Brain biocompatibility and microglia response towards engineered self-assembling (RADA)4 nanoscaffolds.

(RADA)4-based nanoscaffolds have many inherent properties making them amenable to tissue engineering applications: ease of synthesis, ease of customization with bioactive moieties, and amenable for in situ nanoscaffold formation. There is a dearth in the literature on their biocompatibility in brain tissues; where the glia response is key to regulating the local host response. Herein, nanoscaffolds composed of (RADA)4 and (RADA)4-IKVAV mixtures were evaluated in terms of their effect on primary microglia in culture and general tissue (in vivo) biocompatibility (astrocyte and migroglia). Laminin-derived IKVAV peptide was chosen to promote beneficial cell interaction and attenuate deleterious glial responses. Microglia remained ramified when cultured with these nanoscaffolds, as observed using TNF-α and IL-1ß, NO, and proliferation assays. Evidence suggests that cultured microglia phagocytise the matrix whilst remaining ramified and viable, as shown visually and metabolically (MTT). Nanoscaffold intracerebral injection did not lead to microglia migration or proliferation, nor were glial scarring and axonal injury observed over the course of this study. IKVAV had no affect on microglia activation and astrogliosis. (RADA)4 should be advantageous for localized injection as a tuneable-platform device, which may be readily cleared without deleterious effects on tissue-resident microglia. STATEMENT OF SIGNIFICANCE: Self-assembling nanoscaffolds have many inherent properties making them amenable to tissue engineering applications: ease of synthesis, ease of customization with bioactive moieties, and amenable for in situ nanoscaffold formation. A dearth of literature exists on their biocompatibility in brain tissues; where the glia response is key to regulating the local host response. Herein, nanoscaffolds composed of the peptides (RADA)4 and (RADA)4-IKVAV mixtures were evaluated in terms of their effect on microglia cells in culture and general tissue (in vivo) biocompatibility (astrocyte and migroglia). Laminin-derived IKVAV peptide was chosen to promote beneficial cell interaction and attenuate deleterious glial responses. (RADA)4 nanoscaffolds showed no adverse effect from these cell types and should be advantageous for localized injection as a tuneable-platform device.

Broccoli sprout supplementation during pregnancy prevents brain injury in the newborn rat following placental insufficiency.

Chronic placental insufficiency and subsequent intrauterine growth restriction (IUGR) increase the risk of hypoxic-ischemic encephalopathy in the newborn by 40 fold. The latter, in turn, increases the risk of cerebral palsy and developmental disabilities. This study seeks to determine the effectiveness of broccoli sprouts (BrSp), a rich source of the isothiocyanate sulforaphane, as a neuroprotectant in a rat model of chronic placental insufficiency and IUGR. Placental insufficiency and IUGR was induced by bilateral uterine artery ligation (BUAL) on day E20 of gestation. Dams were fed standard chow or chow supplemented with 200mg of dried BrSp from E15 - postnatal day 14 (PD14). Controls received Sham surgery and the same dietary regime. Pups underwent neurologic reflex testing and open field testing, following which they were euthanized and their brains frozen for neuropathologic assessment. Compared to Sham, IUGR pups were delayed in attaining early reflexes and performed worse in the open field, both of which were significantly improved by maternal supplementation of BrSp (p<0.05). Neuropathology revealed diminished white matter, ventricular dilation, astrogliosis and reduction in hippocampal neurons in IUGR animals compared to Sham, whereas broccoli sprout supplementation improved outcome in all histological assessments (p<0.05). Maternal dietary supplementation with BrSp prevented the detrimental neurocognitive and neuropathologic effects of chronic intrauterine ischemia. These findings suggest a novel approach for prevention of cerebral palsy and/or developmental disabilities associated with placental insufficiency.

Prolonged seizures exacerbate perinatal hypoxic-ischemic brain damage.

This study was undertaken to clarify whether seizures in the newborn cause damage to the healthy brain and, more specifically, to determine the extent to which seizures may contribute to the brain-damaging effects of hypoxia-ischemia (HI). Seizures were induced in 10-d-old rat pups with kainic acid (KA). Seizure duration was determined electrographically. HI was induced by common carotid artery ligation followed by exposure to 8% oxygen for either 15 or 30 min. Six groups of animals were assessed: 1) controls [neither KA nor HI (group I)]; 2) group II, KA alone; 3) group III, 15 min HI alone; 4) group IV,15 min HI plus KA; 5) group V, 30 min HI alone; and 6) group VI, 30 min HI plus KA. Animals were assessed neuropathologically at 3 (early) and 20 (late) d of recovery. KA injection without hypoxia resulted in continuous clinical and electrographic seizures lasting a mean of 282 min. No neuropathologic injury was seen in groups I (no HI or KA), II (KA alone), III (15 min HI alone), or IV (15 min HI and KA). Animals in group V (30 min HI alone) displayed brain damage with a mean score of 2.3 and 0.60 at 3 and 20 d of recovery, respectively. Animals in group VI (30 min HI and KA) had a mean score of 12.1 and 3.65 at 3 and 20 d of recovery, respectively. Compared with group V, the increased damage as a result of the seizure activity in group VI occurred exclusively in the hippocampus. Status epilepticus in the otherwise "healthy" neonatal brain does not cause neuropathologic injury. However, seizures superimposed on HI significantly exacerbate brain injury in a topographically specific manner.

Mycoplasma pneumoniae: a cause of coma in the absence of meningoencephalitis.

Mycoplasma pneumoniae encephalitis is a recognized cause of reversible coma in children. As an etiology of infectious encephalitis, it yields a relatively poorer prognosis than most other causes of infectious encephalopathies. Encephalitis is generally diagnosed by a constellation of clinical symptoms and confirmed by a cerebrospinal fluid (CSF) examination revealing cell pleocytosis and elevated protein. That Mycoplasma pneumoniae encephalopathy can occur in the presence of a normal CSF examination is less well appreciated. The authors report two children who presented with coma and normal CSF findings in whom a diagnosis of acute Mycoplasma pneumoniae infection was made. The two children both had rapid and complete recovery over several days. These cases exemplify that coma can result from acute infection with Mycoplasma pneumoniae in the absence of an inflammatory CSF response and that a normal CSF may herald a more favorable prognosis.

The effect of pre hypoxic-ischemic (HI) hypo and hyperthermia on brain damage in the immature rat.

To determine the effect of pre-hypoxic-ischemic (HI) hypo and hyperthermia on neuropathologic outcome in the immature brain, groups of 7-day rat pups underwent unilateral common carotid artery ligation and exposure to hypoxia in 8% oxygen at 37 degrees C for 3 h. Prior to HI, rat pups were divided into three groups and received either: (a) 3-1 h periods, at 8-h intervals, 24 h prior to HI, (b) 1-3 h period, 24 h prior to HI, or (c) 1-3 h period, immediately prior to HI, of exposure to environmental temperatures of 28 degrees C, 31 degrees C, 34 degrees C, 37 degrees C, or 39 degrees C. Following HI, all animals were returned to their dams for neuropathologic assessment at 30 days of age. Mortality was highest among those animals exposed to pre-HI hypothermia at 28 degrees C. Only those animals who were pre-conditioned with hyperthermia at either 37 degrees C or 39 degrees C, immediately prior to HI, displayed a significant reduction in brain damage compared to control (p<0.01). These results indicate that hyperthermia induced prior to HI protects the immature brain from damage. This study further emphasizes the importance of a cautionary approach in implementing systemic hypothermia during clinical trials, and the need to further understand the timing and effects of thermoregulation on the immature brain.

Preferential injury of oligodendroblasts by a short hypoxic-ischemic insult.

One-week-old rat pups were subjected to an acute 10 min severe hypoxic-ischemic insult. Over the next 24 h, during the reperfusion period, O4 immunocytochemistry demonstrated that oligodendroblasts underwent degenerative changes that were coincident with induction of heme oxygenase. We suggest that the increased vulnerability of oligodendroblasts to oxidative stress following an hypoxic-ischemic insult may contribute to the pathogenesis of periventricular leukomalacia.

Transient thalamic changes on MRI in a child with hypernatremia.

Severe hypernatremia has been associated with a wide variety of central nervous system lesions. Neurologic sequelae are the usual outcome in those cases in which a lesion has been documented neuroradiologically. The authors report a 7-month-old male with severe hypernatremia who developed obtundation after correction of the electrolyte imbalance. Magnetic resonance imaging revealed bilateral thalamic signal changes that resolved on follow-up study, in accordance with complete clinical recovery. To the authors' knowledge, bilateral thalamic signal changes are previously unreported findings associated with hypernatremia. Pertinent literature and the clinical course of the authors' patient are the basis for questioning currently recommended guidelines for the rate of correction of hypernatremia.

The effect of age on susceptibility to hypoxic-ischemic brain damage.

Stroke occurs in all age groups, ranging from the new-born to the elderly. Our current understanding of the mechanisms of ischemic brain injury suggests that, despite age, the underlying cascade of events includes the rapid depletion of energy reserves, lactate accumulation, release of excitatory amino acids, high intracellular concentrations of Ca2+, and the production of oxygen free radicals. The extent to which these events affect brain injury, however, is profoundly influenced by age. Hyperglycemia for example, markedly enhances hypoxic-ischemic brain damage in adults, but has a protective effect in new-born rats. Insulin-induced hypoglycemia, on the other hand, protects the adult brain, but may be detrimental to the new-born. Substrate utilization of ketone bodies is markedly enhanced in the new-born, and has now been shown also to protect the brain. The immature brain is generally believed to be more resistant to the damaging effects of cerebrovascular compromise compared to the more mature brain. However, recent experiments suggest that the correlation between brain damage and age is not linear. To further clarify the effects of age and development on hypoxic-ischemic brain damage, we developed a model whereby rats of increasing age received identical cerebrovascular insults. Neuropathologic assessment at 7 days of recovery showed that brain damage was most severe in the 1- and 3-week-old animals followed by those that were 6 months. The 6- and 9-week-old groups had significantly less injury than the other three age groups. Hippocampal damage was most severe in the 3-week and 6-month-old rats compared to all other age groups. These findings contrast previously held beliefs regarding the enhanced tolerance of the immature brain to hypoxic-ischemic damage and demonstrate that the immature brain is, in fact, less resistant to hypoxic-ischemic brain damage than its adult counterpart. The results emphasize the need for a greater understanding of the effects of ontogeny on hypoxic-ischemic brain damage, particularly as it pertains to the development of therapeutic interventions.

Iron deficiency: a cause of stroke in infants and children.

Iron deficiency is a common pediatric problem affecting 20%-25% of the world's infants. Most commonly causing anemia, iron deficiency is also implicated in such neurologic sequelae as irritability, lethargy, headaches, developmental delay, and infrequently papilledema, pseudotumor cerebri, and cranial nerve abnormalities. Rarely has iron deficiency been recognized as a significant cause of stroke in the adult or pediatric populations. We report a series of 6 children, 6 to 18 months of age, who presented with an ischemic stroke or venous thrombosis after a viral prodrome. All patients had iron deficiency as a consistent finding among the group, and other known etiologies of childhood stroke were excluded. These patients provide evidence of a strong association between iron deficiency and ischemic events in children between 6 and 18 months of age.

Dexamethasone prevents hypoxia/ischemia-induced reductions in cerebral glucose utilization and high-energy phosphate metabolites in immature brain.

We examined the potential importance of dexamethasone-mediated alterations in energy metabolism in providing protection against hypoxic-ischemic brain damage in immature rats. Seven-day-old rats (n = 165) that had been treated with dexamethasone (0.1 mg/kg, i.p.) or vehicle were assigned to control or hypoxic-ischemic groups (unilateral carotid artery occlusion plus 2-3 h of 8% oxygen at normothermia). The systemic availability of alternate fuels such as beta-hydroxybutyrate, lactate, pyruvate, and free fatty acids was not altered by dexamethasone treatment, and, except for glucose, brain levels were also unaffected. At the end of hypoxia, levels of cerebral high-energy phosphates (ATP and phosphocreatine) were decreased in vehicle- but relatively preserved in dexamethasone-treated animals. The local cerebral metabolic rate of glucose utilization (lCMRgl) was decreased modestly under control conditions in dexamethasone-treated animals, whereas cerebral energy use measured in a model of decapitation ischemia did not differ significantly between groups. The lCMRgl increased markedly during hypoxia-ischemia (p < 0.05) and remained elevated throughout ischemia in dexamethasone- but not vehicle-treated groups, indicating an enhanced glycolytic flux with dexamethasone treatment. Thus, dexamethasone likely provides protection against hypoxic-ischemic damage in immature rats by preserving cerebral ATP secondary to a maintenance of glycolytic flux.

The effect of age on susceptibility to brain damage in a model of global hemispheric hypoxia-ischemia.

Stroke occurs in all age groups, ranging from the newborn to the elderly. The immature brain is generally believed to be more resistant to the damaging effects of cerebrovascular compromise compared to the more mature brain. However, recent experiments suggest that the correlation between brain damage and age is not linear. To determine the effects of age and development on hypoxic-ischemic brain damage, we developed a model whereby rats of increasing age received identical cerebrovascular insults, and assessed neuropathologic outcome. Male Wistar rats of 1, 3, 6, and 9 weeks and 6 months underwent unilateral common carotid artery ligation and exposure to 12% oxygen for 35 min. Animals were all spontaneously breathing under light halothane anesthesia (0.5%). Core temperatures were maintained at 37 degrees C. Blood pressures were monitored via indwelling carotid artery catheters on the side ipsilateral to the carotid artery ligation. Cerebral blood flow was assessed in separate groups utilizing Laser Doppler flowmetry. Physiologic monitoring revealed that under these experimental conditions, mean arterial blood pressure and cerebral blood flow decreased to the same extent in each of the age groups, verifying that all animals experienced an identical insult. Neuropathologic assessment at 7 days of recovery showed that brain damage was most severe in the 1 and 3 week old animals followed by those that were 6 months. The 6 and 9 week old groups had significantly less injury than the other 3 age groups. Hippocampal damage was most severe in the 3 week and 6 month old rats compared to all other age groups. Our findings contrast previously held beliefs regarding the enhanced tolerance of the immature brain to hypoxic-ischemic damage and demonstrates that, in a physiologically controlled in vivo model of hemispheric global ischemia, (1) the immature brain is, in fact, less resistant to hypoxic-ischemic brain damage than its adult counterpart, (2) the brain damaging effects of hypoxic-ischemia are age dependent, but do not increase linearly with advancing age and development, and (3) the intermediate age groups are more tolerant to hypoxic-ischemic brain injury than either very young or more mature ages.

Effect of mild hypothermia on cerebral energy metabolism during the evolution of hypoxic-ischemic brain damage in the immature rat.

BACKGROUND AND PURPOSE: Intraischemic hypothermia (34 degrees C and 31 degrees C) has a profound neuroprotective effect on the brain of the immature rat. Hypothermia immediately after hypoxia-ischemia is not beneficial. To determine the mechanisms by which mild to moderate hypothermia affects cerebral energy metabolism of the brain of the newborn rat pup, we examined alterations in cerebral glycolytic intermediates and high-energy phosphate compounds during intraischemic and postischemic hypothermia and correlated these findings with known neuropathologic injury. METHODS: Seven-day-old rat pups underwent unilateral common carotid artery ligation and exposure to hypoxia in 8% oxygen at either 37 degrees C, 34 degrees C, or 31 degrees C for 3.0 hours. Separate groups were exposed to hypoxia-ischemia at 37 degrees C for 3 hours but recovered at either 37 degrees C, 34 degrees C, or 31 degrees C. At 60, 120, and 180 minutes of intraischemic hypothermia and at 10, 30, 60, and 240 minutes of postischemic hypothermia, individual rat pups were quick-frozen in liquid nitrogen for later determination of cerebral concentrations of glucose, lactate, ATP, and phosphocreatine. RESULTS: Cerebral glucose was significantly higher and lactate significantly lower in the 31 degrees C animals during hypoxia-ischemia than either the 34 degrees C or 37 degrees C groups. Brain ATP concentrations were completely preserved during hypoxia-ischemia at 31 degrees C, whereas 34 degrees C of hypothermia had no effect on preserving high-energy phosphate compounds compared with those animals in the 37 degrees C group. Postischemic hypothermia of either 34 degrees C or 31 degrees C had no effect on the rate or extent of recovery of glycolytic intermediates or high-energy phosphate compounds compared with the normothermic 37 degrees C rat pups. CONCLUSIONS: Moderate hypothermia of 31 degrees C completely inhibits the depletion of ATP during hypoxia-ischemia, a mechanism that likely accounts for its neuroprotective effect. No preservation of ATP was seen, however, during intraischemic mild hypothermia of 34 degrees C despite the relatively profound neuroprotective effect of this degree of temperature reduction. Thus, the mechanisms by which mild hypothermia is neuroprotective are temperature dependent and may act at more than one point along the cascade of events eventually leading to hypoxic-ischemic brain damage in the immature rat.

Paradoxical mitochondrial oxidation in perinatal hypoxic-ischemic brain damage.

Measurements of cytoplasmic and mitochondrial markers of the oxidation-reduction (redox) state of brain tissue were conducted in a perinatal animal model of cerebral hypoxia-ischemia to ascertain underlying biochemical mechanisms whereby ischemia (reduced oxygen and substrate supply) causes brain damage. Seven-day postnatal rats underwent unilateral common carotid artery ligation followed by exposure to 8% oxygen at 37 degrees C for 3 h. During the course of hypoxia-ischemia, the rat pups were quick frozen in liquid nitrogen and their brains processed for the enzymatic, fluorometric measurement of cerebral metabolites necessary for the calculation of intracellular pH and cytoplasmic and mitochondrial redox states. The results showed an early mitochondrial reduction followed by re-oxidation during the course of hypoxia-ischemia. The oxidation reflected a partial depletion in accumulated reducing equivalents and coincides temporally with the duration of hypoxia-ischemia required to convert selective neuronal necrosis into cerebral infarction. The findings suggest that perinatal cerebral hypoxia-ischemia is characterized more by a limitation of substrate than of oxygen supply to the brain, which may explain why glucose supplementation of the immature animal improves neuropathologic outcome, in contrast to adults.

Cellular mechanisms involved in brain ischemia.

Cellular mechanisms, both destructive and protective, that are associated with cerebral ischemia are reviewed in this paper. Central to understanding the evolution of stroke are the concepts of ischemic core and surrounding penumbral region damage, delayed neuronal death, and neuronal rescue. The role of spreading depression in the evolution of subsequent ATP depletion, ion shifts, glutamate release, activation of glutamate receptors, intracellular Ca2+ changes, and generation of reactive oxygen species in the penumbra in relationship to neuronal and glial cell damage are discussed. We conclude that the most fruitful areas for future stroke research include traditional approaches as well as novel approaches. Traditional approaches include stroke prevention and examination of the effects of combinations of proven and promising effective therapeutic interventions. Novel approaches include delineating mechanisms whereby growth factors and compounds such as deprenyl and staurosporine afford neuroprotection, ultimately leading to direct manipulation of the signal transduction pathways that lead to neuronal dysfunction and death. This includes determining which genes are activated and repressed in specific response to hypoxia-ischemia and determining how such alterations in gene expression affect survival and function of neurons. We also suggest that advantage be taken of the blood-brain barrier compromise during stroke in designing neuroprotective therapies.

Astrocyte survival in the absence of exogenous substrate: comparison of immature and mature cells.

Astrocyte cultures prepared from newborn mouse neopallium were grown for either one or three weeks (representing, respectively, immature and mature astrocytes) and then exposed to deprivation of substrate (glucose and amino acids) for up to 48 hr. Cultures which had been deprived of metabolic substrates for either 24, 30, 36 or 48 hr were examined for lactate dehydrogenase efflux into the medium (an indicator of cell death) and ATP content. Significant cell death in mature astrocytes began after 30 hr of incubation in the substrate-deprived medium, a time when ATP had fallen to approximately 10% of its initial value. Immature astrocytes survived on a substrate-free medium for 48 hr before there was any indication at all of cell death, and this corresponded to a time when ATP values had fallen to 5% of the initial values. These findings are compared to previous observations during simulated ischemia (substrate deprivation plus anoxia) when (1) there was a faster cell death and (2) cell death occurred at higher ATP levels.

Does iron deficiency raise the seizure threshold?

To determine the effect of iron status on the seizure threshold, measures of iron sufficiency were prospectively evaluated in 51 children presenting to a pediatric emergency department with a febrile illness with (26) or without (25) an associated febrile seizure. A higher proportion of children from the febrile seizure group had a family history of mental retardation (5/26 versus 0/25, P = .02) or of previous febrile seizures (10/26 versus 2/23, P = .01). The two groups were otherwise comparable for age, sex, race, family history of afebrile seizures, temperature at presentation, white blood cell count, differential, and vitamin and antibiotic use. Patients with febrile seizures were less frequently iron deficient as defined by a free erythrocyte protoporphyrin level above 0.80 ng/L (2/23 versus 10/25, P < .01), hemoglobin concentration less than 110 g/L (1/26 versus 6/25, P < .03), hematocrit less than 0.30 L/L (0/22 versus 4/25, P < .02), mean corpuscular hemoglobin less than 20 pg (0/25 versus 3/24, P < .04), mean corpuscular volume less than 65 fL (0/26 versus 4/24, P < .02), and platelet count higher than 550 x 10(9)/L (0/26 versus 3/25, P < .04). This association was even stronger when adjusted for differences in family history. None of the patients in the febrile seizure group was being treated for iron deficiency at presentation, whereas three of 25 controls used an iron supplement (P < .04). Iron deficiency may protect against the development of febrile seizures.

Correlation between content of high-energy phosphates and hypoxic-ischemic damage in immature and mature astrocytes.

The effect of 'simulated ischemia', i.e., combined anoxia and substrate deprivation, was studied in 1- and 3-week-old (i.e., immature and mature) primary cultures of mouse astrocytes. Cell survival, as indicated by retention of the high-molecular cytosolic protein lactate dehydrogenase was compared with retained high-energy phosphate compounds (ATP and phosphocreatine). A previously established longer survival of the immature cells during the metabolic insult was confirmed and found to correlate with a more complete maintenance of high-energy phosphates. However, in both the mature and immature cells, no death occurred as long as the ATP content remained at or above 25% of its control value. ATP concentrations below 10% of control were accompanied by almost complete cell death in both age groups. Thus, the better survival of immature astrocytes during simulated ischemia is correlated with better maintenance of the levels of high-energy phosphates and, regardless of age, cell death occurs only once a critically 'low' threshold of ATP has been reached.

Cerebral glucose and energy utilization during the evolution of hypoxic-ischemic brain damage in the immature rat.

The cerebral metabolic rate for glucose (CMRg1) and cerebral energy utilization (CEU) were assessed in immature rats during recovery from cerebral hypoxia-ischemia. CMRg1 was determined using a modification of the Sokoloff technique with 2-deoxy-[14C]glucose (2-DG) as the radioactive tracer. CEU was determined using the Lowry decapitation technique. Seven-day postnatal rats underwent unilateral common carotid artery ligation, followed 4 h thereafter by exposure to 8% oxygen at 37 degrees C for 3 h. At 1, 4, or 24 h of recovery, the rat pups underwent those procedures necessary for the measurement of either CMRg1 or CEU. At 1 h of recovery, the CMRg1 of the cerebral hemisphere ipsilateral to the carotid artery occlusion was 97% of the control rate (8.7 mumol 100 g-1 min-1) but was only 48% of the control in the contralateral hemisphere. At 4 h of recovery, the CMRg1 was increased 49% above baseline in the ipsilateral hemisphere, decreasing thereafter to 84% of the control at 24 h. The CMRg1 of the contralateral hemisphere normalized by 4 h of recovery. An inverse correlation between endogenous concentrations of ATP or phosphocreatine and CMRg1 in the ipsilateral hemisphere was apparent at 4 h of recovery. CEU in the ipsilateral cerebral hemisphere was 64 and 46% of the control (3.47 mmol approximately P/kg/min) at 1 and 24 h, respectively (p < 0.05) and 77% of the control at 4 h of recovery. CEU in the contralateral hemisphere was unchanged from the control at all measured intervals. Correlation of the alterations in CMRg1 with those in CEU at the same intervals indicated that substrate supply exceeds energy utilization during early recovery from hypoxia-ischemia. The discrepancy combined with a persistent disruption of the cerebral energy state implies the existence of an uncoupling of mitochondrial oxidative phosphorylation as one mechanism for the occurrence of perinatal hypoxic-ischemic brain damage.

The effect of focal cerebral cooling on perinatal hypoxic-ischemic brain damage.

We describe a method of focal cooling of the head and its effects on hypoxic-ischemic cerebral damage in neonatal rat. Focal cooling of the head was obtained by positioning a catheter under the scalp ipsilateral to the ligated common carotid artery and by running cold water through the catheter during 2 h of systemic hypoxia. Hypoxia was produced in neonatal rats by breathing 8% oxygen for 2 h in a 37 degrees C chamber. Animals underwent focal cooling with ipsilateral scalp temperatures ranging from 22 degrees C to 35 degrees C. Temperature recordings from the ipsilateral scalp, cerebral hemisphere (dorsal hippocampus) and core (rectal) were obtained. The results suggest that the method is effective in cooling of brain and also to a lesser extent in lowering of the core temperature. At a mean scalp temperature of 28 degrees C, mean hippocampal temperature in hypoxic rat was 29.5 degrees C and mean core temperature in hypoxic rat was 32.8 degrees C. At a lower scalp temperature of 22 degrees C, mean hippocampal temperature in hypoxic rat was 24.7 degrees C and mean core temperature was 31.3 degrees C. Neuropathologic examination 3-4 days following hypoxia-ischemia showed that focal cooling with a scalp temperature of lower than 28 degrees C completely protected from brain damage, and that there was a trend towards greater damage with higher scalp temperatures.

Regional cerebral blood flow following hypothermic circulatory arrest in newborn dogs.

A model of hypothermic circulatory arrest has been developed in newborn dogs which simulates the procedure used for the operative repair of congenital cardiac defects in human infants. Hypothermic circulatory arrest for 1.0 h causes no brain damage, whereas cardiac arrest for 1.75 h results in damage of the cerebral cortex, basal ganglia and to a lesser extent the claustrum and amygdaloid nucleus. In the present study, we determined regional cerebral blood flow (rCBF) during 24 h of recovery from hypothermic circulatory arrest. Newborn nitrous oxide anesthetized and artificially ventilated dogs were cooled to 20 degrees C and subjected to cardiac arrest by the i.v. injection of KCl for either 1.0 or 1.75 h. Thereafter, animals were resuscitated, rewarmed to 37 degrees C, and rCBF measured with [14C]iodoantipyrine at either 2 or 18 h of recovery. Control animals were rendered hypothermic to 20 degrees C without cardiac arrest for 1.0 or 1.75 h prior to rewarming. No alterations in CBF at either 2 or 18 h of recovery were present in any of 16 analyzed structures in animals previously subjected to hypothermic circulatory arrest compared to controls rendered hypothermic alone. A direct linear correlation existed between mean arterial blood pressure and blood flow within frontal, parietal and occipital cortex, occipital white matter, hypothalamus and cerebellar vermis in puppies arrested for 1.75 h and recovered for 2 h, suggesting a loss of CBF autoregulation at this interval. No such association between blood pressure and CBF was apparent at 18 h of recovery.(ABSTRACT TRUNCATED AT 250 WORDS)