency department, and in the ICU. RESULTS The mean time from stroke onset to the time of first blood pressure measurement was 19 +/- 13 minutes. Twenty-four of the 69 patients in the urgent stroke therapy trial had an initial systolic blood pressure of at least 160 mm Hg. Of these, 23 had a significant decline in systolic and diastolic blood pressure during the first 90 minutes after the onset of stroke (mean change in systolic pressure, -29 +/- 22 mm Hg, P < .001; mean change in diastolic pressure, -10 +/- 14 mm Hg, P < .01). No patients received antihypertensive therapy during the time in which the decline in blood pressure was noted. CONCLUSION Mildly or moderately elevated blood pressure frequently declines spontaneously during the first minutes and hours of focal cerebral ischemia and generally does not require urgent pharmacologic treatment.

Hypoxic-ischemic brain injury and the vegetative state: clinical and neuropathologic correlation.

We studied 10 patients who survived for 2 to 8 weeks in a vegetative state, including 8 with cardiopulmonary failure and 2 with subarachnoid hemorrhage. Within days of onset, they regained brainstem function and awoke, but none had evidence of cognitive awareness. All patients opened their eyes within 2 weeks, and eight had roving conjugate eye movements. Pupillary and corneal responses were intact within 1 week, and seven patients had tonic oculovestibular responses (OVR) within 24 hours. By the end of 1 day, only three patients failed to move limbs in response to noxious stimuli. At postmortem, all patients had widespread ischemic neuronal damage in the cerebral hemispheres. The brainstems lacked morphologic abnormality, except that one patient had a single microinfarct in the superior colliculus.

Ancrod in Acute Ischemic Stroke Results of 500 Subjects Beginning Treatment Within 6 Hours of Stroke Onset in the Ancrod Stroke Program

Background and Purpose— Previous studies of multiple-day dosing with the defibrinogenating agent, ancrod, in acute ischemic stroke yielded conflicting results but suggested that a brief dosing regimen might improve efficacy and safety. The Ancrod Stroke Program was designed to test this concept in subjects beginning ancrod or placebo within 6 hours of the onset of acute ischemic stroke. Methods— Five hundred subjects with acute ischemic stroke who could begin receiving study material within 6 hours of symptom onset were infused intravenously with either ancrod (0.167 IU/kg per hour) or placebo over 2 or 3 hours. The primary efficacy outcome was a dichotomized, modified Rankin score at 90 days with less stringent cut-points for higher prestroke modified Rankin score and pretreatment NIHSS total score (“responder analysis”). Safety variables included mortality, major bleeding, and intracranial hemorrhage. Results— Although the desired changes in fibrinogen level were seen in >90% of ancrod subjects, interim analysis for futility led to the study being halted for lack of efficacy. Positive responder status in the interim dataset was seen in 39.6% of ancrod subjects and 37.2% of placebo subjects (P=0.47). Ninety-day mortality did not differ between the 2 groups (ancrod, 15.6%; placebo, 14.1%; P=0.32), and the incidence of symptomatic intracranial hemorrhage within the first 72 hours, although not significantly different in ancrod compared to placebo subjects (P=0.19), was approximately twice as high (3.9% vs 2.0%; P=0.19). Conclusion— These results demonstrate that intravenous ancrod starting within 6 hours after symptom onset in a broad selection of subjects with ischemic stroke did not improve their outcome and revealed a trend to increased bleeding despite successful efforts to achieve rapid initial defibrinogenation and avoid prolonged hypofibrinogenemia.

Experimental cerebral ischemia produces platelet aggregates

Human studies indicate that transient platelet abnormalities accompany acute cerebral ischemia. Although these abnormalities may precipitate the ischemic process, ischemia could also alter platelet function. Platelets were therefore studied in gerbils subjected to 1 hour of unilateral carotid artery occlusion. Venous blood from five clinically affected gerbils contained more aggregated platelets (37.8% ± 6.4) than did blood from eight unaffected animals (11.1% ± 3 .0; p <0.01). Platelets labeled with 3H-serotonin were increased in ishcemic brain; the ratio of radioactivity in the ipsilateral versus contralateral hemisphere was greater in eight dected (1.09 f 0.03) than in 19 unaffected (1.00 ± 0.01; p <0.02) animals. The radioactive serotonin was located predominantly within blood vessels. Cerebral ischemia thus stimulated the formation of platelet aggregates, a response which could contribute to the ischemic process.