Theodore R. Thompson

Controlled trial of dexamethasone therapy in infants with bronchopulmonary dysplasia.

Dexamethasone was compared with placebo in a double-blind, crossover, randomised study of infants with severe bronchopulmonary dysplasia who had required mechanical ventilation for at least four weeks, despite treatment with diuretics, methylxanthines, bronchodilators, fluid restriction, nutritional supplementation, and ligation of the patent ductus arteriosus when indicated. Gestational age ranged from 27 to 33 weeks and birth weight from 800 to 1730 g. Patients received dexamethasone (0 . 5 mg/kg/day) or normal saline for the first 3 days, then treatment was crossed over for the next 3 days. The study was terminated when sequential analysis showed that all six patients had improved during dexamethasone therapy. Significant improvements were seen in ventilator-determined respiratory rate, peak inspiratory pressure, fractional inspired oxygen concentration, and alveolar arterial oxygen gradients (p less than 0 . 05). Although dexamethasone hastened weaning from mechanical ventilation, infection occurred in a substantial proportion of patients.

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

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.

Pulmonary Neuroendocrine Cells in Hyaline Membrane Disease and Bronchopulmonary Dysplasia

Summary: The number and distribution of bombesin immunoreactive pulmonary neuroendocrine cells (PNEC) in fetuses and infants up to 6 months of age was determined on postmortem lung specimens. Individual cells and clusters of cells (neuroepithelial bodies) were found in airways of all sizes, although greater than 95% of the positive cells were located in bronchioles, terminal bronchioles, and respiratory bronchioles. These infants were separated into two groups. In control infants, who died primarily from noncardiopulmonary causes, bombsin immunoreactive neuroendocrine cells were identified throughout the latter half of gestation. As gestation advanced, progressively more positive bronchioles/cm2 of lung tissue and cells/bronchiole were identified. In these control infants, the number of positive bronchioles/cm2 and cells/bronchiole were at the highest level at or near the time of delivery and then gradually declined throughout the first 6 months of life. In contrast, infants who died of acute hyaline membrane disease (1–7 days of life) or bronchiopulmonary dysplasia (2 wk to 6 months of life) demonstrated marked differences in the number of identifiable bombesin immunoreactive neuroendocrine cells when compared to control infants. In early hyaline membrane disease, the number of positive bronchioles/cm2 and cells/bronchiole was markedly decreased. During the transition to chronic bronchopulmonary dysplasia, there appeared to be a marked increase in the number of bombesin immunoreactive cells. The peak number of cells occurred at 2–3 months of life, when substantially more bombesin-immunoreactive cells could be identified in children with bronchopulmonary dysplasia than control infants of similar age.Speculation: This study demonstrates that a specific pulmonary cell type containing bioactive molecules undergoes marked changes during acute and chronic neonatal lung disease. Anatomic and physiologic evidence suggests that these cells may be in an ideal position to exert control on pulmonary vessel and airway tone either at the local level or throughout the entire lung through vascular and neural connections. These data do not prove that alterations in this cell population are the cause of changes noted in airway and in vascular resistance in infants with lung disease. They do identify, however, a new area of potential investigation in these disease states.

Furosemide Promotes Patent Ductus Arteriosus in Premature Infants with the Respiratory-Distress Syndrome

Furosemide stimulates the renal synthesis of prostaglandin E2, a potent dilator of the ductus arteriosus. We administered this drug to 33 premature infants with the respiratory-distress syndrome, to determine whether it increased the incidence of patent ductus arteriosus. Chlorothiazide, a diuretic that does not stimulate prostaglandin E synthesis, was used as the control drug in 33 other infants. During the study, the incidence of patent ductus arteriosus was significantly higher (P less than 0.02) in the furosemide group (18 of 33 infants) than in the chlorothiazide group (8 of 33). Eleven infants in the furosemide group and seven in the chlorothiazide group required ductal ligation (P greater than 0.2). An additional six infants (all from the furosemide group) who did not have evidence of a patent ductus during the study were later found to have one. Overall survival was 76 and 61 per cent in the furosemide and chlorothiazide groups, respectively (P greater than 0.2). Small (less than twofold) increases in the urinary excretion of prostaglandin E were seen after the initial dose of both drugs. When the analysis was repeated after the fifth day of life, prostaglandin E excretion tripled after furosemide administration, whereas no increase occurred with chlorothiazide. We conclude that furosemide increases the incidence of patent ductus arteriosus in premature infants with the respiratory-distress syndrome, probably through a prostaglandin-mediated process.

The management of life-threatening hyperammonemia: A comparison of several therapeutic modalities

THE DEVASTATING central nervous @stem effects of marked hyperammonemia are most clearly evident in congenital defects in the activity of each of the five urea cycle enzymes, the most common of which is ornithine transcarbamylase deficiency? Recent advances in the dietary management of patients with these hyperammonemic syndromes have been demonstrated to prolong or preserve life. 2 Further, temporary hyperammonemia has been described in premature infants? Thus treatment of life-threatening hyperammonemia is important since efficient removal of ammonia in a crisis situation, coupled with steps taken to control NH3 reaccumulation, may be life saving. Recently Donn et aP demonstrated the advantages of hemodialysis over exchange transfusion and peritoneal dialysis in the removal of ammonia from a neonate with OCT deficiency. A newborn infant with extreme hyperammonemia due to this enzyme defect provided us the opportunity to compare the relative effectiveness of these treatments, charcoal hemoperfusion, and resin hemoperfusion as means of NH~ removal.

Transesophageal Study of Infant Supraventricular Tachycardia: Electrophysiologic Characteristics

Programmed electrical stimulation of the heart to initiate and terminate tachycardia and analysis of the temporal relation between ventricular and atrial activation during tachycardia have been useful in the evaluation of supraventricular tachycardia (SVT). Such techniques have rarely been applied to evaluate infants with SVT. We used a silicone rubber-coated bipolar electrode catheter (15 or 22 mm interelectrode spacing), positioned in the esophagus, for electrical stimulation of the heart and recording of electrograms for the evaluation of 14 infants aged 1 to 84 days with SVT. Three infants had electrocardiographic features of Wolff-Parkinson-White syndrome, and no infant had other manifestations of congenital heart disease. Tachycardia cycle lengths ranged from 180 to 295 ms and ventriculoatrial intervals recorded from the esophagus were 80 to 220 ms. In 12 infants, transesophageal atrial stimulation was used to terminate and initiate SVT using stimuli of 9.9 ms and 10 to 20 mA. Initiation and termination of SVT by electrical stimulation suggest that SVT in infants is due to reentry, and the presence of ventriculoatrial intervals greater than 70 ms further suggests that accessory atrioventricular connections (usually concealed) constitute a portion of the reentry circuit.

Correlation of clinical and pathologic findings in early onset neonatal group B streptococcal infection with disease severity and prediction of outcome

This study analyzed the clinical characteristics of 69 neonates who were admitted to the University of Minnesota Hospital between January, 1972, and June, 1984, with early onset Group B streptococcal infection (EOGBS) and determined those features associated with fatal infection. The incidence of EOGBS was 1.6 cases/1000 live births among 7960 inborn infants; the mortality rate for inborn and outborn infants was 28%. Multivariate analysis identified five features adequately predicting fatal outcome: birth weight less than 2500 g, absolute neutrophil count less than 1500 cells/mm3, hypotension, apnea and a pleural effusion on the initial chest radiographs. With these five variables and an initial blood pH less than 7.25, a clinical score was constructed that correctly predicted outcome in 93% of patients in this study (87% sensitivity, 95% specificity). Autopsy findings in 16 of 19 infants with fatal EOGBS suggested that surfactant deficiency respiratory distress syndrome was common in preterm infants with EOGBS and contributed to their higher mortality compared with term infants.

Efficacy and neurologic outcome of profound hypocapneic alkalosis for the treatment of persistent pulmonary hypertension in infancy

Twenty-three newborn infants with severe bilateral pulmonary disease and persistent pulmonary hypertension received mechanical ventilation to pH greater than 7.55 and PaCO2 less than 25 torr. Response, as defined by attainment of a PaO2 greater than 100 torr, occurred in 87% of patients. Analysis of sequential arterial pH determinations revealed a linear increase in the number of infants responding as arterial pH increased. However, individual patients varied greatly in the optimal pH necessary to correct hypoxemia (range pH 7.50 to 7.75). Sixteen patients who had received mechanical hyperventilation were observed for 11.1 +/- 2.3 months. Virtually all had normal growth and development on follow-up physical and neurologic examinations, often despite profound or prolonged alkalosis and hypocarbia. In 11 infants at a corrected gestational age of 1 year, Bayley Scales of Infant Development revealed normal mental developmental indices (mean 106.2 +/- 15.4) and normal, but significantly lower, psychomotor developmental indices (93.2 +/- 11.7) (P less than 0.005). Although response and short-term outcome of neonatal hyperventilation appear favorable, this technique should be reserved for critically ill infants, because its long-term effects on the central nervous system are unknown.

Effect of postnatal steroid administration on serum vitamin A concentrations in newborn infants with respiratory compromise

Antenatal administration of glucocorticoids accelerates the fetal maturation of the lung, liver, and gastrointestinal tract. ~-3 w e previously demonstrated a significant elevation of.serum retinol, retinol-binding protein, and transthyretin concentrations in the cord blood of newborn infants whose mothers received betamethasone antenatally. 4 It was unclear from that study, however, whether this represented an effect primarily on the mother, the placenta, or the fetus. Mammel et al. 5 and others 6 demonstrated that postnatal steroid administration decreases alveolar-arterial oxygen gradients and improves lung mechanics in bronchopulmonary dysplasia, The mechanism of action remains unknown. Vitamin A has also been implicated in the prevention and treatment of bronchopulmonary dysplasia by promoting normal lung development and healing. 78 On the basis of these studies, we investigated the effect of postnatal dexamethasone administration on the vitamin A status of 13 infants who were treated with steroids because of significant respiratory compromise.

Warburg syndrome: Lethal neurodysplasia with autosomal recessive inheritance

Warburg syndrome is a recently recognized autosomal recessive neurodysplasia characterized by ventricular dilation, agyria, disorganized cortical cytoarchitecture, and dysgenesis of multiple other central nervous system structures. Because the disorder is lethal, with a 25% recurrence risk, it is crucial to distinguish Warburg syndrome from nonheritable phenocopies (caused by infectious agents and other teratogens) as well as from genetic disorders with a better prognosis. The clinical presentation of a markedly depressed newborn infant with hydrocephalus or ocular anomalies should suggest the diagnosis; computed tomography may be useful to demonstrate agyria as well as ventricular dilation. However, the distinctive neuropathologic finding of absent cerebral cortical lamination associated with numerous heterotopias appears to be diagnostic. Thus brain biopsy should be considered, especially at the time of ventricular shunting, whenever the clinical presentation suggests Warburg syndrome.