Eduardo Bancalari

Changing trends in the epidemiology and pathogenesis of neonatal chronic lung disease

OBJECTIVE To assess the role of specific risk factors that may predispose preterm infants with mild or no initial respiratory distress syndrome to the development of chronic lung disease (CLD). STUDY DESIGN Clinical data were collected prospectively from 119 ventilator-supported preterm infants with birth weights between 500 and 1000 gm, who survived more than 28 days and required fewer than 3 days of treatment with fraction of inspired oxygen > 25% during the first 5 days of life. Logistic regression analysis was used in a multivariate assessment of risk factors for CLD. RESULTS Chronic lung disease occurred in 44 of the patients (37%). The analysis showed that low birth weight, patent ductus arteriosus (PDA), and sepsis were significant risk factors for CLD. The corresponding odds ratios for CLD and their 95% confidence intervals (CI) were as follows: 2.9 per 100 gm birth weight decrement (CI, 1.7 to 4.8); 6.2 (CI, 2.1 to 18.4) for PDA; and 4.4 (CI, 1.3 to 14.5) for sepsis. When sepsis and PDA occurred simultaneously, the odds ratio for CLD increased to 48.3 (CI, 6.3 to > 100) in comparison with infants without these conditions. Episodes of PDA were categorized as either early (occurring during the first week of life) or late (after the first week), and the respective odds ratios for CLD were 2.8 (CI, 0.8 to 9.4) and 21.1 (CI, 5.6 to 80) in comparison with infants without PDA. For the duration of symptomatic PDA, the odds ratio for CLD was 3.5 per week that the PDA remained open (CI, 1.9 to 6.5). CONCLUSION CLD is a frequent sequela in very low birth weight infants with mild or no respiratory distress syndrome. In this population, the development of late episodes of PDA, usually in association with a nosocomial infection, seems to play a primary role in the pathogenesis of CLD.

Bronchopulmonary dysplasia: clinical presentation.

THE INTRODUCTION of mechanical ventilation in the management of the newborn with respiratory failure has improved the survival of these patients, but it has also increased the incidence of complications associated with this mode of treatment. One of these complications is bronchopulmonary dysplasia, a residual chronic lung disease first described by Northway, R0san, and Porter in 1967.1 Numerous reports have been published subsequently on the subject, but little progress has been made to determine the exact incidence, the pathogenesis, or the best management of this condition.

Bronchopulmonary dysplasia: changes in pathogenesis, epidemiology and definition.

Bronchopulmonary dysplasia (BPD) continues to be one of the most common long-term complications associated with preterm birth. Its incidence is increasing as the survival of extreme premature infants improves, but its clinical presentation is milder than the original description of Northway and collaborators. In contrast to the classic BPD that was strongly related to mechanical injury and oxygen toxicity, current forms of the condition are more related to immaturity, perinatal infection and inflammation, persistent ductus arteriosus and disrupted alveolar and capillary development. Many different definitions of BPD have been proposed, most of which are based on the duration of supplemental oxygen requirement. The different definitions can produce strikingly different incidence figures, which may account for the wide variations in the condition reported in the literature. Some of the limitations of the criteria most commonly used to diagnose BPD are discussed in this article.

Influence of infection on patent ductus arteriosus and chronic lung disease in premature infants weighing 1000 grams or less

OBJECTIVES To test the hypotheses that (1) infection increases ductal dilatory prostaglandins and inflammatory mediators that may influence the closure of a patent ductus arteriosus (PDA), increasing the incidence of late episodes of PDA (after 7 days) and the rate of closure failures, and (2) the concurrence of PDA and infection increases the risk of chronic lung disease (CLD). METHODS One hundred fourteen premature infants (birth weight, 500 to 1000 gm) were prospectively assessed for PDA and infection. Serum levels of 6-ketoprostaglandin F1 alpha and tumor necrosis factor alpha were measured routinely in all infants and when PDA or infection was present. Multivariate assessment of risk factors for PDA closure failure and for CLD was done by logistic regression, and expressed as an odds ratio and as 95% confidence intervals. RESULTS Late PDA episodes were more frequent in infants with infection than in those without infection. A temporally related infection (<5 days between both diagnoses) was associated with an increased risk of PDA closure failure (odds ratio, 19.1 (confidence interval, 4 to 90)). In addition to birth weight and the severity of initial respiratory failure, PDA and infection increased the risk of CLD (odds ratio, 11.7 (confidence interval, 1.7 to 81) for PDA; odds ration, 3.1 (confidence interval, 1 to 11) for infection). Furthermore, when both factors were temporally related, they further increased the risk of CLD (odds ratio, 29.6 (confidence interval, 4.5 to >100)). Infants with infection and those with PDA had higher levels of 6-ketoprostaglandin F1 alpha than did control subjects. Levels of tumor necrosis factor alpha were also elevated in infants with infection and in those with late PDA. CONCLUSIONS Infection adversely influences PDA outcome by increasing the risk of late ductal reopening and PDA closure failures. Increased levels of prostaglandins and tumor necrosis factor alpha in infants with infection may explain the poor PDA outcome. The concurrence of PDA and infection potentiates their negative effects on the risk of CLD.

Serial determination of pulmonary function in infants with chronic lung disease

Pulmonary function was measured in 39 infants with chronic lung disease who had required mechanical ventilation starting during the first week of life for a median of 9 days (range 1 to 46 days) and supplemental oxygen for a median of 48 days (range 28-162 days). Their mean birth weight was 1140 g (range 550 to 2325 g), and mean gestational age 29.8 weeks (range 26 to 37 weeks). Ventilation was measured by pneumotachography, esophageal pressure through a water-filled feeding tube, and functional residual capacity (FRC) by a modified nitrogen washout technique. Lung compliance, pulmonary conductance, and FRC were determined at 1, 3, 6, 12, 18, 24, and 36 months after birth. Pulmonary function was also determined in 40 normal children, ranging in age from neonates to 5 years, who served as controls. In infants with chronic lung disease, growth in weight and length followed the 10th to 25th percentiles of the normal curve. Minute ventilation and respiratory effort remained elevated throughout the follow-up. FRC per kilogram of body weight was decreased at 1, 3, and 6 months after birth, but thereafter was in the normal range. FRC increased in proportion to weight at the same rate as in the controls. Lung compliance was only half of normal at 1 month, increased with growth in close correlation with weight, and was approximately 80% of normal at the end of follow-up. Pulmonary conductance was 50% of normal at 1 month, increased little during the first 6 months, but reached 85% of normal at 3 years of age. There was no evidence of gas trapping. These results indicate that in infants with chronic lung disease after mechanical ventilation, lung volume increases normally, probably by formation of new alveoli, which also leads to improvement in lung compliance. Airway growth is slow during the first 6 months after birth, but the subsequent faster growth leads to conductance values close to normal at 3 years of age.

A Multicenter, Randomized, Masked, Comparison Trial of Lucinactant, Colfosceril Palmitate, and Beractant for the Prevention of Respiratory Distress Syndrome Among Very Preterm Infants

Background and Objective. Evidence suggests that synthetic surfactants consisting solely of phospholipids can be improved through the addition of peptides, such as sinapultide, that mimic the action of human surfactant protein-B (SP-B). A synthetic surfactant containing a mimic of SP-B may also reduce the potential risks associated with the use of animal-derived products. Our objective was to compare the efficacy and safety of a novel synthetic surfactant containing a functional SP-B mimic (lucinactant; Discovery Laboratories, Doylestown, PA) with those of a non–protein-containing synthetic surfactant (colfosceril palmitate; GlaxoSmithKline, Brentford, United Kingdom) and a bovine-derived surfactant (beractant; Abbott Laboratories, Abbott Park, IL) in the prevention of neonatal respiratory distress syndrome (RDS) and RDS-related death. Methods. We assigned randomly (double-masked) 1294 very preterm infants, weighing 600 to 1250 g and of ≤32 weeks gestational age, to receive colfosceril palmitate (n = 509), lucinactant (n = 527), or beractant (n = 258) within 20 to 30 minutes after birth. Primary outcome measures were the rates of RDS at 24 hours and the rates of death related to RDS during the first 14 days after birth. All-cause mortality rates, bronchopulmonary dysplasia (BPD) rates, and rates of other complications of prematurity were prespecified secondary outcomes. Primary outcomes, air leaks, and causes of death were assigned by an independent, masked, adjudication committee with prespecified definitions. The study was monitored by an independent data safety monitoring board. Results. Lucinactant reduced significantly the incidence of RDS at 24 hours, compared with colfosceril (39.1% vs 47.2%; odds ratio [OR]: 0.68; 95% confidence interval [CI]: 0.52–0.89). There was no significant difference in comparison with beractant (33.3%). However, lucinactant reduced significantly RDS-related mortality rates by 14 days of life, compared with both colfosceril (4.7% vs 9.4%; OR: 0.43; 95% CI: 0.25–0.73) and beractant (10.5%; OR: 0.35; 95% CI: 0.18–0.66). In addition, BPD at 36 weeks postmenstrual age was significantly less common with lucinactant than with colfosceril (40.2% vs 45.0%; OR: 0.75; 95% CI: 0.56–0.99), and the all-cause mortality rate at 36 weeks postmenstrual age was lower with lucinactant than with beractant (21% vs 26%; OR: 0.67; 95% CI: 0.45–1.00). Conclusions. Lucinactant is a more effective surfactant preparation than colfosceril palmitate for the prevention of RDS. In addition, lucinactant reduces the incidence of BPD, compared with colfosceril palmitate, and decreases RDS-related mortality rates, compared with beractant. Therefore, we conclude that lucinactant, the first of a new class of surfactants containing a functional protein analog of SP-B, is an effective therapeutic option for preterm infants at risk for RDS.

Chestwall compliance in full-term and premature infants.

Abstract. Gerhardt, T. and Bancalari, E. (Department of Pediatrics, University of Miami, Florida, U.S.A.) Chestwall compliance in full‐term and premature infants. Acta Pediatr Scand, 69: 359, 1980.—Chestwall compliance was determined in 26 premature infants (BW 1 320±410 g, gest. age 32 weeks) and in 10 full‐term infants (BW 3 155±810 g) who were ventilated mechanically. Chestwall compliance in premature infants was 6.4 ml/ (cmH2O×kg), decreasing with advancing gestational age to 4.2 ml/(cmH2O×kg) in full‐term infants. There was a linear correlation (r= 0.95 and 0.79 respectively) between tidal volume and the pressure transmitted to the esophagus throughout the tidal volume range. The portion of airway pressure transmitted to the esophagus depended on the infants lung compliance. Only 5% was transmitted in infants with hyaline membrane disease, 12% in newborns with a patent ductus arteriosus, 17 % in normal prematures and 25% in normal full‐term infants. The findings suggest that during mechanical ventilation the high chestwall compliance and low lung compliance of premature infants prevent a significant rise in intrapleural pressure which could interfere with central venous return and cardiac output. However, using high inspiratory pressures and continuous distending airway pressure in the absence of lung pathology may result in a decreased cardiac output. The highly compliant chestwall of the premature infant may exert insufficient outward recoil and might be one of the causes of a low functional residual capacity and chronic pulmonary failure in the premature infant.

Necrotizing Enterocolitis in Full-Term or Near-Term Infants: Risk Factors

A retrospective case-control study of necrotizing enterocolitis (NEC) affecting infants weighing > 2,000 g at birth was performed to determine those factors which could contribute to the development of NEC. Twenty-four infants met the criteria of definite NEC. For each case the next 2 healthy newborns were matched as controls. When compared with the control group, NEC infants had a significantly higher frequency of prolonged rupture of membranes, chorioamnionitis, Apgar score < 7 at 1 and 5 min, respiratory problems, congenital heart disease, hypoglycemia, and exchange transfusions. Only 3 infants with NEC were healthy newborns with an unremarkable perinatal course before NEC. There were no differences in the frequency of preeclampsia, maternal diabetes, maternal drug abuse, meconium-stained amniotic fluid and polycythemia. These results indicate that most of these more mature infants have a predisposing factor before developing NEC.

Proportional assist ventilation in low birth weight infants with acute respiratory disease: A comparison to assist/control and conventional mechanical ventilation ☆ ☆☆ ★

OBJECTIVES To compare the physiologic efficacy and safety aspects of proportional assist (PA), assist/control (A/C), and intermittent mandatory ventilation (IMV) in very low birth weight infants with acute respiratory illness and to test the hypothesis that ventilatory pressure requirements are lower and arterial oxygenation is improved during PA when compared with IMV or A/C at an equivalent inspired oxygen fraction. STUDY DESIGN Randomized, 3-period, crossover design. METHODS Thirty-six infants were stratified by birth weight (600 to 750, 751 to 900, and 901 to 1200 g) and exposed to consecutive 45-minute epochs of the 3 modalities in a sequence chosen at random. Tidal volumes of 4 to 6 mL/kg were targeted during A/C and IMV. The IMV rate was matched to the rate during an A/C test period. PA was adjusted to unload the resistance of the endotracheal tube and the disease-related increase in lung elastic recoil. RESULTS Compared with A/C and IMV, PA maintained similar arterial oxygenation with lower airway and transpulmonary pressures (15% to 44% reduction depending on the index variable). The oxygenation index decreased by 28% during PA. No adverse events were observed. The number and severity of apneic episodes and periods of arterial oxygen desaturations were similar with the 3 modes. Similar results were obtained within each birth weight subgroup. CONCLUSIONS PA safely maintains gas exchange with smaller transpulmonary pressure changes compared with A/C and IMV. It may therefore offer a way of reducing the incidence of chronic lung disease in low birth weight infants.

Effect of early initiation of intravenous lipid administration on the incidence and severity of chronic lung disease in premature infants

OBJECTIVE To investigate whether intravenous administration of lipid nutrition (Intralipid) within 12 hours of birth to ventilator-dependent premature infants would decrease the incidence or severity, or both, of chronic lung disease. METHOD We randomly assigned 133 infants to Intralipid or control groups, using two weight strata: 42 Intralipid versus 37 control subjects in the 600 to 800 gm stratum, and 28 Intralipid versus 26 control subjects in the 801 to 1000 gm stratum. The Intralipid group received 20% Intralipid at < 12 hours after birth, starting at a dose of 0.5 gm/kg and increasing to a maximum of 1.5 gm/kg, maintained through day 7. Control infants received no lipid until after day 7. Neither group received enteral feedings until after day 7. RESULTS No significant differences in mortality rates were present in the total population (23/70 = 32.9% vs 16/63 = 25.4%; p = 0.35, Intralipid vs control); however, the mortality rate increased significantly in 600 to 800 gm infants receiving Intralipid versus the control infants (20/41 = 47.5% vs 9/37 = 24.3%; p = 0.032). No significant differences were found in the number of infants in whom chronic lung disease developed (requiring oxygen for > or = 28 days), proportion requiring oxygen for > or = 60 days, number of survivors without chronic lung disease, or total oxygen and ventilation requirements. However, 600 to 800 gm infants receiving Intralipid had significantly more pulmonary hemorrhage, and greater numbers of infants receiving Intralipid in both weight categories required supplemental oxygen at day 7. The incidence of other complications of prematurity, time required to regain birth weight, and duration of hospital stay did not differ between groups. CONCLUSION Intralipid administration initiated at < 12 hours after birth failed to protect very low birth weight premature infants from chronic lung disease. Some of the results raise questions about possible deleterious effects of Intralipid when administered early in the first week of life.