Pediatric Pulmonology 49:673–678 (2014)
A Prospective, Randomized, Controlled Study of NIPPV Versus nCPAP in Preterm and Term Infants With Respiratory Distress Syndrome Yuan Shi,
MD, PhD*,
Shifang Tang,
MD,
Jinning Zhao,
MD,
Jie Shen,
MD
Summary. Objective: To evaluate whether nasal intermittent positive pressure ventilation (NIPPV) compared with nasal continuous positive airway pressure (nCPAP) decreases the requirement for endotracheal ventilation in preterm and term infants with respiratory distress syndrome (RDS). Methods: This was a single center, randomized, controlled trial. A total of 179 preterm and term infants with RDS were randomized to NIPPV (n ¼ 88) or nCPAP (n ¼ 91). The clinical data of enrolled infants including blood gas analysis, PaO2/FiO2 ratio, incidence of intubation, and complications, if occurred, were recorded. The primary outcome was the need for endotracheal ventilation. The secondary outcome was the measurement of favorable outcome, which was defined as discharged without any respiratory support and feeding well and gaining weight. Analysis followed slightly modified intention to treat principle. Results: Significantly less number of infants randomized to NIPPV group required intubation and mechanical ventilation compared with nCPAP group (11.4% vs. 20.9%, P < 0.05). A favorable outcome was more likely in infants randomized to NIPPV (93.2% vs. 84.6%, P < 0.05). In subgroup analysis, NIPPV was associated with reduced need for intubation in preterm (9.9% vs. 19.2%) and term (17.6% vs. 27.8%) infants, but the difference was statistically significant only in preterm infants(P < 0.05). Conclusion: Treatment with NIPPV compared with nCPAP decreased the need for endotracheal ventilation and increased favorable outcome in preterm and term infants with RDS. Pediatr Pulmonol. 2014; 49:673–678. ß 2013 Wiley Periodicals, Inc. Key words: infant; newborn; neonatal respiratory distress syndrome; mechanical ventilation; nasal intermittent positive pressure ventilation; nasal continuous positive airway pressure. Funding source: none reported
INTRODUCTION
Nasal intermittent positive pressure ventilation (NIPPV) is widely used as non-invasive support for preterm infants with respiratory distress syndrome (RDS) in neonatal intensive care unit (NICU). As compared with nasal continuous positive airway pressure (nCPAP), NIPPV was suggested to decrease the need for endotracheal ventilation. Several mechanism have been proposed for the beneficial effects of NIPPV.1–3 NIPPV was reported to be associated with increased flow delivery
Department of Pediatrics, Daping Hospital, Third Military Medical University, Chongqing, China. Contributor’s Statement: Yuan Shi was responsible for writing the submitted paper. Shifang Tang and Jinning Zhao were responsible for all data collection. Jie Shen was responsible for computer-related work. Trial registration: clinicaltrials.gov (Protocol ID: NCR 2008053, ClinicalTrials.gov ID: NCT 00780624). Conflict of interest: None.
ß 2013 Wiley Periodicals, Inc.
in the upper airway, increased tidal and minute volumes, increased functional residual capacity, recruitment of collapsed alveoli, improved stability of the chest wall and less asynchrony of thoraco-abdominal movement in newborn infants.4 A few studies have compared NIPPV with nCPAP in neonates with RDS,5–8 but these reports focused on preterm infants. Up to now, there have been no reports in term infants.9 The significant burden of RDS in late-preterm and term infants has been well documented.10 Moreover, RDS in term infants has been shown to have unique characteristics that differed from
Correspondence to: Yuan Shi, MD, PhD, Director and Professor, Department of Pediatrics, Daping Hospital, Third Military Medical University, Chongqing 400042, China. E-mail:
[email protected] Received 5 February 2013; Accepted 29 June 2013. DOI 10.1002/ppul.22883 Published online 4 September 2013 in Wiley Online Library (wileyonlinelibrary.com).
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preterm infants.11 In addition to pulmonary surfactant deficiency, other factors were suggested to be important in the pathogenesis of RDS in term infants.12 The objective of this study was to compare NIPPV with nCPAP in preterm and term infants with RDS on the subsequent need for intubation and mechanical ventilation (MV). We tested the hypothesis that NIPPV reduces the need for endotracheal ventilation in infants with RDS as a primary respiratory support in the early life. METHODS Study Design and Participants
This was a single-center, randomized controlled trial (RCT) conducted in a tertiary NICU from January 2008 to December 2010 at Daping Hospital, Third Military Medical University. The trial was approved by the ethics committee of the hospital and registered with clinicaltrials.gov (Protocol ID: NCR 2008053, ClinicalTrials.gov ID: NCT 00780624). The NICU admitted both in-born infants and out-born infants transported from 61 hospitals in Chongqing and nearby areas. All the out-born infants were transported by an ambulance staffed by a transport team consisting of one neonatologist and one or two nurses. Preterm or term infants diagnosed with RDS were eligible. Preterm was defined as any infant born 37 weeks. The diagnosis of RDS was based on clinical manifestations and chest Xray findings.13 The clinical signs and symptoms of RDS were respiratory distress, tachypnea, nasal flaring, groan, and cyanosis after birth. The typical X-ray picture of RDS showed a grain shadow, air bronchogram, and white lung. X-rays were judged by two radiologists blinded to the patient’s condition. Infants were excluded from this study if they were not fit for the use of NIPPVand met any of the following criteria: major congenital anomalies, respiratory distress caused by infection, perinatal asphyxia, meconium aspiration, and transient tachypnea without evidence of RDS, consent not provided or refused, and intubation at admission to the NICU because of severe conditions such as clinically severe respiratory distress with severe respiratory acidosis (PaCO2 > 60 mmHg), neonatal pulmonary hemorrhage, cardiopulmonary arrest without effective resuscitation needing continued ventilation and rescue, and died or left the NICU within 24 hr after admission. Allocation and Blinding. After documenting parental consent, eligible infants were randomly assigned to NIPPV or nCPAP using a table of random numbers concealed in opaque envelops. Blinding was not possible due to the nature of the intervention. Study Intervention. A time-cycled, pressure-limited, and continuous-flow neonatal ventilator (Babylog 8000, Dra¨ger, Lubeck, Germany) was used for infants assigned Pediatric Pulmonology
to the NIPPV group in a non-synchronized mode. The initial settings were: frequency of 10–20 breaths/min, peak inspiratory pressure (PIP) of 15–20 cm H2O, and positive end expiratory pressure (PEEP) of 4–6 cm H2O. The fraction of inspired oxygen (FiO2) was regulated from 0.25 to 0.50 in order to maintain oxygen saturation (SpO2) from 90% to 95% by a pulse oximeter. Infants assigned to the nCPAP group were initiated on a pressure of 4–6 cm H2O by bubble CPAP system (Stephan Fritz Stephan GmbH, Gackenbach, Germany), with FiO2 from 0.25 to 0.50 to maintain SpO2 from 90% to 95%. When the infant was admitted to the NICU and had fulfilled the entry criteria, NIPPV or nCPAP, was started immediately based on the group assignment. Other care was at the discretion of the attending neonatologist. Pulmonary surfactant (Curosurf, Chiesi Pharmaceuticals, Parma, Italy) was administered with a dosage of 100 mg/ kg as a rescue treatment if an infant needed FiO2 0.50 to maintain the targeted SpO2. Clinical Data. The clinical data of all enrolled infants were recorded including gestational age, birth weight, age, gender, score for neonatal acute physiology-Version II (SNAP-II),14 pulmonary surfactant, arterial blood gas analysis before and after the treatment, PaO2/FiO2 ratio, incidence of intubation, and complications. Evaluation of Outcomes. The primary outcome of this study was to determine the need for endotracheal intubation and MV in infants randomized to the two groups. Infants were intubated if they did not improve and needed MV, which was based on the standard indication.15 The criteria for intubation and MV were as follows: severe respiratory acidosis (PaCO2 > 60 mmHg), severe apnea and bradycardia (defined as recurrent apnea with >3 episodes per hour associated with heart rate 0.5), severe respiratory distress, neonatal pulmonary hemorrhage, and cardiopulmonary arrest without effective resuscitation needing continued ventilation and rescue. A favorable outcome was defined as discharged without any respiratory support and feeding well and gaining weight. An unfavorable outcome was defined as death or continued admission in the NICU or discharged with continued need for respiratory support. Other secondary outcomes included arterial blood gases before and after the treatment, PaO2/FiO2 ratio, and complications. Sample Size Estimation. The sample size estimation was calculated by PASS software (2008 v8.0.3). Based on previous reports on an average 40% failure rate by using nCPAP,5–8 Z-pooled appropriate test determined that a minimized sample size of 56 participants (28 participants in each group) would be required to demonstrate a 10% reduction in the failure rate by using NIPPV as a
NIPPV vs. nCPAP in Preterm and Term Infants
respiratory support, with a power of 80% and two-tailed significant level of 0.05 using Fisher’s test. In order to ensure the reliability, 78 infants were estimated to be enrolled in the study. Statistical Analysis. Continuous variables were compared using the Student’s t-test while Categorical variables were compared using the Fisher’s test. Differences in the primary and other categorical outcomes were estimated together with 95% confidence intervals. Predefined subgroup analysis was conducted for the primary outcome in preterm and term infants. Logistic regression analysis was used to control for related clinical factors. All tests were two-tailed and results with P-value < 0.05 were considered significant. RESULTS
During 3 years, 5,018 neonates were admitted to the NICU and 219 (4.4%) infants were diagnosed with RDS (Fig. 1). Thirty infants were not fit for non-invasive respiratory support and excluded based on the following criteria: severe respiratory acidosis (PaCO2 > 60 mmHg, n ¼ 22), cardiopulmonary arrest without effective resuscitation (n ¼ 4), known major congenital anomalies (n ¼ 3), and neonatal pulmonary hemorrhage (n ¼ 1). The remaining 189 neonates were randomly pre-assigned to NIPPV (n ¼ 93) and nCPAP (n ¼ 96). Analysis according to the intention to treat principle was considered to be the most proper way of analyzing RCT results. Data analyses followed the intention to treat principle. However, post-randomization exclusions unrelated to non-compliance, withdrawal, or losses to follow up were considered, which have been suggested to be described as slightly modified intention to treat principle.16 These unbiased exclusions occurred when patients
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were inappropriately randomized into this clinical trial or when pre-randomization information on their eligibility status was not available at the time of pre-randomization.17 Five infants in the NIPPV group and five infants in the nCPAP group had to be excluded from the trial after pre-randomization because they met the exclusion criteria mentioned above. Reasons for exclusion were: four infants left the NICU within 24 hr, three infants with severe congenital malformations, and three infants died within 24 hr because of severe congenital heart diseases and cardiopulmonary arrest. This procedure of post-randomization exclusions was in accord with the specification of slightly modified intention to treat principle and excluding patients from analysis.16,17 Finally, the trial included 88 infants in NIPPV group and 91 infants in nCPAP group. Among them, there were 71 preterm infants and 17 term infants in NIPPV group, whereas 73 preterm and 18 term infants comprised nCPAP group. Baseline demographic and clinical characteristics were similar in the two groups (Table 1). There were no significant differences in gender, gestational age, ratio of preterm to term, birth weight, 5 min Apgar score, SNAPII and use of pulmonary surfactant between NIPPV and nCPAP groups. There were also no significant differences in blood pH, PaO2, PaCO2, and PaO2/FiO2 ratio before the treatment between the two groups (Table 2). No complications associated with NIPPV or nCPAP were found. For the primary outcome, significantly less number of infants randomized to NIPPV group required intubation and MV compared with nCPAP group (11.4% vs. 20.9%, P < 0.05). In planned subgroup analysis, over 80% of the infants were preterm. NIPPV was associated with reduced need for intubation in preterm (9.9% vs. 19.2%) and term (17.6% vs. 27.8%) infants, but the difference was TABLE 1— The Demographic and Clinical Characteristics of NIPPV and nCPAP Groups
Gender (M/F) Preterm/term GA (weeks) Age (hr) Birth weight (g) Cesarean section/vaginal In-born/out-born 5 min Apgar score SNAP-II Surfactant (%)
Fig. 1. CONSORT flow diagram of the participants.
NIPPV group (n ¼ 8)
nCPAP group (n ¼ 91)
52/36 71/17 34.32 2.79 19.89 18.71 2,421.25 743.56 45/43 11/77 8.55 1.38 14.86 11.32 75 (82.7%)
54/37 73/18 34.20 4.06 21.67 21.25 2,349.66 775.79 45/46 10/81 8.62 1.44 13.48 10.68 76 (83.5%)
P-value 0.75 0.74 0.82 0.55 0.53 0.74 0.59 0.74 0.40 0.60
NIPPV, nasal intermittent positive pressure ventilation; nCPAP, nasal continuous positive airway pressure; M, male; F, female; GA, gestational age; SNAP-II, score for neonatal acute physiology— version II.
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TABLE 2— Blood Gas Analysis and PaO2/FiO2 Ratio Before and After Treatment in NIPPV and nCPAP Groups NIPPV group (n ¼ 88)
nCPAP group (n ¼ 91)
pH, before treatment 7.20 0.10 7.22 0.08 pH, 1 hr after treatment 7.38 0.05 7.35 0.04 50.91 11.17 50.19 11.27 PaO2 (mmHg), before treatment PaO2 (mmHg), 59.39 12.44 55.86 10.88 1 hr after treatment 49.32 7.79 48.97 8.35 PaCO2 (mmHg), before treatment PaCO2 (mmHg), 40.75 6.22 39.95 8.15 1 hr after treatment P/F (mmHg), 203.02 108.91 196.20 99.13 before treatment P/F (mmHg), 273.61 92.11 236.16 93.41 1 hr after treatment
P-value 0.42 0.0000 0.67 0.04 0.77 0.46 0.66 0.01
NIPPV, nasal intermittent positive pressure ventilation; nCPAP, nasal continuous positive airway pressure; P/F, PaO2/FiO2 ratio.
statistically significant only in preterm infants (P < 0.05). A favorable outcome, defined as discharged without any respiratory support and feeding well and gaining weight, was more likely in infants randomized to NIPPV group (93.2% vs. 84.6%, P < 0.05). Similarly, the favorable outcome was found to be more likely to be associated with NIPPV in both preterm (94.4% vs. 84.9%) and term (88.2% vs. 83.3%) infants, but the difference was statistically significant only in preterm infants (P < 0.05; Table 3). The multivariable analysis using binary logistic regression was used to control for important clinical factors listed in Table 1 including gestational age, birth weight, ratio of preterm to term, birth weight, 5 min Apgar score, severity of illness indicated by SNAP-II, and use of pulmonary surfactant. Two variables: the respiratory support mode by NIPPV or nCPAP (P < 0.05, OR ¼ 2.467, 95% CI: 1.018–5.980) and the severity of illness indicated by SNAP-II score (P < 0.05, OR ¼ 1.047, 95% CI: 1.006–1.090) were found to be associated with the TABLE 3— Major Outcomes and Prognosis in the NIPPV and nCPAP Groups NIPPV group No need for endotracheal ventilation Preterm infants Term infants Favorable outcome Preterm infants Term infants
nCPAP group
P-value
88.6% (78/88) 79.1% (72/91)
0.03
90.1% 82.4% 93.2% 94.4% 88.2%
0.04 0.35 0.03 0.03 0.56
(64/71) (14/17) (82/88) (67/71) (15/17)
80.8% 72.2% 84.6% 84.9% 83.3%
(59/73) (13/18) (77/91) (62/73) (15/18)
NIPPV, nasal intermittent positive pressure ventilation; nCPAP, nasal continuous positive airway pressure.
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primary outcome of need for intubation, whereas there was no significant association with other factors. DISCUSSION
Results of this single-center randomized trial showed that NIPPV significantly reduced the need for MV and improved the overall outcomes as compared with nCPAP in preterm and term infants with RDS. The benefit of NIPPV was noted in sub-group analysis for both preterm and term infant, although the difference was not statistically significant in term infants. Similarly, a favorable outcome was higher in both preterm and term infants, but not statistically significant in the term subgroup. Because of small sample size in the term subgroup, the effect of NIPPV in the term infants needs to be studied further. A few reports suggested that NIPPV might have a better effect than nCPAP in reducing the need for MV. However, these studies have been mainly focused on preterm infants, especially extremely preterm infants.5–8 To our knowledge, these has been no report on term infants.18,19 Recently, the burden of RDS in late-preterm and term infants has been highlighted.20 In addition to pulmonary surfactant deficiency, other reasons including cesarean section without labor and deficient clearance of lung fluid, were suggested to explain the pathogenesis of RDS in late-preterm and term infants.12,21 Mortality as a result of RDS has been reduced because of prenatal glucocorticoids, postnatal pulmonary surfactants and MV, but lung injury such as bronchopulmonary dysplasia (BPD) associated with prolonged use of MV might lead to unfavorable outcomes. nCPAP is widely used as a non-invasive respiratory supportive mode for RDS.22 However, nCPAP could not consistently improve ventilation and take effect in newborn infants with poor respiratory effort. In fact, as many as 55% preterm infants at the gestational age of 25–26 weeks and 40% of 27–28 weeks gestational age infants treated with nCPAP developed respiratory failure and needed MV within 5 days.23 NIPPV was assumed to transmit the nasal pressure to the lower airways, enhance tidal volume and minute ventilation, reduce apnea episodes, induce better alveolar recruitment and higher lung volume, help with gas exchange and decrease anatomical dead space.1–4,9,24 Thus, NIPPV has been suggested to have some stronger respiratory supportive effect than nCPAP.25 NIPPV was confirmed to decrease the work of breathing in preterm infants with RDS as compared with nCPAP.26 A very recent study in preterm infants with RDS receiving early surfactants indicated that, compared with nCPAP, NIPPV reduced the need for MV in the first week, decreased the duration of MV, and lowered clinical and physiological BPD.27 The present study involving both preterm and term infants showed that NIPPV could significantly reduce the need for MVand have a better prognosis compared with nCPAP.
NIPPV vs. nCPAP in Preterm and Term Infants
The limitation and weakness of this RCT was that it was a non-blinded study, and the allocation concealment was not performed. Until now, only one RCT study investigated a comparison of NIPPV and MV in preterm infants after pulmonary surfactant administration,28 which suggested that the group treated by NIPPV had a shorter duration of hospitalization, lower BPD and mortality than the group treated by MV. A prospective observational pilot study also suggested that NIPPV was a safe and effective primary mode of ventilation in premature infants.29 NIPPV could reduce the need for intubation and ventilation and finally reduce the complications associated with endotracheal ventilation.30 In conclusion, results of this randomized controlled trial suggest that NIPPV reduce the need for endotracheal ventilation and improve short term neonatal outcomes in preterm and term infants with RDS compared with nCPAP. Further studies, preferably multicenter RCT are needed to assess the effectiveness of NIPPV in preterm and term infants.
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