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The pulmonary effects of hyperventilation following infusion of sodium salicylate into the cisterna magna was studied in 16 spontaneously breathing adult sheep. We found a fall in PaO2, a decrease in the static compliance of the respiratory system, abnormal chest roentgenographic films, and grossly abnormal lungs following 3.5 to 13 h of hyperventilation. A control group of 15 sheep (10 sheep similarly injected with sodium salicylate, but then sedated and paralyzed and ventilated at normal tidal volume and respiratory rate on a mechanical ventilator, and 5 sheep infused with saline alone and breathing spontaneously) showed no pulmonary or arterial blood gas abnormalities. We conclude that prolonged hyperventilation under the conditions of this experiment precipitated events that resulted in acute lung injury.

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We exposed 128- to 130-day-gestation fetal lambs by cesarean section leaving the umbilical cord and placenta undisturbed, and we then treated the lungs with pulmonary conditioning (i.e., repeated prolonged inflations to 35 cm H2O, followed by a continuous positive airway pressure of 15 cm H2O). To investigate the added effect of pulmonary vasodilation upon the increase of total compliance and pulmonary oxygen uptake, we also administered acetylcholine intravenously at a rate of 80 micrograms min-1. Eleven of 13 lambs met the endpoint criteria of either compliance (0.5 ml [cm H2O]-1 kg-1; 1 animal), or pulmonary oxygen uptake (6 ml kg-1 min-1; 6 animals), or both (4 animals), and were delivered within 0.6 +/- 0.3 h. This time was significantly (p less than 0.05) shorter than previously seen in similar studies without the infusion of a vasodilator; all animals so delivered survived 24 h of mechanical ventilation in excellent health. We suggest that pharmacologic pulmonary vasodilation, in addition to deep sustained pulmonary insufflation and distension, is an effective and rapid means of transforming stiff immature lungs into lungs that can sustain normal ventilation and gas exchange.

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A total of 44 preterm fetal lambs at great risk of developing respiratory failure were delivered by Cesarean section, and were then managed on conventional mechanical pulmonary ventilation. Fifteen animals initially fared well, and 14 of these were long term survivors. Twenty-nine other lambs showed a progressive deterioration in arterial blood gases within 30 minutes of delivery, of which 10 lambs were continued on mechanical pulmonary ventilation (20% survival), while the remaining 19 lambs were placed on an extracorporeal membrane lung respiratory assist (79% survival). Extracorporeal membrane lung bypass rapidly corrected arterial blood gas values, and permitted the use of high levels of CPAP instead of the continuation of mechanical pulmonary ventilation at high peak airway pressures. Improvement in lung function was gradual, and predictable. Early institution of extracorporeal respiratory assist using a membrane artificial lung rapidly corrected arterial blood gas values and significantly improved on neonate survival.

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We tested the effectiveness of constant distending pressure applied to immature lungs in preventing respiratory distress syndrome. Fetal lambs of 131 to 134 days gestation were delivered by cesarean section, but the umbilical circulation was kept intact for CO2 removal through the natural in situ placenta. The lungs were inflated to a pressure of 35 cm H2O (Group I, 11 animals) or 25 cm H2O (Group II, 14 animals), after which the airway pressure was maintained at 15 cm H2O through apneic oxygenation until total static compliance exceeded 0.5 ml (cm H2O)- 1kg -1. After a mean of 1.1 and 5.7 h, respectively, the animals were delivered and were given mechanical ventilation for 24 h. Twenty-four animals reached this aimed-for compliance and survived the period of mechanical ventilation in excellent health. A control group of fetal lambs was delivered immediately and treated with mechanical ventilation. Three of 10 control animals developed severe respiratory distress syndrome and died; 1 additional animal survived but with central nervous system involvement from severe hypoxia. We conclude that pulmonary inflation to 35 cm H2O pressure, followed by a constant distending pressure of 15 cm H2O, held until compliance reaches 0.5 ml (cm H2O)- 1kg -1, is an important element in the prevention of respiratory distress syndrome.

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We have explored change in pulmonary compliance before, and after, repeated deep insufflation of the lungs to a pressure of 35 cm H2O, in 130-days gestation fetal lambs delivered by cesarean section, and while still connected to the intact umbilical cord and the ewe. As a group, all 15 out of 28 fetal lambs that had a rise in total compliance to above 0.2 ml (cm H2O)-1 kg-1 after the first inflation, tolerated 24 h of mechanical ventilation with excellent health and good lung function; only 3 animals out of 13 that showed no similar initial rise in compliance after the first inflation, ultimately survived. We believe the first deep insufflation is an important therapeutic intervention and a useful index to rapidly assess chance of survival in a high-risk fetal lamb population.

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Hyaline membrane disease is found only in lungs where pulmonary ventilation has been established, i.e. after birth. We delivered eleven fetal lambs of a gestational age of 128-130 days but instead kept their lungs in total apnea and inflated to constant pressure, while removing all metabolically produced carbon dioxide with an extracorporeal membrane lung. Oxygen was provided by the membrane lung, and by apneic oxygenation through the natural lungs. Hence, arterial blood gases remained always normal, without any pulmonary ventilation. After 6-66 h the lungs had sufficiently cleared to allow normal mechanical pulmonary ventilation in 10 our of 11 lambs so treated. In a control group treated with mechanical ventilation alone, five of seven lambs died within the first 24 h of severe hyaline membrane disease.

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The metabolism of [1-3H]retinol- and [4-14C]cholesterol-labeled chylomicrons was studied in normal and cholesterol-fed dogs in order to estimate the relative contribution of chylomicron remnant cholesterol to diet-induced hypercholesterolemia. The plasma t 1/2 of intravenously administered Sf greater than 400 chylomicrons, Sf 20-400 chylomicrons, and whole lymph doubly labeled with [1-3H]retinol and [4-14C]cholesterol was not significantly prolonged in hypercholesterolemic recipients. When Sf greater than 400 chylomicrons were administered intravenously, 90% of the radioactivity was cleared from the plasma of both normal and cholesterol-fed dogs within 1 hr and 68 +/- 18% appeared in the liver within approximately 2 hr in normal dogs and 4 hr in hypercholesterolemic dogs. The use of the retinol-labeling technique for intestinal lipoproteins provided evidence that some LDL, but essentially none of the HDLc, was derived from d greater than 1.006 g/ml lymph lipoproteins. The failure of significant radioactivity to accumulate in the plasma compartment of hypercholesterolemic dogs after intravenous administration of doubly labeled chylomicrons and the relatively efficient uptake of radioactivity by the liver indicate that the dietary-induced hypercholesterolemia in dogs is not the result of impaired hepatic removal of chylomicron remnants.

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Preterm fetal lambs of a gestational are highly susceptible to hyaline membrane disease were placed on apneic oxygenation while keeping the umbilical circulation intact and still connected to the mother ewe for the removal of metabolically produced CO2. After 4-6 hrs the total lung compliance and the chest x-ray films had markedly improved, allowing normal pulmonary ventilation with a mechanical ventilator. Fetuses older than 135 days gestation were later extubated and allowed to breathe room air unassisted. Fetuses 134 days gestation and younger were kept on mechanical ventilation. None of the animals so treated developed hyaline membrane disease. We believe pulmonary conditioning is an important tool in the prevention and the treatment of hyaline membrane disease. In this animal model we have shown that hyaline membrane disease is a preventable and curable disease.

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In hot climates, only high temperature fluids (are greater than 100 F) may be available for treatment of blood loss shock in combat casualties. Can the hot fluid be used safely and effectively? We compared hot Ringer's lactate (51.7% C/125 F) resuscitation (n=10) to body-temperature (100 F) fluid resuscitation (n=10) in a hemorrhagic shock dog model. One liter of 125 F fluid, as part of the resuscitation, did not cause hyperthermia, red blood cell hemolysis, or any significantly different response in the cardiovascular system when compared to body-temperature fluid. All animals in both groups survived. These findings suggest that battlefield use of hot fluids in controlled amounts can be safe and effective for treatment of blood loss shock in human combat casualties.

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A combination of fentanyl-droperidol was administered intravenously alone or with atropine sulfate (2 doses--0.04 or 0.02 mg/kg of body weight) to determine if stable neuroleptanalgesia could be produced in the dog. Cardiovascular responses were recorded at 5, 15, and 30 minutes. Fentanyl-droperidol given alone caused a significant increase of peripheral resistance and mean arterial pressure at 5 minutes and then a decrease of these values over a postinjection period of 30 minutes. Left ventricular dP/dt increased significantly at postinjection minutes 15 and 30. In dogs given atropine concurrently with fentanyl-droperidol, there was significant increase in heart rate and decrease in stroke volume. Also, there were significant initial increases in diastolic and mean arterial blood pressures, ventricular contractility, and coronary blood flow. The dose of 0.02 mg of atropine/kg seemed optimal for intravenous administration with fentanyl-droperidol in the dog; when the atropine dose was 0.04 mg/kg, large inotropic and chronotropic effects were produced.

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