Sherry E. Courtney

A Controlled Trial of Synthetic Surfactant in Infants Weighing 1250 G or More with Respiratory Distress Syndrome

Background Surfactant-replacement therapy is now recognized as a life-saving and safe intervention in small premature infants, but there is little evidence concerning its risks and benefits in larger premature infants. Methods We conducted a placebo-controlled, blinded trial in 1237 infants with respiratory distress who were enrolled at 23 hospitals in the United States and 13 hospitals in Canada. At entry all the infants weighed at least 1250 g, were receiving mechanical ventilation, and had a ratio of arterial to alveolar oxygen tension below 0.22. The initial dose of either the synthetic surfactant (Exosurf, 5 ml per kilogram of body weight) or air (the placebo) was administered less than 24 hours after birth, with a second dose given 12 hours later. A total of 614 infants were assigned to receive surfactant, and 623 to receive placebo. Results Fewer infants in the surfactant group than in the placebo group died before 28 days of age or survived at 28 days with bronchopulmonary dysplasia (7 percent vs. 12 percent, P = 0.002). In the first 28 days of life, there were fewer deaths due to respiratory distress syndrome in the surfactant group (1 percent vs. 3 percent, P = 0.043), lower overall neonatal mortality (4 percent vs. 7 percent, P = 0.04), and a lower incidence of bronchopulmonary dysplasia (3 percent vs. 6 percent, P = 0.008). There was also a significantly lower incidence of pulmonary air leaks, intraventricular hemorrhage, patent ductus arteriosus, seizures, hypotension, and pulmonary hypertension in the surfactant group. The infants treated with surfactant were weaned from oxygen and mechanical ventilation significantly sooner than those given placebo, and they less often required high-frequency ventilation or extracorporeal membrane oxygenation. The primary side effect observed more frequently among the infants who received surfactant treatment was pulmonary hemorrhage (six infants vs. one infant, P = 0.055). Conclusions In infants weighing at least 1250 g at birth who have respiratory distress syndrome, treatment with two doses of synthetic surfactant improves survival and reduces perinatal morbidity.

Work of breathing during nasal continuous positive airway pressure in preterm infants : A comparison of bubble vs variable-flow devices

OBJECTIVE:To compare work of breathing and breathing asynchrony during bubble nasal continuous positive airway pressure (NCPAP) vs variable-flow (VF)-NCPAP in premature infants.STUDY DESIGN:We studied 18 premature infants of birth weight <1500 g who required NCPAP for mild respiratory distress. Each infant was studied on bubble and VF-NCPAP at 8, 6, 4, and 0 cmH2O. Tidal volumes were obtained by calibrated respiratory inductance plethysmography. Esophageal pressure estimated intrapleural pressure. Inspiratory and resistive work of breathing were calculated from pressure–volume data. Breathing asynchrony was assessed with phase angle. The results at all NCPAP levels were referenced to VF-NCPAP values at 8 cmH2O.RESULTS:Provision of NCPAP with either device decreased inspiratory work of breathing, tidal volume, and minute ventilation relative to NCPAP of 0 cmH2O. Bubble NCPAP did not decrease resistive work of breathing relative to 0 cmH2O. Resistive work of breathing (p=0.01), respiratory rate (p<0.03), and phase angle (p=0.002) were all greater with bubble compared to VF-NCPAP.CONCLUSION:The more labored and asynchronous breathing seen with bubble NCPAP may lead to higher failure rates over the long term than with VF-NCPAP.

Unpredictability of Delivered Bubble Nasal Continuous Positive Airway Pressure: Role of Bias Flow Magnitude and Nares-Prong Air Leaks

Nasal continuous-positive-airway-pressure (NCPAP) is popular for infant respiratory support. We compared delivered to intended intra-prong, proximal-airway, and distal-airway pressures using ventilator (V-NCPAP) and bubble (B-NCPAP) devices. Measurements were repeated at five flows (4, 6, 8, 10, and 12 L/min) and three NCPAP (4, 6, and 8 cm H2O) under no, small, and large nares-prong interface leak conditions. With no-leak, delivered B-NCPAP was systematically greater than intended levels at all pressure sites. The corresponding V-NCPAP flow-dependence was none-to-minimal. Prong and intra-airway B-NCPAP overshoots were also observed with small-leak, while only prong B-NCPAP showed a flow-dependent overshoot for large-leak. Leaks did not affect intra-prong V-NCPAP but resulted in progressively lower than desired, flow-independent intra-airway V-NCPAP. We conclude that the self-adjusting capability of ventilators allows closely matched actual versus intended V-NCPAP. Alternatively, for the range of flows used clinically, intra-prong and intra-airway B-NCPAP are systematically higher at increasing flows than operator-intended levels, even when appreciable nares-prong leak is present. Additionally, the oscillations (noise) characterizing B-NCPAP are substantially attenuated between the proximal and distal airways; therefore, it is unlikely that B-NCPAP engenders ventilation or lung recruitment via this phenomenon. Tubing submersion depth for setting the level of B-NCPAP is highly inaccurate, and operators should instead rely on intra-prong pressure measurement.

Effect of weight and age on respiratory complexity in premature neonates

Very low-birth-weight premature infants often suffer from a variety of respiratory problems, including respiratory distress syndrome (RDS), hypopnea and periodic breathing, and apnea. These conditions are likely related to immaturity of the respiratory centers; yet how respiratory rhythms originating from these centers, including their complexity, relate to demographic measures of prematurity remains largely unknown. In 39 neonates with mild RDS (22 males, 28 +/- 2 wk gestational age, 1,036 +/- 234 g body wt), we derived the univariate association between complexity of two respiratory rhythms [respiratory rate (RR) and tidal volume (Vt)] and postmenstrual age, gestational age, postnatal age, and weight at time of study. RR and Vt rhythm complexities were assessed using approximate entropy, sample entropy, base scale entropy, and forbidden words entropy estimated for 300 consecutive breaths determined from respiratory inductance plethysmography, irrespective of breathing effort rate or amplitude, collected during sleep while the neonates were exposed to nasal continuous positive airway pressure (4-6 cmH(2)O). RR and Vt exhibited increased complexity with increased maturity, but only in terms of base scale entropy and forbidden words entropy, which are based on pattern matching, rather than approximate entropy and sample entropy, which are based on conditional probabilities. Specifically, RR complexity as measured by forbidden word entropy increased with increasing weight (r = 0.502), postconceptional age (r = 0.423), and gestational age (r = 0.493). As measured by base scale entropy, RR complexity increased with increasing weight (r = 0.488) and postconceptional age (r = 0.390). Vt complexity, measured by base scale entropy, was greater with increased postnatal age (r = 0.428). Our results indicate that respiratory rhythms become more complex with increasing levels of maturity, as indicated by increased weight and several age parameters. This emphasizes the importance of the later weeks of gestation in the maturation of respiratory centers in the brain and suggests a promising use of entropy measures in exploring respiratory maturation in infants.

Effects of flow amplitudes on intraprong pressures during bubble versus ventilator-generated nasal continuous positive airway pressure in premature infants.

OBJECTIVES. The goal were to characterize the flow dependence of bubble nasal continuous positive airway pressure delivery in a cohort of preterm infants and to compare the actual (delivered) intraprong continuous positive airway pressure with the intended (set) nasal continuous positive airway pressure for both ventilator-generated nasal continuous positive airway pressure and bubble nasal continuous positive airway pressure delivery. A range of set values and constant flow rates were studied in the same preterm infants. METHODS. For 12 premature infants of <1500 g (birth weight: 1140 ± 267 g; gestational age: 28.5 ± 1.9 weeks; study age: 12.9 ± 8 days; all mean ± SD), intraprong pressures were measured at 3 increasing flow settings, repeated for set nasal continuous positive airway pressures (or desired immersion depths) of 4 and 6 cmH2O. Next, intraprong pressures were measured at bubble nasal continuous positive airway pressure expiratory tubing submersion depths and ventilator-generated nasal continuous positive airway pressure set expiratory pressures of 2, 3, 4, 5, and 7 cmH2O while the flow rate was held constant. RESULTS. Actual (delivered) intraprong pressure during bubble nasal continuous positive airway pressure delivery was highly flow dependent and increased as the flow rate increased. During ventilator-generated nasal continuous positive airway pressure delivery, actual pressure at the nasal prongs closely approximated the pressure set at the ventilator. During bubble nasal continuous positive airway pressure delivery at constant flow rate, the average delivered prong pressure was 1.3 cmH2O (range: 0.5–2.2 cmH2O) higher than that set through submersion of the expiratory tubing, and the relative difference between the set and actual pressures increased at lesser immersion depths. CONCLUSIONS. Prong pressure during bubble nasal continuous positive airway pressure delivery is highly variable and depends on the interaction of submersion depth and flow amplitudes.

Double-blind 1-year follow-up of 1540 infants with respiratory distress syndrome randomized to rescue treatment with two doses of synthetic surfactant or air in four clinical trials☆☆☆★

Synthetic surfactant has been shown to reduce neonatal and 1-year mortality and neonatal morbidity in infants with respiratory distress syndrome. However, less is known about the effects of synthetic surfactant on developmental outcome and long-term morbidity. Four multicenter, randomized, placebo-controlled trials of synthetic surfactant administered as rescue therapy were conducted in the United States and Canada, with a total enrollment of 2224 patients. Double-blind developmental evaluations of survivors were conducted at 1 year of age (adjusted for prematurity) in all four trials. Of the 1802 patients enrolled in the placebo-controlled rescue trials who survived to 1 year, 1540 (85%) completed the 1-year follow-up evaluation. Height, weight, and head circumference measurements were not different in the treatment and control groups. Mean and median Bayley Scores of Infant Development for both the Mental Development Index and the Psychomotor Development Index were also equivalent. The incidence of impairments was not different in the two groups (mild to moderate impairment, 12% (92 of 745) for the air placebo group vs 11% (86 of 771) for the synthetic surfactant group; severe impairment, 15% (114 of 745) for the air placebo group vs 13% (102 of 771) for the synthetic surfactant group). No differences in rates of retinopathy of prematurity or hearing impairment were found in the treatment groups. The need for surgery after day 28 of life (relative risk, 0.779; 95% confidence interval, 0.665, 0.927) and the need for respiratory support at 1 year (relative risk, 0.525; 95% confidence intervals, 0.303, 0.911) were both reduced in the synthetic surfactant group. These results indicate that developmental outcome at 1 year of age is at least as good among infants with respiratory distress syndrome who received rescue therapy with synthetic surfactant as it is in infants who received air placebo; the results also indicate that the incidence of long-term morbidity is reduced.

Measurement of tidal volume using a pneumotachometer during high-frequency oscillation

To assess the accuracy of a pneumotachometer (PN) for tidal volume (VT) measurements during high-frequency oscillation (HFO), we determined simultaneously VT using a PN and a full body plethysmograph (PL) in 12 rabbits. HFO was delivered with an oscillator at a frequency of 10 Hz, mean airway pressure of 8 cm H2O, and inspiratory time of 50%. Pressure amplitude (delta P) was varied as follows: 40, 60, 80, 20, 100, 40 cm H2O. Finally, in ten rabbits a spacer equal in deadspace (VD) to that of the PN (15 ml) was left in-line for 5 min. Blood gases were obtained before and after the spacer was added. We found that VT-PN correlates well with VT-PL (r = .92), although the difference between VT-PN and VT-PL is greater at large VT. Significant respiratory acidosis developed with the spacer in-line. PN may be used to trend VT during HFO but PN must not be left in-line, as increased VD seriously affects ventilation.

Clinical prediction models for bronchopulmonary dysplasia: a systematic review and external validation study

BackgroundBronchopulmonary dysplasia (BPD) is a common complication of preterm birth. Very different models using clinical parameters at an early postnatal age to predict BPD have been developed with little extensive quantitative validation. The objective of this study is to review and validate clinical prediction models for BPD.MethodsWe searched the main electronic databases and abstracts from annual meetings. The STROBE instrument was used to assess the methodological quality. External validation of the retrieved models was performed using an individual patient dataset of 3229 patients at risk for BPD. Receiver operating characteristic curves were used to assess discrimination for each model by calculating the area under the curve (AUC). Calibration was assessed for the best discriminating models by visually comparing predicted and observed BPD probabilities.ResultsWe identified 26 clinical prediction models for BPD. Although the STROBE instrument judged the quality from moderate to excellent, only four models utilised external validation and none presented calibration of the predictive value. For 19 prediction models with variables matched to our dataset, the AUCs ranged from 0.50 to 0.76 for the outcome BPD. Only two of the five best discriminating models showed good calibration.ConclusionsExternal validation demonstrates that, except for two promising models, most existing clinical prediction models are poor to moderate predictors for BPD. To improve the predictive accuracy and identify preterm infants for future intervention studies aiming to reduce the risk of BPD, additional variables are required. Subsequently, that model should be externally validated using a proper impact analysis before its clinical implementation.

Bubble and ventilator-derived nasal continuous positive airway pressure in premature infants: work of breathing and gas exchange

Objective:During bubble nasal continuous positive airway pressure (B-NCPAP), gas flows through the expiratory limb of CPAP tubing submerged underwater to a depth in centimeters considered equal to the desired end expiratory pressure. Ventilator-derived NCPAP (V-NCPAP) controls the delivered pressure at the expiratory orifice. Limited data exist comparing the two forms of NCPAP on work of breathing (WOB) and other short-term respiratory outcomes. We compared WOB and gas exchange between B-NCPAP and V-NCPAP at equivalent delivered nasal prong pressures among a cohort of preterm infants on NCPAP.Study Design:We performed a randomized crossover study in 18 premature infants <1500 g (BW 1101±254 g, GA 28±2 weeks, study age 13±8 days (means±s.d.)), who were already on NCPAP for mild respiratory distress, comparing B-NCPAP to V-NCPAP. Each infant was studied at a constant flow rate and varying pressures of 3, 5, 7, 4 and 2 cm H2O in that order. Tidal volumes were obtained by calibrated respiratory inductance plethysmography. Intrapleural pressure was estimated by an esophageal catheter. WOB (inspiratory, elastic and resistive) was calculated from pressure volume data. Breathing asynchrony was assessed with phase angle. Comparisons of respiratory rate, heart rate, tidal volume, minute ventilation, breathing asynchrony, lung compliance, oxygen saturation and transcutaneous (Tc) O2 and CO2 were also made.Result:WOB and most respiratory parameters were not different between B-NCPAP and V-NCPAP. TcO2 was higher with B-NCPAP compared to V-NCPAP (P=0.01). TcCO2 was not different. None of the other measured parameters was significantly different between the two devices.Conclusion:WOB and ventilation with B-NCPAP and V-NCPAP are similar when equivalent delivered prong pressures are assured. Improved oxygenation with B-NCPAP is intriguing and requires further investigation.

Pilot trial of late booster doses of surfactant for ventilated premature infants.

Objective:Many premature infants at risk for bronchopulmonary dysplasia experience episodes of surfactant dysfunction with reduced surfactant protein B (SP-B). In this study, we investigated the safety and responses to booster doses of surfactant.Study Design:A total of 87 infants, 500 to 1250 g birth weight, who were ventilated at 7 to 10 days received 2 or 3 doses of Infasurf (Calfactant, Forest Pharmaceuticals, St Louis, MO, USA) within a 1-week period.Result:For 184 doses, occurrence rates of transient bradycardia (13) and plugged endotracheal tube (5) were low, and no other adverse effects were noted. Treatment transiently improved the respiratory severity score (FiO2 × mean airway pressure), SP-B content (+75%) and surface properties of isolated surfactant. Levels of eight proinflammatory cytokines in tracheal aspirate were interrelated and unchanged from baseline after surfactant treatment.Conclusion:Booster doses of surfactant for premature infants with lung disease are safe and transiently improve respiratory status as well as composition and function of endogenous surfactant.