Double-blind evaluation of developmental and health status to age 2 years of infants weighing 700 to 1350 grams treated prophylactically at birth with a single dose of synthetic surfactant or air placebo.

In a previously published article, we reported results of a two-center study of outcome to 28 days of 385 infants with birth weights from 700 to 1350 gm who were assigned randomly to receive a single 5 ml/kg intratracheal dose of either synthetic surfactant or air placebo. Infants treated with surfactant had a higher rate of survival to 28 days without bronchopulmonary dysplasia than did control subjects given an air placebo. The present study assessed survivors in early childhood to determine neurodevelopmental outcome and late morbidity. Two hundred fifty-eight surviving infants from both centers were evaluated at 1-year adjusted age; medical histories were obtained, standard physical and neurologic examinations were performed, and Bayley Scales of Infant Development were administered. Ophthalmologic examinations were performed at various times between 28 days and 1-year adjusted age. At 2-years adjusted age, 118 infants from one center were reevaluated with the same procedures and also had hearing and speech evaluations. Neither the 1-year assessment of the entire population nor the 2-year assessment of the one center's cohort revealed physical or neurodevelopmental differences between treatment groups. We conclude that administration of a single prophylactic dose of synthetic surfactant to premature infants with birth weights from 700 to 1350 grams results in improved survival rates to 28 days without bronchopulmonary dysplasia and is not associated with adverse health or neurodevelopmental effects at 1-year or 2-years adjusted age.

Reduced mortality in small premature infants treated at birth with a single dose of synthetic surfactant.

A randomized controlled trial of Exosurf Neonatal, a synthetic exogenous surfactant, was performed. Exosurf was given to premature infants weighing 700-1350 g, by instillation down the endotracheal tube during mechanical ventilation, within 1 h of birth. Control infants were treated with air. Dose administration was performed in secrecy by clinicians who maintained the blind for 2 years. A total of 109 infants received air and 109 received Exosurf; 19 infants with congenital pneumonia or major malformations were excluded from the primary efficacy analysis. By the age of 28 days there were 14 deaths in the air group and 4 deaths in the Exosurf group, a 69% reduction with Exosurf (P = 0.020). Survival without bronchopulmonary dysplasia at the age of 28 days was significantly improved by 15% (P = 0.050). By the age of 1 year post-term there were 19 deaths in the air group and 10 deaths in the Exosurf group, a 42% reduction with Exosurf (P = 0.104). There were no significant changes in the incidence of bronchopulmonary dysplasia, pulmonary air leaks, intraventricular haemorrhage, patent ductus arteriosus, necrotizing enterocolitis or infection. The reduction in mortality indicates important results in high risk premature infants treated soon after birth with a single dose of Exosurf.

Multicenter trial of single-dose modified bovine surfactant extract (Survanta) for prevention of respiratory distress syndrome. Ross Collaborative Surfactant Prevention Study Group.

A multicenter, prospective randomized controlled trial was performed comparing the efficacy of a single intratracheal dose of modified bovine surfactant extract (Survanta, 100 mg/kg, Abbott Laboratory, North Chicago, IL) with air placebo in preventing respiratory distress syndrome. Infants were enrolled if they were estimated to be between 24 and 30 weeks' gestation, weighed between 750 and 1250 g, and were intubated and stabilized within 15 minutes after birth. A total of 160 infants were treated (79 with surfactant, 81 with air placebo) between 4 and 37 minutes after birth (median time 12 minutes). Of these, 5 infants were excluded from the final analysis. The 72-hour average values for the arterial-alveolar oxygen ratio, fraction of inspired oxygen, and mean airway pressure were calculated from the area under the curve of scheduled values measured throughout 72 hours. Clinical status was classified using five ordered categories (no supplemental oxygen or assisted ventilation, supplemental oxygen only, continuous positive airway pressure or assisted ventilation with intermittent mandatory ventilation less than or equal to 6 breaths/min, assisted ventilation with intermittent mandatory ventilation greater than 6 breaths/min, death). Chest radiographs at 24 hours were graded for severity of respiratory distress syndrome. Infants receiving Survanta had less severe radiographic changes at 24 hours of age and decreased average fraction of inspired oxygen (31% vs 42%, P = .002) compared with control infants. No differences were noted in the average arterial-alveolar oxygen ratio, mean airway pressure, or clinical status on days 7 and 28. A beneficial effect was noted in the incidence of pneumothorax (P = .057) and an increase was noted in the incidence of necrotizing enterocolitis (P = .052). No differences in incidence of patent ductus arteriosus, intraventricular hemorrhage, sepsis, or bronchopulmonary dysplasia were seen. According to results of a secondary analysis, there was improvement in the fraction of inspired oxygen and a greater number of survivors without bronchopulmonary dysplasia in the subgroup of infants weighing less than 1000 g who were treated with surfactant. It was concluded that a single dose of Survanta given shortly after birth resulted in decreased severity of chest radiographic findings 24 hours after treatment and improved oxygenation during 72 hours after treatment, but did not improve other acute measures of disease severity or clinical status later in the neonatal period. The group at highest risk for respiratory distress syndrome (infants with birth weights between 750 and 999 g) may benefit the most from preventive therapy.

Inhibition by colchicine of phospholipid secretion induced by lung distension.

The effect of colchicine, a microtubule disruptor, on phospholipid secretion stimulated by distension of fetal rabbit lungs was investigated. After colchicine injection and breathing for 45 min, pups were killed and their lungs were lavaged with colchicine. Controls were injected and lavaged with saline. All lungs were given static air inflation and a final lavage, and the returns were analyzed for phospholipid DNA, and lactate dehydrogenase. The first lavage after breathing yielded 33% less phospholipid with colchicine, 3.83 compared with 5.72 mg/g dry lung wt (P less than 0.05). The postinflation phospholipid yield was also significantly reduced with colchicine from 1.04 to 0.70 mg/g dry lung wt (P less than 0.05). The postinflation DNA was significantly reduced with colchicine, from 1.26 to 0.44 micrograms (P less than 0.01), suggesting reduced alveolar macrophages. Colchicine did not change the recovery by lavage of exogenous radioactive phospholipid. As reflected by ATP and lactate levels, tissue metabolism was well maintained. The results are interpreted to mean that colchicine reduced simultaneously lavage-associated phospholipid secretion, inflation-produced phospholipid secretion, and macrophage migration.

Optimal constant positive airway pressure assessed by arterial alveolar difference for CO2 in hyaline membrane disease.

In a group of infants with hyaline membrane disease, the level of optimal constant positive airway pressure (CPAP) was assessed by raising CPAP in small steps from an initial low value, and after each change measuring the arterial alveolar difference for CO2 (aADCO2) and transmission of airway pressure to the esophagus. Below optimal CPAP there was a progressive increase in mixed alveolar partial pressure of CO2 (PACO2) and no change in arterial partial pressure of CO2 (PaCO2), so that aADCO2 declined and reached a lowest value at optimal CPAP. Correspondingly, transmission of airway pressure increased progressively and reached a highest value at optimal CPAP. Between 1 step below and optimal CPAP, PACO2 rose from 30.9 to 34.0 torr, and aADCO2 declined from 16.6 to 12.7 torr. Between optimal and 1 step above optimal CPAP, PaCO2 increased from 46.7 to 51.0 torr, PACO2 rose slightly, and aADCO2 increased from 12.7 to 15.6 torr. Thus, the aADCO2 was an excellent index of optimal CPAP. In five patients with measurements of PaO2 at constant fractional inspired oxygen, calculated values for arterial oxygen saturation changed from 80.8 to 91.5 to 92.2%, and calculated values for venous admixture changed from 0.61 to 0.48 to 0.46 as CPAP was raised from 1 step below through optimal to 1 step above optimal CPAP. The results are interpreted to mean a progressive improvement in perfusion of well ventilated lung units as CPAP increased to optimal levels, but a significant reduction of both ventilation and perfusion above optimal CPAP.(ABSTRACT TRUNCATED AT 250 WORDS)

Development of beta-adrenergic control of phospholipid secretion in rabbit lung.

Lung distension is associated with increased phospholipid secretion into the air spaces. Basal, lavage-induced, and inflation-produced phospholipid secretion, in postmortem in situ lungs of newborn rabbits, were examined at three different levels of maturity, with and without 10(-3) M dl-propranolol. Lungs were lavaged with saline at successive 3- and 15-min time intervals to separate basal from lavage-induced secretion. Inflation-produced secretion was studied after static inflation at 30 cmH2O for 30 min. At 27.5 days gestation, basal secretion was undetectable, and neither lavage-induced nor inflation-produced secretion were influenced by propranolol. At 29.5 days gestation, basal secretion was only just detectable. Distension-associated secretion was increased over that present at 27.5 days gestation, and propranolol had a significant inhibitory effect, especially on lavage-induced secretion, in which the inhibition was shown to be rapidly reversible. There was a significant increase of basal secretion at 2.5 days postterm, possibly inhibited by propranolol. In addition, there was a further substantial increase of distension-associated secretion, and the inhibitory effect of propranolol persisted. These changes were independent of the sedimentation behavior of lavaged phospholipid. Overall, the results are consistent with evidence, produced in other laboratories, that there is an increasing density of sympathetic neurons and beta-adrenergic receptors in whole lung preparations during late gestation in the rabbit and suggest that granular pneumocytes, the presumed source of secreted phospholipid, take part in this developmental change.

Assessment of ventilation-perfusion inequality by aADN2 in newborn infants.

The contribution (Qo/Qt) of gas-filled air spaces with reduced ventilation-perfusion ratio (VA/Qc) to the production of total venous admixture in nondistressed premature infant and newborn infants with transient tachypnea was assessed by the aADN2 and AaDo2. The mean value for Qo/Qt in both nondistressed prematures and infants with transient tachypnea was 0.08. In both groups this represented about 30% of total venous admixutre.

Hypercarbia at birth: a possible role in the pathogenesis of intraventricular hemorrhage.

To test the hypothesis that birth asphyxia has a role in the etiology of intraventricular hemorrhage (IVH), blood was collected from the umbilical artery (UA) at birth in 28 premature infants of 26 to 29 weeks gestation and analyzed for hydrogen ion concentration [H+], PCO2, standard bicarbonate level, and lactic acid level. The infants were followed up throughout their nursery stay until a diagnosis of IVH could be made or excluded, either by autopsy or clinical findings. Infants with IVH had lower Apgar scores. There were no differences in UA [H+] or bicarbonate or lactic acid levels. However, infants with IVH had a significantly higher UA PCO2. Although the difference appeared relatively small, the increase in PCO2 during labor may have been relatively large. It is concluded that hypercarbia, possibly by increasing cerebral blood flow, may be one important factor in the genesis of IVH.

Effect of aminophyllin and dexamethasone on secretion of pulmonary surfactant in fetal rabbits.

Aminophyllin, dexamethasone, or saline was injected into 27.5-day fetal rabbits 2.5 hr before sacrifice, after which static pressure-volume curves with air were performed. In further similar experiments the lungs were lavaged with physiologic saline which was analysed for total phospholipid content. There were no changes in total lung capacity (TLC) induced with either aminophyllin or dexamethasone. The lungs of fetal rabbits injected with saline retained 44% TLC (+/-3 SE) after deflation to 10 cm H2O trans-pulmonary pressure compared with 48% TLC (+/-3 SE) in those injected with dexamethasone, a difference which was not statistically significant. In contrast, the lungs of fetal rabbits injected with aminophyllin retained 53% TLC (+/-2 SE) after deflation to 10 cm H2O pressure, a significant increase when compared with saline controls (P less than 0.01). There were no changes in lung weight or lung water. These results were interpreted to mean that aminophyllin decreased surface tension and augmented secretion of pulmonary surfactant. This was supported by finding significantly increased total phospholipid recovered in the lung lavage fluid of fetal rabbits injected with aminophyllin, 62 microgram/g dry lung weight (+/-6 SE) compared with 32 microgram/g dry lung weight (+/-3 SE) in saline controls (P less than 0.05). Phospholipid recovered from dexamethasone-injected fetal rabbits was not significantly increased, 38 microgram/g dry lung weight (+/-4 SE).

Role of autonomic nervous system controlling surface tension in fetal rabbit lungs.

After the maternal abdomen was opened under methoxyflurane anesthesia, fetal rabbits of 27.5 days gestation were given injections through the intact uterine wall of saline, pilocarpine, isoxsuprine, muscarine, phenylephrine, atropine, phenoxybenzamine, or propranolo, alone or in appropriate combinations. Fetal rabbits were delivered by hysterotomy and killed without breathing 2.5 h later. Static pressure-volume curves with air showed improved retention on deflation in fetal rabbits that had injections of pilocarpine, or isoxsuprine, but not of muscarine or phenylephrine. The effect of pilocarpine on the pressure-volume curve was blocked by atropine, phenoxybenzamine, and propranolol, and the effect of isoxsuprine was blocked by propranolol but not phenoxybenzamine. The data suggest that pilocarpine produces secretion of surfactant into lung air spaces by exciting the sympathetic nervous system, a known function of pilocarpine, rather than the parasympathetic nervous system. This may result in stimulation of the same beta-adrenergic receptors affected by isoxsuprine which is also thought to stimulate surfactant secretion.

Hyaline membrane disease and acidosis at birth in twins.

To test the hypothesis that the increased incidence of hyaline membrane disease in second-born twins is related to acidosis at birth, umbilical arterial [H+] was measured in 26 sets of premature twins. Although overall Twin B had a lower Apgar score than Twin A, there was no difference in their [H+]. If the delivery interval was prolonged over 8 minutes then Twin B infants were more acidemic and had lower Apgar scores. Infants with hyaline membrane disease had lower Apgar scores, but were not more acidemic than infants without respiratory distress. Our data suggest that acidosis at birth is not an important factor in the development of hyaline membrane disease.

Controlled trial of bicarbonate therapy in high-risk premature newborn infants.

Sixty-two high-risk acidemic premature newborn infants, given maintenance intravascular infusions of 10% glucose, were assigned to liberal or restricted sodium bicarbonate treatment groups. Those infants in the liberal group received 5 to 15 mEq bicarbonate/dl 10% glucose, depending on the degree of acidosis. Among infants given bicarbonate, correction of pH was not more rapid and mortality was not decreased. Instead, there was a small increase in the number of deaths, but the incidence of intraventricular hemorrhage was similar to that in infants not given bicarbonate.

The foam stability test on gastric aspirate in the prediction of respiratory distress syndrome.

To evaluate the usefulness of the foam stability test (FST) on gastric aspirate for predicting respiratory distress syndrome (RDS) in premature infants, samples were collected at delivery or within 30 min from 194 infants less than or equal to 36 weeks gestation. Of 123 samples adequate for complete testing, 44 were positive at 1 : 2 dilution, 43 were positive only at dilutions less than 1 : 2 and 36 were negative at all dilutions. RDS was found in 2%, 21% and 25% of each group respectively. The FST on gastric aspirate at birth gives useful information only if positive at 1 : 2 when a very low incidence of RDS may be expected. However, a large proportion of infants with FST negative at 1 : 1 do not develop RDS, and hence the test is of limited value in screening for those with highest risk.

Postnatal head shrinkage in small infants.

The front-occipital circumference, frontooccipital and biparietal diameters, degree of suture overriding and weight were measured daily during the first week of life in 50 infants of birth weight under 2,000 gm. In a second similar group of 21 infants, fronto-occipital circumference, weight, and sodium balance were measured daily during the first week of life. Head volumes were estimated from the circumference and diameters of the head. The parameters of head size and derived volumes changed maximally and significantly in the direction of intracranial shrinkage around 3 days of age. The degree of shrinkage was significantly correlated (P less than .005) with the degree of weight and cumulative sodium losses, and decreasing gestational age. We postulate that postnatal head shrinkage results from shift of sodium and water outward from the intracranial cavity as a transient phenomenon during the first week of life. The significance of head shrinkage is discussed.

Right-sided diaphragmatic hernia of delayed onset in the newborn infant.

Postnatal herniation of abdominal contents through a defect in the right leaf of the diaphragm is often difficult to diagnose. Two cases of this condition are presented and the use of pneumoperitoneum in assisting with the diagnosis is discussed.

The role of acidosis at birth in the development of hyaline membrane disease.

To test the hypothesis that intarpartum acidosis has a role in the etiology of hyaline membrane disease (HMD), blood was collected from the umbilical artery (UA) at birth from 110 premature infants and analyzed for hydrogen ion concentration ([H+]), PCO2, standard bicarbonate, and lactic acid. The infants were followed until a definite diagnosis was made of HMD (33 infants), type II respiratory distress syndrome (16 infants) or the absence of respiratory distress (61 infants). In general, infants with HMD were more premature and had lower Apgar scores than nondistressed infants; however, there were no significant differences between the two groups in any acid-base measurement. Only in those patients of 32 to 37 weeks' gestational age was it possible to detect a significant increase in UA [H+] in infants with HMD compared to those without respiratory distress. There was evidence that the reduced Apgar score of infants with HMD may be due to immaturity and abnormal pulmonary function secondary to lung disease. It is concluded that acidosis at birth is not a factor in the development of HMD except possibly in more mature infants.