Nitric oxide inhalation in infants with respiratory distress syndrome.

OBJECTIVE: This study was designed to test the hypothesis that nitric oxide inhalation increases systemic arterial blood oxygen tension of prematurely delivered infants with respiratory distress syndrome. METHODS: Nitric oxide was administered to 23 preterm infants with a diagnosis of respiratory distress syndrome. The infants were randomly assigned to receive either 5 or 20 ppm of nitric oxide and were studied between 24 and 168 hours after delivery. The treatment period for each infant lasted 15 minutes and was preceded by and followed by a 15-minute control period. We evaluated all outcome variables by using two-way repeated measures analysis of variance; p values less than 0.01 were considered significant. RESULTS: Nitric oxide inhalation caused significant increases in the following: arterial blood oxygen tension, directly measured arterial oxyhemoglobin saturation, and transcutaneously measured arterial oxyhemoglobin saturation. No differences between the effects of the two nitric oxide concentrations were detected, nor were residual effects detected 15 minutes after either dose of nitric oxide was discontinued. CONCLUSIONS: Inhalation of both 5 and 20 ppm nitric oxide causes concentration-independent increases in the blood oxygen tensions of preterm infants with respiratory distress syndrome. We speculate that nitric oxide inhalation may be a useful adjunctive therapy for these patients.

Early-onset respiratory failure caused by severe congenital neuromuscular disease.

Two unrelated infants with low Apgar scores, pneumothoraces, and severe pulmonary hypertension were treated with extracorporeal membrane oxygenation while receiving chemical sedation and neuromuscular paralysis. After decannulation from extracorporeal membrane oxygenation, hypotonia and hypoventilation persisted. Neurologic evaluation confirmed that both infants had a congenital myopathy.

Hemodynamic interaction of chloralose pretreatment with subsequent beta-adrenergic receptor antagonism in lambs.

alpha-Chloralose is a commonly used anesthetic agent in cardiovascular research despite a paucity of information whether it may have important pharmacologic interaction with subsequently given adrenergic drugs. To assess any potential pharmacologic interaction, we studied the cardiovascular response to beta-adrenergic receptor antagonism (propranolol, 1 mg/kg i.v.) after either chloralose (30 mg/kg i.v.) or saline control in paired studies in 10 chronically instrumented neonatal lambs. Chloralose increased heart rate by 46% as compared to control (283 +/- 37 vs. 194 +/- 48 beats/min, p = 0.0002) and had no significant effect on cardiac output; chloralose also increased mean pulmonary arterial pressure by 45% (27 +/- 13 vs. 19 +/- 6 mm Hg, p = 0.050) and pulmonary vascular resistance by 79% (0.211 +/- 0.13 vs. 0.118 +/- 0.04 mm Hg/ml/kg/min, p = 0.050). The group pretreated with chloralose had significantly elevated heart rate (186 +/- 23 vs. 157 +/- 31 beats/min, p = 0.03), mean pulmonary arterial pressure (29 +/- 9 vs. 22 +/- 6 mm Hg, p = 0.03) and pulmonary vascular resistance (0.228 +/- 0.13 vs. 0.130 +/- 0.05 mm Hg/ml/kg/min, p = 0.05) after propranolol as compared to the conscious saline-treated group. We conclude that pretreatment with chloralose as an anesthetic agent may produce important pharmacologic interaction with subsequent adrenergic drugs in neonatal lambs. While anesthesia may be necessary in animal research, investigators should be aware that the anesthetic agent may also qualitatively and quantitatively influence measured outcome variables.

Systemic and pulmonary vascular effects of selective dopamine receptor blockade and stimulation in lambs.

Vascular dopamine (DA1) receptors may modulate circulatory hemodynamics in lambs. We evaluated resting dopaminergic tone in lambs by pharmacologically manipulating peripheral DA1 receptors with i.v. SCH 23390, (a highly selective, competitive DA1 receptor antagonist) and i.v. fenoldopam, (a highly selective DA1 receptor agonist) in unanesthetized lambs, instrumented for circulatory studies, while measuring the systemic and pulmonary vascular changes that the manipulations induced. We examined both the independent effects of DA1 receptor stimulation and blockade as well as the effects of the agonist and the antagonist infused together (competitive interaction). SCH 23390, infused at 2.5 micrograms/kg.min-1, caused significant increases in left atrial, systemic, and pulmonary artery pressure, as well as an increase in systemic vascular resistance and a decrease in heart rate. Fenoldopam, infused at the dose of 60 micrograms/kg.min-1 caused significant decreases in mean systemic artery pressure and systemic vascular resistance while increasing cardiac index and mean pulmonary artery pressure. SCH 23390 blunted the fenoldopam-induced effects. Our data suggest that dopaminergic influence may be active in the maintenance of resting hemodynamics of the lamb.

Manipulation of dopamine receptors alters hypoxic pulmonary vasoconstriction in isolated perfused rat lungs.

Using an isolated, perfused rat lung model, we examined the hypoxic pulmonary vasoconstriction (HPV). We studied the alterations in HPV induced by the selective DA1 receptor agonist, fenoldopam, the selective DA1 antagonist, SCH 23390, as well as a combination of these agents. Fenoldopam significantly attenuated HPV. SCH 23390 had no effect on HPV, but was ableto block the effect of fenoldopam. These data confirm the presence of vasodilatory DA1 receptors in the pulmonary vascular bed. The data further suggest that ongoing DA1 activity may be important in counterbalancing some pathologic pulmonary hypertensive states.

Pulmonary vascular reactivity of the newborn pony foal.

Adult ponies develop pulmonary hypertension at altitude (Bisgard, Orr and Will 1975), but the neonatal response to acute hypoxaemia is unknown. Seven foals aged five days were instrumented with a systemic and a Swan-Ganz pulmonary artery catheter while anesthetised and intubated. Cardiac index, pulmonary (PAP) and systemic (SAP) vascular pressures were measured as the foals breathed gas mixtures with FI02 of 8 to 94 per cent. Because foramen ovale or ductus arteriosus shunts might have altered thermodilution cardiac index measurements in the stressed foals, the ratio, PAP/SAP was calculated to define relative circulatory reactivity. Three foals, two of which were full siblings, had very marked elevation of PAP/SAP from 0.6 to 1.41 at low inspired oxygen tensions. Four different foals attained maximal PAP/SAP of only 0.2 to 0.92 at similarly low oxygen tensions (P less than 0.0001). Thus, pulmonary vascular reactivity to ventilatory hypoxaemia varied greatly in pony foals of the same age. The exaggerated reactivity in related foals suggested that, as in cattle, a genetic predisposition to develop reactive pulmonary hypertension under hypoxaemic stress may exist.

Ethanol induces acute pulmonary vasoconstriction in salt-perfused rat lungs.

Ethanol is a pulmonary vasoconstrictor in rat lungs perfused in situ with Krebs-Henseleit salt solution. Pentobarbital-anesthetized rats were tracheotomized, and an in situ recirculating isolated lung perfusion was instituted using a Krebs-Henseleit buffer with 3% bovine albumin at 37 degrees C. Changes in pulmonary arterial pressure and tracheal inspiratory pressure during intravenous ethanol infusion at four different cumulative doses were measured in normoxic (n = 6) and hyperoxic (n = 6) lungs, compared to normoxic perfusate (no ethanol infusion) controls (n = 6). Perfusate alcohol levels progressively increased in experimental groups. Perfusate gas and pH values were normal and not altered by ethanol. PAP increased by the end of ethanol infusion from 9.7 +/- 2 to 26 +/- 13 mm Hg in the normoxic group and from 10.6 to 22 +/- 9 mm Hg in the hyperoxic lungs (p less than .02); no change occurred in control lungs. Severe pulmonary edema occurred in 83% of the ethanol exposed lungs (vs. 0% of perfusate controls). Postethanol wet/dry weight ratios were twice normal (p less than .02). Pulmonary arterial pressure rose in two stages. First there was a 25-100% increase before airway pressure increased, representing pulmonary vasoconstriction. This was followed by a precipitous 100-500% transmitted pressure rise as severe pulmonary edema developed. Thus, we conclude that the vasoconstrictor effect of ethanol on the pulmonary circulation occurs in rats as well as in lambs, dogs, and humans. In isolated perfused rat lungs, the response is locally mediated.

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.

Cyclooxygenase blockers inhibit ethanol-induced pulmonary vasoconstriction in lambs.

We investigated the mechanism of ethanol-induced pulmonary vasoconstriction in lambs, by a pharmacological approach. We chronically instrumented 28 lambs to determine whether phentolamine (alpha-block), propranolol (beta-block), promethazine and cimetidine (H1- and H2-block), high-dose indomethacin, or low- and high-dose meclofenamate (cyclooxygenase block) altered the vasoconstriction. Ethanol alone increased pulmonary vascular resistance from 0.14 to 0.49 Torr.ml-1.kg-1.min (U). Only indomethacin (7-8 mg/kg po) and high-dose meclofenamate (7-8 mg/kg iv) abolished the pulmonary vascular response to ethanol infusion. Pulmonary vascular resistance was 0.14 U after ethanol plus indomethacin and was 0.2 U after ethanol plus high-dose meclofenamate (P = NS vs. base line). Low-dose meclofenamate (2 mg/kg) attenuated the vasoconstrictor response. Systemic vascular resistance increased moderately after ethanol and had a similar pattern of inhibition by cyclooxygenase blockade. Cardiac output and heart rate decreased nearly significantly after ethanol (P less than 0.06), a tendency that was also ablated by cyclooxygenase inhibition. Thus the acute cardiocirculatory response to ethanol involves an intact prostaglandin synthase system in lambs. To our knowledge, these data are the first documentation that cyclooxygenase enzyme blockade can eliminate the acute cardiac and vascular effects of ethanol in a whole-animal system.

Chloralose alters circulatory response to alpha-receptor stimulation and blockade.

Chloralose anesthesia is commonly used in animals for cardiovascular research despite limited data on possible receptor-drug interactions. To investigate potential interactions with alpha-adrenergic receptors, we studied the response of chronically instrumented, spontaneously breathing young lambs to alpha-receptor stimulation (by methoxamine) and blockade (by phentolamine) after infusion of 30 mg/kg of chloralose or an equal volume of vehicle. Both experiments were performed in each animal on different days and in alternate order. Chloralose altered the systemic arterial pressure and heart rate response to both alpha-agonist challenge and to alpha-blockade when compared with control. Despite potentiating the systemic arterial pressor response to methoxamine, chloralose attenuated the reflex decrease in heart rate after alpha-agonist-induced hypertension. This observation suggests that the baroreceptor reflex was blunted. Chloralose, commonly considered an ideal anesthetic for cardiovascular studies, may have important effects on the cardiovascular response to alpha-adrenergic test agents. The potential for interactive effects should be considered in experimental designs that couple the use of chloralose and alpha-adrenergic agents.

Effect of prazosin on the cardiopulmonary response to dopamine in awake lambs: comparison with phentolamine and tolazoline.

Combination vasodilator and cardiotonic therapy may help infants with pulmonary vasospasm and low cardiac output. We previously have shown that the alpha 1- and alpha 2- blocking agents tolazoline and phentolamine, plus dopamine, improved cardiac output relative to dopamine alone, without changing pulmonary vascular resistance. To similarly test an agent with selective alpha 1-receptor blocking action, prazosin, we instrumented 6 newborn lambs to measure the pressure in the pulmonary artery, aorta and left atrium and cardiac output. After recovery, the lambs were studied while awake and breathing room air. The response to dopamine, at doses of 2.7, 27 and 270 micrograms/kg/min, was measured alone, and again on a different day after prazosin (1 mg/kg). Dopamine alone raised systemic, pulmonary and left atrial pressure, and systemic vascular resistance at high doses. Pulmonary vascular resistance did not change. Prazosin prevented the dopamine-induced systemic resistance increase and permitted cardiac output to rise relative to dopamine alone (p less than 0.0125), but barely blunted the dopamine-induced pulmonary pressure increase (p less than 0.005 vs. base in both groups). These results are similar to those previously found with tolazoline and phentolamine. Thus, all the tested alpha-blockers facilitate the cardiotonic effect of dopamine, but none ablates its pulmonary pressure effect.

Pulmonary and systemic vascular response to promethazine in conscious lambs.

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.

Cardiac depressant and circulatory effects of prostaglandin D2 in developing lambs.

Pulmonary and systemic vascular and cardiac effects of intravenous prostaglandin D2 (PGD2), given at 0.1, 1.0, and 10 micrograms/kg, were measured in chronically instrumented lambs during normoxia and hypoxia at ages 2-3, 9-14, and greater than or equal to 21 days. During normoxia, PGD2 was not a pulmonary vasodilator at low dose and caused mild pulmonary vasoconstrictor changes at 10 micrograms/kg in young lambs; normoxic older lambs had pulmonary vasoconstriction at both 1 microgram/kg and 10 micrograms/kg doses. With hypoxemia, PGD2 caused mild pulmonary vasodilation at all doses in the youngest lambs, converted the normoxic 9-14-day-old lambs' pressor response to a nonresponse, and attenuated the high-dose pulmonary vasoconstriction in the greater than or equal to 21 day lambs. PGD2 was a directly dose-related systemic pressor (+5-20 mmHg) at all ages during both normoxia and hypoxia. Heart rate and cardiac output decreased in a dose-dependent fashion during both normoxia and hypoxia. The PGD2-induced cardiac depression was unaltered by age or ventilatory hypoxemia. PGD2 response of the lamb pulmonary circulation changes from marginal dilation to constriction during the late postnatal development. During the same period, PGD2 dose-related systemic pressor and cardiac depressant effects remain stable. Thus, the circulatory effects of PGD2 are complexly interrelated with age, dose, and presence of hypoxemia.

Follow-up evaluation of horses after neonatal intensive care.

A follow-up study was conducted on 131 foals that were less than 7 days old when admitted to the University of Florida Veterinary Medical Teaching Hospital between 1981 and 1983. Of the 71 foals (54%) that survived to be discharged, 39 (55%) were alive at follow-up evaluation, 19 (27%) could not be located, and 13 (18%) had died. The owners of surviving foals were sent questionnaires and 72% responded. The horses were visited and examined, if geographically possible, and an age-matched stablemate or a sibling also was evaluated and used as a control. Thirteen foals (10% of total admitted) died 1 day to 2 years after discharge. Four (8%) died from suspected sequelae of their neonatal illness. Three other foals appeared stunted as yearlings, but by 2 years of age equaled or passed their stablemates and/or siblings in physical development. The owners' estimated value of the survivors averaged +29,812. The actual selling price of horses that went through sales ranged from +7,000 to +210,000. Most of the horses became useful, athletic adults; several have won major stakes races. All living foals appeared unaffected by the physiologic disorders and treatments they encountered as neonates and compared favorably with stablemates and siblings.

Intensive care of the neonatal foal.

The basic concepts of diagnosis and treatment in the abnormal neonatal foal are presented. Methods of restraint, sedation, and general nursing care are discussed, as well as more specific techniques of respiratory and circulatory system support.