Cerebral metabolic response to neonatal hypoglycemia in growth-retarded dogs

The cerebral metabolic effects of hypoglycemia due to intrauterine growth retardation were studied in newborn dogs. Intrauterine growth retardation was induced in newborn dogs after 3 days of maternal nutritional deprivation (birth weight 251 +/- 7 versus 227 +/- 7 g, p less than 0.01). After birth, growth retarded pups developed fasting neonatal hypoglycemia which lasted from 3 to 9 h of life. The cerebral arteriovenous differences for glucose, oxygen, and ketone bodies were not different between growth-retarded pups or those from age-matched controls. The cerebral venous efflux of lactate was reduced, whereas the extraction of glucose (relative to blood glucose) was enhanced among growth-retarded pups. Cerebral glycogen content was lower in pups with growth retardation whereas phosphoenolpyruvate and pyruvate concentrations were augmented among growth-retarded pups. The latter may reflect a more oxidized cytoplasmic redox state but may also be due to diminished lactate efflux from the brain. Cerebral ATP content was not affected during periods of reduced blood glucose levels. These results suggest that in newborn dogs hypoglycemia associated with intrauterine growth retardation alters cerebral metabolism by increasing cerebral extraction of glucose and decreasing CNS efflux of lactate. We speculate that the net effect is increased lactate utilization within oxidative pathways and preservation of cerebral oxygen uptake. Cerebral glucose utilization is directed away from glycogen synthesis and toward glycolysis. Lactate oxidation rather than release to the systemic circulation may maintain cerebral ATP production in growth-retarded hypoglycemic newborn dogs.     

Autoradiographic determination of regional cerebral blood flow during hypoglycemia in newborn dogs

To ascertain the regional cerebral blood flow (CBF) responses to hypoglycemia, nine newborn dogs were treated with insulin to blood glucose concentrations ranging from 1 to 35 mg/dl (mean 22 mg/dl). Systemic physiologic monitoring revealed no differences in mean arterial blood pressure, heart rate, paO2, paCO2, pHa, or blood lactate in the hypoglycemis animals and five normoglycemic controls. Significant increases in CBF occurred in 17 of 20 analyzed structures of brain in the hypoglycemic puppies, ranging from 158 to 446% of the normoglyycemic values. The percent increases in CBF were greatest in brainstem structures compared to other major regions of brain. A positive correlation existed between mean arterial blood pressure and cerebral cortical blood flow, suggesting a loss of CBF autoregulation during hypoglycemia. The pathophysiologic mechanism for the elevations in regional CBF might relate to stimulation of beta-adrenergic receptors in brain, as has been shown in adults.     

Hypoglycemic brain injury

Hypoglycemia frequently occurs in newborn infants who previously have suffered asphyxia, who are offspring of diabetic mothers, or who are low birthweight for gestational age (IUGR). Many infants who are hypoglycemic do not exhibit clinical manifestations, while others are symptomatic and at risk for the occurrence of permanent brain damage. This review emphasizes the clinical, neuropathologic, and neuro-imaging features of hypoglycemia in newborn infants, especially those who are symptomatic. Neurologic morbidity occurs particularly in those infants who have suffered severe, protracted, or recurrent symptomatic hypoglycemia. Experimental observations emphasize the resistance of the immature brain to the damaging effect of hypoglycemia; such resistance occurs as a consequence of compensatory increases in cerebral blood flow, lower energy requirements, higher endogenous carbohydrate stores, and an ability to incorporate and consume alternative organic substrates to spare glucose for energy production. Hypoglycemia combined with hypoxia-ischemia (asphyxia) is more deleterious to the immature brain than either condition alone.     

Hypoglycemia and its effects on the brain in children with type 1 diabetes mellitus

The incidence studies on hypoglycemia in Type 1 Diabetes have revealed that the younger the child the more frequent and severe are the hypoglycemic episodes. The brain does not store glycogen and perform gluconeogenesis, it relies on a continuous supply of glucose from blood. There are several studies demonstrating the brain's ability to use lactate, alanine and ketone as alternative fuels yet there is no evidence showing that this mechanism works in diabetic individuals. During hypoglycemia, cerebral blood flow increases very little in children. It is unlikely that this mechanism alone explains the maintenance of glucose utilization. Up regulation of GLUT transporters may be an additional or alternative protective mechanism. Severe hypoglycemic episodes experienced particularly in early childhood can cause deterioration in neurocognitive functions. There are significant individual differences in terms of vulnerability to hypoglycemia. Adaptive responses to hypoglycemia might vary according to both the degree and frequency of prior hypoglycemia and the presence of structural brain changes induced by chronic hyperglycemia.     

The effect of hypotension on brain energy state during prolonged neonatal seizure

Prolonged seizures in the human neonate may be complicated by systemic hypotension. To examine the effect of systemic hypotension on brain metabolic state during seizure, neonatal dogs were made hypotensive (by exsanguination) during bicuculline-induced seizure. Measurement of regional cerebral blood flow showed that moderate hypotension did not impair cerebral perfusion during seizure. Measurement of brain energy state with in vivo 31P nuclear magnetic resonance spectroscopy disclosed a similar pattern of alteration of high energy phosphates in animals subjected to seizure or to the combination of seizure and hypotension. The additional metabolic stress imposed by moderate hypotension during seizure in the neonatal dog appears to be slight.     

糖尿病母亲婴儿低血糖发生情况及其与脑损伤的关系

目的探讨糖尿病母亲婴儿（IDMS）低血糖的发生情况及其与脑损伤的关系。方法分析86例IDMS低血糖的发生情况、母亲孕期血糖控制与低血糖持续时间的关系。分析其脑损伤发生及严重程度与低血糖持续时间、并其他疾病和症状性低血糖的关系。结果短暂性低血糖75例（87.2%）,反复发作性低血糖11例（12.8%）。母亲孕期血糖反复发作性低血糖发生率控制不满意组为19.4%,满意组为8%。反复发作性低血糖组脑损伤总发生率及重度脑损伤发生率高于短暂性低血糖组,并其他疾病组48.5%和无临床症状组57.4%,均有显著性差异（Pa〈0.05）。结论低血糖的持续时间与母亲妊娠期血糖控制情况及脑损伤发生、严重程度有关;低血糖并其他疾病会加重脑损伤,症状性低血糖时常存在严重脑损伤。     

Increased cerebral blood flow and plasma epinephrine in hypoglycemic, preterm neonates

Cerebral blood flow, plasma epinephrine, and plasma norepinephrine were measured in 25 spontaneously breathing, preterm neonates (mean gestational age 30.4 weeks) 2 hours after birth, during a routine screening for low blood glucose levels. Increased cerebral blood flow and plasma epinephrine values were observed when blood glucose levels were low, whereas plasma norepinephrine was constant throughout the blood glucose range. Hypoglycemia (defined as blood glucose concentration less than 30 mg/dL) was found in 13 neonates who were treated with intravenous glucose and milk enterally. Blood glucose levels were normal in the remaining 12 control neonates who received milk by a gastric line. Approximately 30 minutes after treatment with intravenous glucose and/or milk, cerebral blood flow had decreased by a mean of 11.3% in the 13 hypoglycemic neonates but was still 37.5% higher than cerebral blood flow in the control neonates despite normalization of plasma epinephrine concentration. Mean arterial blood pressure and blood gas values were identical between groups throughout the investigation. It is suggested that a normal coupling between cerebral metabolic demands and flow is present in very preterm neonates and that epinephrine may play a role in the cerebral hyperperfusion. Although none of the neonates had clinical signs of hypoglycemia, the data suggest that counterregulatory mechanisms are invoked when blood glucose values are less than 30 to 45 mg/dL.     

Cerebral blood flow, cross-brain oxygen extraction, and fontanelle pressure after hypoxic-ischemic injury in newborn infants

The relationship between mean arterial pressure, intracranial pressure, cerebral blood flow, cross-brain oxygen extraction, cerebral metabolic rate, and outcome was studied during therapy in nine neonates on 3 consecutive days after severe hypoxic-ischemic cerebral injury. Cross-brain oxygen extraction was significantly higher (5.06 +/- 0.5 vs 2.05 +/- 0.8 ml/dl; p = 0.012) in the five neonates who survived with normal neurologic outcome than in the four who died or sustained severe brain damage. In contrast, global cerebral blood flow in the five neonates with normal neurologic outcome was significantly lower (25.6 +/- 8.2 vs 83.2 +/- 44.9 ml/100 gm brain/min; p less than 0.05) during the study period. The differences in cross-brain oxygen extraction and global cerebral blood flow between infants who had neurologic recovery and those who died or sustained brain damage occurred in the presence of acceptable values for intracranial pressure, mean arterial pressure, and cerebral perfusion pressure. Our preliminary data suggest that cross-brain oxygen extraction and possibly global cerebral blood flow may be important variables associated with severe neuronal injury and death after hypoxic-ischemic cerebral injury.     

Effect of mild hypothermia and hypoxia on blood flow and oxygen consumption of the fetal sheep brain

This study was undertaken to measure the effects of mild hypothermia on cerebral blood flow and metabolism and cardiovascular responses to hypoxia in the fetal sheep. Near-term fetal sheep were chronically instrumented with laser Doppler flowmetry in the parietal cortex for measurement of relative changes in cerebral blood flow, as well as with arterial and sagittal sinus catheters for measurement of oxygen extraction by the brain and a cooling coil around the fetal thorax. Fetuses were studied during cooling alone, cooling with superimposed maternal hypoxia to achieve a fetal arterial Po2 of 1.33 to 1.60 kPa, or hypoxia alone. In response to cooling alone [1.6 degrees +/- 0.1 degrees C (mean +/- SEM) decrease in brain temperature], fetal blood pressure and heart rate both increased significantly whereas cerebral blood flow decreased 14 +/- 4%, commensurate with a 24 +/- 8% decline in cerebral metabolic rate. Administration of moderate hypoxia during cooling resulted in a significant increase in cerebral blood flow, decreased heart rate, and no further increase in blood pressure. In response to hypoxia alone, fetal blood pressure was significantly increased, heart rate was decreased, and cerebral blood flow increased by 24 +/- 8%, whereas cerebral metabolic rate decreased by 38 +/- 13%. Arteriovenous oxygen extraction was unchanged by cooling alone but increased significantly in response to hypoxia administered during cooling. We therefore conclude that oxygen delivery to the fetal sheep brain remains coupled to metabolic rate during hypothermia and that hypothermia does not impair the compensatory cardiovascular responses of the fetus to acute moderate hypoxia.     

Alterations in cerebral mitochondria during acute hypoglycemia

To test the hypothesis that acute hypoglycemia leads to free radical induced alterations in cerebral mitochondria, newborn piglets were subjected to 2 h of insulin-induced hypoglycemia (blood glucose 1 mmol/l). The effects of free radicals were determined in cerebral cortical synaptosomes, mitochondria, and neuronal nuclei by measuring membrane lipid peroxidation. Fragmentation of nuclear and mitochondrial DNA was also examined. Lipid peroxidation was significantly increased in hypoglycemic mitochondrial membranes as compared to controls, but no increase in peroxidation in hypoglycemic synaptosomal or nuclear membranes was observed. An increase in low molecular weight DNA fragments was observed only in mitochondrial DNA from hypoglycemic piglets. We speculate that alteration of cerebral mitochondria due to increased free radical production is one of the early events in the pathogenesis of hypoglycemic brain injury.     

Effects of maternal labetalol on the newborn infant.

Forty eight neonates, born to mothers suffering from pregnancy induced hypertension and receiving labetalol for control of blood pressure, were studied for the possible adverse effects of the drug. These were compared with eighty one neonates matched for gestation and weight and born to mothers with pregnancy induced hypertension treated with drugs other than labetalol. Incidence of birth asphyxia and intrauterine growth retardation (IUGR) in the study population was 10.4 and 22.9%, respectively and in the control group 5 and 19.7%, the difference between two groups was not statistically significant (p > 0.05). However, the incidence of hypoglycemia was significantly higher (p < 0.01) in the study group (47.9%) as compared to the control group (17.2%). Two-thirds of the hypoglycemic babies in the study population were asymptomatic and they were managed with sugar-fortified milk feeds. In the study population, the symptomatic hypoglycemic babies had hypoglycemia for prolonged duration of 43.3 +/- 23.3 hours as compared to 11.5 +/- 6.3 hours in symptomatic hypoglycemic babies of the control group (p < 0.01). The mothers of the symptomatic babies in the study group received higher doses of labetalol in the range of 287.6 +/- 142.3 mg/day while rest of the mothers in the same group whose babies had either asymptomatic hypoglycemia or normal blood glucose levels, received 239.5 +/- 118.5 mg/day, though the difference was not statistically significant. It is concluded that maternal labetalol therapy is associated with increased risk of neonatal hypoglycemia.     

Partitioning and extraction of glucose regulates cerebral glucose utilization in newborn dogs

We investigated the amount of fasting steady-state systemic glucose production utilized by the neonatal canine cerebral cortex. The relationship of systemic glucose production and cerebral glucose utilization were analyzed as functions of cerebral blood flow, cerebral oxygen uptake, and indirect measures of alternate fuel utilization. Fasting arterial blood glucose was 3.36 mM and glucose production was 49.6 mumol/kg/min. Average cerebral blood flow was 0.83 ml/g/min, and cerebral glucose uptake was 0.60 +/- 0.15 mumol/g/min. 36.6% of systemic glucose production was utilized by the cerebral cortex. There were no correlations between systemic glucose production, cerebral blood flow, or cerebral glucose uptake with blood glucose concentration. Furthermore, total cerebral glucose uptake was static across a wide range of glucose levels. Nonetheless, the percent of glucose production used by the brain was an inverse function of systemic glucose production (r = -0.71, p less than 0.001). The cerebral extraction of glucose (27.6 +/- 4.1%) decreased as a function of increasing blood glucose levels (r = -0.51, p less than 0.05), while brain uptake index correlated with increasing systemic glucose production (r = 0.61, p less than 0.02). We can conclude that the canine neonatal cerebral cortex may utilize only 37% of systemic glucose production. At low rates of glucose turnover, a larger proportion of systemic glucose production is allotted to the brain. Mechanisms that may regulate total cerebral glucose influx may be glucose permeability, or the increased extraction of glucose at lower blood glucose levels.     

血清脑红蛋白评估新生儿低血糖脑损伤的临床价值

目的探讨血清脑红蛋白（NGB）在新生儿低血糖脑损伤评估中的临床应用价值。方法选择100例低血糖新生儿为研究对象。根据振幅整合脑电图（aEEG）结果和/或临床表现，分为3组：症状性低血糖脑损伤组（n=22）、无症状性低血糖脑损伤组（n=37）和低血糖无脑损伤组（n=41）。比较各组患儿血糖、低血糖持续时间、NGB及神经元特异性烯醇化酶（NSE）水平、改良aEEG评分；分析NGB与NSE水平、改良aEEG评分之间的相关性并绘制受试者工作特征（ROC）曲线等。结果症状性低血糖脑损伤组血糖、改良aEEG评分低于无症状性低血糖脑损伤组及低血糖无脑损伤组（P < 0.05），NGB、NSE、低血糖持续时间高/长于无症状性低血糖脑损伤组及低血糖无脑损伤组（P < 0.05）。无症状低血糖脑损伤组血糖、改良aEEG评分低于低血糖无脑损伤组（P < 0.05），NGB、NSE及低血糖持续时间高/长于低血糖无脑损伤组（P < 0.05）。NGB与NSE、低血糖持续时间呈正相关（分别r=0.922、0.929，P < 0.05），与血糖、改良aEEG评分呈负相关（分别r=-0.849、-0.968，P < 0.05）；NGB、NSE、改良aEEG评分的ROC曲线下面积分别为0.894、0.890、0.941，NGB最佳截断值为108 mg/L，敏感度80.8%，特异度95.8%。结论血清NGB与NSE、改良aEEG评分比较，同样可作为评估低血糖新生儿脑损伤的特异性指标，具有一定的临床应用价值。     

Neonatal hyperinsulinemic hypoglycemia. Two case reports

Neonatal hyperinsulinemic hypoglycemia must be suddenly and appropriately diagnosed and treated to prevent any further neurological dysfunction and damage. Therefore, we report two cases of our observation. Case 1: birth asphyxia, episodes of hypoglycemia after delivery, hyperinsulinism and reduced IGFBP1 blood concentration. Clinical and laboratory pictures resolved progressively after 8 days of life, perfusions were stopped and the neonate began to suck breast milk. Case 2: negative familial and perinatal history. On the 3rd day of life he developed cyanosis, hypotonia, tremors and hypoglycemia. He was discharged with a diagnosis of cerebral injury and neonatal hypoglycemia. At 1 year of life the child showed progressive and heavy neurological damage. The RMN of the brain showed: enlarged ventricles and liquor spaces around the brain, particularly in the frontal region. Hyperinsulinism was diagnosed in our Clinic. He began pharmacological treatment with Diazoxide that permitted euglycemia. The ammonium was normal and excluded glutamate dehydrogenase deficiency (mutation of GLUD1 gene); Diazoxide responsivity excluded mutations of SUR1 and KIR6.3 genes. At 9 years of life he showed motor and language retardation. Newborns with perinatal history of asphyxia may develop transient hyperinsulinism with absent neurological consequences. Persistent hypoglycemic or epileptic-like episodes, in particular on waking up, after meals or during banal infections, must be studied to reveal hyperinsulinism.     

Cerebrovascular hemodynamics during and after recovery from acute asphyxia in the newborn dog

Cerebrovascular volume and transmural pressure loads accompanying acute increases in cerebral blood flow are implicated in the pathogenesis of periventricular-intraventricular hemorrhage in preterm infants. An acute increase in cerebral blood flow would be expected during acute recovery from asphyxia. Therefore, cerebrovascular hemodynamics, including flow (microspheres), were studied during and after acute recovery from asphyxia in seven newborn dogs in order to study the determinants of these volume and pressure loads. During the acute recovery phase, cerebral hemispheric blood flow was 69.6 +/- 10 ml/100 g/min (mean +/- SEM) representing a 250% increase from baseline values of 19.9 +/- 1.8 ml/100 g/min (p less than 0.005), while combined cerebellar-brainstem flow was 204.3 +/- 19.3 ml/100 g/min representing a 536% increase from baseline values of 32.0 +/- 1.5 ml/100 g/min (p less than 0.005). Blood flow to both areas had returned to baseline levels 20 min after the onset of recovery. Associated with this cerebral hyperemia was an acute increase in mean arterial pressure from 21.3 +/- 4.5 mm Hg at end asphyxia to 69.5 +/- 6.0 mm Hg at peak recovery (p less than 0.01), and parallel acute increases in sagittal sinus pressure (from 4.0 +/- 0.4 to 14.6 +/- 1.9 mm Hg, p less than 0.01) and cerebrospinal fluid pressure (from 3.8 +/- 0.4 to 14.3 +/- 1.9 mm Hg, p less than 0.01). Central venous pressure fell from 4.3 +/- 0.6 mm Hg at end asphyxia to 1.6 +/- 0.5 mm Hg, and thus is not a determinant of the elevation in sagittal sinus pressure.(ABSTRACT TRUNCATED AT 250 WORDS)     

Blood flow distribution and brain metabolism during tolazoline-induced hypotension in newborn dogs

Tolazoline is used in neonatal intensive care to treat hypoxia secondary to persistent pulmonary hypertension of the newborn. Its use is often complicated by systemic hypotension. We compared the effect of tolazoline-induced hypotension on organ blood flow, regional brain blood flow, and cerebral metabolism in hypoxic newborn dogs whose mean arterial pressure fell by more than 20% with a second group whose blood pressure fell by less than 20%. Blood flows were measured by the radioactive microsphere technique. We found no changes in organ blood flow, regional brain blood flow, and cerebral metabolism in hypoxic animals whose mean arterial blood pressure decreased less than 20% during tolazoline administration. However, in those animals whose mean arterial blood pressure decreased more than 20%, we found a decrease in cerebral blood flow. As a consequence of decreased cerebral blood flow, cerebral oxygen delivery decreased. However, oxygen extraction increased so that cerebral metabolic rate was preserved.     

Cardiomegaly in neonatal hypoglycemia

Chest. X-rays of 24 hypoglycemic newborns were compared with those of a matched control group of newborns with normal blood glucose levels. In the hypoglycemic group heart size was found to be significantly greater than in the control group.No correlation could be established between the degree of cardiomegaly and the severity of hypoglycemia. 19 of the 24 hypoglycemic children were prematures or small for dates and it is postulated that the low glycogen stores in these infants do not meet the metabolic demands of the myocardium during its postpartum circulatory adaptation.     

Hyperammonemia in hypoglycemic preterm neonates

Plasma glucose, blood urea nitrogen, and ammonia were measured simultaneously in 44 newborns a few hours after birth. When the concentration of plasma glucose was below 30 mg/dl, plasma ammonia concentration was significantly higher (129 +/- 67 mumol/l) than in normoglycemic infants (74 +/- 33 mumol/l; p less than 0.01). Blood urea nitrogen was slightly lower in hypoglycemic infants (3.65 +/- 0.7 mmol/l) than in the control group (4.5 +/- 1 mmol/l) but the difference was not significant. These data show that hyperammonemia can be associated to hypoglycemia in low birth weight infants. Therefore, further investigations are required to determine the link between urea and glucose production rates in hypoglycemic newborns and whether hyperammonemia participates in the deleterious effects of hypoglycemia on the neonatal brain.     

Preferential blood flow increase to the brain stem in moderate neonatal hypoxia: reversal by naloxone

Previous studies have shown that severe neonatal asphyxia and hypoxia lead to a redistribution of cerebral blood flow (CBF) with a preferential perfusion of the brain stem.The present study shows that this mechanism is operative also in moderately hypoxic newborn lambs (oxygen saturation 32.7–65.2) with a threshold of about 25% reduction in oxygen saturation. In hypoxia, the mean increase in total CBF, brain stem and telencephalic blood flow was 44%, 68% and 43%, respectively (five lambs).We found that naloxone reverses this redistribution, and that the effects of naloxone on telencephalic perfusion and cerebral metabolic rate of oxygen (CMRO₂) were proportional. In hypoxia + naloxone (1 mg/kg), a further increase in total CBF, brain stem, and telencephalic blood flow of 30%, 7% and 31% was noted.We therefore suggest that the redistribution of CBF is an important opioid-mediated homeostatic mechaism, which diminishes the metabolic requirements of the newer part of the brain in hypoxia and allows a preferential perfusion of the vital structures of the brain stem.Abbreviations CBF cerebral blood flow - CMRO₂ cerebral metabolic rate of oxygen     

Cerebral metabolic intermediate response following severe canine intrauterine growth retardation

The effect of intrauterine growth retardation and neonatal hypoglycemia on cerebral metabolic intermediates were determined in newborn dogs subjected to 5 days of maternal canine starvation (MCS) before birth. Birth weight was reduced 23% (232 +/- 6 versus 300 +/- 10 g). Circulating blood glucose was reduced after 3 h of neonatal fasting in MCS pups (2.7 +/- 0.4 +/- versus 5.7 +/- 1.1 mM). Cerebral cortical levels of glucose were also reduced at this time. Cerebral glucose-6-phosphate was not altered; nonetheless fructose-6-phosphate was lower in MCS pups at 6 and 9 h, while fructose 1,6-diphosphate appeared elevated at 3 h. These data suggest that cerebral glycolytic activity may be increased by increased activity of phosphofructokinase. Cerebral glutamine appeared reduced in fasting MCS pups at 3, 6, and 8 h of age. A considerable disturbance of the adenine nucleotide pool was noted between 3-9 h in MCS pups; while the cerebral energy reserve was diminished in MCS pups between 3-24 h. The data of reduced cerebral energy status and reserve suggest that cerebral energy production was diminished. Although glucose levels were low at 3 h, subsequent recovery was not immediate as adenine-nucleotides remained low beyond the period of hypoglycemia. The combined effects of intrauterine growth retardation and transient neonatal hypoglycemia appear to result in reduced cerebral oxidative metabolism; this occurs despite an apparent enhanced utilization of alternate fuels.