Effect of pulse dexamethasone therapy on the incidence and severity of chronic lung disease in the very low birth weight infant.

We conducted a prospective, randomized, double-blind trial to assess the efficacy and safety of pulse doses of dexamethasone on survival without supplemental oxygen in very low birth weight infants at high risk of having chronic lung disease. Seventy-eight infants with birth weights < or = 1500 gm who were ventilator dependent at 7 days of postnatal age were randomly assigned to receive pulse doses of dexamethasone, 0.5 mg/kg per day, divided twice daily (n = 39), or an equivalent volume of saline solution placebo (n = 39), for 3 days at 10-day intervals until they no longer required supplemental oxygen or assisted ventilation, or reached 36 weeks of postmenstrual age. At study entry, the groups did not differ by birth weight, gestational age, or severity of lung disease. At 36 weeks of postmenstrual age, there was both a significant increase in survival rates without oxygen supplementation (p = 0.03) and a significant decrease in the incidence of chronic lung disease (p = 0.047) in the group that received pulse therapy. Supplemental oxygen requirements were less throughout the study period in the group that received repeated pulse doses of dexamethasone (p = 0.013). The total numbers of deaths and the durations of supplemental oxygen, ventilator support, and hospital stay did not differ between groups. Recorded side effects in the pulse therapy group were minimal and included an increase in the use of insulin therapy for hyperglycemia (p < 0.05). We conclude that in this population of very low birth weight infants, treatment with pulse doses of dexamethasone resulted in improvement in pulmonary outcome without clinically significant side effects.

One-year follow-up of 273 infants with birth weights of 700 to 1100 grams after prophylactic treatment of respiratory distress syndrome with synthetic surfactant or air placebo. American Exosurf Neonatal Study Group I.

A single dose of synthetic surfactant was administered prophylactically to premature neonates with birth weights between 700 and 1100 gm. The effects of this treatment on neurodevelopmental, neurologic, and ophthalmologic outcomes, impairments, and general health status were examined during a follow-up evaluation at 1-year adjusted age. The study was a multicenter, parallel, randomized, double-blind comparison of 446 infants who received either air placebo (n = 222) or synthetic surfactant (n = 224). Follow-up evaluations were completed for 82% of surviving infants in both treatment groups. Neurodevelopmental outcome and growth were equivalent in the infants treated with synthetic surfactant and in the infants given air placebo. Impairments occurred in 38% of the infants treated with air placebo compared with 31% of those given synthetic surfactant; the difference was not statistically significant (relative risk 0.809, 95% confidence interval 0.585, 1.119). The incidence of asthma was significantly higher in the group of infants given air placebo (4% vs 10% for surfactant and air placebo, respectively, relative risk 0.391, 95% confidence intervals 0.157, 0.972). Other outcomes, including retinopathy of prematurity, hospital readmissions, surgery, and evidence of chronic lung disease, were not different. Administration of a single prophylactic dose of synthetic surfactant increases survival in infants with birth weights between 700 and 110 gm without increasing the number or proportion of impaired survivors.

Synthetic surfactant for rescue treatment of respiratory distress syndrome in premature infants weighing from 700 to 1350 grams: impact on hospital resource use and charges.

To determine the impact of the use of synthetic surfactant on hospital resource use and charges, we analyzed the economic data from a multicenter, randomized, placebo-controlled clinical trial of synthetic surfactant in infants with neonatal respiratory distress syndrome and birth weights between 700 and 1350 gm. Two 5 ml/kg doses of a synthetic surfactant (Exosurf Neonatal) or air placebo were administered to 419 infants who were receiving mechanical ventilation and had an arterial/alveolar oxygen tension ratio < 0.22. In addition to the clinical endpoints for safety and efficacy, data were collected on length of hospital stay, days in the neonatal intensive care unit, days of mechanical ventilation, days of oxygen supplementation, and hospital charges until the infant reached 1 year adjusted age. Growth and development of infants who received synthetic surfactant therapy in the study and survived to 1 year adjusted age were equivalent to those of the survivors in the air placebo group. For 1-year survivors, synthetic surfactant reduced the average length of stay at the different levels of care needed during the hospitalization such as neonatal intensive care unit days, days of mechanical ventilation, and days of oxygen supplementation. For nonsurvivors, synthetic surfactant increased the average length of stay, especially at more intense levels of care. Total hospital charges for the initial hospitalization and through 1 year adjusted age for a hypothetic cohort of 100 infants treated with synthetic surfactant were, on average, the same as those for a comparable cohort of infants in the air placebo group. These results indicate that rescue therapy with synthetic surfactant in infants with respiratory distress syndrome and birth weights from 700 to 1350 gm can result in significantly improved survival without significant increases in hospital charges.

Effects of two rescue doses of a synthetic surfactant on mortality rate and survival without bronchopulmonary dysplasia in 700- to 1350-gram infants with respiratory distress syndrome. The American Exosurf Neonatal Study Group I.

In a multicenter, double-blind, placebo-controlled rescue trial conducted at 21 American hospitals, two 5 ml/kg doses of a synthetic surfactant (Exosurf Neonatal) or air were administered to 419 infants weighing 700 to 1350 gm who had respiratory distress syndrome and an arterial/alveolar oxygen pressure ratio less than 0.22. The first dose was given between 2 and 24 hours of age; the second dose was given 12 hours later to those infants remaining on ventilatory support. Infants were stratified at entry by birth weight and gender. Among infants receiving synthetic surfactant, improvements in alveolar-arterial oxygen pressure gradient, arterial/alveolar oxygen pressure ratio, and oxygen and ventilator needs through 7 days of age were apparent. Death from respiratory distress syndrome was reduced by two thirds (21 vs 7; p = 0.007), and the overall neonatal mortality rate was reduced by half (50 vs 23; p = 0.001). Although there was no significant reduction in the incidence of bronchopulmonary dysplasia (39 vs 31; p = 0.107), the hypothesis that survival through 28 days without bronchopulmonary dysplasia would be enhanced by two rescue doses of synthetic surfactant was proved true (21% improvement, from 132 to 156 patients; p = 0.001). In addition, the incidence of pneumothorax was reduced by one third (62 vs 40; p = 0.022), and the incidence of pulmonary interstitial emphysema was reduced by half (102 vs 51; p = 0.001). The only side effect identified was an increase in the incidence of apnea (102 vs 134; p = 0.001). These findings indicate that rescue use of a synthetic surfactant can improve the morbidity and mortality rates for premature infants with respiratory distress syndrome.

Influence of gestational age on pharmacokinetics of alfentanil in neonates.

Alfentanil's small volume of distribution and short elimination half-life, coupled with its preservation of hemodynamic stability, make it a potentially useful drug for analgesia and anesthesia in neonates. The pharmacokinetics of alfentanil were studied in 5 infants born at 26-35 weeks' gestation and in 5 infants of greater than 36 weeks. All infants were studied in the first 3 days of life. After injection of 25 micrograms/kg alfentanil, there was no significant change in blood pressure or heart rate. No significant difference was observed in volume of distribution (0.84 +/- 0.48 l/kg vs. 0.82 +/- 0.30 l/kg), clearance (1.35 +/- 0.69 ml.kg-1.min-1 vs. 1.7 +/- 0.47 ml.kg-1.min-1), or effective half-life (455 +/- 111 min vs. 328 +/- 48 min) between the two groups. The pharmacokinetic values reported here for both preterm and full-term infants are significantly different from data reported for older children.

The activity pattern of phrenic motoneurons during the aspiration reflex: an intracellular study.

Membrane potential trajectories and discharge characteristics were measured intracellularly in 29 phrenic motoneurons of anesthesized, paralyzed and artificially ventilated cats during hypercapnic respiration and the aspiration reflex. Fifteen 'active' cells discharged spontaneously during inspiration, and the remaining 14 'quiescent' cells exhibited no discharge in spite of strong central respiratory drive. The mean membrane potential of the quiescent cells during inspiration (-62 +/- 4 mV) was significantly lower than the threshold level determined for the active cells -52 +/- 4 mV). The mean axonal conduction velocity was slower for the active (60.4 +/- 8.7 m/s) than quiescent cells (67.4 +/- 6.9 m/s). All phrenic motoneurons discharged during the aspiration reflex with maximum instantaneous frequencies ranging from 6 to 357 Hz. No differences were found for the maximum discharge frequency during the reflex between the active and quiescent cells. Although there were differences in the slopes of the depolarization during inspiration between the groups of cells, no such difference existed in the slopes during the aspiration reflex. The threshold level for the first spike during the reflex was the same as that during inspiration but the level for successive spikes became progressively less negative while spike amplitude decreased and duration increased. Stimulation of the nasopharynx to elicit the aspiration reflex was found to alter the timing of the subsequent respiratory cycles.

The postnatal growth of motoneurons at three levels of the cat neuraxis.

The postnatal growth of motoneuron cell bodies located in the brainstem, cervical and lumbosacral spinal cord was investigated using retrograde transport of horseradish peroxidase in kittens ages 2, 12, 30, 55, 82 and 114 postnatal days and in an adult. The motoneurons innervating an extrinsic tongue muscle, the genioglossus, reached their adult size by eight weeks after birth. In contrast, the phrenic motoneurons innervating the diaphragm achieved adult size by 12 weeks and the motoneurons innervating the medial gastrocnemius muscle continued to grow beyond the twelfth postnatal week. The sizes of these motoneurons relative to one another remained constant during periods of development.

Pharmacokinetics of alfentanil in newborn premature infants and older children.

Because developmental pharmacokinetics appear to be closely associated with anatomic and physiologic changes that occur with growth, we were interested in determining the disposition and elimination of alfentanil in premature infants and older children. The pharmacokinetic profile of alfentanil was determined in 6 premature infants requiring sedation for medical management or analgesia for stressful intensive-care procedures. These pharmacokinetic profiles were compared with pharmacokinetic profiles determined in 9 older infants and children undergoing operative procedures that required invasive monitoring. In both groups the plasma decay curves best fit a 2-compartment model. Compared with older children, premature infants demonstrated a significantly larger apparent volume of distribution (1.0 +/- 0.39 vs. 0.48 +/- 0.19 l/kg), a smaller clearance (2.2 +/- 2.4 vs. 5.6 +/- 2.4 ml/kg/min) and a markedly prolonged elimination half-life (525 +/- 305 vs. 60 +/- 11 min).

Urine screening for metabolic disease in newborn infants.

A new method for urine screening for metabolic disease in newborn infants is described. A battery of bacterial inhibition assays to test urine-impregnated filter paper from 3- to 4-week-old infants for amino acids, purines, and pyrimidines was used. We were able to establish the accuracy and efficiency of the method by examining 289 unknown specimens from other laboratories and by collecting and testing 18,400 newborn infants' urine specimens. The major advantages over existing chromatography methods are that: (1) the technology to perform the test already exists in most laboratories screening for metabolic disorders; (2) it is relatively inexpensive; (3) collection of the sample is easy and cooperation of the parents is good; (4) the false positive rate is low (0.9%); and (5) tests can be targeted to detect clinically significant disorders. In this screening program, we detected two cases of persistent neonatal tyrosinemia, two cases of cystinuria, and one case of citrullinemia. These results suggest that urine screening is a good adjunct to blood screening of newborn infants.