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We have investigated the mechanisms of hypoxic brain cell injury in the immature animal by examining (1) the role of excitatory amino acid neurotransmitter receptors, (2) the receptor-mediated increase in intracellular Ca2+, and (3) the generation of oxygen free radicals. We examined the effect of brain tissue hypoxia on the NMDA receptor-ion channel complex including the glutamate, Mg2+, spermine, CPP, and the non-NMDA receptor kainate sites. Brain tissue hypoxia resulted in modification of the NMDA receptor ion channel and its modulatory sites. Hypoxia increased the affinity of both the ion channel and the glutamate recognition site. Pretreatment of animals with the glutamate antagonist CPP prevented hypoxia-induced modification of the channel. Similarly, pretreatment of animals with Mg2+, a blocker of the NMDA receptor ion channel, prevented the hypoxia-induced modification of the receptor. In addition, an increased agonist-dependent entry of Ca2+ into synaptosomes was observed in hypoxic animals compared with normoxic animals. Increased free radical generation in the cerebral cortex during hypoxia was demonstrated using spin labeling technique and electron spin resonance spectroscopy. We conclude that hypoxia-induced modification of the NMDA receptor-ion channel complex leads to increased intracellular Ca2+ potentiating free radical generation and resulting in hypoxic cell injury.

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To determine whether a shift of potassium ions from the intracellular space to the extracellular space accounts, in part, for the hyperkalemia seen in extremely low birth weight infants, we examined potassium concentration in serum and erythrocytes from extremely low birth weight infants with hyperkalemia (n = 12) or with normokalemia (n = 27). In addition, to determine whether the shift of potassium was associated with low sodium-potassium-adenosinetriphosphatase (Na+,K(+)-ATPase) activity, we studied the activity of ATPase in the last 16 infants enrolled in the study. Fluid intake and output were measured during the first 3 days of life. Infants were considered to have hyperkalemia if the serum potassium concentration was 6.8 mmol/L or greater. Blood was obtained daily for intracellular sodium and potassium levels by means of lysis of erythrocytes. The remaining erythrocyte membranes were frozen and analyzed for Na+,K(+)-ATPase activity. There were significantly lower intracellular potassium/serum potassium ratios in the infants with hyperkalemia for each day of the 3-day study (p < 0.001). In the hyperkalemic group, there was lower Na+,K(+)-ATPase activity than in the infants with normokalemia (p = 0.006). Low Na+,K(+)-ATPase activity was associated with lower intracellular potassium/serum potassium ratios (p = 0.006), higher serum potassium values (p = 0.02), and lower intracellular potassium concentration (p = 0.009). The urinary data demonstrated that there was no difference in glomerulotubular balance between the two groups. We conclude that nonoliguric hyperkalemia in extremely low birth weight infants may be due, in part, to a shift of potassium from the intracellular space to the extracellular space associated with a decrease in Na+,K(+)-ATPase activity.

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To investigate the effect that suctioning of the endotracheal tube has on the cerebral circulation, we monitored brain intravascular hemoglobin saturation (tHbo2%), cerebral blood volume (CBV), and arterial hemoglobin saturation (Spo2) during suctioning in 12 infants (24 to 33 weeks of gestational age) with respiratory distress syndrome treated with mechanical ventilation. The tHbo2% and CBV values were monitored over the forebrain by dual-wavelength near-infrared spectroscopy, and Spo2 was monitored by pulse oximetry of a finger. The monitored variables were stable during the baseline period. With suctioning, Spo2 decreased from 94% +/- 1% to 84% +/- 1%, tHbo2% decreased, and CBV increased (p less than 0.05). Desaturation in the arterial and cerebral circulations began within 5 seconds of the onset of suctioning. Arterial reoxygenation began with the onset of reventilation, whereas reoxygenation in the brain was delayed by 15 seconds. The Spo2, tHbo2%, and CBV values returned to baseline within 1 minute of reventilation. Studies were repeated in six of the infants after the fraction of inspired oxygen was increased to attain a baseline Spo2 of 100%. In the preoxygenated infants, tHbo2%, CBV, and Spo2 remained constant during suctioning. These studies confirm that endotracheal suctioning results in transient hypoxemia, and demonstrate that this is reflected in the brain by vasodilation and deoxygenation. These effects are preventable by preoxygenation before suctioning.

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The incidence and severity of retinopathy of prematurity (ROP) as affected by vitamin E prophylaxis at pharmacologic serum levels (5 mg/dl) were evaluated in a double-masked clinical trial of infants with a birth weight less than or equal to 2000 gm or a gestational age less than or equal to 36 weeks. The infants were enrolled by age 5 days and randomly assigned to receive parenterally administered, and later orally administered, free alpha-tocopherol (vitamin E) or its placebo. Study medication was continued until retinal vascularization was complete or active ROP had subsided, except in infants with a diagnosis of severe disease, in whom vitamin E was substituted for study medication. Acute ROP data were collected on 755 infants. Logistic regression analysis, with control for immaturity, oxygen exposure, and other illness risk factors, showed a decrease in incidence of ROP in vitamin E-treated infants (p = 0.003, all infants; p = 0.035, infants weighing less than or equal to 1500 gm at birth). Among the 424 infants weighing less than or equal to 1500 gm at birth, the age at enrollment influenced treatment effect (age day 0 to 1, p = 0.006 (n = 288) vs age day 2 to 5, p greater than 0.1 (n = 136]. Overall, 77.6% of infants with ROP had mild disease. Moderate to severe ROP was confined to infants weighing greater than or equal to 1500 gm at birth (25 given placebo, 25 given vitamin E), with progression to severe disease in nine placebo-treated versus three vitamin E-treated infants (p = 0.048). The incidence of severe ROP per se was not significantly decreased (all birth weights, p = 0.086; less than or equal to 1500 gm birth weight, p = 0.080); the sample size was too small, however, to assess this end point adequately. An increased incidence of sepsis and late-onset necrotizing enterocolitis was found among vitamin E-treated infants weighing less than or equal to 1500 gm at birth who received study medication for greater than or equal to 8 days (p = 0.006). Because most ROP is mild in degree and regresses completely, the risk/benefit ratio of pharmacologic prophylaxis for ROP is unfavorable. Treatment of moderate and severe ROP with vitamin E above physiologic serum levels (greater than 3 mg/dl) appears promising and should be further investigated. The interpretation of cicatricial outcome was confounded by the small number of patients involved and by subsequent treatment of severe ROP in placebo-treated infants with vitamin E.

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Regional differences in the local cerebral metabolic rate of glucose have been reported in newborn infants. This study was performed to determine if comparable differences exist in neonatal regional cerebral blood flow (rCBF). In 21 infants, rCBF was measured with a modified xenon 133 (133Xe) clearance technique by means of eight extracranial detectors positioned over four homologous regions (frontal, parietal, temporal, and occipital). The rCBF was lowest in the frontal region, higher in the parietal region, and highest in the temporal and occipital regions. Regional differences in rCBF may be caused by regional differences in brain development and function.

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Magnetic resonance (MR) is a technique that permits the noninvasive evaluation of morphologic features and function based on the distribution of protons and other selected elements. We present a basic description of MR and illustrate both 31P-MR spectroscopy and proton imaging applications in pediatric patients. The applications of these techniques are diverse, and are presented concisely in an attempt to give pediatricians an overview of this new technology and its potential role in patient management.

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Exchange transfusions within the first 8 hours of life, as an adjunct to conventional therapy, were evaluated in two groups of infants: (1) infants with birth weights of less than 1,250 gm without severe respiratory distress and (2) infants of any birth weight with evidence of severe respiratory distress syndrome. A total of 63 infants were studied in Group 1. Infants who received an exchange transfusion had a survival rate of 86% as contrasted with a survival rate of 57% in the control group (p less than 0.01). A total of 82 infants were studied in Group 2. Infants who received an exchange transfusion had a 59% survival rate as compared with a 39% survival rate for the control group (p less than 0.04). The mechanism by which early exchange transfusion improves survival rate is unknown.

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