Hypoxic-ischemic cerebral necrosis in midgestational sheep fetuses: physiopathologic correlations

Thirty-eight midgestational sheep fetuses were exposed 120 min to marked hypoxia. The brains in eight that reduced their mean arterial blood pressure to less than 30 mm Hg were markedly damaged. In these same fetuses the serum lactic acid concentrations were elevated during exposure to hypoxia to excessively high values (greater than 15 mM) and remained elevated for a prolonged period during recovery. Twenty-one fetuses exposed to the same magnitude of hypoxia that maintained their blood pressure unchanged showed less marked elevations of serum lactate concentrations and remained brain-intact. Greater quantities of pentobarbital administered to the ewes during hypoxia seemed to protect the brain from hypoxia and this effect was dose-dependent. Exposure of midgestational sheep fetuses to marked hypoxia associated with reductions in cerebral blood flow due to decreased blood pressure and impaired cerebral autoregulation caused major focal cerebral necrosis.     

Brain injury from marked hypoxia in cats: role of hypotension and hyperglycemia

The present study identifies several factors that govern brain pathologic response to marked hypoxia. None of 13 cats exposed to 25 minutes of marked hypoxia (FiO2 = 3.4%; PaO2 = 17 +/- 3 mm Hg, S.D.) that maintained mean arterial blood pressure (MABP) greater than 65 mm Hg were brain injured after reoxygenation and long term survival. In contrast, 12 of 13 exposed to the same hypoxia but that experienced reductions in MABP less than 45 mm Hg for 4 +/- 1 minutes developed a pattern of brain injury closely resembling that of humans surviving in a persistent vegetative state after cardiorespiratory arrest. Higher serum glucose and lactate concentrations and lower blood pH values significantly correlated with development of hypotension during hypoxia. Four of 8 cats exposed to 21 minutes of marked hypoxia followed by 4 minutes of 100% N2 breathing that also led to hypotension similarly developed brain injury. Among the hypoxic/hypotensive cats the magnitude of the hyperglycemic response to hypoxia as modulated by 0, 1, or 2 days of preexposure fasting, strongly correlated with occurrence and extent of brain damage. Peak cisterna magna CSF lactate concentrations 10 to 30 minutes into recovery distinguished those animals that remained brain-intact (less than 13 mM) from those that developed brain damage (greater than 15 mM) with 100% accuracy. Seven cats developed delayed cardiogenic shock 3 to 12 hours into the recovery period. This outcome was predicted by blood pH values less than 6.70 shortly after resuscitation while all 27 surviving cats exhibited values greater than 6.80.     

Injurious effects of acute ethanol exposure during late gestation on developing white matter in fetal sheep

Fetal exposure to maternal alcohol intake can be harmful to the developing brain but the effects of acute exposures are less well documented. Our objective was to determine the effects of acute alcohol exposure on developing white matter and to investigate the potential role of pro-inflammatory cytokines. Fifteen pregnant ewes underwent surgery at 110.0 ± 1.0 days of the 147 day gestation for fetal catheterization. Ethanol (1 g/kg maternal weight) was administered intravenously to 8 ewes for 1 h on 3 consecutive days at 116.0 ± 1.0 days of gestation (0.8 of full term); 7 pregnant control ewes received saline. Fetal brains were collected at necropsy 5 days after the initial ethanol exposure and processed for structural analysis. Maternal and fetal blood ethanol concentrations reached maximal values (0.11 ± 0.01 g/dL) 1 h after infusions commenced, declining to zero thereafter. Ethanol exposure did not cause fetal hypoxemia, acidemia, hypercapnia, hypoglycemia or hypotension. Subcortical white matter injury, defined as microglia/macrophage infiltration, axonal disruption, increased apoptosis, astrogliosis and altered glial cell morphology, was observed in 4 of the 8 ethanol-exposed fetuses. The injury occupied 6.6–18.3% of the cross-sectional area of cerebral white matter examined and was substantial in 2/8 and modest in 2/8 ethanol-exposed fetuses. Three remaining fetuses exhibited astrogliosis and elevated levels of apoptosis in cerebral white matter. There was a positive correlation between maternal and fetal blood ethanol concentrations and the extent of brain damage. There was no significant elevation in concentrations of the pro-inflammatory cytokines tumor necrosis factor-, interleukin-1β and interleukin-6 in fetal plasma. Developing white matter in the late gestation fetus is vulnerable to acute alcohol exposure, but mechanisms remain unclear.     

Chemiluminescence on hypoxic brain--the 1st report: relation between free radical reaction and energy metabolism

To explore the possibility that cerebral ischemia or cerebral hypoxia may initiate a series of free radical reactions of brain tissue lipid constituents, we measured sequential change of chemiluminescence and energy metabolites during brain hypoxia in rat. The hypoxic brain was induced by arterial hypoxemia (PaO2 17-22 mmHg) with normocapnia (PaCO2 28-38 mmHg) and normotension (MABP 100-140 mmHg). 4% O2-96% N2 mixed gas was used as the replacement for obtaining lowered PaO2. We made another attempt to analyze chemiluminescence spectra on purpose of luminous mechanism investigation. No peroxidation occurred in prehypoxic state since there were no photon counts, however, chemiluminescence began to rise up in hypoxic state and remained high value in posthypoxic early state. Namely in hypoxic state, 3-min period showed 231 counts/10 sec X g and 5-min period showed 154 counts/10 sec X g. In posthypoxic state, 5-min period showed 217 counts/10 sec X g and 30-min period showed a similar decrease as prehypoxic state. The chemiluminescence spectroanalysis showed five peaks at 480 nm, 520-530 nm, 570 nm, 620-640 nm, 700 nm in wavelength. As to sequential changes of energy metabolism, hypoxia caused marked brain lactic acidosis, increase in ADP, pyruvate and a fall in glucose. However, all metabolites recovered at 30-min period in posthypoxic state, which suggests this was reversible brain hypoxia. A transition of chemiluminescence and energy metabolites suggests the occurrence of free radical reaction in hypoxic and posthypoxic brain. The spectroanalysis reveals the luminous mechanism as follows 1 delta g # 1 delta g----2(3)O(2) + h nu.     

Chemiluminescence in hypoxic brain--the first report. Correlation between energy metabolism and free radical reaction

The possibility that cerebral ischemia or cerebral hypoxia may initiate a series of free radical reactions in brain tissue lipid constituents was explored by measuring sequential changes in chemiluminescence values and energy metabolism during brain hypoxia in the rat. Brain hypoxia was induced by means of arterial hypoxemia (PaO2 17-22 mmHg), normocapnia (PaCO2 28-38 mmHg) and normotension (MABP 100-140 mmHg). To obtain lowered PaO2, 4% O2--96% N2 mixed gas was used. Analysis of the chemiluminescence spectra for the purpose of luminous mechanism investigation was again attempted. No peroxidation occurred in the pre-hypoxic state since there were no photon counts. Chemiluminescence began to rise in the hypoxic state and remained at a high value in the post-hypoxic state. Specifically in the hypoxic state, the 3 min period showed 231 +/- 35 counts/10 sec X g (n = 5) and the 5 min period showed 154 +/- 62 (n = 19) counts/10 sec X g. In the post-hypoxic state, the 5 min period showed 217 +/- 79 counts/10 sec X g (n = 9) and the 30 min period showed a decrease similar to the pre-hypoxic state. The chemiluminescence spectroanalysis showed five peaks in wavelength at 480 nm, 520-530 nm, 570 nm, 620-640 nm and 680-700 nm. Sequential changes in energy metabolism revealed that hypoxia caused marked brain lactic acidosis, an increase in both ADP and pyruvate, and a fall in glucose. However, all metabolites recovered at 30 min in the post-hypoxic state, which suggests this was reversible brain hypoxia. Sequential changes in chemiluminescence values and energy metabolism imply the occurrence of free radical reaction in the hypoxic and post-hypoxic brain. The spectroanalysis reveals the luminous mechanism as follows: 1 delta g + 1 delta g----23O2 + h mu     

Initiation and propagation of lipid peroxidation in cerebral infarction models. Experimental studies

The possibility that cerebral ischaemia or cerebral hypoxia may initiate a series of free radical reactions in brain lipid constituents was explored by measuring sequential changes in chemiluminescence (CL) and electron spin resonance (ESR) during hypoxia or ischaemia load. Brain hypoxia was induced by means of arterial hypoxaemia (PaO2 17-22 mmHg), normocapnia (PaCO2 28-38 mmHg) and normotension (MABP 100-140 mmHg). To obtain lowered PaO2, 4% O2-96% N2 mixed gas was used for artificial ventilation. Spin trapping technique was used in ESR measurement and applied to the detection of free radicals generated in the ischaemic brain homogenate of three-vessel occlusion rat model (global highly ischaemic model with basilar artery coagulation and bilateral carotid artery clipping). Chemiluminescence (CL) began to rise in hypoxic or ischaemic loading and indicates high amounts at an early period of post-hypoxic or ischaemic state. The CL spectroanalysis by wavelength showed five peaks at 480 nm, 520-530 nm, 570 nm, 620-640 nm and 680-700 nm in both hypoxic and ischaemic brain. ESR measurement revealed the PBN (phenyl-t-butyl nitrone) trapped radical, which has hyperfine splitting constants of AN = 16.2-16.5 G and AH beta = 3.6-3.8 G in ischaemia model. An analysis of sequential change of PBN adduct intensity shows a peak at 30 min of ischaemic loading and a marked increase in the recirculation period. Preservation of ATP and marked lactic acidosis were seen in the 5 min hypoxic loading, elsewhere depletion of ATP and marked lactic acidosis were seen in the 5 min, 30 min ischaemia.(ABSTRACT TRUNCATED AT 250 WORDS)     

Brain metabolic changes in young vs aged rats during hypoxia

Brain energy state and glycolytic metabolites were measured in young (6 month) and aged (28 month) male rats under normoxic (70% nitrous oxide, 30% oxygen) or hypoxic (PaO2 = 25 mm Hg) test conditions. Hypoxic ischemia was induced in one cerebral hemisphere by ligation of one carotid artery. Under normoxic test conditions brain energy metabolite concentrations were similar between young and aged rats. Brain tissue glucose, glycogen, glucose-6-phosphate and critic acid cycle intermediate concentrations were decreased in aged rats during normoxia while fructose-6-phosphate and pyruvate were increased. Decreases in brain energy state and increases in lactate/pyruvate ratios were significant in both young and aged rats during hypoxia and were greater in aged animals in hypoxic-ischemic tissues. These results indicate that brain energy state is normal in aged rats under normoxic conditions but that hypoxic-ischemia produces a greater degree of brain energy failure compared to younger animals.     

Initiation and propagation of lipid peroxidation in cerebral infarction models: Experimental studies

The possibility that cerebral ischaemia or cerebral hypoxia may initiate a series of free radical reactions in brain lipid constituents was explored by measuring sequential changes in chemiluminescence (CL) and electron spin resonance (ESR) during hypoxia or ischaernia load. Brain hypoxia was induced by means of arterial hypoxaernia (Pa_O2, 17-22 mmHg), normocapnia (Pa_CO2 28-38 mmHg) and normotension (MABP 100-140 mmHg). To obtain lowered Pa_O2, 4% O₂-96%N₂ mixed gas was used for artificial ventilation. Spin trapping technique was used in ESR measurement and applied to the detection of free radicals generated in the ischaemic brain homogenate of three-vessel occlusion rat model (global highly ischaemic model with basilar artery coagulation and bilateral carotid artery clipping). Chemiluminescence (CL) began to rise in hypoxic or ischaemic loading and indicates high amounts at an early period of post-hypoxic or ischaemic state. The CL spectroanalysis by wavelength showed five peaks at 480 nm, 520-530 nm, 570 nm, 620-640 nm and 680-700 nm in both hypoxic and ischaemic brain. ESR measurement revealed the PBN (phenyl-t-butyl nitrone) trapped radical, which has hyperfine splitting constants of A_N = 16.2-16.5 G and A_β^H = 3.6-3.8 G in ischaemia model. An analysis of sequential change of PBN adduci intensity shows a peak at 30 min of ischaemic loading and a marked increase in the recirculation period. Preservation of ATP and marked lactic acidosis were seen in the 5 min hypoxic loading, elsewhere depletion of ATP and marked lactic acidosis were seen in the 5 min, 30 min ischaemia. The results of this study indicate that free radical reactions are initiated focally with soluble oxygen in fatty acid part during ischaemia or hypoxia but that overt lipid peroxidation is propagated by oxygen resupply.     

Regulation of local cerebral blood flow in normal and hypoxic newborn dogs

Local cerebral blood flow (LCBF) was measured autoradiographically in newborn puppies by an indicator fractionation technique using 4-iodo-[14C]antipyrine as the diffusible indicator. Measurements were obtained in unanesthetized, normotensive animals, and the sensitivity of blood flow to hypercapnia and acute hypoxia was determined in 32 brain structures. LCBF in normal and hypoxic puppies was correlated with local cerebral glucose utilization (LCGU) obtained under the same experimental conditions (Duffy et al, 1982). In normocapnic (PaCO2 33 mm Hg) control animals, highest rates of blood flow were found in gray matter nuclei of the brainstem, in the medulla oblongata, and in the posterolateral nucleus of the thalamus (50 to 77 ml/100 gm/min); far lower flows were recorded among white matter structures (5 to 11 ml/100 gm/min). The vasodilatory response to both hypercapnia and hypoxia was greatest among brainstem gray matter structures, intermediate among cortical and diencephalic gray matter structures, and least in white matter. When LCBF was plotted as a function of LCGU for control animals, a positive linear correlation was obtained for all structures (p less than 0.001), implying that in newborns, as in adults, cerebral blood flow and metabolism are physiologically coupled. In hypoxic puppies, no consistent relationship between LCGU and LCBF could be demonstrated; however, there was suggestion that the two measurements correlated inversely, presumably reflecting enhanced anaerobic glycolysis in structures (e.g., hemispheric white matter) that were not adequately protected by compensatory hyperemia. White matter damage, a frequent complication of perinatal hypoxia-asphyxia, may be a consequence in part of the limited capacity of white matter to vasodilate in response to te chemical "signals" of hypercapnia and lactic acidosis.     

Acute ultrastructural response of hypoxic hypoxia with relative ischemia in the isolated brain

Summary The acute cortical response to surgical brain isolation and subsequent extracorporal normoxic or 30 min hypoxic (PaO₂=20 mm Hg) perfusions (hypoxic hypoxia with relative ischemia) was evaluated. Cerebral blood flow, arterial pH and CO₂ were maintained constant during both perfusions; only the arterial oxygen content was changed. The isolated brain model used in this and previous investigations produces no qualitative ultrastructural changes in the neocortex following brain isolation and normoxic perfusion. However, the acute cortical structural response to 30 min of hypoxic hypoxia with relative ischemia demonstrated a number of important observations. Hypoxic hypoxia produced ultrastructural responses common to cerebral ischemia such as nuclear chromatin clumping, nucleolar condensation and cytoskeletal breakdown. Although neuronal abnormalities seen after 30 min of hypoxic hypoxia were similar to those acute neuronal changes observed following complete cerebral ischemia without recirculation, they differed three ways: (a) mitochondrial swelling and microvacuolation were observed in many cortical pyramidal neurons. (b) Glycogen particles within astroglial processes were observed even after a 30-min period of hypoxic hypoxia. (c) Perivascular astroglial swelling was minimal despite considerable perineuronal swelling. In contrast, incomplete cerebral ischemia produces mitochondrial changes similar to those in hypoxic hypoxia but also causes the depletion of tissue glycogen and perivascular glial swelling. Thus, hypoxic hypoxia with relative ischemia produces a unique acute ultrastructural response compared to either complete or incomplete cerebral ischemia.Supported by an NIH grant NS05961     

Local cerebral glucose metabolism in newborn dogs: Effects of hypoxia and halothane anesthesia

Local cerebral glucose utilization (LCGU) was measured in 36 neuroanatomical structures of normal awake, halothane-anesthetized, and hypoxic newborn puppies by the autoradiographic 2-[¹⁴C]deoxyglucose method. In normal animals, LCGU was highest in the vestibular nucleus and in other gray matter nuclei of the brainstem and declined in a caudal-to-rostral progression through the neuraxis (i.e., LCGU of cerebellum > thalamus ? caudateputamen > cerebral cortex). Lowest rates of glucose metabolism were detected in white matter structures. Halothane anesthesia (1.5% inspired) caused few changes in local glucose metabolism, the most notable being decreased LCGU among structures of the auditory system (cochlear nucleus, lateral lemniscus, inferior colliculus) and increased LCGU in the interpeduncular nucleus. Acute systemic hypoxia (arterial oxygen tension of approximately 12 mm Hg) produced markedly heterogeneous effects on local glucose metabolism: LCGU was increased in some gray matter structures, decreased in the thalamus, and substantially increased in the subcortical white matter and corpus callosum. In puppies whose brains were frozen in situ after 55 minutes of hypoxia, the concentration of lactate was increased ten- to elevenfold in cortical gray and subcortical white matter, but the concentrations of glucose, adenosine triphosphate, and phosphocreatine declined to a greater extent in the white matter. The results suggest that during hypoxia the high rate of glycolysis in white matter exceeded substrate supply so that glucose availability became the limiting factor for local energy production. Such a mechanism may contribute to the white matter injury that often develops following hypoxic-ischemic insults in the perinatal period.     

Failure to produce germinal matrix or intraventricular hemorrhage by hypoxia, hypo-, or hypervolemia

Our study with midgestational sheep fetuses failed to support a cause-and-effect relation between marked hypoxia with or without hypo- or hypervolemia and rapid surges of blood pressure and the development of germinal matrix or intraventricular hemorrhage. Twenty-nine percent of fetuses exposed to marked hypoxia concomitantly with manipulations of their blood volume and blood pressure developed widespread cerebral necrosis. However, despite this marked anoxic-ischemic brain injury, none developed any germinal matrix or intraventricular hemorrhage. Rapidly and markedly elevating the blood pressure in these fetuses despite the presumed presence of an impaired autoregulation and a probable elevation of their central venous pressure also failed to cause germinal matrix or intraventricular hemorrhage. Marked hypoxia accompanied by reductions in blood pressure brought about by blood withdrawal produced an 80% delayed fetal mortality but not a single instance of germinal matrix or intraventricular hemorrhage.     

Acute effects of perinatal hypoxic insult on concentrations of dopamine, serotonin, and metabolites in fetal monkey brain

Seven monkeys (Macaca mulatta) were laparotomized under general anesthesia (halothane, nitrous oxide, oxygen). Fetal hypoxia was induced in four monkeys by occlusion of the umbilical cord with a hydraulic occluder for 5–6 min. Three sham-operated fetuses served as controls. After unclamping, the fetuses were allowed to reperfuse for 20–30 min. To monitor hypoxia, the fetal electrocardiogram was recorded continuously. Hypoxic insult was associated with a decrease in fetal heart rate during the occlusion. After reperfusion, fetuses were immediately sacrificed and neocortex regions dissected on ice, frozen on dry ice and stored at −70°C. Dopamine, 3,4-dihydroxyphenylacetic acid, homovanillic acid, serotonin, and 5-hydroxyindoleacetic acid were assayed by high performance liquid chromatography with electrochemical detection (HPLC/EC) in hippocampus, caudate nucleus and cortical regions. In the hippocampus, there was a significant increase in 5-hydroxyindoleacetic acid concentration. In prefrontal cortex, there was a trend toward an increase in serotonin but no effects on dopamine and homovanillic acid concentrations. Dopamine, serotonin and metabolites were not altered in the caudate nucleus. These data demonstrate that fetal hypoxia followed by reperfusion produced an increase in serotonin concentration measured within the hippocampus and selected cortical areas known to be targets of hypoxic injury.     

Lactic acidosis and recovery of mitochondrial function following forebrain ischemia in the rat

The effect of different degrees of lactic acidosis on the recovery of brain mitochondrial function, measured as respiratory activity in isolated mitochondria or cortical concentrations of labile phosphates and carbohydrate substrates, was studied during 30 min of recirculation following 15 min of near-complete forebrain ischemia in rats. During ischemia, there was a marked decrease in mitochondrial State 3 respiration in vitro and a depletion of energy stores (i.e., phosphocreatine, ATP, glucose, and glycogen) in vivo that was similar in the high- and low-lactate ischemia groups. However, lactate concentrations differed markedly (20 and 10 mumol g-1, respectively). During recirculation, there was a near-complete recovery of both respiratory activity in vitro and adenylate energy charge (EC) in vivo regardless of the differences in lactic acidosis during ischemia. Respiratory activity and EC were well correlated. The changes in Ca2+ homeostasis during ischemia, an increase in tissue and a decrease in mitochondrial Ca2+ content, were reversed rapidly after ischemia in both high- and low-lactate ischemia animals and did not hinder an early recovery of mitochondrial function. It is concluded that lactic acidosis, with lactate levels reaching 20 mumol g-1 during 15-min ischemia, does not adversely affect early postischemic recovery of mitochondrial function.     

Melatonin provides neuroprotection in the late-gestation fetal sheep brain in response to umbilical cord occlusion

Oxygen free radicals, including the highly toxic hydroxyl radical (*OH), initiate lipid peroxidation and DNA/RNA fragmentation and damage cells. The pineal hormone melatonin is an antioxidant and powerful scavenger of *OH. We hypothesized that maternally administered melatonin could reduce *OH formation, lipid peroxidation, and DNA/RNA damage in the fetal brain in response to asphyxia. In 15 fetal sheep, extracellular *OH was measured by microdialysis in white and gray matter of the parasagittal cortex. In 10 fetuses, asphyxia was induced by umbilical cord occlusion for 10 min using an inflatable cuff - the ewes of these fetuses received either intravenous melatonin (1 mg bolus, then 1 mg/h for 2 h; n = 5) or vehicle (1% ethanol in saline; n = 5), and results were compared to fetuses with sham cord occlusion and vehicle-infused ewes (n = 5). Hypoxemia, acidemia, hypertension and bradycardia produced by cord occlusion was similar in the melatonin- and vehicle-treated groups. In the vehicle-treated group, cord occlusion resulted in a significant increase in *OH in gray matter at 8-9.5 h after occlusion (p < 0.05); in contrast, there was no *OH change in the melatonin-treated group. After cord occlusion, lipid peroxidation (4-hydroxynonenal immunoreactivity) found throughout the brain of vehicle-infused ewes was significantly less in the melatonin-infused group. Melatonin had no significant effect on the distribution of DNA/RNA fragmentation, as shown by 8-hydroxydeoxyguanosine immunoreactivity. Thus, brief asphyxia results in significant and delayed entry of *OH into the extracellular space of cortical gray matter in the fetal sheep brain, and melatonin given to the mother at the time of the insult abrogates this increase. Melatonin, in reducing O2 free radical production, may be an effective neuroprotective treatment for the fetus.     

Effects of ischemia-hypoxia induced by interruption of uterine blood flow on fetal rat liver and brain enzyme activities and offspring behavior

The effects of acute perinatal ischemia-hypoxia on fetal liver and brain energy metabolism, fetal brain total free fatty acid concentration and subsequent offspring behavior were investigated in rats. Ischemia-hypoxia was induced at term either by ligation of the uterine blood vessels or submersion of the entire uterine horn in warmed saline. Fetuses of the adjacent horn served as within-dam controls for all assessments and fetuses of dams which had not undergone the surgical stress served as independent controls for enzyme assays. Ischemia-hypoxia was associated with reduced activity of fatty acid synthase in the liver and brain. Total free fatty acid concentration significantly increased in the fetal hypoxic brain. Pups not used for enzyme analyses were cross-fostered for behavioral assessments. Relative to the enzymatic alterations, there were few behavioral alterations associated with ischemia-hypoxia. At postnatal day 30, rats made hypoxic by ligation of the uterine blood vessels had decreased caudate nucleus and brain stem weights relative to within-dam controls. At postnatal day 85, rats made hypoxic by submersion of the uterine horn had decreased olfactory bulb weight. The results of this study indicate an initial acute response to a brief period of ischemia-hypoxia at term pregnancy in the fetal rat brain and liver.     

Cerebral phosphoinositide, triacylglycerol and energy metabolism during severe hypoxia and recovery

The cerebral concentrations of phosphatidylinositol (PI), phosphatidylinositol 4-phosphate (PIP), phosphatidylinositol 4,5-bisphosphate (PIP2), phosphatidic acid (PA), triacylglycerol (TAG) and free fatty acids (FFA), as well as cerebral metabolites, were measured in rats subjected to 10 min of hypoxia and subsequent recovery of 7 or 30 min duration. The experiments were carried out with control of physiological variables. Hypoxia (paO2 values of about 15 mm Hg) caused a decrease in PI, whereas PIP and PIP2 did not change significantly. A two-fold increase of total FFA was noted, mainly comprising stearic and arachidonic acids. TAG-arachidonate tended to increase, but the other species in TAG decreased. Adenosine triphosphate (ATP) and energy charge (EC) decreased slightly and there was a marked lactate accumulation. PA did not change throughout the experiment. With recovery of 7 min duration, PI decreased further and total FFA continued to increase. TAG-arachidonate increased significantly. ATP remained depressed but EC recovered to the control range. Both tissue and plasma glucose increased. Tissue lactate remained elevated and systemic acidosis occurred. After a recovery period of 30 min, all lipids normalized and the energy state returned toward control. The data suggest that the phosphoinositide alterations during hypoxia are metabolically linked to changes in FFA and the lipid changes are accompanied by alterations in cerebral energy and carbohydrate metabolism. The selective increase in TAG-arachidonate may represent an incorporation of arachidonic acid into TAG, which may serve to reduce the free arachidonic acid level in the brain.     

Effects of hypoxic hypoxia on cerebral phosphate metabolites and pH in the anesthetized infant rabbit

The effects of hypoxic hypoxia on high-energy phosphate metabolites and intracellular pH (pHi) in the brain of the anesthetized infant rabbit were studied in vivo using 31P nuclear magnetic resonance spectroscopy. Five 10- to 16-day-old rabbits were anesthetized with 1.5% halothane. Ventilation was controlled to maintain normocarbia. Inspired O2 fraction was adjusted to produce three states of arterial oxygenation: hyperoxia (PaO2 greater than 250 mm Hg), normoxia (PaO2 approximately 100 mm Hg), and hypoxia (PaO2 25-30 mm Hg). During hypoxia, blood pressure was kept within 20% of control values with a venous infusion of epinephrine. During hyperoxia, the phosphocreatine-to-ATP ratio was 0.86, a value that is 2-2.5 times less than that reported for adults. During normoxia, ATP decreased by 20% and Pi increased by 90% from hyperoxia values. During 60 min of hypoxia, the concentrations of high-energy phosphate metabolites did not change, but intracellular and arterial blood pH (pHa) decreased significantly. When hyperoxia was reestablished, pHi returned to normal and pHa remained low. These results suggest that during periods of hypoxemia, the normotensive infant rabbit maintains intracellular concentrations of cerebral high-energy phosphates better than has been reported for adult animals.     

Cerebrale Vasoparalyse,arterielle Hypertension und Hirnödem

The present studies were performed in order to determine whether "filtration edema" will develop as a consequence of cerebral vasoparalysis, vasoparalysis in combination with arterial hypertension or arterial hypertension alone. A series of dogs, anaesthetised with i.v. Chloralose-Urethane were exposed 1) to cerebral vasoparalysis, produced by hypercapnia (PaCO2 about 150 mm Hg) and hypoxaemia (PaO2 40-60 mm Hg); 2) to arterial hypertension and 3) to a combination of cerebral vasoparalysis and arterial hypertension. Following cerebral vasoparalysis and arterial hypertension, a significant decrease of total cerebrovascular resistance and moderate increase of venous resistance was observed. Regional cerebral blood flow (133Xe), intracranial pressure, as well as the pressure in postcapillary venous outflow (sinus sagittalis wedge pressure and confluence sinuum pressure) were increased. Neither normotonic vasoparalysis nor vasoparalysis in combination with slight arterial hypertension (MABP more than 90 min above 180 mm Hg) resulted in cerebral edema. In contrast, cerebral vasoparalysis in combination with severe arterial hypertension (MABP more than 90 min above 220 mm Hg) resulted in a statistically significant increase in the water content in the white matter without evidence of protein extravasation. Multiple small foci of Evans blue extravasates, however, were found in the cortex following arterial hypertension in combination with vasodilation, indicating a damage of the blood brain barrier. In these blue stained cortical areas the water content was significantly in creased. The following conclusions were drawn from the results. Vasoparalysis during normotension does not produce brain edema despite the slightly elevated hydrostatic pressure gradient between intravasal and extracellular space. Only considerable increase of this hydrostatic pressure gradient caused by a combination of vasoparalysis with severe arterial hypertension is able to produce brain edema in the white matter. In addition, acute hypertension may cause minor multifocal damage of the blood brain barrier in the cerebral cortex. It is concluded that so-called brain swelling, which has been described by several authors in states of cerebral vasoparalysis, is not predominantly caused by brain edema but by vascular congestion. The clinical aspects of the result are discussed.