Delayed profound local brain hypothermia markedly reduces interleukin-1beta gene expression and vasogenic edema development in a porcine model of intracerebral hemorrhage.

White matter (lobar) intracerebral hemorrhage (ICH) can cause edema-related deaths and life-long morbidity. In our porcine model, ICH induces oxidative stress, acute interstitial and delayed vasogenic edema, and up-regulates interleukin-1beta (IL-1beta), a proinflammatory cytokine-linked to blood-brain barrier (BBB) opening. In brain injury models, hypothermia reduces inflammatory cytokine production and protects the BBB. Clinically, however, hypothermia for stroke treatment using surface and systemic approaches can be challenging. We tested the hypothesis that an alternative approach, i.e., local brain cooling using the ChillerPad System, would reduce IL-1beta gene expression and vasogenic edema development even if initiated several hours after ICH. We infused autologous whole blood (3.0 mL) into the frontal hemispheric white matter of 20 kg pentobarbital-anesthetized pigs. At 3 hours post-ICH, we performed a craniotomy for epidural placement of the ChillerPad. Chilled saline was then circulated through the pad for 12 hours to induce profound local hypothermia (14 degrees C brain surface temperature). We froze brains in situ at 16 hours after ICH induction, sampled perihematomal white matter, extracted RNA, and performed real-time RT-PCR. Local brain cooling markedly reduced both IL-1beta RNA levels and vasogenic edema. These robust results support the potential for local brain cooling to protect the BBB and reduce injury after ICH.

Tin-mesoporphyrin, a potent heme oxygenase inhibitor, for treatment of intracerebral hemorrhage: in vivo and in vitro studies.

Spontaneous intracerebral hemorrhage (ICH) is the stroke subtype with highest mortality and morbidity. ICH can also occur following traumatic brain injury and thrombolysis for ischemic stroke and myocardial infarction. Development of ICH-induced hemispheric edema can elevate intracranial pressure and cause death. In survivors, edema-related white matter injury can lead to life-long neurological deficits. At present, there are no scientifically proven treatments for ICH. Heme oxygenase products, particularly iron and bilirubin, can be toxic to cells. In cerebral ischemia models, metalloporphyrins that are potent heme oxygenase inhibitors, reduce edema and infarct size. Tin-mesoporphyrin (SnMP) is a neuroprotectant that has also been used clinically to treat hyperbilirubinemia. Presently, we tested the hypothesis that SnMP treatment would reduce edema development following experimental ICH. We produced hematomas in pentobarbital-anesthetized pigs (9-11 kg) by infusing autologous blood into the frontal white matter. To maximize tissue concentrations, SnMP (87.5 microM in DMSO) or DMSO (vehicle controls) was included in the infused blood. Pig brains were frozen in situ at 24 hrs. following ICH and hematoma and edema volumes were determined on coronal sections by computer-assisted image analysis. We also examined the effects of SnMP in vitro on ferritin iron release, the formation of iron-induced thiobarbituric acid reactive substances (TBARS) and initial clot formation and hemolysis. SnMP treatment significantly reduced intracerebral mass following ICH. This was due to significant decreases in hematoma (0.68+/-0.08 vs. 1.39+/-0.30 cc, vehicle controls p<0.025) and edema volumes (edema = 1. 16+/-0.33 vs. 1.77+/-0.31 cc, p<0.05). In vitro, SnMP did not stabilize ferritin iron against reductive release nor did it decrease iron-induced TBARS formation in brain homogenates. SnMP or DMSO added to pig blood did not alter clot weights. In conclusion, SnMP reduced intracerebral mass in an ICH model by decreasing both hematoma and edema volumes SnMP's mechanism of action is presently unknown but may involve its potent inhibition of heme oxygenase activity. SnMP's effect appears unrelated to ferritin iron release, antioxidant activity or initial clot formation. Since SnMP treatment could be brain protective following ICH, further investigations into neurological and neuropathological outcomes and as well as into its mechanism of action are warranted.

Hypoglycemic brain injury: potentiation from respiratory depression and injury aggravation from hyperglycemic treatment overshoots.

Hypoglycemia can cause brain dysfunction, brain injury, and death. The present study seeks to broaden current information regarding mechanisms of hypoglycemic brain injury by investigating a novel etiology. The cat's high resistance to brain injury from hypoglycemia suggested that additional influences such as respiratory depression might play a facilitating role. Three groups of cats were exposed to fasting and insulin-induced hypoglycemia (HG; n = 6), euglycemic respiratory depression (RD; n = 5), and combined hypoglycemic respiratory depression (HG/RD; n = 10). The HG animals were maintained at <1.5 mmol (mean 1 mmol) serum glucose concentration for 2 to 6.6 hours. The respiratory depression was associated with PaO2 and PaCO2 values of approximately 50 mm Hg for 1 hour and of approximately 35 and approximately 75 mm Hg, respectively, for the second hour. Magnetic resonance diffusion-weighted imaging estimated brain energy state before, during, and after hypoglycemia. The hypoglycemic respiratory depression exposures were terminated either to euglycemia (n = 4) or to hyperglycemia (n = 6). Brain injury was assessed after 5 to 7 days of survival. Cats exposed to hypoglycemia alone maintained unchanged diffusion coefficients; that is, they lacked evidence of brain energy failure and all six remained brain-intact. Only 1 of 5 euglycemic RD but 10 of 10 HG/RD cats developed brain damage (HG and RD vs. HG/RD, P < 0.01). This difference in brain injury rates suggests injury potentiation by hypoglycemia and respiratory depression acting together. Three injury patterns emerged, including activation of microglia, selective neuronal necrosis, and laminar cortical necrosis. Widespread activation of microglia suggesting damage to neuronal cell processes affected all damaged brains. Selective neuronal necrosis affecting the cerebral cortex, hippocampus, and basal ganglia was observed in all but one case. Instances of laminar cortical necrosis were limited to cats exposed to hypoglycemic respiratory depression treated with hyperglycemia. Thus, treatment with hyperglycemia compared with euglycemia after hypoglycemic respiratory depression exposures significantly increased the brain injury scores (24 +/- 6 vs. 13 +/- 2 points; P < 0.05). This new experimental hypoglycemia model's contribution lies in recognizing additional factors that critically define the occurrence of hypoglycemic brain injury.

Phylogenetic evidence for reclassification of Calymmatobacterium granulomatis as Klebsiella granulomatis comb. nov.

By sequencing a total of 2089 bp of the 16S rRNA and phoE genes it was demonstrated that Calymmatobacterium granulomatis (the causative organism of donovanosis) shows a high level of identity with Klebsiella species pathogenic to humans (Klebsiella pneumoniae, Klebsiella rhinoscleromatis). It is proposed that C. granulomatis should be reclassified as Klebsiella granulomatis comb. nov. An emended description of the genus Klebsiella is given.

Anomalous ependyma inducing split cord and meningomyelocele?

The case is that of a female fetus of 17 to 18 weeks' gestation with major defects of the central nervous system: (1) The thoracic vertebrae demonstrated rachischisis, with segmental diplomyelia; the duplicated cords were dissimilar in size and lay side by side within a single meningeal sheath lacking a dividing septum or spur. Cranially to the divided cord lay an unsplit segment of "open cord" lacking the posterior elements and exposing the centrally placed ependyma of the central canal flanked by glial and epidermal lining, respectively; it could be regarded as an example of a meningomyelocele. (2) Heterotopic massed ependymal cells, some of which were actively proliferating, were associated with the choroid plexus in the brain. Minor anomalies included cerebellar heterotopia and the malpositioning of dorsal root ganglia outside the meningeal sheath. Because the ependyma is such a powerful inducer of the development of neighboring tissue, the findings could be united by a common pathogenic theme, viz problematic ependymal development and migration within both the brain and spinal cord. The causative agent responsible for these abnormalities remains unidentified, but the balance of evidence suggests that its effect was felt during the second week of postconceptual age.

Sepsis stimulates release of myofilaments in skeletal muscle by a calcium-dependent mechanism.

Sepsis is associated with a pronounced catabolic response in skeletal muscle, mainly reflecting degradation of the myofibrillar proteins actin and myosin. Recent studies suggest that sepsis-induced muscle proteolysis may reflect ubiquitin-proteasome-dependent protein breakdown. An apparently conflicting observation is that the ubiquitin-proteasome pathway does not degrade intact myofibrils. Thus, it is possible that actin and myosin need to be released from the myofibrils before they can be ubiquitinated and degraded by the proteasome. We tested the hypothesis that sepsis results in disruption of Z-bands, increased expression of calpains, and calcium-dependent release of myofilaments in skeletal muscle. Sepsis induced in rats by cecal ligation and puncture resulted in increased gene expression of micro-calpain, m-calpain, and p94 and in Z-band disintegration in the extensor digitorum longus muscle. The release of myofilaments from myofibrillar proteins was increased in septic muscle. This response to sepsis was blocked by treating the rats with dantrolene, a substance that inhibits the release of calcium from intracellular stores to the cytoplasm. The present results provide evidence that sepsis is associated with Z-band disintegration and a calcium-dependent release of myofilaments in skeletal muscle. Release of myofilaments may be an initial and perhaps rate-limiting component of sepsis-induced muscle breakdown.

The human cerebral cortex: gender differences in structure and function.

Most people are aware of subtle differences in cognitive functions between men and women. Psychometric tests confirm specific gender differences in a number of areas, the most robust being in spatial orientation and mathematical tasks which are better performed by males. Nonetheless, normal males and females perform comparably on intelligence tests and human brains lack sexual dimorphism on routine neuropathological exams--other than mean differences in weight and size. Even so, human brains demonstrate: 1) a sexually dimorphic nucleus in the hypothalamus with twofold neuronal numbers in males than in females; 2) the planum temporale/anterior Sylvian fissure on the left side are larger in males; 3) some studies reveal the posterior corpus callosum to be more bulbous in females while others fail to show this difference; and 4) a cytoarchitectural study demonstrates definite sexual dimorphism of cerebral cortex with significantly higher neuronal densities and neuronal number estimates in males and a reciprocal increase in neuropil/neuronal processes in female cortex as implied by the 2 sexes' similar mean cortical thicknesses. Such morphologic differences may provide the structural underpinning for the gender differences exhibited by the normal and diseased brain. Males manifest a higher prevalence of mental retardation and of learning disabilities than females which may reflect the male fetus' smaller overproduction of nerve cells. Such an inference is supported by the demonstration of 1) better functional recovery following early brain injury than after later insults, 2) substantially overproduced and secondarily reduced nerve cells in human cerebral cortex during gestation, 3) the demonstration of a similar neuronal production and a testosterone-dependent neuronal involution of the sexually dimorphic hypothalamic nucleus in rats, and 4) more cortical neurons present in the adult human male than female. If an overproduced nerve cell population is capable of compensating for pathologic nerve cell losses taking place during the process of neuronal involution, the magnitude of overproduced nerve cells may define the extent of the protection conveyed. Because male fetuses appear to involute fewer overproduced cortical neurons than females, this gender difference could explain in part the boys' greater functional impairments from early brain damage. Women, on the other hand, exhibit a higher incidence and prevalence of dementia than do men. Given the females' overall larger extent of cortical neuropil (neuronal processes) and lower neuronal numbers compared with men, any disease that causes neuronal loss could be expected to lead to more severe functional deficits in women due to their loss of more dendritic connections per neuron lost. In conclusion, superimposed on a strong background of functional and structural equality, human male and female cerebral cortex display distinct, sexually dimorphic features, which can begin to be linked to a complex array of gender-specific advantages and limitations in cognitive functions.

Ultra-early clot aspiration after lysis with tissue plasminogen activator in a porcine model of intracerebral hemorrhage: edema reduction and blood-brain barrier protection.

OBJECT: Ultra-early hematoma evacuation (< 4 hours) after intracerebral hemorrhage (ICH) may reduce mass effect and edema development and improve outcome. To test this hypothesis, the authors induced lobar hematomas in pigs. METHODS: The authors infused 2.5 ml of blood into the frontal cerebral white matter in pigs weighing 8 to 10 kg. In the treatment group, clots were lysed with tissue plasminogen activator ([tPA], 0.3 mg) and aspirated at 3.5 hours after hematoma induction. Brains were frozen in situ at 24 hours post-ICH and hematomal and perihematomal edema volumes were determined on coronal sections by using computer-assisted morphometry. Hematoma evacuation rapidly reduced elevated cerebral tissue pressure from 12.2+/-1.3 to 2.8+/-0.8 mm Hg. At 24 hours, prior clot removal markedly reduced hematoma volumes (0.40+/-0.10 compared with 1.26+/-0.13 cm3, p < 0.005) and perihematomal edema volumes (0.28+/-0.05 compared with 1.46+/-0.24 cm3, p < 0.005), compared with unevacuated control lesions. Furthermore, no Evans blue dye staining of perihematomal edematous white matter was present in brains in which the hematomas had been evacuated, compared with untreated controls. CONCLUSIONS: Hematomas were quickly and easily aspirated after treatment with tPA, resulting in significant reductions in mass effect. Hematoma aspiration after fibrinolysis with tPA enabled removal of the bulk of the hematoma (> 70%), markedly reduced perihematomal edema, and prevented the development of vasogenic edema. These findings in a large-animal model of ICH provide support for clinical trials that include the use of fibrinolytic agents and ultra-early stereotactically guided clot aspiration for treating ICH.

Gender differences in the human cerebral cortex: more neurons in males; more processes in females.

This study's objective was to investigate morphometric gender differences of the cerebral cortex in six males and five females, 12 to 24 years old. Though human brains lack sexual dimorphism on routine neuropathologic examinations, gender-specific brain weight, functional, and morphologic differences exist, suggesting that cortical differences may be found. Yet the cerebral cortex may be exempt from gender differences, as demonstrated by the fact that normal males and females perform comparably on intelligence tests. Stereologic morphometry on standardized histologic sections from 30 bilateral cortical loci determined cortical thickness, neuronal density, and derived neuronal number estimates. The mean +/- SD cortical thickness of the 60 loci examined was similar in males and females with right and left hemispheric gender ratios being balanced. In contrast, the average neuronal density of the same 60 loci was significantly higher in the male group than in the female group, and the corresponding mean male-to-female ratios were 1.18 in the right and 1.13 in the left hemisphere, which differ significantly from each other and from the balanced cortical thickness ratios. Estimates of neuronal numbers -- the product of neuronal thickness times density -- were 13% higher in males than in females, with mean male-to-female ratios of 1.13 in both hemispheres. The data provide morphologic evidence of considerable cerebral cortical dimorphism with the demonstration of significantly higher neuronal densities and neuronal number estimates in males, though with similar mean cortical thickness, implying a reciprocal increase in neuropil/neuronal processes in the female cortex.

Role of blood clot formation on early edema development after experimental intracerebral hemorrhage.

BACKGROUND AND PURPOSE: Blood "toxicity" is hypothesized to induce edema and brain tissue injury following intracerebral hemorrhage (ICH). Lobar ICH in pigs produces rapidly developing, marked perihematomal edema (>10% increase in water content) associated with clot-derived plasma protein accumulation. Coagulation cascade activation and, specifically, thrombin itself contribute to edema development during the first 24 hours after gray matter ICH in rats. In the present study, we sought to determine whether blood clot formation is necessary for edema development by comparing intracerebral infusions of heparinized and unheparinized blood in pig (white matter) and in rat (gray matter). We also examined heparin's effect on thrombin-induced gray matter edema. METHODS: In pigs, we infused autologous blood (with or without heparin) into the cerebral white matter to produce lobar hematomas and froze the brains in situ at 1, 4, or 24 hours after ICH. We determined hematomal and perihematomal edema volumes on coronal sections by computer-assisted morphometry. In rats, we infused either blood or thrombin (with or without heparin) into the basal ganglia and measured water, sodium, and potassium contents at 24 hours after ICH. RESULTS: In pigs, unheparinized blood induced rapid (at 1 hour) and prolonged (24 hours) perihematomal edema (average volume, 1.29+/-0. 20 mL; n=6). No perihematomal edema was present following heparinized blood infusions (n=6). In rats, unheparinized blood produced significantly greater edema than heparinized blood infusions. As with whole blood, thrombin-induced gray matter edema at 24 hours was significantly reduced by coinjection of heparin. CONCLUSIONS: After ICH, blood clot formation is required for rapid and prolonged edema development in perihematomal white and gray matter. Thrombin also contributes to prolonged edema in gray matter.

Stroke assessment: morphometric infarct size versus neurologic deficit.

We presently examine the relation between histologic infarct size and neurologic deficit as endpoints and seek to clarify their sensitivity in defining stroke outcome. Neurologic deficits of 76 cats subjected to middle cerebral artery occlusion were assessed daily and correlated with the corresponding infarct sizes determined morphometrically after 2 weeks' survival. A five-item neurologic deficit score included the time elapsed until hemiparesis, and forced circling resolved (if ever), presence of impaired placing reactions and time elapsed until able to stand and being alert. We then evaluated the two endpoints' statistical powers to detect group differences using two sets of comparison groups. The neurologic deficit score correlated well with infarct size (r = 0.76, p < 0.001) and each of the individual deficit score components named above, in turn, correlated with decreasing power with infarct size. Even so, the number of study subjects required to achieve the same level of statistical significance in assessing group differences was two-fold greater when using the neurologic deficit than the infarct size data: Group sizes of eight and five animals were sufficient for significant infarct size differences while the groups needed be expanded to 15 and 10 animals to similarly achieve significant neurologic score differences. Thus, infarct size emerges as a more sensitive measure of stroke outcome than does the assessment of neurologic deficits.

Early metabolic alterations in edematous perihematomal brain regions following experimental intracerebral hemorrhage.

OBJECT: The authors previously demonstrated, in a large-animal intracerebral hemorrhage (ICH) model, that markedly edematous ("translucent") white matter regions (> 10% increases in water contents) containing high levels of clot-derived plasma proteins rapidly develop adjacent to hematomas. The goal of the present study was to determine the concentrations of high-energy phosphate, carbohydrate substrate, and lactate in these and other perihematomal white and gray matter regions during the early hours following experimental ICH. METHODS: The authors infused autologous blood (1.7 ml) into frontal lobe white matter in a physiologically controlled model in pigs (weighing approximately 7 kg each) and froze their brains in situ at 1, 3, 5, or 8 hours postinfusion. Adenosine triphosphate (ATP), phosphocreatine (PCr), glycogen, glucose, lactate, and water contents were then measured in white and gray matter located ipsi- and contralateral to the hematomas, and metabolite concentrations in edematous brain regions were corrected for dilution. In markedly edematous white matter, glycogen and glucose concentrations increased two- to fivefold compared with control during 8 hours postinfusion. Similarly, PCr levels increased several-fold by 5 hours, whereas, except for a moderate decrease at 1 hour, ATP remained unchanged. Lactate was markedly increased (approximately 20 micromol/g) at all times. In gyral gray matter overlying the hematoma, water contents and glycogen levels were significantly increased at 5 and 8 hours, whereas lactate levels were increased two- to fourfold at all times. CONCLUSIONS: These results, which demonstrate normal to increased high-energy phosphate and carbohydrate substrate concentrations in edematous perihematomal regions during the early hours following ICH, are qualitatively similar to findings in other brain injury models in which a reduction in metabolic rate develops. Because an energy deficit is not present, lactate accumulation in edematous white matter is not caused by stimulated anaerobic glycolysis. Instead, because glutamate concentrations in the blood entering the brain's extracellular space during ICH are several-fold higher than normal levels, the authors speculate, on the basis of work reported by Pellerin and Magistretti, that glutamate uptake by astrocytes leads to enhanced aerobic glycolysis and lactate is generated at a rate that exceeds utilization.

Human cortex development: estimates of neuronal numbers indicate major loss late during gestation.

This morphometric study explores temporal and topographic changes in the estimated neuronal number in human neocortex during the latter half of gestation and early infancy. Neuronal estimates are calculated from standardized measurements of cortical layer thickness and neuronal density in 6 neocortical regions in 9 human brains ranging from 17 weeks of gestation to 13 weeks postnatally. Layer thickness increases linearly with age while the average neuronal density first increases, then reaches a maximum at 20 weeks of gestation, and progressively declines. The sum of layer thickness times layer density estimates the number of neurons in a cortical column with a fixed surface area and a length that is equal to the cortical thickness. To derive an estimate of potentially overproduced neurons, the number of neurons in each cortical column was corrected for surface growth and for cortex gyration. These data show that a large percent of cortical neurons present at 20 weeks of gestation are used to populate the expanding cortex. Nevertheless, the growth-corrected data suggest that a substantial overproduction and secondary reduction of cortical neurons takes place mainly during the last quarter of gestation. The corrected mean number of neurons reaches a maximum at 28 weeks of gestation and then declines by approximately 70% to achieve a stable number of neurons around birth. This estimated number of neurons is significantly higher at 28 to 32 weeks of gestation than at 17 to 20 gestational weeks and at 0 to 13 postnatal weeks. These data imply that physiologic neuronal death (apoptosis) may play a major role in early human cortex development.

Lobar intracerebral hemorrhage model in pigs: rapid edema development in perihematomal white matter.

BACKGROUND AND PURPOSE: The mechanisms underlying brain injury from intracerebral hemorrhage (ICH) are complex and poorly understood. To comprehensively examine pathophysiological and pathochemical alterations after ICH and to examine the effects of hematoma removal on these processes, we developed a physiologically controlled, reproducible, large-animal model of ICH in pigs (weight, 6 to 8 kg). METHODS: We produced lobar hematomas by pressure- controlled infusions of 1.7 mL of autologous blood into the right frontal hemispheric white matter over 15 minutes. We froze brains in situ at 1, 3, 5, and 8 hours after hematoma induction and cut coronal sections of hematoma assessment, morphological brain examination, and immunohistochemical and water content determinations. RESULTS: At 1 hour after blood infusion, "translucent" white matter areas were present directly adjacent to the hematoma. These markedly edematous regions had a greater than 10% increase in water content (>85%) compared with the contralateral white matter (73%), and this increased water content persisted through 8 hours. In addition, these areas were strongly immunoreactive for serum proteins. Intravascular Evans blue dye failed to penetrate into the brain tissue at all time points, demonstrating that this serum protein accumulation and edema development were not due to increased blood-brain barrier permeability. CONCLUSIONS: Experimental lobar ICH in pigs models a prominent pathological feature of human ICH, ie, early perihematomal edema. Our findings suggest that serum proteins, originating from the hematoma, accumulate in adjacent white matter and result in rapid and prolonged edema after ICH. This interstitial edema likely corresponds to the low densities on CT scans and the hyperintensities on T2-weighted MR images that surround intracerebral hematomas acutely after human ICH.

Use of the Morris water maze and acoustic startle chamber to evaluate neurologic injury after asphyxial arrest in rats.

The study was performed to assess the utility of the Morris water maze (MWM) and acoustic startle reflex (ASR) for evaluating neurologic outcome in a rat model of asphyxial cardiac arrest. Rats were anesthetized, intubated, and chemically paralyzed. Control animals were decannulated and, after awakening, were extubated and returned to their housing. Experimental animals were asphyxiated by disconnecting the ventilator. Approximately 3.5 min after the disconnection, there was no measurable pulse. After 7 min of asphyxia, they were then resuscitated with resumed ventilation, chest compressions, epinephrine, and sodium bicarbonate. All animals were assigned to either MWM or ASR testing. The MWM is a 6-ft diameter tank filled with opaque water. In a fixed location of the tank, a 4-inch diameter escape platform is submerged just below the surface. MWM animals were tested on post-injury d 16-21 by recording the path and time taken to escape from three randomly assigned locations per d. ASR animals had s.c. leads placed over the right triceps and tibialis anterior muscles. The latency and rectified amplitude of the ASR was measured by recording the electromyographic impulse generated when the animal was startled by an acoustic stimulus. Animals were tested on post-injury d 6 and 7. After the last test session for each group, the animals' brains were removed for histopathologic examination. Asphyxiated MWM animals took longer to find the platform, and their paths were less direct than control animals (analysis of variance p < 0.05). The ASR of asphyxiated ASR animals had greater amplitude and shorter latency compared with controls (analysis of variance p < 0.05). Histologic examination revealed no abnormalities in control animals, but 80% of asphyxiated brains showed hippocampal neuronal injury and/or reactive gliosis in the CA1 segment. Abnormalities were more commonly detected in animals killed 7 d post-injury (ASR protocol) compared with animals killed 21 d post-injury (MWM protocol). We conclude that the MWM and ASR are useful for detecting neuronal injury in asphyxiated rats.

Normoglycemia (not hypoglycemia) optimizes outcome from middle cerebral artery occlusion.

We examined the effects of serum glucose concentration during middle cerebral artery (MCA) occlusion in the cat on death rates in animals that died from hemispheric edema and on infarct size in animals that survived. We occluded that MCA permanently in some groups and released the clip after 8 h in others. By injecting or infusing glucose solutions, saline, or insulin, we maintained six animal groups steadily either hyper-, normo-, or slightly hypoglycemic before and for 6 or 8 h after permanent or 8-h temporary MCA occlusion. Studies with these groups revealed a distinct optimal outcome with normoglycemic animals. In three additional groups, we altered the glycemia after permanent occlusion from hyper- to normo- or hypoglycemia and from normo- to hyperglycemia. Two of the three hypoglycemic groups (8-h reversible and permanent hyper- to hypoglycemic occlusions) yielded the worst outcomes in this study, with > 10x larger median infarcts than the best outcome group (normoglycemic permanent occlusion). Hyperglycemia also was detrimental and increased infarct size and mortality after permanent occlusion. Restoring the cerebral blood flow after 8 h of occlusion increased the death rate from hemispheric edema compared with a maintained occlusion. Following permanent MCA occlusion, converting from normo- to hyperglycemia or vice versa yielded outcomes intermediate between a sustained normo- or hyperglycemia. A regression analysis of the normo- and hyperglycemic groups and the two groups with glycemia altered after permanent occlusion showed a significant linear correlation between glycemia level at and 1 h after MCA occlusion and median infarct size.

Efficacious experimental stroke treatment with high-dose methylprednisolone.

BACKGROUND AND PURPOSE: Recent studies reveal success in treating spinal cord trauma with early, high-dose methylprednisolone. As in spinal cord research, failure to find therapeutic effects with steroids in studies of acute stroke treatment may reflect institution of treatment too late and at too low dosage. We presently test the efficacy of stroke treatment with methylprednisolone administered early and at high doses using a cat temporary middle cerebral artery occlusion model. METHODS: We occluded the middle cerebral artery for 4 hours in 24 pentobarbital-anesthetized cats. To enhance the probability of brain injury, we maintained the cats' serum glucose concentrations at high levels both during occlusion and for 6 hours afterward. Using a blinded, randomized study design, we treated 12 cats with methylprednisolone (30 mg/kg IV infused over 15 minutes starting 30 minutes after occlusion followed by 5.4 mg.kg-1.h-1 IV for the next 23 hours) and 12 control cats with vehicle. During and for 8 hours after occlusion, we monitored cerebral blood flow, brain and rectal temperatures, and multiple cardiovascular and blood compositional parameters. We assessed brain pathological outcome after animal survival for 4 days or after acute death from hemispheric edema. RESULTS: Experimental and control animals showed similar early mortality rates (treated, 3/12; controls, 4/12). However, surviving methylprednisolone-treated cats (n = 9) showed a mean infarct size more than six times smaller than in the control animals (n = 8) (mean +/- SEM, 2.4 +/- 0.7% versus 15.6 +/- 6.2% of the ischemic territory, respectively; P < .05). The methylprednisolone-treated animals also showed less marked reduction in cerebral blood flow during ischemia than did the controls (mean +/- SEM, 58 +/- 5% versus 74 +/- 4%; P < .005). CONCLUSIONS: Administering methylprednisolone at high doses early after onset of ischemia significantly reduces tissue injury in cats that survive 4 days of temporary middle cerebral artery occlusion. This improvement in outcome occurs in the setting of significant increases in ischemic cerebral blood flow. However, methylprednisolone treatment did not reduce hemispheric edema in animals that died early after temporary middle cerebral artery occlusion.