Erik A. Jensen

Epidemiology of bronchopulmonary dysplasia

Bronchopulmonary dysplasia (BPD) is among the most common and serious sequelae of preterm birth. BPD affects at least one-quarter of infants born with birth weights less than 1500 g. The incidence of BPD increases with decreasing gestational age and birth weight. Additional important risk factors include intrauterine growth restriction, sepsis, and prolonged exposure to mechanical ventilation and supplemental oxygen. The diagnosis of BPD predicts multiple adverse outcomes including chronic respiratory impairment and neurodevelopmental delay. This review summarizes the diagnostic criteria, incidence, risk factors, and long-term outcomes of BPD.

Definitions of extubation success in very premature infants: a systematic review

Objective Studies of extubation in preterm infants often define extubation success as a lack of reintubation within a specified time window. However, the duration of observation that defines extubation success in preterm infants has not been validated. The purpose of this study was to systematically review published definitions of extubation success in very preterm infants and to analyse the effect of the definition of extubation success on the reported rates of reintubation. Design Studies including very preterm infants published between 1 January 2002 and 30 June 2012 that reported reintubation as an outcome were reviewed for definitions of extubation success. Stepwise multivariable linear regression was used to explore variables associated with rate of reintubation. Results Two independent reviewers performed the search with excellent agreement (κ=0.93). Of the 44 eligible studies, 31 defined a window of observation that ranged from 12 to 168 h (7 days). Extubation and reintubation criteria were highly variable. The mean±SD reintubation rate across all studies was 25±9%. In studies of infants with median birth weight (BW) ≤1000 g, reintubation rates steadily increased as the window of observation increased, without apparent plateau (p = 0.001). This trend was not observed in studies of larger infants (p = 0.85). Conclusions Variability in the reported definitions of extubation success makes it difficult to compare extubation strategies across studies. The appropriate window of observation following extubation may depend on the population. In infants with BW ≤1000 g, even a week of observation may fail to identify some who will require reintubation.

Effects of a Birth Hospital's Neonatal Intensive Care Unit Level and Annual Volume of Very Low-Birth-Weight Infant Deliveries on Morbidity and Mortality

IMPORTANCE The annual volume of deliveries of very low-birth-weight (VLBW) infants has a greater effect on mortality risk than does neonatal intensive care unit (NICU) level. The differential effect of these hospital factors on morbidity among VLBW infants is uncertain. OBJECTIVE To assess the independent effects of a birth hospitals annual volume of VLBW infant deliveries and NICU level on the risk of several neonatal morbidities and morbidity-mortality composite outcomes that are predictive of future neurocognitive development. DESIGN, SETTING, AND PARTICIPANTS Retrospective, population-based cohort study (performed in 2014) of all VLBW infants without severe congenital anomalies delivered in all hospitals in California, Missouri, and Pennsylvania between January 1, 1999, and December 31, 2009 (N = 72,431). Risk-adjusted odds ratios and risk-adjusted probabilities were determined by logistic regression. MAIN OUTCOMES AND MEASURES The primary study outcomes were the individual composites of death or bronchopulmonary dysplasia, necrotizing enterocolitis, retinopathy of prematurity, and severe intraventricular hemorrhage. RESULTS Among the 72,431 VLBW infants in the present study, birth at a hospital with 10 or less deliveries of VLBW infants per year was associated with the highest risk-adjusted probability of death (15.3% [95% CI, 14.4%-16.3%]), death or severe intraventricular hemorrhage (17.5% [95% CI, 16.5%-18.6%]), and death or necrotizing enterocolitis (19.3% [95% CI, 18.1%-20.4%]). These complications were also more common among infants born at hospitals with a level I or II NICU compared with infants delivered at hospitals with a level IIIB/C NICU. The risk-adjusted probability of death or retinopathy of prematurity was highest among infants born at hospitals with a level IIIB/C NICU and lowest among infants born at hospitals with a level IIIA NICU. When the effects of NICU level and annual volume of VLBW infant deliveries were evaluated simultaneously, the annual volume of deliveries was the stronger contributor to the risk of death, death or severe intraventricular hemorrhage, and death or necrotizing enterocolitis. CONCLUSIONS AND RELEVANCE The risk of death or severe intraventricular hemorrhage and death or necrotizing enterocolitis was lowest among infants born in hospitals that had both a high volume of VLBW infant deliveries and a high-level NICU. Antenatal transfer of high-risk pregnancies to these hospitals may reduce mortality and improve outcomes.

Effects of Multiple Ventilation Courses and Duration of Mechanical Ventilation on Respiratory Outcomes in Extremely Low-Birth-Weight Infants

IMPORTANCE Extubation failure is common in extremely preterm infants. The current paucity of data on the adverse long-term respiratory outcomes associated with reinitiation of mechanical ventilation prevents assessment of the risks and benefits of a trial of extubation in this population. OBJECTIVE To evaluate whether exposure to multiple courses of mechanical ventilation increases the risk of adverse respiratory outcomes before and after adjustment for the cumulative duration of mechanical ventilation. DESIGN, SETTING, AND PARTICIPANTS We performed a retrospective cohort study of extremely low-birth-weight (ELBW; birth weight <1000 g) infants born from January 1, 2006, through December 31, 2012, who were receiving mechanical ventilation. Analysis was conducted between November 2014 and February 2015. Data were obtained from the Alere Neonatal Database. EXPOSURES The primary study exposures were the cumulative duration of mechanical ventilation and the number of ventilation courses. MAIN OUTCOMES AND MEASURES The primary outcome was bronchopulmonary dysplasia (BPD) among survivors. Secondary outcomes were death, use of supplemental oxygen at discharge, and tracheostomy. RESULTS We identified 3343 ELBW infants, of whom 2867 (85.8%) survived to discharge. Among the survivors, 1695 (59.1%) were diagnosed as having BPD, 856 (29.9%) received supplemental oxygen at discharge, and 31 (1.1%) underwent tracheostomy. Exposure to a greater number of mechanical ventilation courses was associated with a progressive increase in the risk of BPD and use of supplemental oxygen at discharge. Compared with a single ventilation course, the adjusted odds ratios for BPD ranged from 1.88 (95% CI, 1.54-2.31) among infants with 2 ventilation courses to 3.81 (95% CI, 2.88-5.04) among those with 4 or more courses. After adjustment for the cumulative duration of mechanical ventilation, the odds of BPD were only increased among infants exposed to 4 or more ventilation courses (adjusted odds ratio, 1.44; 95% CI, 1.04-2.01). The number of ventilation courses was not associated with increased risk of supplemental oxygen use at discharge after adjustment for the length of ventilation. A greater number of ventilation courses did not increase the risk of tracheostomy. CONCLUSIONS AND RELEVANCE Among ELBW infants, a longer cumulative duration of mechanical ventilation largely accounts for the increased risk of chronic respiratory morbidity associated with reinitiation of mechanical ventilation. These results support attempts of extubation in ELBW infants receiving mechanical ventilation on low ventilator settings, even when success is not guaranteed.

Non-invasive respiratory support for infants in low- and middle-income countries

The overwhelming majority of neonatal deaths worldwide occur in low- and middle-income countries. Most of these deaths are attributable to respiratory illnesses and complications of preterm birth. The available data suggest that non-invasive continuous positive airway pressure (CPAP) is a safe and cost-effective therapy to reduce neonatal morbidity and mortality in these settings. Bubble CPAP compared to mechanical ventilator-generated CPAP reduces the need for subsequent invasive ventilation in newborn infants. There are limited data on the safety and efficacy of high-flow nasal cannulae in low- and middle-income countries, requiring further study prior to widespread implementation.

Has enough evidence accumulated to consider CPAP a first-line standard of care in developing countries?

Deciding when sufficient evidence has accumulated for a new therapy to become the ‘standard of care’ is a trade-off between absolute certainty obtained from myriads of trials and insufficient ‘proof.’ In developing countries, the financial and technical resources needed to make new therapies widely available further complicate this balance. Moreover, expensive, large-scale trials are often conducted in industrialised countries. Can the evidence provided by these studies inform treatment selection in resource-limited settings? Or, are ‘local’ studies always necessary? Decisions to adopt new therapies in developing countries should be determined individually, but the underlying clinical and methodological questions that influence these decisions are likely similar. We suggest they include: What is the burden of disease treated by the new therapy? What is the strength of all available evidence for both efficacy and harm? Are there relevant differences between the studies conducted in developed versus developing countries? Finally, is use of the new therapy in resource-limited settings feasible? Martin et al 1 report an important systematic review of studies evaluating bubble continuous positive airway pressure (CPAP) for the treatment of neonatal respiratory distress in resource-limited countries. The authors conclude ‘bubble CPAP is a promising intervention which reduces the need for high cost mechanical ventilators… however there is need for more research into the impact of bubble CPAP on neonatal mortality and into effective implementation methods...’ An implication is made that further prospective trials in resource-limited settings are needed. We respectfully emphasise that if CPAP remains an experimental therapy …

Reliability of a Noninvasive Measure of V./Q. Mismatch for Bronchopulmonary Dysplasia

RATIONALE Currently used definitions of bronchopulmonary dysplasia (BPD) lack a continuous measure of disease severity. OBJECTIVES To determine if an indirect measure of V./Q. mismatch is reliable when simplified to facilitate more widespread use for grading disease severity in BPD at 36 weeks postmenstrual age. METHODS We used prospectively collected data from 32 preterm infants undergoing an oxygen reduction test at 36 weeks postmenstrual age to perform a simplified indirect assessment of V./Q. mismatch for each infant. Independent raters applied the model, and interrater reliability for a quantitative measure of mismatch was measured by intraclass correlation coefficient. A receiver operating characteristic curve evaluated the impact of increasing degrees of V./Q. mismatch on diagnosing BPD as defined by oxygen reduction test failure. MEASUREMENTS AND MAIN RESULTS Concordance for the quantitative measure of V./Q. mismatch between independent raters improved from 0.72 (confidence interval [CI], 0.48-0.86) to 0.93 (CI, 0.87-0.96) after refinement of instructions for applying the simplified model. Higher degrees of mismatch were increasingly predictive of oxygen reduction test failure, with a receiver operating characteristic curve analysis area under the curve of 0.83 (CI, 0.68-0.99; P = 0.03). CONCLUSIONS A simplified indirect measure of V./Q. mismatch for diagnosing and grading disease severity in BPD has high reliability and can be performed with data obtained during a standard oxygen reduction test. This should facilitate more widespread investigation of this model as a technique for characterizing BPD severity.

Determinants of Severe Metabolic Bone Disease in Very Low-Birth-Weight Infants with Severe Bronchopulmonary Dysplasia Admitted to a Tertiary Referral Center.

OBJECTIVE Nonrespiratory comorbidities are common among preterm infants with severe bronchopulmonary dysplasia (BPD) referred to tertiary perinatal centers. We evaluated the incidence, severity, and risk factors for metabolic bone disease (MBD) in this population. STUDY DESIGN We conducted a retrospective cohort study of all infants born ≤ 1,500 g who were diagnosed with severe BPD in our single, tertiary referral center between September 2010 and October 2012. MBD severity was classified by serial radiography. RESULTS Among the 83 infants diagnosed with severe BPD, 26 (31%) developed severe MBD (rickets). Male gender and lower gestational age and birth weight were associated with increased odds of severe MBD. After adjustment for these potential confounders, cytomegalovirus infection, postnatal growth restriction, surgical necrotizing enterocolitis, and blood culture confirmed sepsis were associated with increased odds of severe MBD. The cumulative duration of therapy with furosemide, hydrocortisone, and prednisolone each correlated with significantly greater probability of severe MBD. CONCLUSIONS Severe MBD was common in this referral-based cohort with severe BPD. The high incidence in this population is likely explained by the coexistence of multiple exposures and comorbidities associated with bone demineralization.

Duration of continuous positive airway pressure in premature infants.

Continuous positive airway pressure (CPAP) has been used for respiratory support in premature infants for more than 40 years and is now a cornerstone of modern neonatal care. Clinical research on CPAP has primarily focused on understanding which devices and pressure sources best implement this therapy. In contrast, less research has examined the optimal duration over which CPAP is administered. We review this aspect of CPAP therapy.

Anti-gastroesophageal reflux surgery in infants with severe bronchopulmonary dysplasia.

Gastroesophageal reflux may exacerbate lung disease in infants with bronchopulmonary dysplasia (BPD). Anti‐reflux surgery may therefore reduce the severity of this disease in some infants. We report a retrospective series of 22 infants with severe BPD who underwent anti‐reflux surgery. Our experience indicates that these procedures can be safely performed in this population and that early post‐operative initiation of gastric feeds is well tolerated. Modest post‐operative reductions in required oxygen and median respiratory rate were observed. Pediatr Pulmonol. 2015; 50:584–587.