Interobserver agreement for the assessment of handicap in stroke patients was investigated in a group of 10 senior neurologists and 24 residents from two centers. One hundred patients were separately interviewed by two physicians in different combinations. The degree of handicap was recorded by each observer on the modified Rankin scale, which has six grades (0-5). The agreement rates were corrected for chance (kappa statistics). Both physicians agreed on the degree of handicap in 65 patients; they differed by one grade in 32 patients and by two grades in 3 patients. Kappa for all pairwise observations was 0.56; the value for weighted kappa (with quadratic disagreement weights) was 0.91. Our results confirm the value of the modified Rankin scale in the assessment of handicap in stroke patients; nevertheless, further improvements are possible.

Interobserver agreement for the assessment of handicap in stroke patients.

Background Cardiac arrest outside the hospital is common and has a poor outcome. Studies in laboratory animals suggest that hypothermia induced shortly after the restoration of spontaneous circulation may improve neurologic outcome, but there have been no conclusive studies in humans. In a randomized, controlled trial, we compared the effects of moderate hypothermia and normothermia in patients who remained unconscious after resuscitation from out-of-hospital cardiac arrest. Methods The study subjects were 77 patients who were randomly assigned to treatment with hypothermia (with the core body temperature reduced to 33°C within 2 hours after the return of spontaneous circulation and maintained at that temperature for 12 hours) or normothermia. The primary outcome measure was survival to hospital discharge with sufficiently good neurologic function to be discharged to home or to a rehabilitation facility. Results The demographic characteristics of the patients were similar in the hypothermia and normotherm...

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Treatment of Comatose Survivors of Out-of-Hospital Cardiac Arrest with Induced Hypothermia

Background: Cardiac arrest with widespread cerebral ischemia frequently leads to severe neurologic impairment. We studied whether mild systemic hypothermia increases the rate of neurologic recovery after resuscitation from cardiac arrest due to ventricular fibrillation. Methods: In this multicenter trial with blinded assessment of the outcome, patients who had been resuscitated after cardiac arrest due to ventricular fibrillation were randomly assigned to undergo therapeutic hypothermia (target temperature, 32°C to 34°C, measured in the bladder) over a period of 24 hours or to receive standard treatment with normothermia. The primary end point was a favorable neurologic outcome within six months after cardiac arrest; secondary end points were mortality within six months and the rate of complications within seven days. Results: Seventy-five of the 136 patients in the hypothermia group for whom data were available (55 percent) had a favorable neurologic outcome (cerebral-performance category, 1 [good recovery] or 2 [moderate disability]), as compared with 54 of 137 (39 percent) in the normothermia group (risk ratio, 1.40; 95 percent confidence interval, 1.08 to 1.81). Mortality at six months was 41 percent in the hypothermia group (56 of 137 patients died), as compared with 55 percent in the normothermia group (76 of 138 patients; risk ratio, 0.74; 95 percent confidence interval, 0.58 to 0.95). The complication rate did not differ significantly between the two groups. Conclusions: In patients who have been successfully resuscitated after cardiac arrest due to ventricular fibrillation, therapeutic mild hypothermia increased the rate of a favorable neurologic outcome and reduced mortality.

Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest

This review is directed at understanding how neuronal death occurs in two distinct insults, global ischemia and focal ischemia. These are the two principal rodent models for human disease. Cell dea...

Ischemic Cell Death in Brain Neurons

BACKGROUND\nCardiac arrest outside the hospital is common and has a poor outcome. Studies in laboratory animals suggest that hypothermia induced shortly after the restoration of spontaneous circulation may improve neurologic outcome, but there have been no conclusive studies in humans. In a randomized, controlled trial, we compared the effects of moderate hypothermia and normothermia in patients who remained unconscious after resuscitation from out-of-hospital cardiac arrest.\n\n\nMETHODS\nThe study subjects were 77 patients who were randomly assigned to treatment with hypothermia (with the core body temperature reduced to 33 degrees C within 2 hours after the return of spontaneous circulation and maintained at that temperature for 12 hours) or normothermia. The primary outcome measure was survival to hospital discharge with sufficiently good neurologic function to be discharged to home or to a rehabilitation facility.\n\n\nRESULTS\nThe demographic characteristics of the patients were similar in the hypothermia and normothermia groups. Twenty-one of the 43 patients treated with hypothermia (49 percent) survived and had a good outcome--that is, they were discharged home or to a rehabilitation facility--as compared with 9 of the 34 treated with normothermia (26 percent, P=0.046). After adjustment for base-line differences in age and time from collapse to the return of spontaneous circulation, the odds ratio for a good outcome with hypothermia as compared with normothermia was 5.25 (95 percent confidence interval, 1.47 to 18.76; P=0.011). Hypothermia was associated with a lower cardiac index, higher systemic vascular resistance, and hyperglycemia. There was no difference in the frequency of adverse events.\n\n\nCONCLUSIONS\nOur preliminary observations suggest that treatment with moderate hypothermia appears to improve outcomes in patients with coma after resuscitation from out-of-hospital cardiac arrest.

Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia☆

We have tested whether small intraischemic variations in brain temperature influence the outcome of transient ischemia. To measure brain temperature, a thermocouple probe was placed stereotaxically into the left dorsolateral striatum of rats prior to 20 min of four-vessel occlusion. Rectal temperature was maintained at 36-37 degrees C by a heating lamp, and striatal temperature prior to ischemia was 36 degrees C in all animals. Six animal subgroups were investigated, including rats whose intraischemic striatal brain temperature was not regulated, or was maintained at 33, 34, 36, or 39 degrees C. Postischemic brain temperature was regulated at 36 degrees C, except for one group in which brain temperature was lowered from 36 degrees C to 33 degrees C during the first hour of recirculation. Energy metabolites were measured at the end of the ischemic insult, and histopathological evaluation was carried out at 3 days after ischemia. Intraischemic variations in brain temperature had no significant influence on energy metabolite levels measured at the conclusion of ischemia: Severe depletion of brain ATP, phosphocreatine, glucose, and glycogen and elevation of lactate were observed to a similar degree in all experimental groups. The histopathological consequences of ischemia, however, were markedly influenced by variations in intraischemic brain temperature. In the hippocampus, CA1 neurons were consistently damaged at 36 degrees C, but not at 34 degrees C. Within the dorsolateral striatum, ischemic cell change was present in 100% of the hemispheres at 36 degrees C, but in only 50% at 34 degrees C. Ischemic neurons within the central zone of striatum were not observed in any rats at 34 degrees C, but in all rats at 36 degrees C. In rats whose striatal temperature was not controlled, brain temperature fell from 36 to 30-31 degrees C during the ischemic insult. In this group, no ischemic cell change was seen within striatal areas and was only inconsistently documented within the CA1 hippocampal region. These results demonstrate that (a) rectal temperature unreliably reflects brain temperature during ischemia; (b) despite severe depletion of brain energy metabolites during ischemia at all temperatures, small increments of intraischemic brain temperature markedly accentuate histopathological changes following 3-day survival; and (c) brain temperature must be controlled above 33 degrees C in order to ensure a consistent histopathological outcome. Lowering of the brain temperature by only a few degrees during ischemia confers a marked protective effect.

https://journals.sagepub.com/doi/pdf/10.1038/jcbfm.1987.127

Small Differences in Intraischemic Brain Temperature Critically Determine the Extent of Ischemic Neuronal Injury

We have demonstrated previously that mild intraischemic hypothermia confers a marked protective effect on the final histopathological outcome. The present study was carried out to evaluate whether this protective effect involves changes in the degree of local cerebral blood flow reductions, tissue accumulation of free fatty acids, or alterations in the extracellular release of glutamate and dopamine. Rats whose intraischemic brain temperature was maintained at 36 degrees C, 33 degrees C, or 30 degrees C were subjected to 20 minutes of ischemia by four-vessel occlusion combined with systemic hypotension. Levels of local cerebral blood flow, as measured autoradiographically, were reduced uniformly in all experimental animals at the end of ischemia by gas chromatography after tissue extraction and separation by thin layer chromatography. A massive ischemia-induced accumulation of individual free fatty acids was observed in animal groups whose intraischemic brain temperature was maintained at either 36 degrees C or 30 degrees C. Extracellular neurotransmitter levels were measured by microdialysis; the perfusate was collected before, during, and after ischemia. In rats whose intraischemic brain temperature was maintained at 36 degrees C, dopamine and glutamate increased significantly during ischemia and the early period of recirculation (by 500-fold and sevenfold, respectively). In animals whose brain temperature was maintained at 33 degrees C and 30 degrees C, the release of glutamate was completely inhibited, and the release of dopamine was significantly attenuated (by 60%). These results suggest that mild intraischemic hypothermia does not affect the ischemia-induced local cerebral blood flow reduction or free fatty acid accumulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of mild hypothermia on ischemia-induced release of neurotransmitters and free fatty acids in rat brain.

We have previously described a marked attenuation of postischemic striatal neuronal death by prior substantia nigra (SN) lesioning. The present study was carried out to evaluate whether the protective effect of the lesion involves changes in the degree of local cerebral blood flow (ICBF) reduction, energy metabolite depletion, or alterations in the extracellular release of striatal dopamine (DA), glutamate (Glu), or gamma-aminobutyric acid (GABA). Control and SN-lesioned rats were subjected to 20 min of forebrain ischemia by four-vessel occlusion combined with systemic hypotension. Levels of ICBF, as measured by the autoradiographic method, and energy metabolites were uniformly reduced in both the ipsi- and contralateral striata at the end of the ischemic period, a finding implying that the lesion did not affect the severity of the ischemic insult itself. Extracellular neurotransmitter levels were measured by microdialysis; the perfusate was collected before, during, and after ischemia. An approximately 500-fold increase in DA content, a 7-fold increase in Glu content, and a 5-fold increase in GABA content were observed during ischemia in nonlesioned animals. These levels gradually returned to baseline by 30 min of reperfusion. In SN-lesioned rats, the release of DA was completely prevented, the release of GABA was not affected, and the release of Glu was partially attenuated. However, excessive extracellular Glu concentrations were still attained, which are potentially toxic. This, taken together with the previous neuropathological findings, suggests that excessive release of DA is important for the development of ischemic cell damage in the striatum.

Effect of Ischemia on the In Vivo Release of Striatal Dopamine, Glutamate, and γ-Aminobutyric Acid Studied by Intracerebral Microdialysis

We studied whether small variations in intraischemic brain temperature influence the response of the blood-brain barrier (BBB) to transient forebrain global ischemia. Six animal subgroups included rats whose brain temperature was maintained at 30, 33, 36 or 39 degrees C during 20 minutes (min) of 4-vessel occlusion. Control rats without ischemia had brain temperature maintained between 30 and 39 degrees C for a 20 min period. After a 45 min postischemic recirculation period, rats were injected with the protein tracer, horseradish peroxidase (HRP), and perfusion fixed 5 or 15 min later. Control rats showed no leakage of the tracer protein. Postischemic rats in which brain temperature was controlled at either 30 or 33 degrees C failed to demonstrate consistent BBB alterations. In contrast, foci of cortical HRP extravasation were consistently documented in rats whose intraischemic brain temperature was 36 degrees C. Permeability alterations were more widespread in the 39 degrees C ischemic group and occurred in cortical, thalamic, hippocampal and striatal regions. The HRP extravasation frequently involved arterioles surrounded by perivascular spaces. Routes of increased permeability to HRP included endothelial pinocytosis, opening of the interendothelial tight junctions and diffuse leakage through damaged endothelial cells. These results demonstrate that brain temperature is a critical factor in determining whether BBB dysfunction is an acute consequence of a transient cerebral ischemic insult.

The importance of brain temperature in alterations of the blood-brain barrier following cerebral Ischemia

We compared the neuropathological consequences of global forebrain ischemia under normothermia versus mild hyperthermia. Twenty-one rats underwent 20 minutes of four-vessel occlusion during which brain temperature was maintained at either 37 degrees C (normothermia, n = 9) or 39 degrees C (hyperthermia, n = 12). Quantitative neuropathological assessment was conducted 1 or 3 days later. At 1 day following the ischemic insult, normothermic rats demonstrated neuronal injury mainly confined to the most dorsolateral striatum. By 3 days, ischemic cells were present throughout the striatum and CA1 hippocampus in normothermic animals. Compared with normothermic rats, intraischemic hyperthermia significantly increased the extent and severity of brain damage at 1 day after the ischemic insult. Areas of severe neuronal necrosis and frank infarction included the cerebral cortex, CA1 hippocampus, striatum, and thalamus. Morphologic damage was also detected in the cerebellum and pars reticulata of the substantia nigra. An overall mortality rate of 83% was demonstrated at 3 days in the hyperthermic ischemic group. We conclude that intraischemic hyperthermia 1) markedly augments ischemic brain damage and mortality compared with normothermia, 2) transforms ischemic cell injury into frank infarction, and 3) accelerates the morphological appearance of ischemic brain injury in regions usually demonstrating delayed neuronal necrosis. These observations on mild hyperthermia may have important implications for patients undergoing cardiac or cerebrovascular surgery as well as patients following cardiac arrest or those with stroke-in-evolution.

https://www.ahajournals.org/doi/pdf/10.1161/01.str.21.9.1318?origin=publication_detail

I. Valdes

Papers

Small Differences in Intraischemic Brain Temperature Critically Determine the Extent of Ischemic Neuronal Injury

Effect of mild hypothermia on ischemia-induced release of neurotransmitters and free fatty acids in rat brain.

Effect of Ischemia on the In Vivo Release of Striatal Dopamine, Glutamate, and γ-Aminobutyric Acid Studied by Intracerebral Microdialysis

The importance of brain temperature in alterations of the blood-brain barrier following cerebral Ischemia

Effects of normothermic versus mild hyperthermic forebrain ischemia in rats.