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ABSTRACT: Treatment of unanesthetized newborn pigs with indomethacin trihydrate (5 ± 1 mg/kg, intravenous) decreased cerebral blood flow uniformly throughout the brain by 18-28% without changing cardiac output, arterial pressure, or arterial blood gases and pH. Breathing 10% O2, 9% CO2with the balance N2(hypoxia/hypercapnia) caused cerebral blood flow to increase from 102 ± 12 to 218 ± 19 ml/100 g-min. Intravenous administration of indomethacin during hypoxia/hypercapnia caused a uniform decrease in cerebral flow throughout the brain to levels (94 ± 5 ml/100 g-min) indistinguishable from those when the piglet was breathing ambient air. Further, 2.5 h later, the cerebral hyperemia caused by hypoxia/hypercapnia was attenuated markedly (129 ± 19 ml/100 g-min). Vehicle treatment did not alter resting cerebral blood flow or cerebral hyperemia in response to hypoxia/hypercapnia. Measurements of 6-keto-prostaglandin F1α, thromboxane B2, and prostaglandin E2demonstrated that intravenously administered indomethacin crossed the blood-brain barrier of newborn pigs in sufficient quantity to inhibit prostanoid release into the cerebrospinal fluid passing over the surface of the brain. The mechanism by which indomethacin reduces cerebral blood flow and attenuates cerebral hyperemia cannot be determined from the present experiments. We conclude that intravenous administration of indomethacin decreases cerebral blood flow and attenuates cerebral hyperemia induced by severe, combined hypoxia/hypercapnia in newborn pigs.

Summary: Inhibition of prostaglandin cyclooxygenase augments hypoxic pulmonary vasoconstriction. We used a neonatal lamb lung preparation perfused with Krebs' bicarbonate buffer to characterize and quantify prostanoids produced by the pulmonary vasculature from endogenous arachidonic acid in the absence of formed blood elements during ventilation with normoxic and hypoxic gas mixtures. Prostaglandin (PG) I2synthesis increased from 6.4 ± 2.7 ng/min (SEM) during normoxic ventilation to 14.3 ± 5.4 ng/min during hypoxia and returned to 4.7 ± 1.2 ng/min with resumption of normoxia. These data demonstrate that hypoxia stimulates pulmonary vascular synthesis of prostaglandin I2from endogenous substrate in neonatal lambs and suggest that the augmentation of hypoxic pulmonary vasoconstriction by prostaglandin cyclooxygenase inhibition is due, at least in part, to interference with the synthesis of this vasodilator prostanoid.

A model based on the course of 31 infants with uncomplicated hyaline membrane disease is described. Based on data collected over the first 12 hr of life, it predicts the course of an infant for the next 60 hr, and estimates the outcome in terms of length of oxygen requirement and assisted ventilation. For the construction of the model, right-to-left intra- and extra-pulmonary shunting, expressed as venous admixture, was considered as the principal mechanism of hypoxemia in hyaline membrane disease and mean applied proximal airway pressure was used to quantify management. The model provides an objective estimate of severity early in the course of the disease, uses variables routinely available in an intensive care unit, and its use would strengthen the interpretation of clinical studies in which the comparability of experimental and control groups is critical.Speculation: A quantitative model for hyaline membrane disease, which can course over the first 72 hr of life, provides an objective research tool to evaluate prospectively modifications or additions to current regimens of treatment.

Summary: To initiate an investigation into the biochemistry and mechanism of group B β-hemolytic Streptococcus virulence, bacterial cultures grown in suspension were centrifuged, and the bacteria and media were subjected to extensive fractionation. Each fraction was assayed for physiologic activity by repeated intravenous infusion into adult unanesthetized sheep. Pulmonary artery pressure, arterial Po2, and rectal temperature were monitored. The media fraction, but not the bacteria, contained a component (molecular weight, 2 X 106) composed of 84% carbohydrate and 16% protein with physiological activity. Two mg quantities, when infused, caused the pulmonary artery pressure to increase 100%, Po2to decrease by 20% and chills and fever. The active component could be degraded by hot phenol-water extraction into a pure polysaccharide (molecular weight, 200,000). This lower molecular weight polysaccharide retained the identical physiologic properties when infused in the sheep. The degraded component precipitated with group B-specific antiserum.This study demonstrates that, in the sheep, a pure polysaccharide is the physiologically active part of a high-molecular-weight toxin synthesized by group B β-hemolytic Streptococcus type III and that this component has a different carbohydrate composition from the group B capsular antigen.Speculation: The clinical syndrome associated with group B β-hemolytic Streptococci in early onset disease is caused by the interactions of an extracellular bacterial component and a specific target tissue in the infected infant.

Summary: To study the effects of Group B β-hemolytic Streptococcus on the pulmonary circulation and lung fluid balance, live and heat-killed bacteria and their toxin were infused into an awake sheep lung-lymph preparation. In every case, the response was biphasic; there was an initial period of marked pulmonary hypertension and high flow of protein-poor lymph associated with tachypnea, chills, and fever. A second phase followed during which pulmonary vascular pressures returned to near baseline and remained stable, but lymph flow remained high. The changes seen in the initial phase resemble the previously reported response to mechanically increased pulmonary vascular pressure and suggest that the increase in fluid filtration is secondary to increased microvascular pressure. During the second phase after toxin infusion, the increase in lung lymph flow was paralleled by an increase in lymph protein clearance. This cannot be accounted for by the hemodynamic changes alone and suggests that the permeability of lung microvascular walls to protein was increased. It is concluded that group B β-hemolytic streptococcal toxin in the sheep model causes pulmonary hypertension and increased pulmonary vascular permeability.Speculation: The effects caused by group G β-hemolytic Streptococcus toxin on the pulmonary circulation may be relevant to the pathogenesis of the respiratory distress and shock seen in newborns with this infection. Further understanding of the effects of this toxin could provide means for therapeutic intervention.

Abstract: The response of circulating catecholamines to asphyxia in unanesthetized, spontaneously breathing neonatal piglets was measured before and after treatment with indomethacin. Prior to treatment with indomethacin, baseline levels [geometric mean, pg/ml (95% confidence limits)] of D, E, and N were 162 (99-266), 174 (52-579), and 380 (286-506), respectively. Inhalation of 10% O2/9% CO2for 20 min caused significant increases in arterial levels of all three catecholamines to 389 (230-659, 1514 (993-2306), and 3802 (2731-5293), respectively. Treatment with indomethacin (5 mg/kg, intravenous) did not significantly alter either baseline levels of the catecholamines or the levels after 20 min of the asphyxiating gas. In time control piglets, baseline levels and the response to asphyxia were similar before and after placebo. These results suggest that the circulating catecholamine response to asphyxia of the neonatal piglet is independent of the prostaglandin system.

Summary: The purpose of the present study was to determine if pulmonary prostacyclin synthesis was stimulated by spontaneous onset of breathing by unanesthetized fetuses at birth. Cannulae were implanted and flow cuffs placed in fetal lambs and goats (0.93 term). Fetuses were delivered by cesarean section at 0.95 term and began breathing spontaneously. Prostacyclin in blood was determined by radioimmunoassay of its hydrolysis product, 6-ketoprostaglandin F1ausing methods that produced the same values in duplicate samples as did gas chromatography with electron capture detection. Fetal pulmonary prostacyclin production (left lung) [(left pulmonary venous concentration — pulmonary arterial concentration) × left pulmonary blood flow] was undetectable [-1.7 ± 1.0 (SEM) ng PGI2·kg-1·min-1] and fetal pulmonary vascular resistance (left lung) high (5.1 ± 0.9 mm Hg · kg·min · ml-1). Pulmonary prostacyclin production increased to 30.1 ± 12.3 ngPGI2· kg-1· min-1and pulmonary vascular resistance declined to 0.5 ± 0.1 mm Hg · kg · min · ml-115 min after-birth. Pulmonary vascular resistance remained low even though pulmonary prostacyclin production fell 2-5 h after birth. These results, coupled with earlier studies using indomethacin to inhibit prostaglandin synthesis, support the hypothesis that pulmonary prostacyclin synthesis participates in the decline of pulmonary vascular resistance that accompanies the onset of ventilation at birth, but may be less important in maintenance of low pulmonary vascular resistance once reduced pulmonary vascular tone has been established.

Summary: We compared the concentration-response relationship of intralobar pulmonary arteries to l-norepinephrine with that of femoral arteries from newborn lambs. In addition, the effect of inhibition of the neuronal and extra-neuronal uptake mechanisms on these concentration-response relationships was examined.Concentration-response curves on 10 intralobar pulmonary arteries were performed with and without inhibition of the uptake mechanisms. Uptake inhibition shifts the curve to the left; thus, the-log EC50with uptake inhibition (6.63 ± 0.15) is greater than that without uptake inhibition (6.13 ± 0.14). Similar curves on 10 femoral arteries demonstrated that the-log EC50with and without uptake inhibition (6.20 ± 0.13 and 6.00 ± 0.04, respectively) are not statistically different.Because, in the presence of intact uptake mechanisms the concentration of l-norepinephrine in the a-receptor microenvironment is less than that placed in the organ bath, the appropriate comparison of pulmonary and femoral arterial response to l-norepinephrine stimulation requires uptake inhibition in both vessels. The concentration-response curve with uptake inhibition for the intralobar pulmonary artery is significantly to the left of that for the femoral; the-log EC50for the pulmonary vessel (6.63 ± 0.15) is greater than that of the femoral vessel (6.20 ± 0.13). The intralobar pulmonary artery in vitro is more sensitive to l-norepinephrine stimulation than is the femoral.