David Millar

A Trial Comparing Noninvasive Ventilation Strategies in Preterm Infants

BACKGROUND To reduce the risk of bronchopulmonary dysplasia in extremely-low-birth-weight infants, clinicians attempt to minimize the use of endotracheal intubation by the early introduction of less invasive forms of positive airway pressure. METHODS We randomly assigned 1009 infants with a birth weight of less than 1000 g and a gestational age of less than 30 weeks to one of two forms of noninvasive respiratory support--nasal intermittent positive-pressure ventilation (IPPV) or nasal continuous positive airway pressure (CPAP)--at the time of the first use of noninvasive respiratory support during the first 28 days of life. The primary outcome was death before 36 weeks of postmenstrual age or survival with bronchopulmonary dysplasia. RESULTS Of the 497 infants assigned to nasal IPPV for whom adequate data were available, 191 died or survived with bronchopulmonary dysplasia (38.4%), as compared with 180 of 490 infants assigned to nasal CPAP (36.7%) (adjusted odds ratio, 1.09; 95% confidence interval, 0.83 to 1.43; P=0.56). The frequencies of air leaks and necrotizing enterocolitis, the duration of respiratory support, and the time to full feedings did not differ significantly between treatment groups. CONCLUSIONS Among extremely-low-birth-weight infants, the rate of survival to 36 weeks of postmenstrual age without bronchopulmonary dysplasia did not differ significantly after noninvasive respiratory support with nasal IPPV as compared with nasal CPAP. (Funded by the Canadian Institutes of Health Research; NIPPV ClinicalTrials.gov number, NCT00433212; Controlled-Trials.com number, ISRCTN15233270.).

Evidence-based neonatal drug therapy for prevention of bronchopulmonary dysplasia in very-low-birth-weight infants.

Corticosteroids, intramuscular vitamin A and caffeine reduce the risk of bronchopulmonary dysplasia (BPD) in very-low-birth-weight infants. We compared the size of the beneficial drug effects on BPD and evaluated long-term drug safety by estimating the number needed to treat (NNT) and the number needed to harm (NNH) for the outcome of cerebral palsy (CP). When given prophylactically during the first 4 days of life, corticosteroids increase the risk of CP (NNH 22; 95% CI: 12–133). When prescribed between days 7 and 14, corticosteroids reduce the 28-day mortality rate in addition to reducing BPD. Their effect on CP remains uncertain: the limited data available are consistent with a best-case scenario (NNT 15) and a worst-case scenario (NNH 14). Although repeated intramuscular injections of vitamin A during the 1st month of life reduce BPD (NNT 12; 95% CI: 6–94), estimates for CP range from an NNT of 11 to an NNH of 33. Early use of caffeine reduces both BPD and CP. The NNT for BPD is 10 (95% CI: 7–16), while the NNT for CP is 34 (95% CI: 20–132). We conclude that caffeine is the drug of choice for the prevention of BPD in very-low-birth-weight infants. Corticosteroids should be avoided during the first few days of life. However, when given during the 2nd week of life to infants at high risk of BPD corticosteroids may have important short- and long-term benefits. These should be urgently confirmed or refuted in well-designed controlled trials.

Noninvasive respiratory support for neonates.

Purpose of the review Noninvasive respiratory support for neonates is growing in popularity as clinicians increasingly recognize the dangers of prolonged invasive ventilation. The purpose of this review is to critically evaluate the existing evidence for safety and efficacy of these modes of respiratory support in neonates. Recent findings In recent years, multiple randomized controlled trials (RCTs) have evaluated several modes of noninvasive support, most importantly nasal intermittent positive pressure ventilation and high flow nasal cannulae, in comparison to the standard therapy of continuous positive airway pressure (CPAP). The three largest RCTs were recently published in 2013. One demonstrated no difference in death or survival with bronchopulmonary dysplasia between nasal intermittent positive pressure ventilation and CPAP, both when used as primary support and as postextubation support. Two others demonstrated that high flow nasal cannulae are noninferior to or no better than CPAP when used to support preterm infants after extubation. These trials showed no serious safety concerns with current modalities. Summary The optimal forms of noninvasive respiratory support for neonates remain to be determined. Continued evaluation of these technologies with large, well-designed RCTs is warranted.

A comparison of bilevel and ventilator-delivered non-invasive respiratory support

Objective To compare the rates of death or bronchopulmonary dysplasia (BPD) in infants who received nasal intermittent positive pressure ventilation (NIPPV) delivered by a conventional mechanical ventilator (CMV) or a bilevel device. Design A preplanned non-randomised comparison of infants randomised to the NIPPV arm of the NIPPV trial. Setting Thirty-six tertiary neonatal units in three continents. Patients Infants <1000 g and <30 weeks gestational age at birth. Interventions Infants received treatment with CMV NIPPV or bilevel NIPPV, as a primary mode of respiratory support or following first extubation. Results 241 received mainly bilevel NIPPV and 215 mainly CMV NIPPV. No difference was found in death or BPD at 36 weeks corrected age (adjusted OR 0.88 (95% CI 0.57 to 1.35)). More deaths occurred in infants receiving bilevel NIPPV (9.4%) than in CMV NIPPV (2.3%) (adjusted OR 5.01: 95% CI 1.74 to 14.4). There was a corresponding but not statistically significant decrease in BPD in the bilevel NIPPV group (30% vs 37%) (adjusted OR 0.64 (95% CI 0.41 to 1.02)). No difference was observed in extubation failure or age at last extubation. A post hoc test of interaction between device type and synchronisation was not statistically significant. Conclusions We did not observe a statistically significant difference in the composite outcome of death or BPD between infants who received mostly bilevel NIPPV compared with mostly CMV NIPPV. Differences in component outcomes of morbidity and BPD may be due to the competing nature of these outcomes or differences in baseline characteristics of infants. Trial registration number NCT00433212.

Variation in Positive End-Expiratory Pressure Levels for Mechanically Ventilated Extremely Low Birth Weight Infants

Objective To test the hypothesis that significant positive end‐expiratory pressure (PEEP) level variation exists between neonatal centers. Study design We performed a secondary analysis cohort study of the Nasal Intermittent Positive‐Pressure Ventilation trial. Our study population was extremely low birth weight infants requiring mechanical ventilation within 28 days of life. The exposure was neonatal center; 34 international centers participated in the trial. Subjects from centers with fewer than 5 eligible cases were excluded. The main outcome was the maximal PEEP level used during the first course of mechanical ventilation. Infant characteristics judged a priori to directly influence clinical PEEP level selection and all characteristics associated with PEEP at P <.05 in bivariable analyses were included with and without center in multivariable linear regression models. Variation in PEEP level use between centers following adjustment for infant characteristics was assessed. Results A total of 278 extremely low birth weight infants from 17 centers were included. Maximal PEEP ranged from 3 to 9 cm H2O, mean = 5.7 (SD = 0.9). Significant variation between centers remained despite adjustment for infant characteristics (P < .0001). Further, center alone explained a greater proportion of the PEEP level variation than all infant characteristics combined. Conclusions Marked variation in PEEP levels for extremely low birth weight infants exists between neonatal centers. Research providing evidence‐based guidance for this important aspect of respiratory care in preterm infants at high risk of lung injury is needed. Trial registration ClinicalTrials.gov: NCT00433212.

171 Nippv Does not Reduce Bronchopulmonary Dysplasia (Bpd) or Death in Extremely Low Birth Weight Infants - A Randomised Trial

Background Standard care of preterm infants includes nCPAP & NIPPV. We compared rates of BPD or death in a randomised trial of NIPPV or nCPAP. Methods Eligible infants were preterm, birth weight < 1000g; requiring either (i) non-invasive respiratory support within first seven days, “no intubation/early extubation group”, or (ii) were < 28 days at first extubation - “prior intubation”. Central block randomisation to NIPPV or nCPAP was conducted via the web. Primary outcome was a composite of death (prior to 36 weeks’ gestational age [GA]) or BPD at 36 weeks’ GA: defined as requiring ventilation; FiO2 > 30%; or positive oxygen reduction test (ORT). Sample size 1000 (β 80%; 2-tailed α 5%) to demonstrate 20% reduction in primary outcome. Results 36 international sites enrolled 1007 infants. Observed rates of BPD or death were similar in the two groups. BPD outcome, in the 21 infants with no ORT, assessed by clinical definition of oxygen at 36 weeks’ GA: no alteration in treatment differences. Abstract 171 Table 1 Outcome data Outcome NIPPV nCPAP Adjusted OR (95%CI) p Primary analysis: death or ORT-BPD n (%) 192/497 (38.6) 179/487 (36.8) 1.09 (0.83, 1.44) 0.53 Supporting analysis: death or imputed BPD 198/504 (39.3) 191/501 (38.1) 1.05 (0.80, 1.38) 0.72 Primary outcome by subgroup No intubation/Early extubation n (%) 72/241 (29.9) 72/252 (28.6) 1.1 (0.72, 1.69) 0.64 Prior intubation 120/256 (46.9) 107/235 (45.5) 1.1 (0.73, 1,54) 0.76 Conclusions In infants < 1000g NIPPV does not confer further benefit nor risk for survival free of BPD at 36 weeks’ GA compared to nCPAP.

Contents Vol. 93, 2008

S. Andersson, Helsinki E. Bancalari, Miami, Fla. G. Buonocore, Siena W.A. Carlo, Birmingham, Ala. V.P. Carnielli, Ancona W.J. Cashore, Providence, R.I. I.A. Choonara, Derby T. Curstedt, Stockholm O. Dammann, Boston, Mass. C. Dani, Florence B. Darlow, Christchurch P. Gluckman, Auckland M. Hallman, Oulu B. Jonsson, Stockholm S.E. Juul, Seattle, Wash. A. Llanos, Santiago R.J. Martin, Cleveland, Ohio C.J. Morley, Melbourne J. Neu, Gainesville, Fla. P.C. Ng, Hong Kong M. Obladen, Berlin A.G.S. Philip, Palo Alto, Calif. M. Post, Toronto E. Saliba, Tours O.D. Saugstad, Oslo B. Schmidt, Hamilton E. Shinwell, Rehovot J. Smith, Cape Town B. Sun, Shanghai H. Togari, Nagoya F. van Bel, Utrecht N. Vain, Buenos Aires M. Vento Torres, Valencia M. Weindling, Liverpool J.A. Widness, Iowa City, Iowa Fetal and Neonatal Research