The effect of post-asphyxial reoxygenation with 21% vs. 100% oxygen on Na+,K(+)-ATPase activity in striatum of newborn piglets.

To compare the effect of 21% vs. 100% oxygen during post-asphyxial reoxygenation on brain cell membrane function in the striatum, 20 anesthetized, ventilated newborn piglets were studied: group 1 (normoxia, n = 5), group 2 (asphyxia, no reoxygenation, n = 5), group 3 (asphyxia followed by reoxygenation with 21% O2, n = 5), and group 4 (asphyxia followed by reoxygenation with 100% O2, n = 5). Asphyxia was induced by a stepwise reduction in FiO2 at 20 min intervals from 21% to 14%, 11%, and 8%. Following a total 60 min of asphyxia, piglets in groups 3 and 4 were recovered for 2 h with either 21% or 100% O2. Na+,K(+)-ATPase activity (mumol Pi/mg protein/h) in striatal cell membranes was 31 +/- 1, 22 +/- 2, 32 +/- 2 and 26 +/- 1 in groups 1, 2, 3 and 4, respectively. Na+,K(+)-ATPase activities in groups 2 and 4 were significantly lower than in groups 1 and 3 (p < 0.01). Piglets recovered post-asphyxia for 2 h with 21% O2 had restoration of Na+,K(+)-ATPase activity to baseline levels, while those treated with 100% O2 during recovery had persistent Na+,K(+)-ATPase inhibition of 16%. This could result from increased free radical production during reoxygenation with 100% O2 which could contribute to post-asphyxial cellular injury in the striatum.

Effect of nordihydroguaiaretic acid on cerebral blood flow and metabolism during hypoxia in newborn piglets.

Nordihydroguaiaretic acid (NDGA), a lipoxygenase inhibitor, was investigated for its effect on cerebral blood flow (CBF) and cortical oxygen consumption during hypoxia in 9 anesthetized, ventilated newborn piglets. CBF was measured by radioactive microspheres while brain cortical metabolism was evaluated by continuous 31P-NMR spectroscopy. Five piglets were treated with NDGA (3 mg/kg i.v. in 50% ethanol as vehicle) prior to hypoxia and had CBF measured before NDGA (control), 15 min after NDGA (baseline) and then after 15 and 45 min of hypoxia following NDGA. Another 4 piglets were treated with vehicle (2 ml/kg 50% ethanol) under the same protocol. In the NDGA-treated piglets, cerebral cortical O2 consumption for a given PCr/Pi was significantly increased (p < 0.05) compared to non-NDGA. Since NDGA inhibits production of vasoconstricting leukotrienes during hypoxia, cortical capillary beds otherwise constricted may be perfused following NDGA, thus increasing the O2-consuming tissue area.

Cerebral blood flow and metabolism during repeated asphyxias in newborn piglets: influence of theophylline.

The effect of theophylline on cerebral blood flow (CBF), oxygen transport, and energy metabolism was investigated during and following brief episodes of asphyxia. CBF was determined by microspheres during control, asphyxia, and recovery with reventilation after a single asphyxia (recovery I) and after 7 repeated asphyxias (recovery II). In addition, cerebral energy metabolism by 31P NMR spectroscopy and cerebral oxygen consumption (CMRO2) in newborn piglets treated with 30 mg/kg theophylline (serum levels 22-25 micrograms/ml) were compared with nontreated piglets. Theophylline increased CMRO2 during recovery I (348 mumol O2/min/100 g vs. 144 for non-theophylline) but not during control, asphyxia, or recovery II. There was no significant difference between the theophylline and non-theophylline groups in depletion of phosphoenergetics as measured by 31P NMR.

Nuclear magnetic resonance imaging and spectroscopy following asphyxia.

Nuclear magnetic resonance imaging and spectroscopy have added significant new information about the newborn brain during and following asphyxia. NMR imaging has permitted sequential in vivo analysis of CNS maturation in the perinatal period that is superior in anatomic resolution, and especially in the characterization of myelination, to either cranial ultrasound or radiographic computed tomography. As a result, the accurate detection and recognition of the brain lesions associated with hypoxic-ischemic encephalopathy is now possible, including PVL, cerebral infarction, intraparenchymal and intraventricular hemorrhage, and delayed myelination. This has improved our understanding of the associated potential risk for abnormal neuro-developmental outcome with specific lesions. NMR spectroscopy has provided a metabolic window into the biochemical events during and following asphyxia. 31P MRS captures the phosphorous metabolites as levels rise and fall and shift in relation to each other to maintain cellular energy homeostasis in the face of oxygen depletion. Meanwhile, proton NMR spectroscopy promises to sustain the metabolic purview beyond the immediate cellular response to asphyxia to the chronic adaptation phase. Appropriately applied, this noninvasive technology may yet enable us to identify brain injury that is reversible in sufficient time to intervene and to diagnose accurately what is irreversible for timely prognostication. Furthermore, the integration of clinical imaging and spectroscopy capabilities is both feasible and desirable; information provided by each being mutually complementary. Imaging could improve spectroscopy interpretation by identifying the observed tissue, whereas MRS should clarify diagnosis of anatomic lesions detected by MRI. Advances in spatial resolution and speed of data acquisition may soon make integrated MRI/MRS a clinical reality.

Decreased erythrocyte Na+,K(+)-ATPase activity associated with cellular potassium loss in extremely low birth weight infants with nonoliguric hyperkalemia.

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.

Pharmacokinetics and effect of cocaine on cerebral blood flow in the newborn.

The present study investigated the effect of cocaine (COC) on cerebral circulation (CBF) and oxidative metabolism (CMRO2) in the newborn piglet and aimed to relate pharmacokinetics of cocaine to cerebrovascular effects. COC decreased CBF and CMRO2 from 75 to 64 and 4.27 to 3.91 ml/min/100 g, respectively, at 4 min with reduced flow to all brain regions (p < 0.05) which returned to baseline by 10 min. COC was rapidly metabolized with a t1/2 of 43 min and peak plasma concentration of 1,172 ng/ml. Norcocaine (NOR) appeared in plasma and CSF within 3 min of cocaine administration and remained elevated for the duration of the study along with COC in the CSF. These data show that the timing of the peak plasma COC level is associated with maximal decreased CBF. Further, the stable elevated level of COC and NOR in the CSF suggests that biotransformation does not occur in the brain. As a result, accumulation of these drugs may occur in the brain with successive COC use and affect the developing CNS in a deleterious manner.

Delivery room management and outcome issues in the neonate.

Issues relevant to term newborns include screening for functional neurologic deficits that may be improved by early detection and intervention. Papers are presented that consider ocular, acoustic, and cognitive evaluations in the term neonate. Delivery room management of the meconium-stained infant remains controversial and is discussed by several authors. Data are presented regarding intubation and its role in the prevention of meconium aspiration syndrome, causes of meconium passage in utero, and its significance for neonatal outcome. In addition, illicit drug use, especially cocaine, is a significant problem among pregnant women with multiple sequelae for the fetus and newborn. Papers reviewed include a comparison of neonatal drug screening techniques, fetal effects of subacute maternal cocaine use, and follow-up data in a large cocaine-exposed cohort. The impact of the cocaine problem is growing nationally, overwhelming existing programs for medical care and rehabilitation, and mandating change at all levels of intervention. Finally, the search for a definitive indicator or predictor of birth asphyxia continues to generate literature in both the pediatric and obstetric journals.

Hyperalimentation associated hepatotoxicity in the newborn.

Total parenteral nutrition (TPN) has become a mainstay of modern neonatal care for the increasing population of premature infants who survive their initial pulmonary disease. As with other advances in neonatal therapy, hyperalimentation has associated complications and limitations, primary among them its toxicity to the liver. The basic pathologic lesion is bile cholestasis which is probably multifactorial in etiology. Amino acid solutions, excessive calorie-to-nitrogen ratios, and deficient trace elements and antioxidants have all been implicated in this process. Total parenteral nutrition-cholestasis can progress to portal fibrosis and irreversible cirrhosis if long-term hyperalimentation is required. Most at-risk for this iatrogenic condition are those premature infants less than 1500 g birth weight who are exposed to TPN for longer than two weeks. Enteral feedings providing as little as 10 percent of caloric intake are beneficial, and the prognosis for recovery is good once enteral feedings are established.

Brain cell membrane dysfunction following acute asphyxia in newborn piglets.

Brain cell membrane function during and following single and repeated episodes of asphyxia was investigated. Asphyxia in 24 anesthetized, paralyzed, mechanically-ventilated newborn piglets was produced by stopping ventilation for 2-3 min followed by recovery with reventilation. Measurements of cerebral Na+,K(+)-ATPase activity and of lipid peroxidation products, conjugated dienes and fluorescent compounds, were made during control (n = 12), asphyxia (n = 5), recovery after a single asphyxia event (n = 4), and recovery following 7 repeated asphyxia episodes (n = 3). Cerebral Na+,K(+)-ATPase activity remained unchanged from control during asphyxia (14.57 +/- 2.43 compared to 15.33 +/- 4.27 mumol Pi/mg protein/h, mean +/- SD), but was significantly reduced both during recovery after single (3.87 +/- 1.66) and after repeated (2.59 +/- 1.58) asphyxias, representing a 73 and 82% reduction in enzyme activity, respectively. Conjugated dienes and fluorescent compounds were similarly unchanged during asphyxia compared to control, but increased during recovery from single and from repeated episodes. Decreased cerebral Na+,K(+)-ATPase activity, simultaneous with an increase in lipid peroxidation products, reflects significant cellular membrane damage consistent with oxygen free radical formation during the recovery from acute asphyxia in the newborn piglet.

Sympathetic nerve modulation of regional cerebral blood flow during asphyxia in newborn piglets.

Regional cerebral blood flow (rCBF) during asphyxia suggests a reflex vasoconstrictor mechanism active principally in brain cortex. Present studies in newborn piglets investigate sympathetic modulation of the cerebrovasculature both during and after acute asphyxia. Unilateral superior cervical sympathetic ganglionectomy (SCSG) was performed in 13 newborn piglets, after which asphyxia was produced by discontinuing ventilation. In 8 animals, blood flow was measured during control and sequentially 1, 2, and 3 min after ventilation was stopped. In 5 piglets with unilateral SCSG, cortical flow decreased in the innervated hemisphere, -34 +/- 14% after 2 min, and -25 +/- 9% at 3 min of asphyxia compared with control (104 +/- 22 ml.min-1.100 g-1; mean +/- SE). In contrast, the sympathetically denervated hemisphere showed -13 +/- 17% at 2 min and +7 +/- 23% at 3 min, representing 45 +/- 6% and 30 +/- 9% left-right (L-R) flow differences, respectively. Bilateral SCSG (3 piglets) similarly attenuated the cortical CBF vasoconstrictor response to asphyxia, +6 +/- 21% at 2 min and -8 +/- 5% at 3 min. Significant innervated-denervated rCBF differences were present during asphyxia in cerebral gray (55% +/- 24), cerebral white (41% +/- 16), caudate (25% +/- 7), hippocampus (36% +/- 12), and choroid plexus (145% +/- 42), indicating sympathetic nerve modulation. Brain stem structures showed increasing rCBF throughout asphyxia and no L-R differences.(ABSTRACT TRUNCATED AT 250 WORDS)

Regional cerebral blood flow response during and after acute asphyxia in newborn piglets.

The hemodynamic response during and after acute asphyxia was studied in 14 newborn piglets. An apnea-like asphyxial insult was produced in paralyzed mechanically ventilated piglets by discontinuing ventilation until the piglets became bradycardic (heart rate less than 80 beats/min). Seven piglets had organ blood flow measured by microspheres at control, during asphyxia (PO2 = 16 +/- 11 Torr, pH = 7.31 +/- 0.07, PCO2 = 47 +/- 9 Torr), and during recovery from asphyxia. During acute asphyxia, rapid organ blood flow redistribution occurred, producing decreased renal and skeletal muscle blood flow, while coronary blood flow increased. Although total brain blood flow changed little during asphyxia, regional cerebral blood flow (rCBF) analysis revealed significant nonhomogeneous blood flow distribution within the brain during asphyxia, with decreases to the cerebral gray and white matter and the choroid plexus, whereas brain stem structures had increased flow. During recovery with reventilation, total brain blood flow increased 24% above control, with a more uniform distribution and increased flow to all brain regions. The time course of rCBF changes during acute asphyxia was then determined in seven additional piglets with CBF measurements made sequentially at 30-60 s, 60-120 s, and 120-180 s of asphyxia. The vasoconstriction seen in cortical structures, concurrent with the reduction in skeletal and kidney blood flow, known to be sympathetically mediated, suggest a selective reflex effect in this brain region. The more gradual and progressive vasodilation in brain stem regions during asphyxia is consistent with chemical control. These findings demonstrate significant regional heterogeneity in CBF regulation in newborn piglets.

Principles in cellular oxygenation: fetal and neonatal intestines.

Complex biochemical consequences are the result of a series of secondary biochemical changes caused by oxygen depletion. Hypoxia in the fetus and neonate results in decreased GI blood flow, especially to the GI mucosa. Although severe O2 deprivation cannot be entirely compensated for, an increase in tissue O2 extraction does occur in cases of moderate hypoxemia. In the neonate increased demands for O2 during feedings result in increased blood flow. The occurrence of hypoxia during feedings causes a decrease in intestinal motility, suggesting a clinical correlate to feeding intolerance and increased vulnerability to necrotizing enterocolitis.

Physiology of the placenta--gas exchange.

The placenta serves as the fetus' organ of gas exchange throughout intra-uterine life. While the dependence of fetal well-being on an intact maternal-placental unit has been recognized for centuries, it is only in the last several decades that research with fetal animals has begun to unravel the mechanisms by which it regulates blood supply and oxygen, as well as its role in the maternal-to-fetal transfer of carbohydrates, proteins, fats, water, and inorganic salts. The anatomy and physiology of the placenta are presented here as they relate specifically to gas exchange. In addition, compensatory adaptations of the fetus and placenta to acute asphyxial events will be discussed.