Pulmonary vascular response to aerosolized cromolyn sodium and repeated epochs of isocapneic alveolar hypoxia in lambs

We investigated the effect of aerosolized cromolyn sodium (CS) on the pulmonary vascular response to isocapneic alveolar hypoxia in chronically instrumented lambs aged 11-12 days. Each lamb underwent two operations: chest instrumentation for measurements of pulmonary arterial, systemic arterial, and left atrial pressures, and pulmonary blood flow; and a tracheotomy for drug administration. The animals were recovered 3 days before study. Each lamb received an aerosol of normal saline (placebo) and CS in paired experiments 24 h apart. In the first set of experiments (n = 8), placebo or CS (30 mg) was given, followed by four 15-min epochs of alveolar hypoxia (8% O2, 5% CO2, 87% N2) each separated by 30 min of alveolar normoxia (21% O2). During hypoxia after both placebo and CS, pulmonary arterial pressure and resistance increased. This response was unchanged with repeated epochs. In the second set of experiments (n = 8), normal saline or CS (30 mg) was administered three times over a 90-min period, followed by one 15-min epoch of hypoxia. Pulmonary arterial pressure and resistance increased during hypoxia after placebo, but did not change after CS. Thus, the single dose of aerosolized CS did not alter the pulmonary vascular response to alveolar hypoxia, whereas the triple dose of CS attenuated the response. Additionally, the pulmonary vascular response to hypoxia alone was not altered by repeated exposures to hypoxia. We conclude that CS interferes with the mechanism(s) responsible for hypoxic pulmonary vasoconstriction in newborn lambs.     

Chloralose alters both basal hemodynamics and cardiovascular responses to alveolar hypoxia in chronically instrumented, spontaneously breathing lambs

We studied the effects of chloralose anesthesia on the basal hemodynamic state and on the cardiovascular response to alveolar hypoxia in chronically instrumented, spontaneously breathing lambs, compared with responses to the saline vehicle. Chloralose significantly increased heart rate (23%), mean systemic arterial pressure (11%), systemic vascular resistance (21%), mean pulmonary arterial pressure (23%), and pulmonary vascular resistance (46%) (n = 30, p less than 0.05, ANOVA). These changes were unrelated to baseline tone of the circulation, cardiac output, mean left atrial pressure, or physiologically important changes in arterial blood gas tensions. In addition, chloralose-treated lambs had increased heart rate, systemic vascular resistance, and pulmonary vascular resistance compared to controls during alveolar hypoxia (13-15% FiO2). Importantly, chloralose-treated lambs did not increase their cardiac output during alveolar hypoxia as did control lambs. During hypoxia, systemic vascular resistance remained elevated in chloralose-treated lambs, but declined in control lambs. Chloralose has been recommended as an ideal anesthetic agent for cardiovascular experimentation. Our data suggest that chloralose-induced alterations in basal hemodynamics and in cardiovascular responses to alveolar hypoxia represent an uncontrolled variable in acute experimental studies. Complex cardiovascular alterations caused by anesthesia should be considered in experimental design.     

Alveolar hypoxia increases small pulmonary wedge pressure in awake young lambs

Alveolar hypoxia increases pulmonary artery pressure in lambs and sheep but increases lung lymph flow only in lambs; the reasons for this are unknown. To test the hypothesis that hypoxia-induced pulmonary venous constriction could in part explain the fluid filtration response in young lambs, eight young lambs (13 +/- 3 days old) and four older lambs (60 +/- 4 days old) were prepared for chronic studies of pulmonary hemodynamics, gas exchange, and fluid filtration. In all animals, a 5 Fr catheter was intermittently wedged into a distal pulmonary artery to indirectly estimate pulmonary venous pressure. The pressure measured in this manner was termed the "small wedge pressure." Animals were awake, spontaneously breathing, and unsedated, and were exposed to both acute and chronic isocarbic hypoxia (FIO20.12). We found that hypoxia significantly increased both small pulmonary wedge pressure and lung lymph flow in young lambs but that neither of these effects occurred in the older lambs. In young lambs, the hypoxia-induced increase in small wedge pressure could be lowered by sodium nitroprusside administration, and small wedge pressure could be increased by angiotensin II infusion. We conclude that alveolar hypoxia increases pulmonary venous tone and the critical pressure of pulmonary veins in young lambs, and that these effects disappear with maturation. These data suggest that alterations in pulmonary venous tone can have important effects on lung fluid balance in the newborn.     

The circulatory effects of nifedipine in the conscious newborn lamb

The cardiac, pulmonary vascular, and systemic vascular effects of bolus injections (2.5, 25, 50 micrograms/kg) and 5-min infusions of 50 micrograms/kg/min of Nifedipine were tested in conscious, chronically instrumented newborn lambs. While breathing room air, bolus injections of 50 micrograms/kg into the pulmonary artery caused the cardiac index and left ventricular dp/dt to fall as did systemic arterial pressure and calculated resistance (all changes significant p less than 0.05). Pulmonary artery, pulmonary vein, and left atrial pressure all tended to increase and there was a shift in flow away from the injected lung (14 +/- 0.05%). Pulmonary arteriolar resistance in the injected lung increased significantly (p less than 0.05). Nifedipine failed to prevent hypoxia-induced pulmonary vasoconstriction, and when given during hypoxia, caused a further rise in pulmonary artery pressure with a marked fall in left ventricular dp/dt and systemic vascular resistance. These acute effects peaked 30 s to 2 min after injection and all hemodynamic variables returned to baseline by 10 min. Five-min infusions caused similar effects which completely reversed 20 min after the infusion was stopped. Nifedipine causes significant cardiac depression combined with systemic vasodilatation and pulmonary arteriolar constriction in conscious newborn lambs. Assuming similar actions in humans, it seems quite unsuitable for the therapy of pulmonary hypertensive problems of newborn infants.     

Thromboxane is not responsible for the high pulmonary vascular resistance in fetal lambs

The factors responsible for the high pulmonary vascular resistance in the fetus are not well known. Thromboxane (TX) A2 is a potent pulmonary vasoconstrictor. To determine whether TXA2 may play a role in fetal pulmonary vasoconstriction, we infused the specific TX synthetase inhibitor U63,557A into eight chronically instrumented fetal lambs (134-137 days gestational age, full term 145 days) and measured pulmonary blood flow, pulmonary and systemic arterial pressure, and heart rate. U63,557A (3 mg/kg as a bolus then 3 micrograms/kg/min for 120 min infused in the main pulmonary artery) did not change pulmonary blood flow, pulmonary mean arterial pressure, and pulmonary vascular resistance during the infusion and during 2 h following the end of the infusion. During the infusion, TXB2 arterial plasma concentrations decreased from 106.1 +/- 17.5 to 8.7 +/- 2.9 pg/ml. In three of the fetal lambs, immediately after the 2-h infusion of U63,557A, we infused the leukotriene end-organ antagonist FPL 57231 into the main pulmonary artery (1 mg/kg/min for 60 min). TXA2 synthesis inhibition did not prevent the pulmonary vasodilation induced by FPL 57231. Pulmonary blood flow increased from 64.8 +/- 24.4 to 669.5 +/- 65.6 ml/min/100 g lung tissue during the FPL 57231 infusion. We conclude that TXA2 does not play a role in the maintenance of elevated fetal pulmonary vascular tone, either directly or as a mediator of leukotriene action.     

Arousal from sleep during rapidly developing hypoxemia in lambs

Arousal is an important protective response that may prevent severe hypoxemia and death during sleep. However, very little is known about arousal from sleep in response to respiratory stimuli in newborns. Experiments were therefore done to investigate the arousal response from sleep to rapidly developing hypoxemia in eight lambs. Each lamb was anesthetized and instrumented for recordings of electrocorticogram, electrooculogram, nuchal and diaphragm electromyograms, and measurements of arterial hemoglobin oxygen saturation. A tracheotomy was done and a tracheostomy tube placed in the trachea so that the fraction of inspired oxygen could be changed quickly. No sooner than 3 days after surgery, measurements were made in quiet sleep and active sleep (AS) during 30-s control periods when the animals were breathing 21% oxygen and during experimental periods of hypoxemia when the animals were breathing either 10, 5, or 0% oxygen in nitrogen. During quiet sleep, arousal occurred at similar arterial hemoglobin oxygen saturations (81 +/- 6% on 10% O2, 80 +/- 5% on 5% O2 and 83 +/- 5% on 0% O2) suggesting that arousal was independent of the rate of change of arterial oxygen. However, during AS arousal occurred at different arterial hemoglobin oxygen saturations (76 +/- 6% on 10% O2, 55 +/- 11% on 5% O2, and 44 +/- 17% on 0% O2) suggesting that arousal was dependent on the rate of change of arterial oxygen. During some epochs of AS, electrocortical signs of cerebral hypoxia and primary apnea occurred before arousal. These data provide evidence that arousal from quiet sleep in response to hypoxemia occurs once an arousal threshold has been reached.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of dopamine infusion on pulmonary gas exchange in lambs

We studied the effects of dopamine HCl, a potent vasoactive catecholamine, on ventilation-perfusion matching and pulmonary hemodynamics in infant lambs breathing room air and a hypoxic gas mixture. Neither alveolar hypoxia alone, nor dopamine infusion alone during room air breathing, significantly altered the ventilation-perfusion (VA/Q) distribution or intrapulmonary shunt size. Dopamine infusion during room air breathing did increase pulmonary blood flow (PBF; p less than 0.05). Dopamine infusion plus alveolar hypoxia was associated with a significant increase in minute ventilation, PBF, and pulmonary arterial pressure (Ppa), a doubling (p less than 0.01) of the fraction of PBF to low VA/Q lung regions, and a significant increase (p less than 0.05) in intrapulmonary shunt when compared to results obtained during hypoxic gas breathing without dopamine infusion. We conclude the dopamine infusion increased PBF during room air breathing, and perturbed ventilation-perfusion matching and increased Ppa and minute ventilation with no net change in arterial pO2 during the breathing of a hypoxic gas mixture.     

Influence of an antagonist of slow-reacting substance of anaphylaxis on the cardiovascular manifestations of hypoxia in piglets

Leukotrienes have been implicated in the pathogenesis of hypoxic pulmonary hypertension in adult animals and in persistent pulmonary hypertension with accompanying hypoxemia in the neonate. In order to elucidate the role of leukotrienes in hypoxic pulmonary hypertension in a young animal model, the effects of a leukotriene antagonist, FPL 57231, were evaluated in anesthetized piglets. Cardiac output and vascular pressures were measured and pulmonary and systemic vascular resistances calculated prior to and during hypoxia. These measurements were compared during continued hypoxia between a control and treatment group which received FPL 57231. FPL 57231 infusion resulted in significant decreases in mean pulmonary artery pressure (p less than 0.04), pulmonary vascular resistance (p less than 0.01) and the ratio of pulmonary/systemic vascular resistance (p less than 0.01). Systemic vascular resistance fell approximately 25% from hypoxic baseline (p less than 0.01) while PVR decreased 54%. There were no differences between groups in mean systemic arterial pressure, cardiac output, pH, or PaCO2. In addition, pretreatment with FPL 57231 attenuated the hemodynamic response to hypoxia. These data suggest that leukotrienes may, in part, mediate hypoxic pulmonary vasoconstriction in piglets.     

The effect of methylprednisolone on hypoxic pulmonary vasoconstriction in the newborn late-gestation lamb

Methylprednisolone (30 mg/kg), which inhibits a number of mediators of hypoxic pulmonary vasoconstriction derived from arachidonic acid, has been found to alleviate hypoxic pulmonary vasoconstriction in adult humans and in the isolated rat lung preparation. We studied the effect of 30 mg/kg of methylprednisolone on the pulmonary vascular response to hypoxia in six late-gestation newborn lambs. During hypoxia, pulmonary vascular resistance nearly doubled compared with the baseline hyperoxic state. This was true both before and after administration of methylprednisolone. We conclude that methylprednisolone, when administered at the dosage used in previous studies of adult humans and animals, does not affect the response of the pulmonary vascular bed to hypoxia in newborn lambs.     

Effects of dopamine and nifedipine infusions on the pulmonary circulation of the lamb

The purpose of this study was to test the hypothesis that nifedipine when given with dopamine will lower pulmonary vascular resistance in hypoxic lambs without altering systemic vascular resistance. We studied six unanesthetized lambs (ranging in age from 13 to 35 days) as they breathed air or on a separate day as they breathed 10% O2 and 3% CO2 in nitrogen. First, we infused dopamine at progressively higher rates (10, 20, 40, 80, and 160 micrograms/kg/min) while measuring mean aortic, pulmonary arterial, and left atrial pressures and heart rate continuously and cardiac output and arterial blood gas tensions at frequent intervals. Then, while maintaining the dopamine infusion at 160 micrograms/kg/min, we infused boluses of nifedipine intravenously (10 micrograms/kg) every 5 min until a cumulative dose of 50 micrograms/kg had been administered. In both groups of lambs, cardiac output increased with increasing rates of dopamine infusion (baseline to maximum dopamine: 260 +/- 20 ml/kg/min to 420 +/- 60 ml/kg/min for normoxic lambs and 400 +/- 50 ml/kg/min to 560 +/- 80 ml/kg/min for hypoxic lambs). While systemic vascular resistance and pulmonary vascular resistance did not change significantly in either group during dopamine infusion, the ratio of pulmonary vascular resistance to systemic vascular resistance increased at low rates of infusion and decreased at high rates. The peak in this ratio occurred at a rate of infusion of 20-40 micrograms/kg/min in normoxic lambs and 40-80 micrograms/kg/min in hypoxic lambs. Infusion of nifedipine did not affect cardiac output in normoxic lambs but decreased it significantly in hypoxic lambs. Nifedipine infusion did not affect pulmonary vascular resistance in the normoxic lambs and increased pulmonary vascular resistance in the hypoxic lambs. We conclude that nifedipine, even when given with high doses of dopamine, is not a specific pulmonary vasodilator.     

Repeated exposure to rapidly developing hypoxemia influences the interaction between oxygen and carbon dioxide in initiating arousal from sleep in lambs

Experiments were done on 12 lambs to determine if repeated exposure to hypoxemia influences the interaction between oxygen and carbon dioxide in causing arousal response from sleep. Each lamb was anesthetized and instrumented for sleep staging and measurements of arterial Hb oxygen saturation. No sooner than 3 days after surgery, measurements were made in quiet and active sleep during control periods when the lambs were breathing 21% oxygen and during experimental periods when the lambs were breathing either 5% O2-0% CO2, 5% O2-5% CO2 or 5% O2-10% CO2. Each experimental period was terminated during each epoch by changing the inspired gas mixture back to 21% oxygen once the animal aroused from sleep. The lambs were divided into two groups. One group (n = 7) was studied without prior exposure to hypoxemia and the other group (n = 5) was studied after exposure to 5% oxygen during approximately 100 epochs of sleep until they aroused. In lambs not previously exposed to hypoxemia, there was evidence for a slight interaction between oxygen and carbon dioxide in initiating arousal but only from quiet sleep. Repeated exposure to hypoxemia resulted in an arousal response decrement to hypoxemia. In lambs previously exposed to hypoxemia, there was evidence for an interaction between oxygen and carbon dioxide in initiating arousal from both quiet and active sleep (i.e. the time to arousal decreased and the saturation at arousal increased as increasing amounts of carbon dioxide were added to the hypoxic gas mixture).(ABSTRACT TRUNCATED AT 250 WORDS)     

Lung fluid balance in hypoxic lambs

In spontaneously breathing newborn lambs, alveolar hypoxia increases lung microvascular pressure, which causes lung lymph flow to increase and the concentration of protein in lymph to decrease. To see if this response derives from hypoxia itself rather than from the change in breathing pattern that occurs during hypoxia, we measured lung vascular pressures, pleural pressure, cardiac output, and lung lymph flow in 12 anesthetized lambs that were ventilated at a fixed rate and tidal volume, first with air, then with 10-14% O2 in nitrogen. Alveolar hypoxia did not affect pleural pressure, but pulmonary arterial pressure increased from 19 to 32 torr, lung lymph flow increased from 2.20 to 3.83 ml/h and lymph protein concentration decreased from 3.4 to 2.8 g/dl. To be certain that the increased lymph flow associated with hypoxia is not simply the result of an acute release of fluid from the lungs and to assess the effects of carbon dioxide on lymph flow during hypoxia, we next studied six unanesthetized lambs kept hypoxic for a total of 12 h. After a 2-4-h period in air the lambs breathed 9-11% O2 in nitrogen for 2-4 h, then 8-11% O2 and 3-5% CO2 in nitrogen for 8-10 h. In these lambs we injected intravenously radioactive albumin and measured its uptake in lymph to see if sustained hypoxia alters microvascular permeability to protein in the lungs. In these experiments pulmonary arterial pressure increased from 17 to 37 torr, lung lymph flow increased from 1.74 to 3.28 ml/h, and lymph protein concentration decreased from 3.8 to 3.1 g/dl during hypoxia.(ABSTRACT TRUNCATED AT 250 WORDS)     

Tumor necrosis factor-induced neonatal pulmonary hypertension: effects of dazmegrel pretreatment

The endogenously produced cytokine, tumor necrosis factor-alpha (TNF-alpha), has been shown in adult animal models to be associated with many of the pathophysiologic effects of sepsis, including systemic hypotension and hemorrhagic necrosis. TNF-alpha can induce the release of various vasoactive arachidonic acid metabolites, suggesting that TNF-alpha may act either directly or via intermediary substances in producing its effects. The pathophysiologic role of TNF-alpha in neonatal sepsis, especially its potential effect on pulmonary vascular tone, is presently unknown. To assess the role of TNF-alpha in neonatal sepsis, 19 piglets (19 +/- 5 d old) were anesthetized, intubated, paralyzed, mechanically ventilated, and catheterized to assess pulmonary and systemic vascular hemodynamics and pulmonary gas exchange. The multiple inert gas elimination technique was used to assess ventilation perfusion matching. A 30-min infusion of human recombinant TNF-alpha (250 micrograms/kg total dose) was administered to animals pretreated with either 10 mg/kg dazmegrel, a thromboxane synthase inhibitor (n = 9) or placebo (n = 10). TNF-alpha alone induced a prompt and sustained rise in pulmonary arterial pressure and pulmonary vascular resistance that continued at least for 2 h after onset of the infusion. In contrast, the animals pretreated with dazmegrel demonstrated no rise in pulmonary vascular resistance until 2 h after the onset of the infusion. Neither group of animals demonstrated a significant decline in arterial PO2 or evidence from inert gas analysis of VA/Q mismatching or increase in intrapulmonary shunt.(ABSTRACT TRUNCATED AT 250 WORDS)     

Nicotine delays arousal during hypoxemia in lambs

A decreased ability to arouse from sleep in response to arterial hypoxemia may lead to severe asphyxia and has been proposed as a mechanism of sudden infant death syndrome. Based on previous observations that nicotine exposure, a major environmental risk factor for sudden infant death syndrome, may impair hypoxic defense in neonates, we hypothesized that a short-term infusion of nicotine could impair hypoxic arousal through interference with oxygen-sensing mechanisms. Seven chronically instrumented unanesthetized lambs were studied at the age of 4.6 +/- 1.3 d during normoxia and acute hypoxia (0.1 fraction of inspired oxygen) for 5 min. Ventilation, transcutaneous Hb oxygen saturation, blood pressure, heart rate, and time to arousal were compared during a control saline infusion and during a 0.5 microg x kg(-1) x min(-1) nicotine infusion. Activity states, i.e. wakefulness and quiet sleep as well as arousal, were defined by EEG, nuchal electromyogram, and electrooculogram. Each lamb acted as its own control. Arousal from quiet sleep occurred significantly later during nicotine infusion compared with control (177 +/- 93 versus 57 +/- 41 s, p < 0.01) and at a lower transcutaneous Hb oxygen saturation (60 +/- 12 versus 79 +/- 12%, p < 0.01) (paired t test). The ventilatory response to hypoxia in wakefulness was similar during both conditions but was significantly attenuated in quiet sleep during nicotine infusion (p < 0.001, 2-way ANOVA repeated-measures design). Blood pressure and heart rate responses were similar during both conditions. These results suggest that a brief nicotine exposure blunts oxygen sensitivity in young lambs, a finding of potential relevance for sudden infant death syndrome.     

Influence of repeated upper airway obstruction on the arousal and cardiopulmonary response to upper airway obstruction in lambs

Experiments were done on five lambs to determine if repeated obstruction of the upper airway influences the arousal and cardiopulmonary response to upper airway obstruction. Each lamb was anesthetized and instrumented for recordings of electrocorticogram, electrooculogram, nuchal and diaphragm electromyograms, and measurements of arterial blood pressure and arterial hemoglobin oxygen saturation. A tracheostomy was done and a fenestrated tracheostomy tube placed in the trachea. The animals were studied after a 3-day recovery period. During a study, a 5F balloon-tipped catheter was inserted into the tracheostomy tube so that air flow could be obstructed by inflating the balloon. The balloon was inflated each time the animal went to sleep for approximately 100 consecutive epochs (17 to 30 h) and the time to arousal and the arterial hemoglobin oxygen saturation at arousal were recorded. Upper airway obstruction was terminated by deflating the balloon once the animal aroused from sleep. Arousal occurred from both sleep states during upper airway obstruction but was delayed in active sleep compared to quiet sleep. The time to arousal and the decrease in arterial hemoglobin oxygen saturation were significantly increased with repeated upper airway obstruction only during active sleep. Inasmuch as it is possible that alterations in the arousal response to respiratory stimuli play a role in sudden infant death, studies to investigate the mechanisms of the state-specific changes in the arousal response to upper airway obstruction are warranted.     

Hemodynamic effects of heat-killed group B beta-hemolytic streptococcus in newborn lambs: role of leukotriene D4.

Group B beta-hemolytic streptococcus (GBS) infection is an important cause of neonatal pneumonia and sepsis. GBS infection is frequently associated with persistent pulmonary hypertension of the newborn. To better understand the early pulmonary hypertension phase of GBS-induced acute lung injury in a conscious animal, we characterized the pulmonary and systemic hemodynamic response of spontaneously breathing, chronically instrumented newborn lambs to injections of heat-killed type Ib GBS, 0.1-9.0 x 10(9) colony forming units. Heat-killed GBS caused marked dose-dependent increases in mean pulmonary arterial pressure and calculated pulmonary vascular resistance, 190 and 370% at the maximum dose, respectively. Similarly, GBS caused dose-dependent increases in mean systemic arterial pressure and systemic vascular resistance (28.5 and 108% at the maximum dose, respectively) and a decrease in cardiac output (33.5%). Arterial oxygen tension worsened at the higher doses. GBS-induced pulmonary hypertension was decreased by two structurally unrelated, putative leukotriene D4 receptor antagonists. Pretreatment with LY171883 blocked GBS-induced pulmonary hypertension by 95%, and WY48,252 attenuated this effect by 27%. Both drugs completely blocked the hemodynamic effects of exogenous leukotriene D4. For comparison, several lambs received bolus injections of live GBS, either alone or after pretreatment with LY171883. The hemodynamic response to live GBS and attenuation of that response by LY171883 were similar to those caused by similar doses of heat-killed GBS. Thus, bolus injections of heat-killed GBS provide a reproducible model of pulmonary hypertension in conscious newborn lambs. In addition, the sulfidopeptide leukotrienes appear to be important mediators of GBS-induced pulmonary hypertension in newborn lambs.     

Pulmonary and systemic vascular response to promethazine in conscious lambs

Summary Promethazine is an antihistamine commonly used for sedation in clinical pediatric medicine. We studied the cardiovascular effects of promethazine in normoxic, conscious, chronically instrumented neonatal lambs. Eight lambs received 1.3 mg/kg of promethazine intravenously (i.v.) while at rest. In all lambs, promethazine led to elevations of pulmonary vascular resistance, mean pulmonary arterial pressure, mean transpulmonary pressure, mean left atrial pressure, and the ratio of pulmonary-to-systemic vascular resistance. In addition, five (63%) of the lambs demonstrated an increase in mean systemic arterial pressure and systemic vascular resistance to promethazine. A subgroup of three lambs, which tended to be younger, failed to demonstrate the systemic vascular response to promethazine. Promethazine given i.v. has important cardiovascular effects. We hypothesize that promethazine used for sedation before cardiac catheterization in children may alter subsequent hemodynamic observations.Dr. Gimotty is now located at Michigan Cancer Foundation, 110 East Warren Avenue, Detroit, Michigan, USA.This research was performed at the University of Florida.A portion of this research was presented at the Southern Society for Pediatric Research in New Orleans, Louisiana, USA, January 1981.     

Ligating the ductus arteriosus before birth causes persistent pulmonary hypertension in the newborn lamb

We determined whether closing the ductus arteriosus of the fetal lamb several d before birth would cause persistent pulmonary hypertension after birth. Six experimental fetuses who had their ductus arteriosus ligated 3-17 d before delivery, three control fetuses who had sham ligation of the ductus arteriosus 14 d before delivery, and six control fetuses who had no prenatal surgery were delivered by cesarean section between 138 and 144 d of gestation. Each was instrumented to measure pulmonary and systemic arterial pressures and pulmonary blood flow. Each newborn lamb was ventilated with room air during the first 45 min after birth and then with decreasing amounts of inspired oxygen from 100 to 9%. Pulmonary arterial pressure decreased significantly when ventilation was begun in the control lambs but not in the lambs who had their ductus arteriosus ligated before delivery. Throughout the experiment, pulmonary arterial pressure and total pulmonary resistance were significantly higher, and pulmonary blood flow was significantly lower in the lambs who had their ductus arteriosus ligated before delivery. In two of them, pulmonary arterial pressure was greater than or equal to systemic arterial pressure, even during ventilation with 100% oxygen. This animal preparation provides a method of investigating persistent pulmonary hypertension in the newborn lamb and may provide insight into an etiology of the syndrome of persistent pulmonary hypertension of the newborn.     

Pulmonary vascular response to digoxin in newborn lambs

The effects of digoxin on pulmonary vascular resistance (PVR) were evaluated in normoxic (N) and hypoxic (H) newborn lambs with normal and elevated PVR, respectively. Lambs were anesthetized and instrumented to enable continuous measurement of mean pulmonary arterial pressure (PPA), mean left atrial pressure (PLA), mean pulmonary blood flow (Qp), and mean aortic pressure (PAO). Digoxin (10-20 micrograms/kg) was injected via central venous catheters in 11 N lambs and 4 H lambs. Under N conditions, baseline PVR was equal to 0.12 mm Hg/ml/min/kg, PPA was 33 mm Hg, PLA was 6 mm Hg, Qp was 235 ml/min/kg, and PAO was 69 mm Hg. Following digoxin, mean PVR increased by 24% (P less than 0.001) and PPA increased by 23% (P less than 0.001) for an average duration of 199 sec while QP increased by 5% (P less than 0.02) and PLA was constant suggesting a direct vasoconstrictive effect. Under H conditions, baseline PVR was equal to 0.26 mm Hg/ml/min/kg, PPA was 58 mm Hg, PLA was 4 mm Hg, Qp was 208 ml/min/kg, and PAo was 65 mm Hg. Following digoxin, mean PVR, Qp, PLA, and PAo did not change appreciably although PPA had a uniform increase of 5% (P less than 0.001). The blunted response may suggest that either the pulmonary vascular bed was maximally constricted or that digoxin and hypoxia share a common mechanism. In conclusion, digoxin has a direct pulmonary vasoconstrictor action in newborn lambs. Because of its short duration, this action probably should not alter the clinical use of this drug in newborn humans.     

Naloxone does not alter the arousal response decrement after repeated exposure to hypoxemia during sleep in lambs.

Experiments were done to determine if endogenous opiates cause the arousal response decrement that follows repeated exposure to hypoxemia during sleep in lambs. Five lambs were anesthetized and instrumented for sleep staging and measurement of arterial Hb oxygen saturation. No sooner than 3 d after surgery, measurements were made in quiet sleep and active sleep during control periods when the lambs were breathing 21% oxygen and during experimental periods when the lambs were breathing 5% oxygen. The experimental period was terminated during each epoch by changing the inspired gas mixture back to 21% oxygen, once the lamb aroused from sleep. After each lamb had been exposed to 5% oxygen during 100 consecutive epochs of sleep, naloxone--an opiate antagonist--was given i.v. in a dose of 3 mg/kg as a bolus. The animals continued to be exposed to 5% oxygen during six more epochs of sleep after the administration of naloxone. Arousal occurred from both sleep states during rapidly developing hypoxemia but was delayed in active sleep compared to quiet sleep. The arterial Hb oxygen saturation at arousal was significantly lower, and the time to arousal was significantly longer with repeated exposure to hypoxemia during both quiet sleep and active sleep. Naloxone did not alter this arousal response decrement to hypoxemia. Thus, our data provide evidence that endogenous opiates do not play a major role in causing the arousal response decrement that follows repeated exposure to hypoxemia during sleep in lambs.