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.     

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.     

Cromolyn sodium decreases the pulmonary vascular response to alveolar hypoxia in lambs

We investigated the effect of cromolyn sodium, a mast cell stabilizing agent, on the pulmonary vascular response to alveolar hypoxia in six chronically instrumented lambs aged 9 to 11 days. Each lamb was instrumented on day 6 or 7 for measurements of systemic arterial, pulmonary arterial and left atrial pressures, and pulmonary blood flow. The animals were allowed to recover from surgery at least 3 days before they were studied. Each animal was studied twice, once with a cromolyn sodium infusion and once with a normal saline infusion (placebo). These paired experiments were separated by 24 h. Physiologic measurements were made during a 1-min predose control period, after an 8-min drug or placebo infusion, and after a 15-min period of alveolar hypoxia. Cromolyn sodium infusion alone did not affect baseline cardiovascular variables. Alveolar hypoxia following placebo infusion produced an increase in pulmonary arterial pressure and pulmonary vascular resistance; these responses were blocked in the animals given cromolyn sodium prior to induction of hypoxia. These results show that cromolyn sodium blocks the pulmonary vascular response to hypoxia and provide indirect evidence that mast cell degranulation, with subsequent release of vasoactive agents, mediates the pulmonary vascular response to hypoxia in newborn lambs.     

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.     

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.     

Supranormal Cardiac Output in the Dopamine- and Dobutamine-Dependent Preterm Infant

To evaluate the incidence of low cardiac output in preterm infants with respiratory distress syndrome (RDS), we measured cardiac output, stroke volume, heart rate, mean arterial blood pressure, and systemic vascular resistance at 8–48 hours of age in 30 preterm infants with RDS who were dependent on inotropic support. We then compared them to 23 normotensive preterm infants with RDS and 27 preterm infants without RDS. RDS infants had a higher cardiac output and lower systemic vascular resistance and blood pressure than infants without RDS. Infants treated with dopamine and dobutamine had a higher cardiac output and heart rate than infants on dopamine alone or the normotensive controls but a lower blood pressure and systemic vascular resistance than the normotensive controls. Supranormal cardiac output (>400 ml/min/kg) was detected in 57% of the infants in the dopamine + dobutamine subgroup (p= 0.009) versus 17% in the normotensive RDS subgroup and 12% in the dopamine subgroup. These data show that high cardiac output is relatively common in infants with RDS dependent on dopamine and dobutamine but is not reflected in the blood pressure.     

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.     

The differential effects of leukotriene C4 and D4 on the pulmonary and systemic circulations in newborn lambs

Leukotriene (LT) C4 or D4 may mediate pulmonary hypertension induced by hypoxia. LT have also been isolated from patients with persistent pulmonary hypertension of the newborn syndrome and the adult respiratory distress syndrome. To compare the effects of LTC4 and D4 on the pulmonary and systemic circulations, we performed dose-response studies on spontaneously breathing newborn lambs. To determine whether the hemodynamic effects of LT are mediated through alpha-adrenergic stimulation, some lambs were pretreated with the alpha-adrenergic antagonist phentolamine mesylate before LT injection. These results were compared to the effects of pretreatment with the LT receptor antagonist FPL57231. To determine whether the LT-induced decrease in cardiac output was mediated by the decrease in heart rate, other lambs had their heart rate maintained by left atrial pacing. We found that LTC4 and D4 increased systemic arterial pressure and decreased cardiac output and heart rate. However, LTD4, but not LTC4, increased pulmonary arterial pressure. The hemodynamic effects of LTC4 and LTD4 were completely blocked by FPL57231 but not by phentolamine mesylate. Maintenance of heart rate by left atrial pacing did not alter the LT-induced decrease in cardiac output. We conclude that LTC4 and D4 have similar effects on the systemic circulation. However, LTD4 produces more pulmonary vasoconstriction. Because FPL57231 did block the pulmonary vasoconstriction caused by LT, LT antagonists may be useful in treating patients with pulmonary hypertension.     

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.     

Cerebral vascular responses to tolazoline infusions in the piglet

Ventilated piglets were studied to determine the effects of intravenous tolazoline infusions during hypoxia on the cerebral circulation and to assess whether cerebral responses reflect tolazoline-induced alterations in the systemic vasculature. We measured cerebral blood flow (CBF), cardiac output (CO), mean arterial pressure (MAP) and cerebral arteriovenous differences of O2 content during normoxia, isocapnic hypoxia (FiO2 14%), and hypoxia (FiO2 14%) with infusions of either saline (n = 7) or tolazoline (n = 10). Hypoxia alone resulted in comparable cardiovascular alterations in both groups. During hypoxia + saline MAP remained stable, but decreased during hypoxia + tolazoline, reflecting reductions in systemic vascular resistance (SVR) and variable changes in CO (reductions in 4 piglets, increases in 6). In both groups CBF rose during hypoxia alone and remained elevated during hypoxia with saline or tolazoline. Cerebral O2 delivery, extraction and uptake were unchanged in both groups. Although mean CBF was similar during hypoxia with saline or tolazoline, CBF was variable during tolazoline, decreasing in 4 of 10 piglets; CBF never fell with saline. Tolazoline-induced changes in MAP correlated with CBF (r = 0.90, P less than 0.001) emphasizing the importance of MAP in maintaining CBF during hypoxia. Importantly, decreases in CBF also paralleled falls in CO. In the presence of a pressure-passive cerebral vasculature, the adequacy of increases in CO to offset tolazoline-induced reductions in SVR determines MAP and ultimately CBF. Thus, cerebral vascular responses to tolazoline infusions during hypoxia reflect tolazoline-induced systemic circulatory derangements.     

Sildenafil reverses hypoxic pulmonary hypertension in highland and lowland newborn sheep

Perinatal exposure to chronic hypoxia induces sustained hypertension and structural and functional changes in the pulmonary vascular bed. We hypothesized that highland newborn lambs (HLNB, 3600 m) have a higher pulmonary arterial pressure (PAP) due in part to a higher activity/expression of phosphodiesterase 5 (PDE5). We administered sildenafil, a PDE5 inhibitor, during basal and hypoxic conditions in the pulmonary hypertensive HLNB and compared them to lowland newborn lambs (LLNB, 580 m). Additionally, we compared the vasodilator responses to sildenafil in isolated small pulmonary arteries and the PDE5 mRNA expression and evaluated the vascular remodeling by histomorphometric analysis in these newborn lambs. Under basal conditions, HLNB had a higher PAP and cardiac output compared with LLNB. Sildenafil decreased the PAP during basal conditions and completely prevented the PAP increase during hypoxia in both groups. HLNB showed a greater contractile capacity and a higher maximal dilation to sildenafil. PDE5 mRNA expression did not show significant differences between HLNB and LLNB. The distal pulmonary arteries showed an increased wall thickness in HLNB. Our results showed that HLNB are more sensitive to sildenafil and therefore could be useful for treatment of pulmonary hypertension in high-altitude neonates.     

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)     

The effect of naloxone on the hemodynamics of the newborn piglet with septic shock

Naloxone has been shown to reverse the hemodynamic sequelae of experimental septic shock in adult animal models. Its effectiveness in the newborn has not been studied. To further investigate the efficacy of naloxone, we instrumented 18 piglets for continuous measurement of mean arterial pressure, mean pulmonary arterial pressure, central venous pressure, heart rate, left ventricular pressure, contractility, cardiac output, and O2. Oxygen consumption, systemic vascular resistance, and pulmonary vascular resistance were calculated. Following a stabilization period, group B beta-hemolytic Streptococci were infused over 30 min. Following the infusion, naloxone (1 mg/kg) was given followed by a continuous infusion of 1 mg/kg/h in nine treatment animals. Nine control animals were given an equal volume of saline. Both groups developed significant increases in mean pulmonary arterial pressure followed by a return to baseline. Oxygen consumption, cardiac output, contractility and mean arterial pressure decreased in both groups. Treatment with naloxone was associated with a cessation in the fall in the mean arterial pressure and the contractility. The difference in mean arterial pressure and contractility between groups was significant. The naloxone group had significantly improved 5-h survival. We speculate that naloxone may reverse some of the hemodynamic sequelae and improve survival in newborns with septic shock.     

Conventional vs high-frequency jet ventilation in a piglet model of meconium aspiration: comparison of pulmonary and hemodynamic effects

The pulmonary and cardiovascular effects of high-frequency jet (HFJV) and conventional (CV) ventilation were evaluated in a piglet model of meconium aspiration. A mixture of 20% human meconium and 0.9% saline solution was instilled deep into the trachea of 10 piglets, after which either HFJV or CV was administered for 4 hours. Arterial blood gases, cardiac output, mean pulmonary and systemic arterial pressures, pulmonary and systemic vascular resistances, and pulmonary mechanics were compared between groups. During the 4 hours of ventilation, PaO2 and PaCO2 were not statistically different between groups. The peak inspiratory pressure necessary to maintain PaCO2 in the preset range was approximately half as much in the HFJV group as in the CV group (P less than 0.002). Mean airway pressure was lower in the HFJV group only during the second hour (P less than 0.03). Cardiac output, mean aortic and pulmonary artery pressures, systemic and pulmonary vascular resistance, dynamic lung compliance, and pulmonary resistance were not statistically different between groups. Our results suggest that HFJV may be more effective than CV in the early stages of meconium aspiration syndrome because HFJV allows more efficient ventilation and adequate oxygenation at lower peak inspiratory pressures.     

Leukotriene inhibition prevents and reverses hypoxic pulmonary vasoconstriction in newborn lambs

The effects of the leukotriene antagonist FPL 57231 on the circulation were studied in spontaneously breathing normoxic and hypoxic newborn lambs in order to evaluate the role of leukotrienes in the perinatal control of hypoxic pulmonary vasoconstriction. Hypoxia produced a 58% increase in pulmonary arterial pressure (p less than 0.05) and a 37% increase in pulmonary vascular resistance (p less than 0.05). Hypoxic pulmonary vasoconstriction was abolished by the prior infusion of FPL 57231. Pulmonary arterial pressure increased by only 8% and pulmonary vascular resistance decreased by 10% from normoxia. The infusion of FPL 57231 during hypoxia-induced pulmonary vasoconstriction reversed the increase in pulmonary arterial pressure (p less than 0.05) and pulmonary vascular resistance (p less than 0.05). The hypoxia-induced increase in cardiac output was maintained during the infusion of FPL 57231. Leukotrienes may play a significant role in the mediation of hypoxic pulmonary vasoconstriction. Leukotriene inhibition with FPL 57231 may be useful in the management of infants with persistent pulmonary hypertension syndrome.     

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.     

Inhalation of nebulized nitroglycerin in dogs with experimental pulmonary hypertension induced by U46619

BACKGROUND: Pulmonary hypertension (PH) causes mortality in some congenital and acquired heart and lung diseases. However, inhalation of NO gas requires complicated and expensive instruments and elaborate preparations to avoid toxic gas administration. We tested the effectiveness and safety of inhaled nebulized nitroglycerin (Neb-NTG) in dogs with experimental PH. METHODS: Experimental PH was induced by continuous infusion of a thromboxane analog (U46619). The U46619 infusion rate was adjusted to maintain a systolic pulmonary artery pressure (PAP) at 40 mmHg in 10 anesthetized and mechanically ventilated dogs. Then, 20 micrograms/kg of NTG liquid nebulized by compressed air was inhaled. RESULTS: After infusion of U46619, the systolic, diastolic and mean PAP increased by 119%, 228% and 169%, respectively, and the systolic, diastolic and mean systemic arterial pressures (SAP) increased by 19%, 29% and 23%, respectively. The systolic pulmonary to systemic pressure ratio (Pp/Ps) and mean Pp/Ps increased by 83% and 113%, respectively, and the pulmonary vascular resistance (PVR), systemic vascular resistance (SVR) and pulmonary to systemic resistance ratio (Rp/Rs) increased by 341%, 100% and 145%, respectively. After inhalation of Neb-NTG in dogs with experimental PH, systolic, diastolic and mean PAP and PVR decreased by 25 +/- 4, 26 +/- 11, 25 +/- 9 and 31 +/- 21%, respectively. There were no significant changes in systolic, diastolic and mean SAP, SVR, cardiac output and plasma methemoglobin concentrations. The systolic and mean Pp/Ps decreased by 18 +/- 7 and 20 +/- 7%, respectively. The Rp/Rs decreased by 25 +/- 13%. CONCLUSIONS: The results of this study demonstrate that Neb-NTG is an effective and selective pulmonary vasodilator and may offer a new therapeutic option for PH.     

Direct and indirect pulmonary vascular effects of tolazoline in the newborn lamb.

The pulmonary vascular effects of tolazoline were studied in unsedated newborn lambs during normal oxygenation and hypoxia. Direct and indirect pulmonary vascular responses were analyzed separately. During normal oxygenation, tolazoline (1 mg/kg) given into a branch pulmonary artery increased cardiac output while decreasing systemic and pulmonary resistances. Pulmonary flow distribution did not change, suggesting that the fall in pulmonary resistance was due to an indirect rather than a direct action of the drug. Tolazoline had similar effects on systemic and pulmonary resistances in the hypoxic lamb; however, there was a shift in blood flow toward the injected lung, indicating local pulmonary vasodilation induced by the drug. In either case, tolazoline did not alter the resistance ratio between the injected lung and the systemic circulation. We conclude that tolazoline is a direct pulmonary vasodilator in the hypoxic lamb, but does not appear to lower the pulmonary to systemic resistance ratio.     

Bipyridine derivatives lower arteriolar resistance and improve left ventricular function in newborn lambs

Milrinone may be used in the treatment of pulmonary hypertensive diseases of the newborn. We have studied its effects in chronically instrumented newborn lambs over a dose range from 1-100 micrograms/kg. These actions have been compared with those of amrinone. We have also tested the effect of milrinone on hypoxia and leukotriene D4-induced pulmonary vasoconstriction. Injected into the right pulmonary artery, both amrinone and milrinone cause a dose-related fall in pulmonary arteriolar resistance with milrinone being approximately 20 times more potent than amrinone and possessing an ED50 of about 10 micrograms/kg. Both agents increase left ventricular dp/dt significantly and tend to increase cardiac output. Systemic vascular resistance falls with both drugs but the change is significant only with milrinone. While milrinone attenuates the increase in pulmonary arteriolar resistance induced by leukotriene D4 and hypoxia, this is probably an indirect effect. Milrinone does not modify either the increases in left atrial, aortic pressure, and systemic vascular resistance or the decreases in cardiac output and left ventricular dp/dt induced by leukotriene D4. These findings suggest that milrinone deserves clinical trial in newborn infants with pulmonary hypertension in whom myocardial depression often coexists.     

Hemodynamic and ventilatory effects of high-frequency jet and conventional ventilation in piglets with lung lavage

The cardiovascular and ventilatory effects of high-frequency jet ventilation (HFJV) and conventional ventilation (CV) were evaluated in a saline lung lavage model in piglets. After saline lavage and stabilization on CV, animals were randomized to either mode of ventilation for 4 h. Arterial blood gases, cardiac output, mean pulmonary and arterial blood pressures, and pulmonary and systemic vascular resistances were compared between groups. Alveolar-arterial oxygen gradient (AaDO2) was lower in the HFJV than in the CV group after 3 h of ventilation (p less than 0.04). The peak inspiratory pressure necessary to maintain PaCO2 within the normal range was approximately half as much in the HFJV group as in the CV group (p less than 0.005) throughout the entire study period. Mean airway pressure, cardiac output, mean pulmonary and arterial blood pressures as well as pulmonary and systemic vascular resistances were not statistically different between groups. These results suggest that in this model, HFJV produces better oxygenation with lower peak airway pressures compared to CV without producing hemodynamic compromise.