Avi Rotschild

Increased compliance in response to salbutamol in premature infants with developing bronchopulmonary dysplasia

We compared the effect of salbutamol and placebo in a double-blind study of preterm infants with bronchopulmonary dysplasia, using a randomized, crossover design with several replicates per subject. Sixty-two tests were performed on 20 ventilator-dependent infants weighing less than 1500 gm. Patients were entered as early as the first week of life and studied for at least 4 weeks or until extubation. Each subject was his own control subject and was randomly assigned to a placebo-salbutamol or salbutamol-placebo sequence administered on 2 consecutive days of each week. Static compliance, expiratory resistance of the respiratory system, and changes in transcutaneous oxygen and carbon dioxide tension were measured. Static compliance improved by 0.240 ml/cm H2O/kg (35.3%) after salbutamol and by 0.010 ml/cm H2O/kg (2.8%) after placebo (p less than 0.0001). The presence of a predetermined decrease in carbon dioxide tension correlated with large changes in static compliance per kilogram and with the need for a high level of fractional inspired oxygen. The magnitude of the clinical and physiologic improvement observed, and the early response suggest that long-term bronchodilator therapy starting as early as the second week of life may be beneficial for very low birth weight infants with early bronchopulmonary dysplasia.

Randomized, double-blind, controlled trial of long-term diuretic therapy for bronchopulmonary dysplasia.

The effects of continuous therapy with hydrochlorothiazide and spironolactone on pulmonary function in 34 premature infants with severe bronchopulmonary dysplasia were assessed in a randomized double-blind controlled trial. Subjects were greater than or equal to 30 days old, were supported by mechanical ventilation in greater than or equal to 30% oxygen, and had radiographic evidence of bronchopulmonary dysplasia. The treatment group (n = 19) and the placebo group (n = 15) were similar in all respects except for distribution of gender. Anthropometrics, ventilatory measurements, and the results of pulmonary function tests were evaluated at study entry and at 1, 4, and 8 weeks into therapy. Poststudy chest radiographs were compared with those obtained before the study. The proportion of infants alive at discharge was significantly increased (84%) in the treatment group compared with the placebo group (47%) (p = 0.05). There were no statistically significant differences in total hospital days or in total ventilator days. Total respiratory system compliance at 4 weeks was higher in the treatment group (0.61 +/- 0.18) than in the placebo group (0.45 +/- 0.13) (p = 0.016). No difference in outcome was detected between male and female infants in the treatment group. These results suggest that long-term diuretic therapy improves outcome in infants with bronchopulmonary dysplasia.

Biochemical, clinical, and morphologic studies on lungs of infants with bronchopulmonary dysplasia

We correlated clinical, biochemical, and morphologic findings in the lungs of 48 infants dying of either bronchopulmonary dysplasia (BPD) or hyaline membrane disease (HMD) to obtain a better idea of the disease process. The infants ranged from 24 weeks of gestation to 1½ postnatal years. The lungs of BPD and HMD infants had higher contents of DNA, alkali‐soluble protein, hydroxyproline, and desmosine, as well as increased concentrations of DNA, hydroxyproline, and desmosine when compared with the lungs of 72 control infants. BPD was classified histologically into 4 groups: Group I was a phase of acute lung injury; Group II the proliferative phase; Group III the phase of early repair; and Group IV the phase of late repair. We saw a significant increase in hydroxyproline concentration in Groups II and III. The ratio of type VIII collagen decreased in BPD Groups II to IV. Desmosine was significantly higher only in Group III than in controls. When the pathological classification was related to biochemical and clinical features of BPD, the classification showed dependence on the number of days the infant survived postnatally and not on the gestational age of the infant. The number of days on assisted ventilation was a slightly better predictor of the disease classification than days on > 60% oxygen. A statistical model correctly predicted the pathologic classification 83% of the time. Pediatr Pulmonol. 1996; 22:215–229.

Effect of triamcinolone acetonide on the development of the pulmonary airways in the fetal rat

Triamcinolone acetonide (TAC) has a potent teratogenic effect on various mammalian fetal tissues as well as a steroid effect on the lung. Less well documented is the fact that it produces profound oligohydramnios. We wished to determine what effect TAC would have on branching morphogenesis and other aspects of lung development, using an in vivo model described previously. Thirty rats were randomized to receive 0.6 mg/kg of TAC or saline on days 12, 13, and 14 of gestation. At gestational days 15, 17, 18, and 21, the left lungs of 365 fetuses were studied by dissecting microscopy, histology, and morphometry. TAC produced profound pulmonary hypoplasia (dry lung weight/body weight 0.025, compared with 0.06 in controls) on day 21. TAC decreased maternal weight gain, fetal weight, placental weight, amniotic fluid, and pole to pole length (PTP), while it increased the peripheral airway count (PAC). The number of central and intermediate airway branches was reduced, and they were dilated. Growth of peripheral airways was enhanced. In treated fetuses epithelial cells lining these airspaces were histologically more mature and the mesenchyme thinner than in controls. These findings were confirmed by the morphometric measurements. We conclude that when TAC is administered in the early phase of fetal rat lung development, the lungs become hypoplastic, with hypoplasia of the intermediate airways, an increase in the number of peripheral airways, and increased differentiation. We speculate that these effects are primarily due to the steroid action of TAC and that the mechanisms of monopodial branching are different from those of dichotomous branching. Pediatr Pulmonol. 1997; 23:76–86.

Development of the pulmonary airways in the fetal rat and its relation to the prenatal environment

We studied the left lung using multi‐focus microphotography in 378 rat fetuses, assessing airway branching from day 13 to day 19 of gestation, and lung growth variables from day 13 to day 21. Longitudinal growth, and monopodial and dichotomous branching brought about a consistent airway pattern with variations within each day of gestation and a small overlap between adjacent days. Amniotic fluid weight and pole to pole (PTP) distance of the lung increased quadratically with age, while fetal weight and the peripheral airway count (PAC) increased exponentially. The location of the fetus within the uterus had no effect no fetal variables, but correlations were found between maternal weight gain and both fetal weight and PTP. Fetal weight was the best predictor of PAC from gestational ages 15 to 19 days (P < 0.008). The method described allows for observations that are reproducible within the environmental variations present in normal gestation and can be used to study the effect of external factors on lung development. Pediatr Pulmonol. 1996; 21:219–226.

BECKWITH WIEDEMANN SYNDROME PRESENTING IN PREMATURE INFANTS

Beckwith-Wiedemann syndrome (BWS) is characterized in most reported cases by the triad of Exomphalous, Macroglossia and Gigantism (EMG syndrome). However, these major manifestations probably represent the extremes of this syndrome while cases with minor or time-dependent manifestations are usually not published. We present the variable expressions of BWS syndrome in 3 preterm infants.The first had 75th percentile measurements at her birth (32 weeks) with macroglossia, large fontanel, ear creases and omphalocele. At corrected age of 7 months she was diagnosed to have hepatoblastoma.The second had 60-75th percentile measurements at her 28 week birth. Dysmorphia was not noted at birth or during life. At corrected age of 2-1/2 months, she developed signs of puberty, and at 4 months, hepatomegaly. The liver histologically showed extensive hepatoblastoma. At autopsy adrenal cytomegaly, pancreatic islet cell hyperplasia and umbilical hernia were also noted to be present.The third had 97% weight, 75% height and 30% OFC at his 32 week birth. No anomalies were present at birth. Four weeks after birth he developed an umbilical hernia, facial coarsening and macroglossia (causing difficulty in breathing and feeding) but no visceromegaly. By the age of 3 months, the clinical presentation was highly suggestive of BWS. Extensive investigation failed to show any metabolic or endocrine abnormality.