Robert B. Cotton

Randomized trial of early closure of symptomatic patent ductus arteriosus in small preterm infants.

As a result of randomized assignment, 15 preterm infants weighing 1,500 gm or less at birth and who had a symptomatic PDA were treated according to a medical management protocol, and ten according to an early surgical closure protocol. All infants required mechanical ventilation at the time of study entry, which was one week after birth. Birth weight, gestational age, age at onset of congestive failure, age at study entry, and the initial morbidity of members of the two groups were similar. The nine surviving infants managed according to the surgical closure protocol were weaned from mechanical ventilation sooner, had a decreased need for digoxin and furosemide, achieved gastrointestinal function sooner, and had a smaller hospital bill than the 12 survivors of the medical management group. These results indicate that infants with a symptomatic PDA still requiring mechanical ventilation at one week after birth will benefit from surgical closure of the ductus at that time.

A Controlled Trial of Synthetic Surfactant in Infants Weighing 1250 G or More with Respiratory Distress Syndrome

Background Surfactant-replacement therapy is now recognized as a life-saving and safe intervention in small premature infants, but there is little evidence concerning its risks and benefits in larger premature infants. Methods We conducted a placebo-controlled, blinded trial in 1237 infants with respiratory distress who were enrolled at 23 hospitals in the United States and 13 hospitals in Canada. At entry all the infants weighed at least 1250 g, were receiving mechanical ventilation, and had a ratio of arterial to alveolar oxygen tension below 0.22. The initial dose of either the synthetic surfactant (Exosurf, 5 ml per kilogram of body weight) or air (the placebo) was administered less than 24 hours after birth, with a second dose given 12 hours later. A total of 614 infants were assigned to receive surfactant, and 623 to receive placebo. Results Fewer infants in the surfactant group than in the placebo group died before 28 days of age or survived at 28 days with bronchopulmonary dysplasia (7 percent vs. 12 percent, P = 0.002). In the first 28 days of life, there were fewer deaths due to respiratory distress syndrome in the surfactant group (1 percent vs. 3 percent, P = 0.043), lower overall neonatal mortality (4 percent vs. 7 percent, P = 0.04), and a lower incidence of bronchopulmonary dysplasia (3 percent vs. 6 percent, P = 0.008). There was also a significantly lower incidence of pulmonary air leaks, intraventricular hemorrhage, patent ductus arteriosus, seizures, hypotension, and pulmonary hypertension in the surfactant group. The infants treated with surfactant were weaned from oxygen and mechanical ventilation significantly sooner than those given placebo, and they less often required high-frequency ventilation or extracorporeal membrane oxygenation. The primary side effect observed more frequently among the infants who received surfactant treatment was pulmonary hemorrhage (six infants vs. one infant, P = 0.055). Conclusions In infants weighing at least 1250 g at birth who have respiratory distress syndrome, treatment with two doses of synthetic surfactant improves survival and reduces perinatal morbidity.

Medical management of small preterm infants with symptomatic patient ductus arteriosus

During 1975, 38 of 44 infants with a birth weight of less than or equal to 1,500 gm who developed pulmonary edema and congestive heart failure due to a patent ductus arteriosus were managed medically until the ductus closed spontaneously days or weeks later. Overall survival was 71%, and there were no deaths among 11 infants weighing more than 1,250 gm. Pulmonary complications were prevalent and were attributed to the extensive use of mechanical ventilation required to control pulmonary edema. The results of this study document the results to be expected when small preterm infants with a symptomatic patent ductus arteriosus are managed without surgical or pharmacologic intervention and provide a basis for the rational design of clinical trials evaluating other management approaches.

Pharmacokinetics of Indomethacin in the Neonate: Relation of Plasma Indomethacin Levels to Response of the Ductus Arteriosus

To identify factors affecting the efficacy of indomethacin in closing symptomatic patent ductus arteriosus (PDA), we studied the pharmacokinetics of intravenous indomethacin, 0.2 mg per kilogram of body weight, in 35 premature infants with symptomatic PDA. Most infants responded to indomethacin with ductus constriction. Indomethacin infusions that were ineffective (seven doses in six patients) were associated with significantly faster clearance, a shorter half-life, and lower plasma levels (p less than 0.05). Six infants had later reopening of the ductus. All six received indomethacin in the first postnatal week; they could not be distinguished from infants with permanent closure on the basis of indomethacin kinetics, but they were of low gestational age. There was a 20-fold variation in plasma indomethacin levels 24 hours after a dose. In view of this variation and the relation between plasma levels and ductus constriction, we suggest that measurement of the plasma indomethacin level could be of value in infants with no response to a first dose.

Evidence from twin study implies possible genetic susceptibility to bronchopulmonary dysplasia

To investigate the possibility that susceptibility to bronchopulmonary dysplasia (BPD) is affected by genetic factors, we analyzed risk factors for BPD in 108 twin pairs of infants having birth weight < or = 1,500 g. When BPD occurred in a first born twin (n = 23), it also occurred in 65% (n = 15) of the second born twins, and when BPD did not occur in the first twin (n = 85), it only occurred in 8% (n = 7) of the second twins (crude odds ratio = 20.9). After adjusting for potentially significant risk factors including birth weight, gestational age, gender, diagnosis of hyaline membrane disease, pneumothorax, symptomatic patent ductus arteriosus, and year of admission, using multiple logistic regression on the entire database (1,872 admissions < or = 1,500 g), BPD status of a first twin remained a highly significant predictor of BPD in the second twin (adjusted odds ratio = 12.3, P < .001). Other factors including birth order of twins, twin gestation, inborn/outborn status, cesarean section delivery, 1- and 5-minute Apgar scores, maternal race, maternal diabetes, and antepartum corticosteroid treatment were not significant predictors of BPD. These results are consistent with genetic factors affecting the susceptibility of very low birth weight premature infants to BPD, but we cannot exclude the possibility that factors not included in our analysis are also involved.

The Physiologic Effects of Surfactant Treatment on Gas Exchange in Newborn Premature Infants with Hyaline Membrane Disease

ABSTRACT: To describe the physiologic effects of surfactant treatment on gas exchange in human premature infants with hyaline membrane disease, functional residual capacity (FRC), tidal volume (VT), the alveolar portion of tidal volume (VA), alveolar ventilation (VA), nitrogen clearance index, effective breath fraction calculated as VA/VT, compliance of the respiratory system, and arterial oxygen and carbon dioxide tensions were measured in 17 patients before and 0.5, 2, and 6 h after the administration of a single dose of either a synthetic surfactant (SS), Exosurf (n = 10), or a bovine surfactant (BS), Survanta (n = 7). By 2 h, treatment with either BS or SS was followed by an increase in the arterial/alveolar ratio of Po2 (a/A) and in FRC (p < 0.01 for both a/A and FRC). The a/A and FRC improved sooner (p < 0.001) and to a greater extent (p < 0.01) after BS than after SS. Compliance of the respiratory system and VT were decreased after either BS or SS at 0.5 h (p < 0.01) and remained decreased after SS at 2 h (p < 0.01). There was no significant change in VA or VA after either BS or SS. Because FRC and a/A increased without an accompanying increase in VA, VA, or compliance of the respiratory system, we believe that the immediate increase in FRC in this study was caused by stabilization of gas exchange units already being ventilated in addition to recruitment of new units. Nitrogen clearance index decreased and effective breath fraction increased after treatment, indicating an improved efficiency in gas mixing also thought to result from stabilization and maintenance of patency of distal airways by surfactant.

Prevention of symptomatic patent ductus arteriosus with a single dose of indomethacin

To determine the efficacy of indomethacin to prevent the occurrence of symptomatic patent ductus arteriosus (PDA), a randomized clinical trial was conducted involving 32 preterm infants weighing 750 to 1500 g at birth who had hyaline membrane disease. By random assignment, 15 infants were given a single dose of indomethacin, 0.2 mg/kg intravenously, 24 hours after birth. Seventeen infants composed a control group for which indomethacin was reserved as treatment for symptomatic PDA. Birth weight, gestational age, male/female ratio, black/white ratio, and severity of disease were similar for both groups. Only one of the 14 survivors who received prophylactic indomethacin had symptomatic PDA, compared with nine of the 16 survivors in the control group (P = 0.007). There was no difference between the groups in development of bronchopulmonary dysplasia, duration of time endotracheal intubation, was required, duration in oxygen, duration to reach full feedings and regain birth weight, and duration of hospital stay. There was no difference between the two groups in incidence of intraventricular hemorrhage, and none developed necrotizing enterocolitis. These results indicate that the use of prophylactic indomethacin is beneficial in prevention of symptomatic PDA; the lack of differences in pulmonary sequelae or other complications may have been related to a population sample size not large enough to impart sufficient statistical power.

Recurrence of symptomatic patent ductus arteriosus in extremely premature infants, treated with indomethacin

The administration of a single intravenous injection of indomethacin was followed by a major constrictive effect on the ductus in 36 of 42 very-low-birth-weight (less than or equal to 1000 gm) infants with symptomatic patent ductus arteriosus (PDA). In 26 of the 36 responders, the effect was sustained; symptomatic PDA recurred in the remaining 10. Infants who experienced a recurrence of symptomatic PDA had lower birth weights and had received indomethacin at an earlier postnatal age than did infants with a sustained effect. These results may be explained by differences in the production and clearance of prostaglandins or in the sensitivity of the ductus to prostaglandin effects between infants with a recurrence and infants with sustained constriction of PDA.

Nursery epidemic due to multiply-resistant Klebsiella pneumoniae: epidemiologic setting and impact on perinatal health care delivery.

Gram-negative bacilli frequently cause epidemics in high-risk newborn intensive care units. Recently, an epidemic caused by a multiply-resistant K. pneumoniae, serotype 21, occurred in the Vanderbilt University intensive care nursery. The background of this outbreak included an increasing endemic nosocomial sepsis rate, operation of the facility in excess of rated capacity, and increasingly inadequate nurse-to-patient staffing ratios. The epidemic lasted 11 weeks; 26 (12%) of the 232 infants at risk in the unit became colonized. Five infants developed systemic illness and one died. Cohorting, reinforcement of strict handwashing and isolation procedures, and closure of the unit to outborn admissions resulted in rapid termination of the outbreak. Followup studies performed on infants colonized with the epidemic bacterium demonstrated persistent fecal shedding up to 13 months following discharge from the hospital. This epidemic had a detrimental influence on high-risk newborn and obstetric health care delivery in an area encompassing portions of three states. Under a system of progressively more sophisticated referral units, nosocomial infections occurring at a tertiary center can have an impact on other hospitals within the network.

Early prediction of symptomatic patent ductus arteriosus from perinatal risk factors. A discriminant analysis model

ABSTRACT. Cotton, R. B., Lindstrom, D. P. and Stahlman, M. T. (Depaitment of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA). Early prediction of symptomatic patent ductus arteriosus from perinatal risk factors: a discriminant analysis model. Acta Paediatr Scand, 70:723,.–A scoring system based on discriminant analysis was devised to predict, within 24 hours after birth, whether or not a premature infant will subsequently develop a symptomatic PDA. Five risk factors including birth weight, the diagnosis of hyaline membrane disease, intrauterine growth retardation, acute perinatal stress, and treatment with distending airway pressure were reduced to a discriminant score which separated infants with symptomatic PDA from infants without sympomatic PDA. Based on this score, the likelihood that an individual infant would later develop symptomatic PDA could be expressed as a probability function. When applied prospectively, this score predicted the correct outcome of 80 % of infants in a test population. This predictive model should be useful in clinical trials and other applications requiring a quantitative expression of risk for developing symptomatic ductus shunting.