http://informahealthcare.com/jmf ISSN: 1476-7058 (print), 1476-4954 (electronic) J Matern Fetal Neonatal Med, Early Online: 1–6 ! 2014 Informa UK Ltd. DOI: 10.3109/14767058.2014.997203
ORIGINAL ARTICLE
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Nasal intermittent positive pressure ventilation with or without very early surfactant therapy for the primary treatment of respiratory distress syndrome _scan, Mustafa Dilek, Nuray Duman, Funda Tu¨zu¨n, Ali Haydar Sever, Meltem Koyuncu Arslan, Burc¸in I¸ Abdullah Kumral, and Hasan Ozkan Department of Pediatrics, Faculty of Medicine, Dokuz Eylul University, Izmir, Turkey
Abstract
Keywords
Aim: Current evidence suggests that nasal intermittent positive pressure ventilation (NIPPV) as a primary treatment for RDS reduces the duration of invasive mechanical ventilation (MV) comparing with nasal continuous airway pressure (NCPAP). We aimed to evaluate whether very early surfactant treatment decreases the need for MV when used in premature infants treated with early NIPPV soon after birth. Methods: The inclusion criteria of this prospective cohort study were a gestational age of 24–316/7 weeks and supplemental oxygen with the evidence of labored breathing within 60 min. Infants were stabilized on NCPAP and then continued with NIPPV, following early surfactant treatment, or were only put on NIPPV. Thirty infants in the NIPPV group and 29 infants in the NIPPV + SURFACTANT group met the inclusion criteria. Primary end-point was the need of MV in the first 72 h of life according to the predefined criteria. Results: The failure rate was significantly lower in the NIPPV + SURFACTANT group compared with the NIPPV group (37.9% and 66.7% respectively, p50.05). All other results, including bronchopulmonary dysplasia and death, were similar between the groups. Conclusion: NIPPV failure was significantly lower when combined with surfactant treatment, which indicates the critical role of early surfactant treatment in reducing the need for invasive ventilation.
Bronchopulmonary dysplasia, NIPPV, preterm, respiratory distress syndrome, surfactant
Introduction Respiratory distress syndrome (RDS) is a disease of newborn infants that increases in prevalence with the decreasing of gestational age. Despite the effectiveness of surfactant treatment in the acute phase of RDS and new ventilation techniques, bronchopulmonary dysplasia (BPD) remains an important adverse outcome in preterm infants, and its incidence is correlated with the use of mechanical ventilation [1]. The trend today is to minimize the use of mechanical ventilation and to use nasal respiratory support in premature infants [2]. The most important message of the recently published randomized controlled trials is that an approach that utilizes early nasal continuous airway pressure (NCPAP) is safe in very preterm infants and leads to a reduction in the number of infants who are intubated and given surfactant treatment. However, these studies have also indicated that a significant number of infants treated with early NCPAP
Address for correspondence: Prof. Dr. Hasan Ozkan, Department of Pediatrics, Subdivision of Neonatology, Faculty of Medicine, Dokuz Eylul University, Inciralti 35340, Izmir, Turkey. Tel: +90 232 412 36 43. Fax: +90 232 259 05 41. E-mail: [email protected]
History Received 25 January 2014 Revised 8 October 2014 Accepted 8 December 2014 Published online 26 December 2014
required invasive mechanical ventilation (MV), and early NCPAP did not show a reduction in BPD [3–6]. Efforts to reduce the failure rates of early NCPAP prompted the use of early NIPPV, as it may provide sufficient support to avoid endotracheal intubation in some infants [7]. Although the precise mechanism of action is not known, NIPPV augments the infant’s spontaneous breath efforts by providing a backup rate. Synchronized as well as nonsynchronized NIPPV have been shown to be effective in preterm infants requiring respiratory support by reducing the incidence of apnea of prematurity and atelectasis, improving ventilation–perfusion matching and decreasing extubation failures [8–10]. Randomized controlled studies and meta-analyses comparing NIPPV and NCPAP as primary treatments for RDS suggested that NIPPV reduced the duration of invasive MV. Also, NIPPV might be an important modifier of the outcome of BPD, irrespective of the duration of mechanical ventilation [11–13]. Large randomized trials revealed that prophylactic surfactant treatment, in combination with NCPAP, was not better than NCPAP with selective surfactant treatment in premature infants with RDS [3,4]. However, few randomized studies
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indicated that very-early surfactant treatment in combination with early NCPAP improved outcomes of very preterm babies with RDS [14,15]. None of the published studies addressed the question of whether the addition of very-early surfactant therapy to the early NIPPV may further improve the outcomes of preterm infants with RDS. NIPPV is increasingly being used as a primary treatment during the acute phase of RDS, and the recommendations for early NCPAP may not be applied to early NIPPV. The purpose of this study was to determine whether the addition of very-early surfactant therapy to the early NIPPV is superior to NIPPV alone in its ability to reduce the need of mechanical ventilation in premature infants with RDS.
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Patients and methods This single-center, prospective cohort trial was conducted from December 2010 to December 2012 in a tertiary care neonatal unit in Izmir, Turkey. Inclusion criteria were a gestational age of 24–316/7 weeks, a postnatal age within 60 min, and a supplemental oxygen requirement with evidence of labored breathing with a Silverman Anderson score 43 [16]. Exclusion criteria were an Apgar score of 3 or less at 5 min, a requirement of intubation during the first hour of life, a prenatal or postnatal diagnosis of major congenital malformations, severe cardiovascular instability or poor respiratory efforts, and the absence of parental consent. The Institute Ethics Committee gave ethical approval for the trial. Parental written informed consent was required before delivery of the potentially eligible infants. Baseline variables were recorded: gestation, birth weight, sex, use of antenatal corticosteroids, presence of chorioamnionitis (clinical or histological), mode of delivery, resuscitation details, and Apgar scores. At birth, all infants were resuscitated in a standardized manner according to Neonatal Resuscitation Program guidelines [17]. A constant-flow, positive-pressure ventilation (PPV) system (Neopuff Infant Resuscitator [Fisher & Paykel Healthcare, Inc., Auckland, New Zeeland]) with a peak pressure of 18–20 cm H2O and a positive-end expiratory pressure (PEEP) of 5 cm H2O was used if PPV was needed. Subjects in both groups were initially stabilized with NCPAP with a PEEP of 6 cm H2O. Patients meeting the inclusion criteria were switched to NIPPV within the first hour. The decision for very-early surfactant treatment was left to the preference of the treating medical team. If the clinician decided to administer an early surfactant, a modified natural lung surfactant (Poractant alpha, Curosurf-Chiesi Farmaceutici, Parma, Italy) was administered at a dose of 200 mg/kg in single aliquot. After the surfactant instillation, PPV was administered for 1 min by the Neopuff infant resuscitator, followed by extubation to NIPPV. We used Drager Babylog 8000 plus (Drager Medicals Inc., Lubeck, Germany) ventilators for non-invasive ventilation. Non-invasive support was delivered through bi-nasal prongs (Vygon SA, E´couen, France). In every patient, a 6-french orogastric tube was used and kept open to decompress the stomach. All patients were initiated with the following: a frequency if 40 per min, a peak inspiratory pressure (PIP) of 18 cm of water, PEEP of 6 cm of water, an inspiratory time of 0.4 s with a flow of 6–8 l/min. In neonates weighing 51000 g, the
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maximum permissible PIP was 24 cm, while in those41000 g, it was 26 cm of water. The maximum permissible PEEP was 8 cm of water. Targeted SpO2 saturation was 88–93% during the study period. Settings in both groups were adjusted based on arterialized capillary blood gases (ABG) and clinical parameters. ABG was performed after 40 min of starting respiratory support and then at least every 6 h and as indicated. All participating infants received a loading dose of caffeine (20 mg/kg intravenously), followed by a maintenance dose of 5 mg/kg every 24 h. During weaning, PIP was reduced by decrements of 2 cm H2O until it reached a minimum PIP level of 14 cm (for infants 51000 g) or 18 cm of H2O (for infants 41000 g). The respiratory rate was then reduced by elongating the expiratory time by up to 3 s. Finally, neonates were weaned from a PIP of 14–18 cm, a PEEP of 6 cm, a rate of 18/min and fraction of inspired oxygen (FiO2) of 0.3, with an acceptable ABG. NIPPV for neonates requiring respiratory support after weaning was restarted on initial settings following the first 72 h after weaning. The primary outcome was ‘‘failure’’ of non-invasive respiratory support, necessitating intubation, and mechanical ventilation within the first 72 h after randomization. The criteria for ‘‘failure’’ were the same in both groups and included at least one of (i) PaCO2465 mmHg or pH57.2 or (ii) apneas of more than three episodes per hour (defined as cessation of breathing for 20 s or 520 s if associated with cyanosis and/or bradycardia [heart rate5100 per min]) or (iii) any episode of apnea requiring positive pressure ventilation or (iv) the fraction of the inspired oxygen (FiO2) requirement above 45% to maintain the SpO2 level between 88 and 93%. Surfactant therapy was administered to either group (repeat dose for NIPPV + SURFACTANT and first dose for NIPPV) if the infants needed a FiO2 of 40.45 to maintain the targeted saturation; then they continued with invasive MV. The secondary outcomes were ‘‘failure’’ within the first 7 d, need of surfactant therapy, a hemodynamically significant patent ductus arteriosus (hsPDA) needing medical or surgical treatment, duration of respiratory support, duration of oxygen, need of postnatal steroid therapy, pneumothorax, severe IVH (grades 3 and 4) [18], BPD (oxygen dependency at postnatal week 36) [19], sepsis (blood culture-positive nosocomial sepsis), necrotizing enterecolitis (NEC, Bell stages 2 and 3) [20], length of hospital stay and in-hospital mortality. Statistical analysis Data from the same population in our unit showed that 60% of premature infants that were started on early NIPPV for RDS required invasive mechanical ventilation within 72 h. A sample size of 29 per group was required to detect a 50% absolute-reduction in the need for intubation in the ‘‘NIPPV + SURFACTANT’’ group, with an alpha error of 5% and power of 80%. Statistical analyses were performed using SPSS 15.0 for Windows (SPSS Inc., Chicago, IL). Continuous normally distributed data were analyzed using Students’ t-test. Categorical data were compared between groups using Chi-square tests or, when expected counts were small, Fisher’s exact test. For all tests, two-tailed tests were used.
NIPPV with or without surfactant
DOI: 10.3109/14767058.2014.997203
The Mann–Whitney U-test was used to compare ordinal or non-parametric data. A p value of 50.05 was considered statistically significant. Odds ratios with 95% CI and Chisquare tests were used to compare proportions between the two groups for main dichotomous outcomes and multivariate logistic regression to control for potentially confounding effects of BW and GA. Post hoc analyses were performed for subgroups that were defined by gestational age: infants delivered earlier than 28 weeks’ gestation and those delivered after 28 weeks.
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Results A total of 85 neonates were evaluated, of which 25 were excluded. Of the 59 enrolled neonates, 30 were allocated to the NIPPV group and 29 to the ‘‘NIPPV + SURFACTANT’’ group (Figure 1). The demographic and baseline clinical characteristics were similar in the two groups (Table 1). Primary outcome Eleven (37.9%) infants in the NIPPV + SURFACTANT group needed MV within the first 72 h compared with 20 (66.7%) in the NIPPV group (p ¼ 0.027; OR: 0.27; 95% CI: 0.105– 0.888). When adjusted for gestational age and birth weight, very-early surfactant treatment was still an independent variable for primary outcome (p ¼ 0.014, 95% CI: 1.36– 15.86). However, a post hoc subgroup analysis revealed that in the infants in the subgroup of 528 week, early-surfactant treatment did not have any effect on the MV requirement within the first 72 h, so there was no difference between the two groups in terms of the primary outcome (Table 2). Non-invasive ventilation failed in the first 72 h of life in 31 patients, and 21 (67%) of them required intubation and MV within the first 24 h. The reasons for failure in the NIPPV + SURFACTANT group were an increased FiO2 requirement in four patients, respiratory acidosis in two patients, and frequent/severe apnea in two patients. Three of the infants had more than one criterion for failure in
Figure 1. Infant enrollment into study.
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NIPPV + SURFACTANT. The reasons for failure in the NIPPV group were as follows: an increasing FiO2 requirement in seven patients, hypercapnic acidosis in four patients, frequent/severe apnea in three patients, and more than one criterion for failure in six patients in the NIPPV group. The mean times of intubation were similar in the NIPPV and NIPPV + SURFACTANT groups (11.71 ± 14.62 and 11.27 ± 11.61 h, respectively). Secondary outcomes While none of the infants in the NIPPV + SURFACTANT group required intubation between days 3 and 7, only one additional infant in the NIPPV group required intubation between these days Therefore, the results were similar for those in the primary outcome. The failure rate within the first 7 d was significantly less in the NIPPV + SURFACTANT group than the NIPPV group (p ¼ 0.013; OR: 0.262, 95% CI: 0.089–0.773). When adjusted for gestational age and birth weight, very-early surfactant treatment was still an independent variable for the need of MV within the first 7 d (p ¼ 0.008; 95% CI: 1.55–17.87). However, in the subgroup of infants with gestational ages 528 weeks, early-surfactant treatment did not affect the failure rate within the first 7 d. In the NIPPV group, nine infants (30%) never required intubation and never received a surfactant. In the NIPPV + SURFACTANT group, 11 (37.9) infants had to receive a repeat surfactant. However, the median surfactant dose requirements did not vary between the two groups (Table 3). There were no significant differences between the groups for any secondary outcome, even when the two gestational age subgroups were analyzed separately (Table 3).
Discussion Non-invasive ventilation has been increasingly used as a strategy to minimize or avoid invasive mechanical ventilation in an attempt to reduce the incidence of BPD. While the use
Assessed for eligibility N=85 Excluded n=26 • Refused or did not get consent = 7 • Did not require respiratory support = 10 • Need entubaon = 5 • Did not meet other inclusion criteria=4
Included in the study n= 59
NIPPV n=30
NIPPV+SURFACTANT n=29
Lost to follow up=0
Lost to follow up=0
Analyzed n=30
Analyzed n=29
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Table 1. Baseline demographic and clinical characteristics of the patients.
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GA, mean ± SD, week GA 24–276/7 week, n (%) Birth weight, mean ± SD, g Small for gestational age, n (%) Chorioamnionitis, n (%) Antenatal corticosteroids, n (%) Cesarean delivery, n (%) Male gender, n (%) Multiple births, n (%) Apgar score at 5 min, median (min–max) Delivery room resuscitation, n (%) Retraction score, median (min–max)
NIPPV (N ¼ 30)
NIPPV + surfactant (N ¼ 29)
p
29.1 ± 2.3 11 (36.6) 1225 ± 465 4 (13.3) 3 (10.0) 16 (53.3) 26 (86.7) 14 (46.7) 9 (30.0) 7 (6–9) 7 (23.3) 4.5 (3–6)
28.8 ± 2.0 12 (40.0) 1184 ± 311 4 (13.8) 4 (13.8) 20 (66.6) 25 (86.2) 15 (51.7) 9 (31.0) 7 (6–9) 4 (13.8) 5 (3–6)
0.637 0.711 0.765 0.627 0.480 0.218 0.959 0.698 0.931 0.915 0.347 0.486
Table 2. Primary outcome: need for MV within 72 h. NIPPV n/N* (%)
NIPPV + surfactant n/N*(%)
OR (95% CI)
p
20/30 (66.7) 9/11 (81.8) 11/19 (57.9)
11/29 (37.9) 8/12 (66.7) 3/17 (17.6)
0.554 (0.316–0.970) 0.630 (0.186–2.127) 0.463 (0.250–0.858)
0.027 0.408 0.013
Gestational age 6/7
24–31 24–276/7 28–316/7
*n/N: number of infants that need mechanical ventilation/total number of infants in the group. Bold values represent p50.05. Table 3. Secondary outcomes.
Outcomes Need for MV within 7 d n (%) 24–276/7 week 28–316/7 week MV duration, day* (mean ± SD) Non-invasive MV duration, hour** (mean ± SD) Time to intubation, hour (mean ± SD) Total surfactant dose, median (min–max) Systemic postnatal corticosteroids, n (%) Pneumothorax, n (%) Intra ventricular hemorrhage (grades 3 and 4), n (%) Patent ductus arteriosus, n (%) Necrotising enterecolitis (stages 2 and 3), n (%) Sepsis, n (%) Retinopathy of prematurity (stage 2), n (%) O2 requirement at 28 d, n (%) Moderate and severe BPD in survivors, n (%) Death, n (%) Death or BPD, n (%) Length of hospital stay (mean ± SD)
NIPPV, N ¼ 30
NIPPV + surfactant, N ¼ 29
p
21 (70.0) 9 (81.8) 12 (63.2) 3.06 ± 3.89 42.56 ± 20.80 11.71 ± 14.62 1 (0–3) 6 (20.0) 1 (3.6) 3 (10.0) 20 (66.7) 2 (6.7) 18 (60.0) 2 (6.7) 12 (41.4) 4 (13.3) 2 (6.6) 14 (46.7) 49.3 ± 31.4
11 (37.9) 8 (66.7) 3 (17.6) 5.03 ± 6.79 38.16 ± 18.42 11.27 ± 11.61 1 (1–4) 4 (13.8) 0 (0.0) 2 (6.9) 16 (55.2) 1 (3.4) 18 (62.1) 4 (13.8) 11 (35.7) 5 (17.2) 1 (3.4) 11 (37.9) 47.9 ± 28.3
0.013 0.408 0.006 0.319 0.581 0.993 0.195 0.388 0.305 0.516 0.365 0.513 0.871 0.319 0.661 0.478 0.574 0.497 0.864
*Among subjects requiring MV. **Among subjects not requiring MV. Bold values represent p50.05.
of early NCPAP met with some success, significant failure rates (22–60%) have been reported, especially in infants younger than 28 weeks’ gestation [21–23]. Although there are conflicting results surfactant therapy, probably depending on timing, may be an important modifier of NCPAP success [3,4,14,15]. NIPPV may have advantages over NCPAP in stabilizing a borderline functional residual capacity, reducing dead space, preventing atelectasis, and improving lung mechanics [7]. Because of these advantages, NIPPV may improve the effectiveness of an exogenous surfactant by providing a
homogeneous distribution of the surfactant on the surface of the lung. The absence of any study comparing the outcomes of early NIPPV with or without surfactant use in primary treatment for RDS encouraged us to design this study. In this single-center prospective trial, we found a significantly reduced need for invasive mechanical ventilation overall within the first 72 h in the NIPPV + SURFACTANT group (37.9%) when compared with NIPPV alone (66.7%). The failure of NIPPV + SURFACTANT was also lower than NIPPV when we evaluated the need for mechanical ventilation during the first 7 d. The results of the present study were
NIPPV with or without surfactant
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DOI: 10.3109/14767058.2014.997203
similar to the results from previous randomized studies evaluating the effect of early-surfactant therapy on NCPAP success [14,15]. Rojas et al. conducted a multicenter trial (Colombian study) to evaluate whether the use of very-early surfactant therapy, in addition to the early use of NCPAP in preterm infants (27–316/7 weeks) with RDS, would further improve their outcomes in comparison with early NCPAP and a selective surfactant. The timing of surfactant administration in the treatment group was comparable to the present study because the treatment group received a ‘‘very-early surfactant’’ once the first RDS signs appeared, instead of by a prophylactic administration. The authors found that the need for mechanical ventilation, as well as the incidence of air leaks, was significantly reduced in early NCPAP with the early surfactant group compared with only the NCPAP group, and there was a trend towards a lower incidence of BPD [14]. The Colombian study included infants between 27 and 31 weeks and encouraging results obtained with very-early surfactant therapy might be related to the enrollment of relatively moremature infants. Consistent with this study, we found a decreased need for mechanical ventilation with very-early surfactant therapy in a subgroup of infants between 28 and 32 weeks. The European CURPAP study investigated whether a prophylactic surfactant, followed by nCPAP compared with early nCPAP with an early selective surfactant, would reduce the need for MV in the first 5 d of life in preterm infants born at 25–28 weeks’ gestation. Results of this trial showed that in spontaneously breathing preterm newborns that were treated with NCPAP, a prophylactic surfactant was not superior to an early-selective surfactant with respect to the requirement of MV and other clinical outcomes [4]. Although there were some differences in entry criteria and study protocols between the trials, the multicenter Delivery Room Management trial met with similar results to the CURPAP trial [3]. As a difference, we used very-early surfactant therapy instead of prophylactic therapy in the NIPPV + SURFACTANT group; however, our results indicated that very-early surfactant therapy did not affect the failure rate of NIPPV in the subgroup of infants with a smaller gestational age (528 weeks) in parallel to these studies. In comparison with the previous NIPPV studies, the failure rate within 72 h was higher in our study, even in the NIPPV + SURFACTANT group [11–13,24,25]. The higher failure rate in this study group might be due to the heterogeneity of the studied populations and a higher incidence of infants in our study with significant risk factors, such as the absence of antenatal steroid therapy, resuscitation in the delivery room, and severe forms of respiratory disease. Another important reason for this lower success is probably due to the differences among MV criteria. Some of these studies used a late INSURE procedure for rescue or repeated doses of surfactant, but we did not use the INSURE procedure in such cases. The risk of BPD ranges from 510% to 440% among the Neonatal Research Network centers in infants weighing 51250 g at birth. Avoidance of mechanical ventilation might decrease the risk of lung injury and BPD, and might explain some of the center-to-center differences in BPD rates [26]. Despite the higher failure of early NIPPV as a primary treatment for RDS in our study population, BPD incidence
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was similar in comparison with previous studies. We did not find any difference in the incidence of BPD or the combined outcome of mortality and BPD between the study groups. This may have resulted from the smallness of the sample size. However, consistent with our results, recent large clinical trials comparing NCPAP following prophylactic or very-early surfactant therapy to NCPAP with early-selective surfactant treatment did not find a significant difference between the groups in relation to the incidence of BPD [3,4,14]. RCT’s comparing of early NIPPV and early NCPAP as a primary treatment for RDS suggested that NIPPV reduced the duration of invasive mechanical ventilation [11,25,27] and NIPPV might be an important modifier of the outcome of BPD, irrespective of the duration of mechanical ventilation [11–13,28]. In a recently published meta-analysis including three RCT’s (n ¼ 360) [11,12,25] early NIPPV was found to be superior compared with early NCPAP in terms of a mechanical ventilation requirement within 72 h. However, no difference between groups was found in the incidence of BPD [29]. Similar to meta-analysis, results of a recent, large international RCT indicated that among extremely low-birthweight infants (n ¼ 1009), the rate of survival to 36 weeks of postmenstrual age without BPD did not differ significantly after NIPPV as compared with nasal NCPAP. Moreover, NIPPV was not superior to NCPAP with respect to the other clinical outcomes [30]. Respiratory and feeding-related complications are the leading causes of prolonged hospitalization in preterm infants. Strategies that shorten the duration of hospital stay are needed, especially in low-resource and crowded intensive-care units. However, no difference was found between the two groups in the duration of hospital stay, similar to the meta-analysis [29]. Consistent with the previous studies, there were no gastrointestinal complications in the present study [11,12,25]. Finally, a number of important limitations need to be considered. The main weakness of this study was the lack of randomization. However, it was designed prospectively, and demographic characteristics of either group were similar. The same objective failure criteria and management protocols were used to reduce the possibility of such a bias. Therefore, we considered that the differences between the two groups could not have been explained by changes in clinical practice other than very-early surfactant administration. Another important limitation was the small sample size; caution must be applied, since the sample size was underpowered to detect the secondary endpoints.
Conclusion The evidence from this study suggests that the administration of NIPPV following a very-early surfactant decreases the need of intubation and mechanical ventilation within 72 h compared with NIPPV without a surfactant in primary treatment of RDS. Especially, in the subgroup of infants with a gestational age greater than 28 weeks, NIPPV failure was significantly lower when combined with a very-early surfactant, which indicates the critical role of early surfactant treatment in reducing the need for invasive ventilation in this subgroup of patients. Larger randomized trials involving the most vulnerable preterm infants are needed to assess the
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effects of these strategies on BPD and other comorbidities in preterm infants with RDS.
Declaration of interest The authors declare no conflict of interest. They did not have any sponsor involved in (1) study design; (2) the collection, analysis, and interpretation of data; (3) the writing of the report; and (4) the decision to submit the paper for publication.
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ORIGINAL ARTICLE
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Nasal intermittent positive pressure ventilation with or without very early surfactant therapy for the primary treatment of respiratory distress syndrome _scan, Mustafa Dilek, Nuray Duman, Funda Tu¨zu¨n, Ali Haydar Sever, Meltem Koyuncu Arslan, Burc¸in I¸ Abdullah Kumral, and Hasan Ozkan Department of Pediatrics, Faculty of Medicine, Dokuz Eylul University, Izmir, Turkey
Abstract
Keywords
Aim: Current evidence suggests that nasal intermittent positive pressure ventilation (NIPPV) as a primary treatment for RDS reduces the duration of invasive mechanical ventilation (MV) comparing with nasal continuous airway pressure (NCPAP). We aimed to evaluate whether very early surfactant treatment decreases the need for MV when used in premature infants treated with early NIPPV soon after birth. Methods: The inclusion criteria of this prospective cohort study were a gestational age of 24–316/7 weeks and supplemental oxygen with the evidence of labored breathing within 60 min. Infants were stabilized on NCPAP and then continued with NIPPV, following early surfactant treatment, or were only put on NIPPV. Thirty infants in the NIPPV group and 29 infants in the NIPPV + SURFACTANT group met the inclusion criteria. Primary end-point was the need of MV in the first 72 h of life according to the predefined criteria. Results: The failure rate was significantly lower in the NIPPV + SURFACTANT group compared with the NIPPV group (37.9% and 66.7% respectively, p50.05). All other results, including bronchopulmonary dysplasia and death, were similar between the groups. Conclusion: NIPPV failure was significantly lower when combined with surfactant treatment, which indicates the critical role of early surfactant treatment in reducing the need for invasive ventilation.
Bronchopulmonary dysplasia, NIPPV, preterm, respiratory distress syndrome, surfactant
Introduction Respiratory distress syndrome (RDS) is a disease of newborn infants that increases in prevalence with the decreasing of gestational age. Despite the effectiveness of surfactant treatment in the acute phase of RDS and new ventilation techniques, bronchopulmonary dysplasia (BPD) remains an important adverse outcome in preterm infants, and its incidence is correlated with the use of mechanical ventilation [1]. The trend today is to minimize the use of mechanical ventilation and to use nasal respiratory support in premature infants [2]. The most important message of the recently published randomized controlled trials is that an approach that utilizes early nasal continuous airway pressure (NCPAP) is safe in very preterm infants and leads to a reduction in the number of infants who are intubated and given surfactant treatment. However, these studies have also indicated that a significant number of infants treated with early NCPAP
Address for correspondence: Prof. Dr. Hasan Ozkan, Department of Pediatrics, Subdivision of Neonatology, Faculty of Medicine, Dokuz Eylul University, Inciralti 35340, Izmir, Turkey. Tel: +90 232 412 36 43. Fax: +90 232 259 05 41. E-mail: [email protected]
History Received 25 January 2014 Revised 8 October 2014 Accepted 8 December 2014 Published online 26 December 2014
required invasive mechanical ventilation (MV), and early NCPAP did not show a reduction in BPD [3–6]. Efforts to reduce the failure rates of early NCPAP prompted the use of early NIPPV, as it may provide sufficient support to avoid endotracheal intubation in some infants [7]. Although the precise mechanism of action is not known, NIPPV augments the infant’s spontaneous breath efforts by providing a backup rate. Synchronized as well as nonsynchronized NIPPV have been shown to be effective in preterm infants requiring respiratory support by reducing the incidence of apnea of prematurity and atelectasis, improving ventilation–perfusion matching and decreasing extubation failures [8–10]. Randomized controlled studies and meta-analyses comparing NIPPV and NCPAP as primary treatments for RDS suggested that NIPPV reduced the duration of invasive MV. Also, NIPPV might be an important modifier of the outcome of BPD, irrespective of the duration of mechanical ventilation [11–13]. Large randomized trials revealed that prophylactic surfactant treatment, in combination with NCPAP, was not better than NCPAP with selective surfactant treatment in premature infants with RDS [3,4]. However, few randomized studies
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indicated that very-early surfactant treatment in combination with early NCPAP improved outcomes of very preterm babies with RDS [14,15]. None of the published studies addressed the question of whether the addition of very-early surfactant therapy to the early NIPPV may further improve the outcomes of preterm infants with RDS. NIPPV is increasingly being used as a primary treatment during the acute phase of RDS, and the recommendations for early NCPAP may not be applied to early NIPPV. The purpose of this study was to determine whether the addition of very-early surfactant therapy to the early NIPPV is superior to NIPPV alone in its ability to reduce the need of mechanical ventilation in premature infants with RDS.
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Patients and methods This single-center, prospective cohort trial was conducted from December 2010 to December 2012 in a tertiary care neonatal unit in Izmir, Turkey. Inclusion criteria were a gestational age of 24–316/7 weeks, a postnatal age within 60 min, and a supplemental oxygen requirement with evidence of labored breathing with a Silverman Anderson score 43 [16]. Exclusion criteria were an Apgar score of 3 or less at 5 min, a requirement of intubation during the first hour of life, a prenatal or postnatal diagnosis of major congenital malformations, severe cardiovascular instability or poor respiratory efforts, and the absence of parental consent. The Institute Ethics Committee gave ethical approval for the trial. Parental written informed consent was required before delivery of the potentially eligible infants. Baseline variables were recorded: gestation, birth weight, sex, use of antenatal corticosteroids, presence of chorioamnionitis (clinical or histological), mode of delivery, resuscitation details, and Apgar scores. At birth, all infants were resuscitated in a standardized manner according to Neonatal Resuscitation Program guidelines [17]. A constant-flow, positive-pressure ventilation (PPV) system (Neopuff Infant Resuscitator [Fisher & Paykel Healthcare, Inc., Auckland, New Zeeland]) with a peak pressure of 18–20 cm H2O and a positive-end expiratory pressure (PEEP) of 5 cm H2O was used if PPV was needed. Subjects in both groups were initially stabilized with NCPAP with a PEEP of 6 cm H2O. Patients meeting the inclusion criteria were switched to NIPPV within the first hour. The decision for very-early surfactant treatment was left to the preference of the treating medical team. If the clinician decided to administer an early surfactant, a modified natural lung surfactant (Poractant alpha, Curosurf-Chiesi Farmaceutici, Parma, Italy) was administered at a dose of 200 mg/kg in single aliquot. After the surfactant instillation, PPV was administered for 1 min by the Neopuff infant resuscitator, followed by extubation to NIPPV. We used Drager Babylog 8000 plus (Drager Medicals Inc., Lubeck, Germany) ventilators for non-invasive ventilation. Non-invasive support was delivered through bi-nasal prongs (Vygon SA, E´couen, France). In every patient, a 6-french orogastric tube was used and kept open to decompress the stomach. All patients were initiated with the following: a frequency if 40 per min, a peak inspiratory pressure (PIP) of 18 cm of water, PEEP of 6 cm of water, an inspiratory time of 0.4 s with a flow of 6–8 l/min. In neonates weighing 51000 g, the
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maximum permissible PIP was 24 cm, while in those41000 g, it was 26 cm of water. The maximum permissible PEEP was 8 cm of water. Targeted SpO2 saturation was 88–93% during the study period. Settings in both groups were adjusted based on arterialized capillary blood gases (ABG) and clinical parameters. ABG was performed after 40 min of starting respiratory support and then at least every 6 h and as indicated. All participating infants received a loading dose of caffeine (20 mg/kg intravenously), followed by a maintenance dose of 5 mg/kg every 24 h. During weaning, PIP was reduced by decrements of 2 cm H2O until it reached a minimum PIP level of 14 cm (for infants 51000 g) or 18 cm of H2O (for infants 41000 g). The respiratory rate was then reduced by elongating the expiratory time by up to 3 s. Finally, neonates were weaned from a PIP of 14–18 cm, a PEEP of 6 cm, a rate of 18/min and fraction of inspired oxygen (FiO2) of 0.3, with an acceptable ABG. NIPPV for neonates requiring respiratory support after weaning was restarted on initial settings following the first 72 h after weaning. The primary outcome was ‘‘failure’’ of non-invasive respiratory support, necessitating intubation, and mechanical ventilation within the first 72 h after randomization. The criteria for ‘‘failure’’ were the same in both groups and included at least one of (i) PaCO2465 mmHg or pH57.2 or (ii) apneas of more than three episodes per hour (defined as cessation of breathing for 20 s or 520 s if associated with cyanosis and/or bradycardia [heart rate5100 per min]) or (iii) any episode of apnea requiring positive pressure ventilation or (iv) the fraction of the inspired oxygen (FiO2) requirement above 45% to maintain the SpO2 level between 88 and 93%. Surfactant therapy was administered to either group (repeat dose for NIPPV + SURFACTANT and first dose for NIPPV) if the infants needed a FiO2 of 40.45 to maintain the targeted saturation; then they continued with invasive MV. The secondary outcomes were ‘‘failure’’ within the first 7 d, need of surfactant therapy, a hemodynamically significant patent ductus arteriosus (hsPDA) needing medical or surgical treatment, duration of respiratory support, duration of oxygen, need of postnatal steroid therapy, pneumothorax, severe IVH (grades 3 and 4) [18], BPD (oxygen dependency at postnatal week 36) [19], sepsis (blood culture-positive nosocomial sepsis), necrotizing enterecolitis (NEC, Bell stages 2 and 3) [20], length of hospital stay and in-hospital mortality. Statistical analysis Data from the same population in our unit showed that 60% of premature infants that were started on early NIPPV for RDS required invasive mechanical ventilation within 72 h. A sample size of 29 per group was required to detect a 50% absolute-reduction in the need for intubation in the ‘‘NIPPV + SURFACTANT’’ group, with an alpha error of 5% and power of 80%. Statistical analyses were performed using SPSS 15.0 for Windows (SPSS Inc., Chicago, IL). Continuous normally distributed data were analyzed using Students’ t-test. Categorical data were compared between groups using Chi-square tests or, when expected counts were small, Fisher’s exact test. For all tests, two-tailed tests were used.
NIPPV with or without surfactant
DOI: 10.3109/14767058.2014.997203
The Mann–Whitney U-test was used to compare ordinal or non-parametric data. A p value of 50.05 was considered statistically significant. Odds ratios with 95% CI and Chisquare tests were used to compare proportions between the two groups for main dichotomous outcomes and multivariate logistic regression to control for potentially confounding effects of BW and GA. Post hoc analyses were performed for subgroups that were defined by gestational age: infants delivered earlier than 28 weeks’ gestation and those delivered after 28 weeks.
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Results A total of 85 neonates were evaluated, of which 25 were excluded. Of the 59 enrolled neonates, 30 were allocated to the NIPPV group and 29 to the ‘‘NIPPV + SURFACTANT’’ group (Figure 1). The demographic and baseline clinical characteristics were similar in the two groups (Table 1). Primary outcome Eleven (37.9%) infants in the NIPPV + SURFACTANT group needed MV within the first 72 h compared with 20 (66.7%) in the NIPPV group (p ¼ 0.027; OR: 0.27; 95% CI: 0.105– 0.888). When adjusted for gestational age and birth weight, very-early surfactant treatment was still an independent variable for primary outcome (p ¼ 0.014, 95% CI: 1.36– 15.86). However, a post hoc subgroup analysis revealed that in the infants in the subgroup of 528 week, early-surfactant treatment did not have any effect on the MV requirement within the first 72 h, so there was no difference between the two groups in terms of the primary outcome (Table 2). Non-invasive ventilation failed in the first 72 h of life in 31 patients, and 21 (67%) of them required intubation and MV within the first 24 h. The reasons for failure in the NIPPV + SURFACTANT group were an increased FiO2 requirement in four patients, respiratory acidosis in two patients, and frequent/severe apnea in two patients. Three of the infants had more than one criterion for failure in
Figure 1. Infant enrollment into study.
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NIPPV + SURFACTANT. The reasons for failure in the NIPPV group were as follows: an increasing FiO2 requirement in seven patients, hypercapnic acidosis in four patients, frequent/severe apnea in three patients, and more than one criterion for failure in six patients in the NIPPV group. The mean times of intubation were similar in the NIPPV and NIPPV + SURFACTANT groups (11.71 ± 14.62 and 11.27 ± 11.61 h, respectively). Secondary outcomes While none of the infants in the NIPPV + SURFACTANT group required intubation between days 3 and 7, only one additional infant in the NIPPV group required intubation between these days Therefore, the results were similar for those in the primary outcome. The failure rate within the first 7 d was significantly less in the NIPPV + SURFACTANT group than the NIPPV group (p ¼ 0.013; OR: 0.262, 95% CI: 0.089–0.773). When adjusted for gestational age and birth weight, very-early surfactant treatment was still an independent variable for the need of MV within the first 7 d (p ¼ 0.008; 95% CI: 1.55–17.87). However, in the subgroup of infants with gestational ages 528 weeks, early-surfactant treatment did not affect the failure rate within the first 7 d. In the NIPPV group, nine infants (30%) never required intubation and never received a surfactant. In the NIPPV + SURFACTANT group, 11 (37.9) infants had to receive a repeat surfactant. However, the median surfactant dose requirements did not vary between the two groups (Table 3). There were no significant differences between the groups for any secondary outcome, even when the two gestational age subgroups were analyzed separately (Table 3).
Discussion Non-invasive ventilation has been increasingly used as a strategy to minimize or avoid invasive mechanical ventilation in an attempt to reduce the incidence of BPD. While the use
Assessed for eligibility N=85 Excluded n=26 • Refused or did not get consent = 7 • Did not require respiratory support = 10 • Need entubaon = 5 • Did not meet other inclusion criteria=4
Included in the study n= 59
NIPPV n=30
NIPPV+SURFACTANT n=29
Lost to follow up=0
Lost to follow up=0
Analyzed n=30
Analyzed n=29
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Table 1. Baseline demographic and clinical characteristics of the patients.
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GA, mean ± SD, week GA 24–276/7 week, n (%) Birth weight, mean ± SD, g Small for gestational age, n (%) Chorioamnionitis, n (%) Antenatal corticosteroids, n (%) Cesarean delivery, n (%) Male gender, n (%) Multiple births, n (%) Apgar score at 5 min, median (min–max) Delivery room resuscitation, n (%) Retraction score, median (min–max)
NIPPV (N ¼ 30)
NIPPV + surfactant (N ¼ 29)
p
29.1 ± 2.3 11 (36.6) 1225 ± 465 4 (13.3) 3 (10.0) 16 (53.3) 26 (86.7) 14 (46.7) 9 (30.0) 7 (6–9) 7 (23.3) 4.5 (3–6)
28.8 ± 2.0 12 (40.0) 1184 ± 311 4 (13.8) 4 (13.8) 20 (66.6) 25 (86.2) 15 (51.7) 9 (31.0) 7 (6–9) 4 (13.8) 5 (3–6)
0.637 0.711 0.765 0.627 0.480 0.218 0.959 0.698 0.931 0.915 0.347 0.486
Table 2. Primary outcome: need for MV within 72 h. NIPPV n/N* (%)
NIPPV + surfactant n/N*(%)
OR (95% CI)
p
20/30 (66.7) 9/11 (81.8) 11/19 (57.9)
11/29 (37.9) 8/12 (66.7) 3/17 (17.6)
0.554 (0.316–0.970) 0.630 (0.186–2.127) 0.463 (0.250–0.858)
0.027 0.408 0.013
Gestational age 6/7
24–31 24–276/7 28–316/7
*n/N: number of infants that need mechanical ventilation/total number of infants in the group. Bold values represent p50.05. Table 3. Secondary outcomes.
Outcomes Need for MV within 7 d n (%) 24–276/7 week 28–316/7 week MV duration, day* (mean ± SD) Non-invasive MV duration, hour** (mean ± SD) Time to intubation, hour (mean ± SD) Total surfactant dose, median (min–max) Systemic postnatal corticosteroids, n (%) Pneumothorax, n (%) Intra ventricular hemorrhage (grades 3 and 4), n (%) Patent ductus arteriosus, n (%) Necrotising enterecolitis (stages 2 and 3), n (%) Sepsis, n (%) Retinopathy of prematurity (stage 2), n (%) O2 requirement at 28 d, n (%) Moderate and severe BPD in survivors, n (%) Death, n (%) Death or BPD, n (%) Length of hospital stay (mean ± SD)
NIPPV, N ¼ 30
NIPPV + surfactant, N ¼ 29
p
21 (70.0) 9 (81.8) 12 (63.2) 3.06 ± 3.89 42.56 ± 20.80 11.71 ± 14.62 1 (0–3) 6 (20.0) 1 (3.6) 3 (10.0) 20 (66.7) 2 (6.7) 18 (60.0) 2 (6.7) 12 (41.4) 4 (13.3) 2 (6.6) 14 (46.7) 49.3 ± 31.4
11 (37.9) 8 (66.7) 3 (17.6) 5.03 ± 6.79 38.16 ± 18.42 11.27 ± 11.61 1 (1–4) 4 (13.8) 0 (0.0) 2 (6.9) 16 (55.2) 1 (3.4) 18 (62.1) 4 (13.8) 11 (35.7) 5 (17.2) 1 (3.4) 11 (37.9) 47.9 ± 28.3
0.013 0.408 0.006 0.319 0.581 0.993 0.195 0.388 0.305 0.516 0.365 0.513 0.871 0.319 0.661 0.478 0.574 0.497 0.864
*Among subjects requiring MV. **Among subjects not requiring MV. Bold values represent p50.05.
of early NCPAP met with some success, significant failure rates (22–60%) have been reported, especially in infants younger than 28 weeks’ gestation [21–23]. Although there are conflicting results surfactant therapy, probably depending on timing, may be an important modifier of NCPAP success [3,4,14,15]. NIPPV may have advantages over NCPAP in stabilizing a borderline functional residual capacity, reducing dead space, preventing atelectasis, and improving lung mechanics [7]. Because of these advantages, NIPPV may improve the effectiveness of an exogenous surfactant by providing a
homogeneous distribution of the surfactant on the surface of the lung. The absence of any study comparing the outcomes of early NIPPV with or without surfactant use in primary treatment for RDS encouraged us to design this study. In this single-center prospective trial, we found a significantly reduced need for invasive mechanical ventilation overall within the first 72 h in the NIPPV + SURFACTANT group (37.9%) when compared with NIPPV alone (66.7%). The failure of NIPPV + SURFACTANT was also lower than NIPPV when we evaluated the need for mechanical ventilation during the first 7 d. The results of the present study were
NIPPV with or without surfactant
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DOI: 10.3109/14767058.2014.997203
similar to the results from previous randomized studies evaluating the effect of early-surfactant therapy on NCPAP success [14,15]. Rojas et al. conducted a multicenter trial (Colombian study) to evaluate whether the use of very-early surfactant therapy, in addition to the early use of NCPAP in preterm infants (27–316/7 weeks) with RDS, would further improve their outcomes in comparison with early NCPAP and a selective surfactant. The timing of surfactant administration in the treatment group was comparable to the present study because the treatment group received a ‘‘very-early surfactant’’ once the first RDS signs appeared, instead of by a prophylactic administration. The authors found that the need for mechanical ventilation, as well as the incidence of air leaks, was significantly reduced in early NCPAP with the early surfactant group compared with only the NCPAP group, and there was a trend towards a lower incidence of BPD [14]. The Colombian study included infants between 27 and 31 weeks and encouraging results obtained with very-early surfactant therapy might be related to the enrollment of relatively moremature infants. Consistent with this study, we found a decreased need for mechanical ventilation with very-early surfactant therapy in a subgroup of infants between 28 and 32 weeks. The European CURPAP study investigated whether a prophylactic surfactant, followed by nCPAP compared with early nCPAP with an early selective surfactant, would reduce the need for MV in the first 5 d of life in preterm infants born at 25–28 weeks’ gestation. Results of this trial showed that in spontaneously breathing preterm newborns that were treated with NCPAP, a prophylactic surfactant was not superior to an early-selective surfactant with respect to the requirement of MV and other clinical outcomes [4]. Although there were some differences in entry criteria and study protocols between the trials, the multicenter Delivery Room Management trial met with similar results to the CURPAP trial [3]. As a difference, we used very-early surfactant therapy instead of prophylactic therapy in the NIPPV + SURFACTANT group; however, our results indicated that very-early surfactant therapy did not affect the failure rate of NIPPV in the subgroup of infants with a smaller gestational age (528 weeks) in parallel to these studies. In comparison with the previous NIPPV studies, the failure rate within 72 h was higher in our study, even in the NIPPV + SURFACTANT group [11–13,24,25]. The higher failure rate in this study group might be due to the heterogeneity of the studied populations and a higher incidence of infants in our study with significant risk factors, such as the absence of antenatal steroid therapy, resuscitation in the delivery room, and severe forms of respiratory disease. Another important reason for this lower success is probably due to the differences among MV criteria. Some of these studies used a late INSURE procedure for rescue or repeated doses of surfactant, but we did not use the INSURE procedure in such cases. The risk of BPD ranges from 510% to 440% among the Neonatal Research Network centers in infants weighing 51250 g at birth. Avoidance of mechanical ventilation might decrease the risk of lung injury and BPD, and might explain some of the center-to-center differences in BPD rates [26]. Despite the higher failure of early NIPPV as a primary treatment for RDS in our study population, BPD incidence
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was similar in comparison with previous studies. We did not find any difference in the incidence of BPD or the combined outcome of mortality and BPD between the study groups. This may have resulted from the smallness of the sample size. However, consistent with our results, recent large clinical trials comparing NCPAP following prophylactic or very-early surfactant therapy to NCPAP with early-selective surfactant treatment did not find a significant difference between the groups in relation to the incidence of BPD [3,4,14]. RCT’s comparing of early NIPPV and early NCPAP as a primary treatment for RDS suggested that NIPPV reduced the duration of invasive mechanical ventilation [11,25,27] and NIPPV might be an important modifier of the outcome of BPD, irrespective of the duration of mechanical ventilation [11–13,28]. In a recently published meta-analysis including three RCT’s (n ¼ 360) [11,12,25] early NIPPV was found to be superior compared with early NCPAP in terms of a mechanical ventilation requirement within 72 h. However, no difference between groups was found in the incidence of BPD [29]. Similar to meta-analysis, results of a recent, large international RCT indicated that among extremely low-birthweight infants (n ¼ 1009), the rate of survival to 36 weeks of postmenstrual age without BPD did not differ significantly after NIPPV as compared with nasal NCPAP. Moreover, NIPPV was not superior to NCPAP with respect to the other clinical outcomes [30]. Respiratory and feeding-related complications are the leading causes of prolonged hospitalization in preterm infants. Strategies that shorten the duration of hospital stay are needed, especially in low-resource and crowded intensive-care units. However, no difference was found between the two groups in the duration of hospital stay, similar to the meta-analysis [29]. Consistent with the previous studies, there were no gastrointestinal complications in the present study [11,12,25]. Finally, a number of important limitations need to be considered. The main weakness of this study was the lack of randomization. However, it was designed prospectively, and demographic characteristics of either group were similar. The same objective failure criteria and management protocols were used to reduce the possibility of such a bias. Therefore, we considered that the differences between the two groups could not have been explained by changes in clinical practice other than very-early surfactant administration. Another important limitation was the small sample size; caution must be applied, since the sample size was underpowered to detect the secondary endpoints.
Conclusion The evidence from this study suggests that the administration of NIPPV following a very-early surfactant decreases the need of intubation and mechanical ventilation within 72 h compared with NIPPV without a surfactant in primary treatment of RDS. Especially, in the subgroup of infants with a gestational age greater than 28 weeks, NIPPV failure was significantly lower when combined with a very-early surfactant, which indicates the critical role of early surfactant treatment in reducing the need for invasive ventilation in this subgroup of patients. Larger randomized trials involving the most vulnerable preterm infants are needed to assess the
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effects of these strategies on BPD and other comorbidities in preterm infants with RDS.
Declaration of interest The authors declare no conflict of interest. They did not have any sponsor involved in (1) study design; (2) the collection, analysis, and interpretation of data; (3) the writing of the report; and (4) the decision to submit the paper for publication.
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