Christine A Gleason

Cerebral and peripheral circulatory responses to intracranial hypertension in fetal sheep.

Fetal head compression during normal labor can increase intracranial pressure (ICP). We studied the cerebral and peripheral blood flow responses to ICP elevation in utero in chronically catheterized fetal sheep using the radiolabeled microsphere technique. ICP was elevated, stepwise, in increments of 6±1 mm Hg by infusion of artificial cerebrospinal fluid into a lateral ventricle. When ICP was raised to within 28 mm Hg of baseline mean arterial blood pressure (i.e., ICP above 22 mm Hg), arterial pressure began to increase. Above this ICP level, up to 41 mm Hg, mean cerebral perfusion pressure was maintained by equivalent increases in arterial pressure. Cerebral blood flow and O2 uptake at the highest ICP levels were not different from baseline values. Changes in peripheral organ blood flow were graded according to the level of ICP. At the highest level (ICP=41 nun Hg), renal, gastrointestinal, and skin blood flow decreased by 68percent;, 69percent;, and 65percent;, respectively. Myocardial and adrenal blood flow doubled, whereas heart rate and cardiac output were unchanged. Placenta! blood flow increased in proportion to arterial pressure. Arterial plasma epinephrine, norepinephrine and arginine vasopressin increased by nearly two orders of magnitude. Therefore, as ICP approaches baseline mean arterial pressure, fetal lambs are capable of sustaining cerebral perfusion by initiating profound visceral vasoconstriction without curtailing placental blood flow. Since cerebral O2 uptake was maintained, there is no evidence that stimulation of the peripheral response requires pronounced cerebral ischemia. This highly developed Gushing response may be important for ensuring cerebral viability when the fetal head is compressed during parturition.

Possible antioxidant effect of vitamin A supplementation in premature infants

BACKGROUND Increased lipid peroxidation caused by oxygen free radicals is thought to be one of the common pathogenetic mechanisms for the so-called oxygen radical diseases of prematurity. Since in vitro studies have shown that various forms of vitamin A can exert antioxidant effects that are more potent than those of vitamin E (treatment with which has been ineffective in these diseases), the purpose of this prospective, controlled study was to determine whether administration of supplemental vitamin A to premature infants deficient in this vitamin would have an antioxidant effect in vivo. METHODS Fourteen infants (1181 +/- 35 g; gestational age 29 +/- 0.04 weeks) with a serum retinol concentration at 7 +/- 2 days of age in the deficient range, lower than 0.7 mumol/l (< 20 micrograms/dl), were enrolled in the study. Infants were randomized to receive the standard amount of vitamin A or standard plus supplemental (2.6 mumol/l [2500 IU] orally each day) vitamin A, beginning at 1 week of age. Antioxidant effects of supplementation were assessed by a decrease in lipid peroxidation, quantified by the ethane content of expired air. RESULTS Three weeks after study enrollment, total daily vitamin A intake in the infants receiving supplements was 4.565 +/- 0.236 mumol (4354 +/- 225 IU) versus 1.879 +/- 0.317 mumol/l (1792 +/- 302 IU) in infants receiving standard amounts of the vitamin. In spite of the difference in intake of vitamin A, 3 weeks after study enrollment, serum retinol concentrations did not differ between the infants given supplements and those receiving standard amounts of vitamin A, 0.70 +/- 0.21 versus 0.66 +/- 0.07 mumol/l (20 +/- 6 micrograms/dl versus 19 +/- 2 micrograms/dl, respectively). In the infants receiving supplemental vitamin A, breath ethane values declined from baseline values. There was an inverse correlation between the number of weeks of supplementation and breath ethane values, whereas there was no significant correlation between the duration of the study and breath ethane values in the infants not given supplements. CONCLUSIONS Our data suggest that supplementation with vitamin A in a small group of vitamin A-deficient preterm infants was associated with an antioxidant effect. Although no immediate clinical benefits were associated with supplementation, the data provide the rationale for future investigations of possible antioxidant effects of (larger amounts?) of vitamin A in higher risk premature infants born with subnormal serum retinol concentrations.

Effect of Extracorporeal Membrane Oxygenation on Cerebral Blood Flow and Cerebral Oxygen Metabolism in Newborn Sheep

ABSTRACT: Extracorporeal membrane oxygenation (ECMO) supplies respiratory support to term or near-term infants with respiratory failure. Although infants requiring this therapy may have already sustained significant hypoxia and/or ischemia predisposing them to neurologic injury, the high incidence of neuroimaging abnormalities in the ECMO population raises concerns about the additional neurologic risk associated with the ECMO procedure itself. Our study was undertaken to evaluate the effects of ECMO on the normal neonatal cerebral circulation. Thirteen newborn lambs (1-7 d of age) were placed on normothermic venoarterial ECMO using a silicone membrane oxygenator and roller occlusion pump. Regional brain blood flows, cerebral oxygen consumption, fractional oxygen extraction, and oxygen transport were determined 30 and 120 min after initiation of ECMO. Neither cerebral blood flow (baseline, 60.2 ± 23.6; 30 min, 56.1 ± 18.1; 120 min 56.1 ± 12.9 mL/100 g/min) nor oxygen metabolism (cerebral oxygen consumption: baseline, 4.48 ± 1.48; 30 min, 3.86 ± 1.53; 120 min, 4.10 ± 1.32 mL/100 g/min and oxygen extraction: baseline, 0.52 ± 0.09; 30 min, 0.47 ± 0.14; 120 min, 0.46 ± 0.14 mL/100 g/min) changed after the initiation of ECMO. Regional and left/right blood flow differences were not noted. These findings suggest that in healthy newborn lambs, initiation of ECMO does not alter cerebral blood flow or oxygen metabolism.

Effects of First Trimester Binge Alcohol Exposure on Developing White Matter in Fetal Sheep

Heavy prenatal alcohol exposure is associated with neurodevelopmental abnormalities. Neuropathologic and neuroimaging studies have shown a wide range of structural problems, including abnormal neuronal migration and volume reduction in specific brain regions, including white matter. We identified foci of significant fetal white matter microglia-macrophage immunoreactivity in a “binge” model of early prenatal alcohol exposure in sheep. Ewes of alcohol-exposed fetuses received daily 90 min alcohol (1.5 gm/kg i.v.) infusions at 30–60 d gestation (term = 147 d). Ewes of control fetuses received same volume infusions of normal saline intravenously. Near-term (125 d gestation) fetal brains were labeled with microglia-macrophages using HAM56 antibody. We quantified dense immunoreactive cellular regions across sections and anatomical locations using computer-assisted microscopy and quantitative morphometry. The proportional HAM56-positive area in cortical white matter was greater in the alcohol-exposed fetuses (1.6%) compared with the saline controls (0.7%). The areas were localized to the frontal gyral white matter, temporal gyral white matter, optic radiation, and others (corpus callosum, septum pellucidum, fasciculus subcallosus, and external capsule), with a greater distribution in the gyral white matter. The greater area of macrophage-rich regions in near-term fetal sheep brain suggests a vulnerability of developing white matter that is enhanced by early alcohol exposure.

Newborn Cerebrovascular Responses after First Trimester Moderate Maternal Ethanol Exposure in Sheep

S Fetal alcohol syndrome is one of the leading causes of mental retardation in the United States, but the pathogenesis of the associated brain damage is unknown. We tested the hypothesis that neonatal cerebrovascular responses to CO2 and/or hypoxia may be altered by moderate chronic maternal ethanol exposure early in gestation. We studied 26 newborn lambs (1-4 d old). Their mothers had received daily i.v. infusions of either ethanol (1 g/kg; ethanol concentration = 167 ± 3 mg/dL; mean ± SEM) or a similar volume of saline for 3 wk during the first trimester. In nine lambs, we studied cerebral responses to CO2 (saline, n = 4; ethanol,n = 5) and in 17 lambs, cerebral responses to hypoxia (saline,n = 7; ethanol, n = 10). Cerebrovascular responses to CO2 were not different between the groups. However, the cerebral vasodilatory response to hypoxemia was significantly attenuated in the ethanol lambs, such that cerebral O2 delivery was not maintained. During severe hypoxia (arterial Po2 = 30 mm Hg), cerebral blood flow increased 106± 23% (mean ± SEM) above baseline in the saline-treated group, but increased only 32 ± 15% above baseline in the ethanol-treated group(p < 0.02). Similarly, cerebrovascular resistance in the saline group decreased 52 ± 6% from baseline, but decreased only 16 ± 11% in the ethanol group (p < 0.02). We conclude that moderate maternal ethanol infusion early in pregnancy attenuates neonatal hypoxic, but not CO2, cerebrovascular responsivity.

Cerebral Responses to Acute Maternal Alcohol Intoxication in Immature Fetal Sheep

ABSTRACTS: Previous studies in mature fetal sheep have shown that alcohol depresses cerebral blood flow (CBF), cerebral O2 consumption (CMRO2), and cerebral glucose consumption (CMRglu). This effect earlier in gestation might contribute to the pathogenesis of fetal alcohol syndrome. Physiologic studies of immature fetal sheep have demonstrated lower CBF, CMRO2, and CMRglu as well as a blunted vasodilatory response to hypoxia compared with mature fetal sheep. The purpose of this study was to determine whether immature fetal responses to alcohol are blunted compared with near-term fetal responses. We studied seven immature fetal sheep in utero at 92 ± 1 d gestation (term = 147 d) 2 d after placement of vascular catheters. Pure ethanol (1 g/kg) was infused i.v. to the mother over 1 h. We measured CBF and myocardial blood flow by radioactive microspheres and calculated CMRO2 and CMRglu using arterial and sagittal sinus O2 and glucose concentrations. At a fetal ethanol concentration of 33 + 8 mmol/L (150 ± 37 mg/dL), there were no significant changes in CBF, CMRO2, or CMRglu. There was mild hypoglycemia (glucose concentration = 1.05 ± 0.2 versus 1.33 ± 0.2 mM baseline) and lactic acidemia (lactate concentration = 1.29 ± 0.3 versus 1.07 ± 0.2 mM baseline). Cardiovascular variables were unchanged as was myocardial blood flow. The immature fetal sheep brain shows no significant cerebrovascular and metabolic response to acute alcohol intoxication compared with mature fetal sheep. Mild hypoglycemia and lactic acidemia did develop. The reason for the developmental differences in response to alcohol and their relationship to fetal alcohol syndrome remain to be elucidated.

Cerebrovascular response to carbon dioxide in lambs receiving extracorporeal membrane oxygenation

ObjectiveTo determine if the institution of extracorporeal membrane oxygenation (ECMO) alters the cerebrovascular response to changes in Paco2. DesignProspective, randomized, controlled animal trial. SubjectsAnesthetized 1− to 7-day-old lambs of mixed breed (n = 16). SettingUniversity research laboratory. InterventionsThe experimental group was placed on ECMO. Both experimental and control groups (n = 8) were exposed to three concentrations of Paco2 (hypocarbia, normocarbia, and hypercarbia) by varying mechanical ventilation and by adding carbon dioxide to the ventilator gases. Measurements and Main ResultsCerebral blood flow was measured by the radiolabeled microsphere method. Arterial blood gases and sagittal sinus blood gases were drawn at the time of cerebral blood flow measurement so that cerebral metabolism, cerebral oxygen transport, and extraction could be calculated. In the control group, as Paco2 increased from 34 ± 2 (SD) to 53 ± 4 torr (4.5 ± 0.3 to 7.1 ± 0.5 kPa), cerebral blood flow increased from 53 ± 12 to 147 ± 50 mL/min/100 g. This increase in cerebral blood flow was not different from that of the ECMO group, where Paco2 increased from 33 ± 2 to 56 ± 3 torr (4.4 ± 0.3 to 7.5 ± 0.4 kPa) and cerebral blood flow increased from 48 ± 17 to 106 ± 38 mL/min/100 g. As Paco2 decreased from 34 ± 2 to 19 ± 2 torr (4.5 ± 0.27 to 2.5 ± 0.27 kPa), cerebral blood flow decreased from 53 ± 12 to 43 ± 8 mL/min/100 g in the control group. This decrease was not different from that of the ECMO group, where cerebral blood flow decreased from 48 ± 17 to 39 ± 10 mL/min/100 g as Paco2 decreased from 33 ± 2 to 22 ± 3 torr (4.4 ± 0.3 to 2.9 ± 0.4 kPa). When regional cerebral blood flow was analyzed, no regional differences in the cerebrovascular responses to Paco2 between ECMO and control groups were found.The cerebral metabolic rate was not different between ECMO and control groups at any level of Paco2, nor was the cerebral metabolic rate affected by changes in Paco2. Oxygen extraction increased with hypocarbia and decreased with hypercarbia in a similar fashion in both ECMO and control groups. ConclusionThe cerebrovascular response to changes in Paco2 was unaffected by ECMO. (Crit Care Med 1994; 22:291–298)

Somatosensory Evoked Potential and Brain Water Content in Post-Asphyxic Immature Piglets

ABSTRACT: Depression of somatosensory evoked potentials (SEP) after a single episode of complete asphyxia with near cardiac arrest was evaluated to determine whether persistent SEP depression is related to postresuscitation edema in cortical gray matter or subcortical white matter. Piglets (<7 d of age) were anesthetized with sodium pentobarbital and fentanyl. Asphyxia was produced by occlusion of the endotracheal tube for 7 min. Arterial O2 saturation fell to 5%. Resuscitation was achieved in <2 min with ventilation, epinephrine, and chest compressions. Regional brain water content was determined from the difference between wet and dry weight. Two control groups were also analyzed; one immediately after (n = 5) and one 6 h after induction (n = 7) of anesthesia. SEP amplitude became isoelectric during asphyxia and recovered to 50 ± 13% (n = 7) of baseline 6 h after resuscitation. In the 6-h control group, SEP amplitude remained above baseline. The percent water content (mean ± SEM) among the three groups (asphyxia versus time control versus brief anesthesia control) was not different in the cortical gray matter (83.0 ± 0.7% versus 82.4 ± 0.4% versus 83.2 ± 0.3%) or subcortical white matter (75.6 ± 0.8% versus 74.8 ± 0.9% versus 75.6 ± 0.5%). In seven other piglets, cerebral blood flow and O2 consumption recovered to baseline by 1 h after asphyxia. Therefore, we found that the sustained depression of SEP amplitude, after 7 min of asphyxia in immature piglets, is not related to brain edema or persistent decreases in global cerebral O2 consumption.

Cerebral Responses to Single and Multiple Cocaine Injections in Newborn Sheep

ABSTRACT: Newborn infants exposed to cocaine near birth display a wide range of neurologic abnormalities, but the mechanism or mechanisms for these injuries remain unknown. We studied the cerebral effects of a single acute dose (4 mg/kg; n = 7) and multiple binge doses (4 mg/kg hourly for 5 h; n = 7) of i.v. cocaine in unancsthetized newborn (5 ± 1 d old) sheep. We measured cerebral blood flow, mean arterial blood pressure, arterial blood gases, and cerebral O2 metabolism. Measurements were made at baseline; 30 s; and 5,15, and 60 min after a single injection of cocaine in the acute group and at the same time intervals after the 5th dose of cocaine in the binge group. CBF increased by 98 ± 68% (mean ± SD) at 30 s after a single acute dose and by 97 ± 94% at 30 s after the 5th of five hourly binge doses. Although it returned to baseline by 5 min in the acute group, cerebral blood flow remained elevated 5, 15, and 60 min after the 5th cocaine dose in the binge group. At 30 s, mean arterial blood pressure increased by 57 ± 21% in the acute group and 46 ± 15% in the binge group. In both groups, mean arterial blood pressure remained elevated at 5 min. Although no change occurred in cerebral O2 metabolism in the acute group, an increase in cerebral O2 consumption (7.4 ±1.3 mL/100 g/ min versus 5.5 ± 1.1 at baseline) was observed at 5 min in the binge group. Thus, injection of cocaine as a single acute dose or after multiple binge doses results in acute cerebral vasodilation and hypertension in newborn sheep. Acute cerebral vasodilation, when combined within hypertension, may partially explain the pathogenesis of cocaine-associated neonatal neurologic abnormalities.

Hepatic oxygen consumption, lactate uptake, and glucose production in neonatal lambs.

ABSTRACT: Previous studies have evaluated neonatal hepatic metabolism in vitro, and neonatal hepatic oxygen consumption has been measured in vivo, but direct measurements of neonatal hepatic metabolism have not been reported. We studied seven neonatal lambs at age 7-10 days after placing catheters chronically in the hepatic vein, portal vein, descending aorta, left ventricle, and inferior vena cava. Hepatic blood flow was measured by the radioactive microsphere technique. Oxygen consumption and glucose and lactate fluxes were measured using the Fick principle. 14C-lactate was infused intravenously and lactate and glucose specific activities were measured and used to calculate hepatic gluconeogenesis from lactate. Neonatal hepatic blood flow was 254.5 ± 50.3 ml/min/100 g (mean ± SD) with 5.4 ± 4.6% from the hepatic artery and 94.6 ± 4.6% from the portal vein. Hepatic oxygen consumption was 7.2 ± 2.4 ml/min/100 g and oxygen extraction was 44.9 ± 15.4%. Oxygen extraction correlated inversely with oxygen delivery. In the seven Iambs, there was net hepatic lactate uptake of 10.2 ± 5.0 mg/min/100g (1.13 ± 0.56 mM) and hepatic glucose production of 30.8 ± 1 1 .3 mg/min/100 g (1.71 ± 0.62 mM). In the five lambs in which hepatic gluconeogenesis was measured, 12.4 ± 5 mg (1.37 ± 0.56 mM) of lactate was converted to glucose per 100 g liver, accounting for 38.4% of the hepatic glucose production in these lambs. Blood flow and oxygen and substrate delivery to the neonatal liver are lower than those to the fetal liver but the neonatal liver extracts more oxygen and substrates and is able to produce glucose by gluconeogenesis from lactate.