T. Bruce Ferrara

Survival and follow-up of infants born at 23 to 26 weeks of gestational age: Effects of surfactant therapy

Abstract Little information is available regarding the effect of surfactant on outcome for infants born at or before 26 weeks of gestation. We addressed this issue by reviewing records of 310 infants born at gestational ages of 23 through 26 weeks who were admitted to our nursery from 1986, when surfactant was introduced, through 1990. Surfactant was administered to 154 infants (5 during a single-dose prevention study, 25 during a multiple-dose prevention study, 124 while receiving a Food and Drug Administration treatment investigational new drug); 156 infants were not treated with surfactant. Seventy-three percent of the treated infants survived, compared with 55% of the nontreated infants. Increased survival occurred at all gestational ages between 23 and 26 weeks but were greatest in infants born at 23 and 24 weeks. At follow-up, no differences in neurologic outcome were detected between surfactant-treated and nontreated infants. We conclude that surfactant use in extremely premature infants improves survival rates without increasing the proportion of impaired survivors. (J P EDIATR 1994;124: 119-24)

Effects of exogenous surfactant therapy on dynamic compliance during mechanical breathing in preterm infants with hyaline membrane disease

In a prospective, randomized, controlled clinical trial, the immediate and the longitudinal effects of exogenous surfactant therapy on pulmonary mechanics were evaluated in extremely premature infants during mechanical respiration. Ninety-four infants weighing between 600 and 1250 gm received either exogenous surfactant or sham (air) therapy in the delivery room and up to three additional doses in the first 48 hours of life if they were ventilator-dependent, had fractional inspiratory oxygen requirements greater than or equal to 0.30, and radiographic findings consistent with hyaline membrane disease. Each infant underwent pulmonary mechanics assessment (dynamic compliance, total pulmonary resistance, tidal volume) immediately before and 1 hour after each dose, and at 24, 48, and 72 hours and 7 days of age. There were no significant differences in dynamic compliance, total pulmonary resistance, and tidal volume in the surfactant (n = 47) and control (n = 47) groups before and 1 hour after each dose. However, dynamic compliance was 50% greater in the surfactant group at 24 hours of age (p less than or equal to 0.009); this difference steadily increased to 94% at 7 days of age (p less than or equal to 0.009). Oxygenation, assessed by the ratio of alveolar to arterial oxygen pressure, was significantly greater in the surfactant group during the first 72 hours of life; the greatest difference was noted at 24 hours (p less than or equal to 0.001). Mean airway pressure requirements in the surfactant group were significantly less than in the control group at all times during the first week. We conclude that exogenous surfactant therapy, administered at birth and during the first 48 hours of life in extremely premature infants with hyaline membrane disease, improves dynamic compliance and gas exchange during mechanical breathing.

Effectiveness of dexamethasone in preventing extubation failure in preterm infants at increased risk for airway edema

We studied 50 preterm infants who had multiple or traumatic endotracheal intubations, or whose duration of endotracheal intubation was > or = to 14 days, and who were considered at high risk for airway edema. These infants were enrolled in a prospective, randomized, controlled clinical trial to assess whether prophylactic dexamethasone therapy would be effective in the prevention of postextubation stridor and respiratory distress. At study entry, both groups had similar weights, postnatal ages, methylxanthine use, ventilator settings, blood gas values, and pulmonary function test results (dynamic compliance, total respiratory resistance, tidal volume, peak-to-peak transpulmonary pressure, minute ventilation, and peak inspiratory and expiratory flow rates). Patients underwent blood gas studies, physical examinations, and pulmonary function testing at baseline (4 hours before extubation) and again 2 to 4 hours and 18 to 24 hours after extubation. Twenty-seven infants received dexamethasone, 0.25 mg/kg per dose, at baseline, and then every 8 hours for a total of three doses; 23 infants received saline solution at corresponding times. Eighteen to twenty-four hours after extubation, total pulmonary resistance increased by 225% from baseline in the control group compared with 33% in the dexamethasone group (p < 0.006), and the dexamethasone group had a greater tidal volume, a greater dynamic compliance, and a lower arterial carbon dioxide pressure. Of 23 control infants, 10 had postextubation stridor compared with 2 of 27 dexamethasone-treated patients (p < 0.006). Of the 23 control patients, 4 required reintubation compared with none of the treated group (p < 0.05). We conclude that the prophylactic use of corticosteroids for the prevention of postextubation stridor and respiratory distress is efficacious in low birth weight, high-risk preterm infants.

Prophylactic indomethacin therapy in the first twenty-four hours of life for the prevention of patent ductus arteriosus in preterm infants treated prophylactically with surfactant in the delivery room

OBJECTIVE To determine whether a course of low-dose indomethacin therapy, when initiated within 24 hours of birth, would decrease ductal shunting in premature infants who received prophylactic surfactant in the delivery room. DESIGN Ninety infants, with birth weights of 600 to 1250 gm, were entered into a prospective, randomized, controlled trial to receive either indomethacin, 0.1 mg/kg per dose, or placebo less than 24 hours and again every 24 hours for six doses. Echocardiography was performed on day 1 before treatment and on day 7, 24 hours after treatment. A hemodynamically significant patent ductus arteriosus (PDA) was confirmed with an out-of-study echocardiogram, and the nonresponders were treated with standard indomethacin or ligation. RESULTS Forty-three infants received indomethacin (birth weight, 915 +/- 209 gm; gestational age, 26.4 +/- 1.6 weeks; 25 boys), and 47 received placebo (birth weight, 879 +/- 202 gm; gestational age, 26.4 +/- 1.8 weeks; 22 boys) (P = not significant). Of 90 infants, 77 (86%) had a PDA by echocardiogram on the first day of life before study treatment; 84% of these PDAs were moderate or large in size in the indomethacin-treated group compared with 93% in the placebo group. Nine of forty indomethacin-treated infants (21%) were study-dose nonresponders compared with 22 (47%) of 47 placebo-treated infants (p < 0.018). There were no significant differences between both groups in any of the long-term outcome variables, including intraventricular hemorrhage, duration of oxygen therapy, endotracheal intubation, duration of stay in neonatal intensive care unit, time to regain birth weight or reach full caloric intake, incidence of bronchopulmonary dysplasia, and survival. No significant differences were noted in the incidence of oliguria, elevated plasma creatinine concentration, thrombocytopenia, pulmonary hemorrhage, or necrotizing enterocolitis. CONCLUSION The prophylactic use of low doses of indomethacin, when initiated in the first 24 hours of life in low birth weight infants who receive prophylactic surfactant in the delivery room, decreases the incidence of left-to-right shunting at the level of the ductus arteriosus.

Monoclonal antibody identification of a type II alveolar epithelial cell antigen and expression of the antigen during lung development

A monoclonal antibody identifying an antigen expressed by rat type II alveolar epithelial cells, but not by type I epithelial cells or other mature lung cells, was produced by immunization of mice with cells of the rat L2 cell line. The antigen recognized by the antibody was present on the microvillous luminal surface of type II epithelial cells. In adult rat lung, only type II epithelial cells bound the antibody. During fetal development the antigen was expressed by cuboidal epithelial cells lining the respiratory ducts of the first divisions of the tracheal bud, but not by epithelial cells lining the esophagus or trachea. The antigen continued to be expressed by cuboidal epithelial cells lining the larger respiratory ducts until approximately 19 days gestational age. Thereafter, expression was increasingly limited to selected single cells or clusters of two to four cuboidal cells in the smallest ducts. By the 21st postnatal day, the antigen was expressed only by type II alveolar epithelial cells. Type II alveolar epithelial cells isolated from adult lung and the L2 cell line in culture expressed the antigen on the cell surface. A protein of approximately 146,000 Mr was isolated by immunoadsorption of the antigen from non-ionic detergent extracts of type II cells and L2 cells. Preliminary studies of the binding of the antibody to other rat tissues indicate that the antibody binds to renal proximal tubular epithelial cells of the kidney and the luminal surface of the small bowel epithelial cells.

Effects of surfactant therapy on outcome of infants with birth weights of 600 to 750 grams

Replacement therapy with exogenous surfactant has been studied for both prevention and treatment of respiratory distress syndrome. Although reports demonstrate improved survival rates for surfactant-treated infants with RDS, the impact of this therapy on outcome of extremely low birth weight infants is unknown. TM Previous studies have not reported outcome after surfactant treatment for the subset of premature infants who are born at ELBWs and who are at the highest risk for complications of prematurity. We report the outcome of infants born with birth weights between 600 and 750 gm who underwent prospective random selection to receive either surfactant or placebo as part of a multidose prevention study.

Effects of surfactant therapy on outcome of extremely premature infants.

Limits of viability of extremely premature infants have recently been addressed both in Europe and the United States. These reports, which demonstrate frequent adverse outcome of infants born before 26 weeks of gestation, have not considered the impact of surfactant therapy. We reviewed records of 445 infants born between 23 and 36 weeks gestation who were admitted to our nursery following the availability of surfactant treatment in 1986 through 1992. Two hundred and eighty-five infants were treated with surfactant (Survanta, Ross Laboratories) as part of controlled, prospective trials or as routine treatment under Food and Drug Administration approval. One hundred and fifty-six infants were unable to be treated with surfactant, as either they received placebo therapy during prospective trials or were born prior to approval of routine surfactant use in the United States. Four additional infants born following the commercial availability of surfactant did not receive surfactant therapy. Survival of untreated infants was 56% compared to 75% in treated infants (P<0.001). Infants born at all gestational ages between 23 and 26 weeks had an increased likelihood of survival as a result of surfactant treatment. No differences in neurologic outcome between surfactant treated and non-treated infants were demonstrated at subsequent follow-up. We conclude that survival of extremely premature infants is improved following surfactant therapy and that subsequent neurologic outcome is not compromised as a result of this therapy.

Treatment of pulmonary manifestations of gastroesophageal reflux in children two years of age or less

Apnea and worsening bronchopulmonary dysplasia as well as recurrent aspiration pneumonia have been found to be consequences of gastroesophageal reflux in infants and young children. Antireflux procedures are effective in preventing gastroesophageal reflux; however, the effect of this operation on the course of these respiratory problems in very young patients is not known. We reviewed the results in 51 patients 2 years of age or less who underwent an antireflux fundoplication for pulmonary problems attributable to severe gastroesophageal reflux unresponsive to medical treatment. Twenty-eight patients had recurrent episodes of aspiration pneumonia, 14 had nonimproving or worsening bronchopulmonary dysplasia, and 9 had unexplained apneic episodes. Seventy-three percent of these patients had coexisting congenital anomalies or acquired problems. No operative deaths and no major surgical complications occurred. There were eight late deaths occurring between 1 and 25 months postoperatively: three were due to associated congenital anomalies or acquired problems, three to sepsis, and two to sudden infant death syndrome. Of the 43 surviving children, 91 percent with preoperative recurrent aspiration pneumonia had no additional episodes after Nissen procedure. Eighty-eight percent of the infants with unexplained apneic episodes showed marked benefit and 83 percent of those with bronchopulmonary dysplasia had clinical improvement. There were no late problems attributed to the operation even when it was performed in preterm infants. Therefore, we recommend fundoplication for patients 2 years of age or less who have a persistent pulmonary problem attributed to gastroesophageal reflux that does not respond to medical therapy.

Prophylactic furosemide in severe respiratory distress syndrome: Blinded prospective study

To further characterize the place for furosemide in the treatment of newborn infants with respiratory distress syndrome requiring mechanical ventilation, we conducted a blinded, prospective study comparing early prophylactic use (1 mg/kg every 12 hours for four doses beginning at 24 hours of age) with prn use of this drug. Prophylactic administration of furosemide produced no beneficial effect on any measure of pulmonary function compared with use of this drug as needed (prn). However, patients receiving the prophylactic furosemide regimen were found to have more rapid postnatal weight loss, higher pulse rate, and greater sympathomimetic drug requirement during the period of diuretic administration. Patients in the prophylactic group did not demonstrate the moderate expansion in plasma volume between 48 and 96 hours of age seen in the control group. These data suggest that the prophylactic regimen produced an undesirable degree of volume depletion. Further studies should be conducted to develop objective criteria for the selection of the subgroup of patients with respiratory distress syndrome who may benefit from furosemide.

Maternal Phenylketonuria-Chronology of the Detrimental Effects on Embryogenesis and Fetal Development: Pathological Report, Survey, Clinical Application

Maternal phenylketonuria (PKU) is likely to have detrimental effects on embryogenesis and fetal development. Manifestations in the offspring include spontaneous abortion, various congenital malformations, intrauterine growth retardation, and microcephaly. The time at which the metabolic abnormalities induce pathologic embryogenesis can be documented by knowing the time of the development of specifically damaged organ systems. This review reveals that, while the most recognized congenital malformations occur in the heart, the most common abnormality is growth inhibition occurring throughout pregnancy. The organ system most commonly affected by this growth inhibition is the brain, resulting in a high incidence of micrencephaly. It appears that maternal phenylketonuria interferes with appropriate fetal growth and that this effect occurs during the entire course of pregnancy and has no tissue specificity. This information can be both informative to pathologists and useful to clinicians.