- Email: [email protected]
Nasal Intermittent Positive Pressure Ventilation Versus Nasal Continuous Positive Airway Pressure to Prevent Primary Noninvasive Ventilation Failure in Extremely Low Birthweight Infants
BRIEF REPORTS Nasal Intermittent Positive Pressure Ventilation Versus Nasal Continuous Positive Airway Pressure to Prevent Primary Noninvasive Ventilation Failure in Extremely Low Birthweight Infants Stephanie L. Bourque, MD, MSCS1, Robin S. Roberts, MSc2, Clyde J. Wright, MD1, Haresh Kirpalani, BM, MSc3, Brigitte Lemyre, MD4, David Millar, MB, FRCPCH5, and Nicolas A. Bamat, MD, MSCE3 Reducing the risk of primary noninvasive ventilation failure in extremely low birthweight infants is linked to reducing bronchopulmonary dysplasia. In a secondary analysis of randomized data, we identified that failure rates and time to failure were similar for nasal intermittent positive pressure ventilation vs nasal continuous positive airway pressure. (J Pediatr 2019;-:1-4).
B
ronchopulmonary dysplasia (BPD) remains the most common chronic morbidity for preterm infants, affecting 40% of infants born at 22-28 weeks of gestation.1,2 Exposure to invasive mechanical ventilation is a significant risk factor for developing BPD,3,4 and strategies such as the routine use of nasal continuous positive airway pressure (NCPAP),1 are critical to BPD prevention. When compared with intubation and surfactant administration, the use NCPAP reduces the need for postnatal corticosteroids, results in fewer days of mechanical ventilation, and decreases death and the combined outcome of death or BPD.5-8 However, NCPAP failure remains common in the extremely low birthweight (ELBW) population. When NCPAP is used as the primary respiratory support, defined as the first mode of respiratory support following admission, failure rates approach 50%, with rates increasing with progressive prematurity.9-13 Compared with NCPAP, potential advantages of nasal intermittent positive-pressure ventilation (NIPPV) include increased tidal volume and minute ventilation and improved oxygen saturation.14,15 The use of NIPPV as primary respiratory support is one strategy that may help delay or avoid intubation and exposure to mechanical ventilation.14,16 Pooling available randomized controlled trial data, a Cochrane review concluded that when compared with NCPAP, NIPPV prevented intubation of preterm infants, with an overall risk ratio of 0.78 (95% CI 0.64-0.94).17 However, this meta-analysis included few ELBW infants and included infants previously intubated for surfactant administration. The conclusions that NIPPV is superior to NCPAP for the prevention of intubation may not generalize to ELBW infants who do not require immediate endotracheal intubation for surfactant administration and/or mechanical ventilation in
BPD ELBW NCPAP NIPPV PMA
Bronchopulmonary dysplasia Extremely low birthweight Nasal continuous positive airway pressure Nasal intermittent positive-pressure ventilation Postmenstrual age
the early postnatal period.18 The primary objective of this study was to compare noninvasive ventilation failure rates (by day 7 of randomization) in intubation-na€ıve ELBW infants randomized to NIPPV vs NCPAP. Our secondary objectives were to compare time to noninvasive failure and etiologies of noninvasive ventilation failure between groups.
Methods We performed a secondary cohort study using NIPPV randomized control trial data. The NIPPV trial (NCT00433212) was conducted between 2007 and 2011 and enrolled a total of 1009 ELBW infants, randomized to either NCPAP or NIPPV. Inclusion criteria were birth weight <1000 g, gestational age <30 weeks, and eligible for noninvasive ventilation within the first 28 days of life.16 For this secondary analysis, inclusion was restricted to infants who were never intubated prior to enrollment and randomization. The primary exposure was noninvasive respiratory support with either NIPPV or NCPAP. The primary outcome was failure of the noninvasive route of respiratory support, defined as endotracheal intubation at any time in the first 7 days after randomization. Prespecified secondary outcomes included time to death or noninvasive respiratory support failure, death at <36 weeks of postmenstrual age (PMA), the combined outcome of death or BPD at 36 weeks of PMA, and etiologies of failure. BPD was defined, as in the original trial, by the receipt of any form of positive-airway-pressure support or
From the 1Section of Neonatology, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO; 2Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada; 3Division of Neonatology, Children’s Hospital of Philadelphia, Philadelphia, PA; 4Department of Pediatrics, Division of Neonatology, University of Ottawa, Ottawa, Ontario, Canada; and 5Department of Neonatology, Royal Maternity Hospital, Belfast, United Kingdom Original NIPPV trial supported by the Canadian Institutes of Health Research (MCT80246). D.M. has received honoraria and travel expenses from Cheisi Ltd UK for teaching on management courses for senior trainees in neonatal medicine. C.W. serves on the Editorial Board for The Journal of Pediatrics. The authors declare no conflicts of interest. 0022-3476/$ - see front matter. ª 2019 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.jpeds.2019.08.064
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supplemental oxygen at 36 weeks of PMA. Etiologies of failure included apnea/bradycardia; increased oxygen requirements; hypercarbia; aspiration; sepsis; procedures or surgery; fatigue; increased work of breathing; nasal excoriation; acute lung deterioration (including pneumothorax and pulmonary hemorrhage); and medication side effect. More than 1 etiology was possible. We describe the most common etiologies, occurring in ³20% of failures. Statistical Analyses For the outcome of time to death or noninvasive failure, we performed a survival analysis with death or endotracheal intubation, with time measured as days from enrollment up to a maximum of 7 days. Groups were compared through the log-rank test for equality of survivor functions estimated as Kaplan‒Meier curves. We tested the proportional hazard assumption through Schoenfeld residuals. We performed stratified analyses by birthweight (less or greater than 800 g) and prerandomization receipt of caffeine, and tested for interactions between allocation and stratifying variables through Cox proportional hazards models. For all other comparisons, we used c2chi-square or Fisher exact tests (if expected cell sizes were less than 5) for categorical variables and the Wilcoxon rank-sum test for continuous variables. Statistical analyses were performed with STATA v 14 (StataCorp, College Station, Texas). The use of deidentified data from the NIPPV trial was designated as nonhuman subjects research by Institutional Review Board of the Children’s Hospital of Philadelphia.
Results Of the 1009 ELBW infants enrolled in the NIPPV trial, we included 142 infants never intubated prior to randomization; 69 were randomized to NIPPV and 73 were randomized to NCPAP. Mean age at randomization was 15.4 hours in the NIPPV group vs 19.8 hours in the NCPAP group (P = .29). There was no significant difference in the baseline maternal and infant demographic and clinical characteristics between groups (Table I; available at www.jpeds.com). For the primary outcome, 27.5% (19 of 69) of the infants in the NIPPV group and 30.1% (22 of 73) of the infants in the NCPAP group experienced failure of noninvasive support within the first 7 days after randomization with a relative risk of 0.91 (95% CI 0.54-1.53). Time to noninvasive failure within 7 days of randomization is depicted in Figure 1, hazard ratio 1.09 (95% CI 0.59-2.01, log-rank P = .79). The incidence rate for the NIPPV cohort was 5.0 failures/100 days at risk (19 failures/ 379.15 days at risk) vs 5.7 failures/100 days at risk (22 failures/387.71 days at risk) for the NCPAP cohort. No infants eligible for this analysis died within 7 days of enrollment. Death prior to 36 weeks of PMA occurred in 1.4% (1 of 69) of infants randomized to NIPPV vs 4.1% (3 of 73) in the infants randomized to NCPAP; risk ratio 0.35 (95% CI 0.04-3.31). The combined outcome of death prior to 36 weeks of PMA or BPD was not different in the 2
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NIPPV vs CPAP groups (19.7% [13 of 66] vs 16.7% [12 of 72], respectively; risk ratio 1.18 [95% CI 0.58-2.40]). The most frequently observed etiologies of noninvasive failure did not differ by treatment allocation and included apnea/ bradycardia, increased oxygen, and increased work of breathing (Table II). There was no significant difference in postrandomization air-leak syndrome between NIPPV and NCPAP groups (2.9% [2 of 69] vs none ([0 of 73], respectively, P = .23). For analyses stratified by birthweight and prerandomization administration of caffeine, there were no significant interactions in overall noninvasive failure rates within 7 days of randomization (Figure 2; available at www.jpeds.com).
Discussion In this secondary analysis of a large multicenter international randomized controlled trial, we found no significant differences in failure rates over the first 7 days of life between NIPPV vs NCPAP as primary noninvasive respiratory support in intubation and surfactant na€ıve ELBW infants. The comparative use of NIPPV vs NCPAP for noninvasive support for preterm infants is well reported, with data supporting the use of NIPPV for prevention of both extubation failure and decreased frequency of apnea of prematurity.19,20 Early use of NIPPV to prevent respiratory failure and need for intubation in the first week of life has also been evaluated in systematic reviews and found to be superior when compared with NCPAP.17,21 However, these reviews examined a large population, with a preponderance of more mature infants. Furthermore, these studies did not assess the comparative effectiveness of NCPAP vs NIPPV as primary respiratory support in a population with a goal to completely avoid invasive respiratory support. The NIPPV trial enrolled a less mature population than other trials comparing NIPPV to NCPAP, with an average gestational age of 26 weeks and a mean birth weight of approximately 800 g. The outcome of noninvasive failure has previously been evaluated as a dichotomous outcome occurring within a predefined period, without specific attention to the time until failure. In ELBW infants, delaying endotracheal intubation and mechanical ventilation in the first few critical days may be particularly beneficial.3 We, therefore, used a time-toevent survival analysis to examine avoiding this potentially injurious exposure and did not find a difference between treatment groups for this outcome. Our study is limited by a relatively small sample size that lacks power to detect small but clinically important differences between groups. In addition, this cohort received antenatal corticosteroids at very high rates (97.1% of infants in the NIPPV group, 95.9% of infants in the NCPAP group) that may not be generalizable to the broader ELBW infant population. For instance, during a similar time period to the NIPPV trial, the Neonatal Research Network reported an antenatal corticosteroid administration rate of 78.3% for infants 22-26 weeks of gestational age.22 Others have Bourque et al
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Figure 1. Time to noninvasive failure within 7 days of randomization.
Reprint requests: Stephanie L. Bourque, MD, MSCS, Section of Neonatology, Department of Pediatrics, University of Colorado School of Medicine, Neonatology MS 8402, 13121 E 17th Ave, Aurora, CO 80045. E-mail: [email protected]
Table II. Etiologies of noninvasive failure by allocation* Etiologies Apnea/bradycardia Increased oxygen Increased work of breathing
NIPPV no/ total no (%)
NCPAP no./ total no. (%)
P value
10/19 (52.6%) 13/19 (68.4%) 10/19 (52.6%)
10/22 (45.4%) 15/22 (68.2%) 9/22 (40.9%)
.65 .99 .45
*Includes etiologies present in ³20% of cases, multiple etiologies per failure allowed.
demonstrated that primary NCPAP failure in such immature infants typically occurs within 4-6 hours after delivery,9,11,23,24 and infants experiencing noninvasive respiratory support failure very early in the postnatal period are not represented in this cohort of infants who did not undergo endotracheal intubation between birth and study enrollment. However, our study population captures subjects for whom there would be sufficient time to evaluate the relative benefit of NIPPV over NCPAP, making the comparison relevant to practice. In conclusion, we found no significant improvement in the prevention of noninvasive failure with the use of NIPPV as a primary respiratory support modality in intubation and surfactant na€ıve ELBW infants. Our data do not support the routine use of NIPPV over NCPAP for primary respiratory support in this population. Further research is needed to investigate strategies to improve noninvasive ventilation success in the high-risk ELBW population. n We acknowledge the original NIPPV trial group including Aaron Chiu MD, and Bradley Yoder, MD. Submitted for publication Jun 17, 2019; last revision received Aug 16, 2019; accepted Aug 30, 2019.
References 1. Stoll BJ, Hansen NI, Bell EF, Walsh MC, Carlo WA, Shankaran S, et al. Trends in care practices, morbidity, and mortality of extremely preterm neonates, 1993-2012. JAMA 2015;314:1039-51. 2. Schmidt B, Asztalos EV, Roberts RS. Impact of bronchopulmonary dysplasia, brain injury, and severe retinopathy on the outcome of extremely low-birth-weight infants at 18 months: results from the trial of indomethacin prophylaxis in preterms. JAMA 2003;289:1124-9. 3. Jensen EA, DeMauro SB, Kornhauser M, Aghai ZH, Greenspan JS, Dysart KC. Effects of multiple ventilation courses and duration of mechanical ventilation on respiratory outcomes in extremely low-birthweight infants. JAMA Pediatr 2015;169:1011-7. 4. Gagliardi L, Bellu R, Lista G, Zanini R. Network Neonatale Lombardo Study Group. Do differences in delivery room intubation explain different rates of bronchopulmonary dysplasia between hospitals? Arch Dis Child Fetal Neonatal Ed 2011;96:F30-5. 5. Schmolzer GM, Kumar M, Pichler G, Aziz K, O’Reilly M, Cheung PY. Noninvasive versus invasive respiratory support in preterm infants at birth: systematic review and meta-analysis. BMJ 2013;347:f5980. 6. Fischer HS, Buhrer C. Avoiding endotracheal ventilation to prevent bronchopulmonary dysplasia: a meta-analysis. Pediatrics 2013;132: e1351-60. 7. Wright CJ, Polin RA, Kirpalani H. Continuous positive airway pressure to prevent nonatal lung injury: how did we get here, and how do we improve? J Pediatr 2016;173:17-24.e2. 8. Finer NN, Carlo WA, Walsh MC, Rich W, Gantz MG, Laptook AR, et al. Early CPAP versus surfactant in extremely preterm infants. N Engl J Med 2010;362:1970-9. 9. Fuchs H, Lindner W, Leiprecht A, Mendler MR, Hummler HD. Predictors of early nasal CPAP failure and effects of various intubation criteria on the rate of mechanical ventilation in preterm infants of <29 weeks gestational age. Arch Dis Child Fetal Neonatal Ed 2011;96:F343-7. 10. Dargaville PA, Aiyappan A, De Paoli AG, Dalton RG, Kuschel CA, Kamlin CO, et al. Continuous positive airway pressure failure in preterm
Nasal Intermittent Positive Pressure Ventilation Versus Nasal Continuous Positive Airway Pressure to Prevent Primary Noninvasive Ventilation Failure in Extremely Low Birthweight Infants
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11.
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infants: incidence, predictors and consequences. Neonatology 2013;104: 8-14. De Jaegere AP, van der Lee JH, Cante C, van Kaam AH. Early prediction of nasal continuous positive airway pressure failure in preterm infants less than 30 weeks gestation. Acta Paediatr 2012;101:374-9. Ammari A, Suri M, Milisavljevic V, Sahni R, Bateman D, Sanocka U, et al. Variables associated with the early failure of nasal CPAP in very low birth weight infants. J Pediatr 2005;147:341-7. Dargaville PA, Gerber A, Johansson S, De Paoli AG, Kamlin CO, Orsini F, et al. Incidence and outcome of CPAP failure in preterm infants. Pediatrics 2016;138:1-10. Meneses J, Bhandari V, Alves JG. Nasal intermittent positive-pressure ventilation vs nasal continuous positive airway pressure for preterm infants with respiratory distress syndrome: a systematic review and metaanalysis. Arch Pediatr Adolesc Med 2012;166:372-6. Aghai ZH, Saslow JG, Nakhla T, Milcarek B, Hart J, Lawrysh-Plunkett R, et al. Synchronized nasal intermittent positive pressure ventilation (SNIPPV) decreases work of breathing (WOB) in premature infants with respiratory distress syndrome (RDS) compared to nasal continuous positive airway pressure (NCPAP). Pediatr Pulmonol 2006;41:875-81. Kirpalani H, Millar D, Lemyre B, Yoder BA, Chiu A, Roberts RS, et al. A trial comparing noninvasive ventilation strategies in preterm infants. N Engl J Med 2013;369:611-20. Lemyre B, Laughon M, Bose C, Davis PG. Early nasal intermittent positive pressure ventilation (NIPPV) versus early nasal continuous positive
18. 19.
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Volume airway pressure (NCPAP) for preterm infants. Cochrane Database Syst Rev 2016;12:CD005384. Bancalari EH, Jobe AH. The respiratory course of extremely preterm infants: a dilemma for diagnosis and terminology. J Pediatr 2012;161:585-8. Lemyre B, Davis PG, de Paoli AG. Nasal intermittent positive pressure ventilation (NIPPV) versus nasal continuous positive airway pressure (NCPAP) for apnea of prematurity. Cochrane Database Syst Rev 2002:CD002272. Lemyre B, Davis PG, De Paoli AG, Kirpalani H. Nasal intermittent positive pressure ventilation (NIPPV) versus nasal continuous positive airway pressure (NCPAP) for preterm neonates after extubation. Cochrane Database Syst Rev 2017;2:CD003212. Silveira CS, Leonardi KM, Melo AP, Zaia JE, Brunherotti MA. Response of preterm infants to 2 noninvasive ventilatory support systems: nasal CPAP and nasal intermittent positive-pressure ventilation. Respir Care 2015;60:1772-6. Rysavy MA, Bell EF, Iams JD, Carlo WA, Li L, Mercer BM, et al. Discordance in antenatal corticosteroid use and resuscitation following extremely preterm birth. J Pediatr 2019;208:156-62.e5. Sandri F, Plavka R, Ancora G, Simeoni U, Stranak Z, Martinelli S, et al. Prophylactic or early selective surfactant combined with nCPAP in very preterm infants. Pediatrics 2010;125:e1402-9. Rocha G, Flor-de-Lima F, Proenca E, Carvalho C, Quintas C, Martins T, et al. Failure of early nasal continuous positive airway pressure in preterm infants of 26 to 30 weeks gestation. J Perinatol 2013;33:297-301.
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Figure 2. Time to noninvasive failure within 7 days of randomization, stratified by birth weight group.
Table I. Selected baseline maternal and infant demographics and clinical characteristics Demographic and clinical characteristics Maternal race/ethnicity White Black Asian Other Antenatal corticosteroids Yes No Chorioamnionitis Yes No Unknown Delivery mode Vaginal delivery Cesarean delivery Sex Male Female Birthweight (g)* <800 g – no. (%) 800-999 g – no. (%) Gestational age (completed wk)* Caffeine therapy Yes No SNAP II score† Age at randomization (h)* Respiratory support at randomization NIPPV NCPAP Low flow nasal cannula None Unknown
NIPPV (n = 69)
NCPAP (n = 73)
38 (55.1%) 18 (26.1%) 9 (13.0%) 4 (5.8%)
50 (68.5%) 15 (20.6%) 4 (5.5%) 4 (5.5%)
67 (97.1%) 2 (2.9%)
70 (95.9%) 3 (4.1%)
8 (11.6%) 58 (84.1%) 3 (4.4%)
10 (13.7%) 56 (76.7%) 7 (9.6%)
20 (29.4%) 48 (70.6%)
16 (21.9%) 57 (78.1%)
36 (52.7%) 33 (47.8%) 905 (800, 960) 18 (26.1%) 51 (73.9%) 27 (26, 28)
31 (42.5%) 42 (57.5%) 875 (780, 940) 20 (27.4%) 53 (72.6%) 28 (26, 29)
45 (65.2%) 24 (34.8%) 35.2 9.4 15.4 (8.6, 22.9)
44 (60.3%) 29 (39.7%) 36.7 9.8 19.8 (7, 26.2)
8 (11.6%) 60 (87%)
9 (12.3%) 62 (84.9%) 1 (1.4%)
P value .30
.70 .42
.31 .25 .25 .51 .54
0 1 (1.4%) 0
.35 .29 .56
0 1 (1.4%)
*Median (IQR). †Mean SD.
Nasal Intermittent Positive Pressure Ventilation Versus Nasal Continuous Positive Airway Pressure to Prevent Primary Noninvasive Ventilation Failure in Extremely Low Birthweight Infants
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B
ronchopulmonary dysplasia (BPD) remains the most common chronic morbidity for preterm infants, affecting 40% of infants born at 22-28 weeks of gestation.1,2 Exposure to invasive mechanical ventilation is a significant risk factor for developing BPD,3,4 and strategies such as the routine use of nasal continuous positive airway pressure (NCPAP),1 are critical to BPD prevention. When compared with intubation and surfactant administration, the use NCPAP reduces the need for postnatal corticosteroids, results in fewer days of mechanical ventilation, and decreases death and the combined outcome of death or BPD.5-8 However, NCPAP failure remains common in the extremely low birthweight (ELBW) population. When NCPAP is used as the primary respiratory support, defined as the first mode of respiratory support following admission, failure rates approach 50%, with rates increasing with progressive prematurity.9-13 Compared with NCPAP, potential advantages of nasal intermittent positive-pressure ventilation (NIPPV) include increased tidal volume and minute ventilation and improved oxygen saturation.14,15 The use of NIPPV as primary respiratory support is one strategy that may help delay or avoid intubation and exposure to mechanical ventilation.14,16 Pooling available randomized controlled trial data, a Cochrane review concluded that when compared with NCPAP, NIPPV prevented intubation of preterm infants, with an overall risk ratio of 0.78 (95% CI 0.64-0.94).17 However, this meta-analysis included few ELBW infants and included infants previously intubated for surfactant administration. The conclusions that NIPPV is superior to NCPAP for the prevention of intubation may not generalize to ELBW infants who do not require immediate endotracheal intubation for surfactant administration and/or mechanical ventilation in
BPD ELBW NCPAP NIPPV PMA
Bronchopulmonary dysplasia Extremely low birthweight Nasal continuous positive airway pressure Nasal intermittent positive-pressure ventilation Postmenstrual age
the early postnatal period.18 The primary objective of this study was to compare noninvasive ventilation failure rates (by day 7 of randomization) in intubation-na€ıve ELBW infants randomized to NIPPV vs NCPAP. Our secondary objectives were to compare time to noninvasive failure and etiologies of noninvasive ventilation failure between groups.
Methods We performed a secondary cohort study using NIPPV randomized control trial data. The NIPPV trial (NCT00433212) was conducted between 2007 and 2011 and enrolled a total of 1009 ELBW infants, randomized to either NCPAP or NIPPV. Inclusion criteria were birth weight <1000 g, gestational age <30 weeks, and eligible for noninvasive ventilation within the first 28 days of life.16 For this secondary analysis, inclusion was restricted to infants who were never intubated prior to enrollment and randomization. The primary exposure was noninvasive respiratory support with either NIPPV or NCPAP. The primary outcome was failure of the noninvasive route of respiratory support, defined as endotracheal intubation at any time in the first 7 days after randomization. Prespecified secondary outcomes included time to death or noninvasive respiratory support failure, death at <36 weeks of postmenstrual age (PMA), the combined outcome of death or BPD at 36 weeks of PMA, and etiologies of failure. BPD was defined, as in the original trial, by the receipt of any form of positive-airway-pressure support or
From the 1Section of Neonatology, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO; 2Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada; 3Division of Neonatology, Children’s Hospital of Philadelphia, Philadelphia, PA; 4Department of Pediatrics, Division of Neonatology, University of Ottawa, Ottawa, Ontario, Canada; and 5Department of Neonatology, Royal Maternity Hospital, Belfast, United Kingdom Original NIPPV trial supported by the Canadian Institutes of Health Research (MCT80246). D.M. has received honoraria and travel expenses from Cheisi Ltd UK for teaching on management courses for senior trainees in neonatal medicine. C.W. serves on the Editorial Board for The Journal of Pediatrics. The authors declare no conflicts of interest. 0022-3476/$ - see front matter. ª 2019 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.jpeds.2019.08.064
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supplemental oxygen at 36 weeks of PMA. Etiologies of failure included apnea/bradycardia; increased oxygen requirements; hypercarbia; aspiration; sepsis; procedures or surgery; fatigue; increased work of breathing; nasal excoriation; acute lung deterioration (including pneumothorax and pulmonary hemorrhage); and medication side effect. More than 1 etiology was possible. We describe the most common etiologies, occurring in ³20% of failures. Statistical Analyses For the outcome of time to death or noninvasive failure, we performed a survival analysis with death or endotracheal intubation, with time measured as days from enrollment up to a maximum of 7 days. Groups were compared through the log-rank test for equality of survivor functions estimated as Kaplan‒Meier curves. We tested the proportional hazard assumption through Schoenfeld residuals. We performed stratified analyses by birthweight (less or greater than 800 g) and prerandomization receipt of caffeine, and tested for interactions between allocation and stratifying variables through Cox proportional hazards models. For all other comparisons, we used c2chi-square or Fisher exact tests (if expected cell sizes were less than 5) for categorical variables and the Wilcoxon rank-sum test for continuous variables. Statistical analyses were performed with STATA v 14 (StataCorp, College Station, Texas). The use of deidentified data from the NIPPV trial was designated as nonhuman subjects research by Institutional Review Board of the Children’s Hospital of Philadelphia.
Results Of the 1009 ELBW infants enrolled in the NIPPV trial, we included 142 infants never intubated prior to randomization; 69 were randomized to NIPPV and 73 were randomized to NCPAP. Mean age at randomization was 15.4 hours in the NIPPV group vs 19.8 hours in the NCPAP group (P = .29). There was no significant difference in the baseline maternal and infant demographic and clinical characteristics between groups (Table I; available at www.jpeds.com). For the primary outcome, 27.5% (19 of 69) of the infants in the NIPPV group and 30.1% (22 of 73) of the infants in the NCPAP group experienced failure of noninvasive support within the first 7 days after randomization with a relative risk of 0.91 (95% CI 0.54-1.53). Time to noninvasive failure within 7 days of randomization is depicted in Figure 1, hazard ratio 1.09 (95% CI 0.59-2.01, log-rank P = .79). The incidence rate for the NIPPV cohort was 5.0 failures/100 days at risk (19 failures/ 379.15 days at risk) vs 5.7 failures/100 days at risk (22 failures/387.71 days at risk) for the NCPAP cohort. No infants eligible for this analysis died within 7 days of enrollment. Death prior to 36 weeks of PMA occurred in 1.4% (1 of 69) of infants randomized to NIPPV vs 4.1% (3 of 73) in the infants randomized to NCPAP; risk ratio 0.35 (95% CI 0.04-3.31). The combined outcome of death prior to 36 weeks of PMA or BPD was not different in the 2
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NIPPV vs CPAP groups (19.7% [13 of 66] vs 16.7% [12 of 72], respectively; risk ratio 1.18 [95% CI 0.58-2.40]). The most frequently observed etiologies of noninvasive failure did not differ by treatment allocation and included apnea/ bradycardia, increased oxygen, and increased work of breathing (Table II). There was no significant difference in postrandomization air-leak syndrome between NIPPV and NCPAP groups (2.9% [2 of 69] vs none ([0 of 73], respectively, P = .23). For analyses stratified by birthweight and prerandomization administration of caffeine, there were no significant interactions in overall noninvasive failure rates within 7 days of randomization (Figure 2; available at www.jpeds.com).
Discussion In this secondary analysis of a large multicenter international randomized controlled trial, we found no significant differences in failure rates over the first 7 days of life between NIPPV vs NCPAP as primary noninvasive respiratory support in intubation and surfactant na€ıve ELBW infants. The comparative use of NIPPV vs NCPAP for noninvasive support for preterm infants is well reported, with data supporting the use of NIPPV for prevention of both extubation failure and decreased frequency of apnea of prematurity.19,20 Early use of NIPPV to prevent respiratory failure and need for intubation in the first week of life has also been evaluated in systematic reviews and found to be superior when compared with NCPAP.17,21 However, these reviews examined a large population, with a preponderance of more mature infants. Furthermore, these studies did not assess the comparative effectiveness of NCPAP vs NIPPV as primary respiratory support in a population with a goal to completely avoid invasive respiratory support. The NIPPV trial enrolled a less mature population than other trials comparing NIPPV to NCPAP, with an average gestational age of 26 weeks and a mean birth weight of approximately 800 g. The outcome of noninvasive failure has previously been evaluated as a dichotomous outcome occurring within a predefined period, without specific attention to the time until failure. In ELBW infants, delaying endotracheal intubation and mechanical ventilation in the first few critical days may be particularly beneficial.3 We, therefore, used a time-toevent survival analysis to examine avoiding this potentially injurious exposure and did not find a difference between treatment groups for this outcome. Our study is limited by a relatively small sample size that lacks power to detect small but clinically important differences between groups. In addition, this cohort received antenatal corticosteroids at very high rates (97.1% of infants in the NIPPV group, 95.9% of infants in the NCPAP group) that may not be generalizable to the broader ELBW infant population. For instance, during a similar time period to the NIPPV trial, the Neonatal Research Network reported an antenatal corticosteroid administration rate of 78.3% for infants 22-26 weeks of gestational age.22 Others have Bourque et al
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Figure 1. Time to noninvasive failure within 7 days of randomization.
Reprint requests: Stephanie L. Bourque, MD, MSCS, Section of Neonatology, Department of Pediatrics, University of Colorado School of Medicine, Neonatology MS 8402, 13121 E 17th Ave, Aurora, CO 80045. E-mail: [email protected]
Table II. Etiologies of noninvasive failure by allocation* Etiologies Apnea/bradycardia Increased oxygen Increased work of breathing
NIPPV no/ total no (%)
NCPAP no./ total no. (%)
P value
10/19 (52.6%) 13/19 (68.4%) 10/19 (52.6%)
10/22 (45.4%) 15/22 (68.2%) 9/22 (40.9%)
.65 .99 .45
*Includes etiologies present in ³20% of cases, multiple etiologies per failure allowed.
demonstrated that primary NCPAP failure in such immature infants typically occurs within 4-6 hours after delivery,9,11,23,24 and infants experiencing noninvasive respiratory support failure very early in the postnatal period are not represented in this cohort of infants who did not undergo endotracheal intubation between birth and study enrollment. However, our study population captures subjects for whom there would be sufficient time to evaluate the relative benefit of NIPPV over NCPAP, making the comparison relevant to practice. In conclusion, we found no significant improvement in the prevention of noninvasive failure with the use of NIPPV as a primary respiratory support modality in intubation and surfactant na€ıve ELBW infants. Our data do not support the routine use of NIPPV over NCPAP for primary respiratory support in this population. Further research is needed to investigate strategies to improve noninvasive ventilation success in the high-risk ELBW population. n We acknowledge the original NIPPV trial group including Aaron Chiu MD, and Bradley Yoder, MD. Submitted for publication Jun 17, 2019; last revision received Aug 16, 2019; accepted Aug 30, 2019.
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BRIEF REPORTS
Figure 2. Time to noninvasive failure within 7 days of randomization, stratified by birth weight group.
Table I. Selected baseline maternal and infant demographics and clinical characteristics Demographic and clinical characteristics Maternal race/ethnicity White Black Asian Other Antenatal corticosteroids Yes No Chorioamnionitis Yes No Unknown Delivery mode Vaginal delivery Cesarean delivery Sex Male Female Birthweight (g)* <800 g – no. (%) 800-999 g – no. (%) Gestational age (completed wk)* Caffeine therapy Yes No SNAP II score† Age at randomization (h)* Respiratory support at randomization NIPPV NCPAP Low flow nasal cannula None Unknown
NIPPV (n = 69)
NCPAP (n = 73)
38 (55.1%) 18 (26.1%) 9 (13.0%) 4 (5.8%)
50 (68.5%) 15 (20.6%) 4 (5.5%) 4 (5.5%)
67 (97.1%) 2 (2.9%)
70 (95.9%) 3 (4.1%)
8 (11.6%) 58 (84.1%) 3 (4.4%)
10 (13.7%) 56 (76.7%) 7 (9.6%)
20 (29.4%) 48 (70.6%)
16 (21.9%) 57 (78.1%)
36 (52.7%) 33 (47.8%) 905 (800, 960) 18 (26.1%) 51 (73.9%) 27 (26, 28)
31 (42.5%) 42 (57.5%) 875 (780, 940) 20 (27.4%) 53 (72.6%) 28 (26, 29)
45 (65.2%) 24 (34.8%) 35.2 9.4 15.4 (8.6, 22.9)
44 (60.3%) 29 (39.7%) 36.7 9.8 19.8 (7, 26.2)
8 (11.6%) 60 (87%)
9 (12.3%) 62 (84.9%) 1 (1.4%)
P value .30
.70 .42
.31 .25 .25 .51 .54
0 1 (1.4%) 0
.35 .29 .56
0 1 (1.4%)
*Median (IQR). †Mean SD.
Nasal Intermittent Positive Pressure Ventilation Versus Nasal Continuous Positive Airway Pressure to Prevent Primary Noninvasive Ventilation Failure in Extremely Low Birthweight Infants
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