A randomized controlled trial of synchronized nasal intermittent positive pressure ventilation in RDS

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1 (2007) 27, r 2007 Nature Publishing Group All rights reserved /07 $30 ORIGINAL ARTICLE A randomized controlled trial of synchronized nasal intermittent positive pressure ventilation in RDS V Bhandari 1,2, RG Gavino 1, JH Nedrelow 2, P Pallela 2, A Salvador 1, RA Ehrenkranz 2 and NL Brodsky 1,3 1 Department of Pediatrics, Albert Einstein Medical Center, Philadelphia, PA, USA and 2 Division of Perinatal Medicine, Department of Pediatrics, Yale University School of Medicine, New Haven, CT, USA Objective: Comparison of outcomes of infants with respiratory distress syndrome (RDS), post-surfactant, extubated to synchronized nasal intermittent positive pressure ventilation (SNIPPV) or continued on conventional ventilation (CV). Study Design: Prospective post-surfactant randomized controlled trial of primary mode SNIPPV compared with CV in infants (born from July 2000 to March 2005) with birth weights (BW) of 600 to 1250 g. Primary mode SNIPPV was defined as its use in the acute phase of RDS, following the administration of the first dose of surfactant. Result: There were no significant differences in the maternal demographics, antenatal steroid use, mode of delivery, BW, gestational age, gender or Apgar at 5 min between infants continued on CV (n ¼ 21) and those extubated to primary mode SNIPPV (n ¼ 20). Significantly, more babies in the CV group had the primary outcome of bronchopulmonary dysplasia (BPD)/death, compared to the SNIPPV group (52 versus 20%, P ¼ 0.03). There was no difference in the incidence of other common neonatal morbidities. There were no differences in the Mental or Psychomotor Developmental Index scores on follow-up between the two groups. Conclusion: Infants of BW 600 to 1250 g with RDS receiving surfactant with early extubation to SNIPPV had a significantly lower incidence of BPD/death. Primary mode SNIPPV is a feasible method of ventilation in small premature infants. (2007) 27, ; doi: /sj.jp ; published online 16 August 2007 Keywords: premature newborn; surfactant; nasal ventilation; noninvasive ventilation. Correspondence: Dr V Bhandari, Division of Perinatal Medicine, Department of Pediatrics, Yale University School of Medicine, Children s Hospital WP 493, PO Box , New Haven, CT , USA. vineet.bhandari@yale.edu 3 Current address: Department of Neonatology, Children s Hospital of Philadelphia, Philadelphia, PA, USA. Received 5 February 2007; revised 18 June 2007; accepted 26 June 2007; published online 16 August 2007 Introduction Respiratory distress syndrome (RDS) and its sequelae, bronchopulmonary dysplasia (BPD) are both frequent complications of prematurity, and account for 21% of infant deaths each year due to complications of prematurity. 1 Despite the advent of antenatal steroids and surfactant replacement therapy for management of RDS, the incidence of BPD has not changed significantly in the last decade. 2 The pathogenesis of BPD is multifactorial. 3 Although chorioamnionitis is an important factor implicated in the pathogenesis of BPD, the roles of hyperoxia, ventilator-induced injury, pulmonary edema, late-onset sepsis and genetic predisposition are also major contributors. There appears to be a major role for inflammation causing significant lung damage and interfering with the normal development of airways and alveoli, culminating in BPD. 3 In an effort to decrease ventilator-induced lung injury, alternative techniques of invasive ventilation have been employed. 4 7 Recent studies have shown little or no difference in outcomes when these methods have been used as a primary mode of ventilation for infants with RDS. 5 7 This has led to suggestions for a non-invasive approach to the ventilation of the newborn with RDS. 8,9 Although use of nasal continuous positive airway pressure (NCPAP) post-surfactant (InSUrE, intubation, surfactant and extubation) has met with some success, 9 12 some infants have failed that approach. 13,14 Nasal intermittent positive pressure ventilation (NIPPV) is a form of non-invasive respiratory support that combines NCPAP with intermittent ventilator breaths. The use of synchronized NIPPV (SNIPPV) for supporting infants who are extubated has been advocated by many investigators. 8,15,16 SNIPPV has been found to be more effective than NCPAP in weaning infants with RDS from mechanical ventilation and has been recommended as the modality of choice for extubation, especially for extremely low birth weight (ELBW) infants. 8 A decrease in BPD and retinopathy of prematurity (ROP) had also been noted in the same study. 8 In view of benefits noted when SNIPPV was used in the secondary mode (that is, for extubation after a prolonged weaning phase of mechanical ventilation in the recovery phase of RDS), we

2 698 Primary mode SNIPPV in preterm infants hypothesized that SNIPPV use in the primary mode (that is, in the acute phase of RDS) would be safe and useful in preterm infants. The prospective observational study in the use of SNIPPV as a primary mode of ventilation in infants of 28 to 34 weeks of gestational age (GA) with RDS requiring surfactant, reported that babies with an early extubation to SNIPPV had a shorter duration of intubation, and decreased need for oxygen as compared to conventional ventilation (CV). 17 There was also a significant decrease in the duration of parenteral nutrition and hospitalization. It was concluded that SNIPPV was feasible as a primary mode of ventilation in larger premature infants. 17 In the present study, we hypothesized that primary mode SNIPPV (defined as its use in the acute phase of RDS, following the administration of the first dose of surfactant) initiated shortly after birth would decrease the incidence of BPD or death in smaller premature babies when compared to conventional endotracheal mode of ventilation. The purpose of this study was to conduct a randomized controlled trial (RCT) to test the feasibility of comparing SNIPPV versus CV in infants (BW ¼ 600 to 1250 g) with RDS requiring at least one dose of surfactant. Methods Materials The ventilators used for infants in the CV group were either the Bear Cub (Model BP 2001; Bear Medical Systems Inc., Riverside, CA, USA) or the Infant Star 500/950 (Infrasonics Inc., San Diego, CA, USA). The Infant Star with the synchronized intermittent mandatory ventilation (IMV) box (Star Sync; Infrasonics Inc.) was used in the infants assigned to SNIPPV primary or secondary modes. Methods Subjects. Preterm infants admitted to the neonatal intensive care unit (NICU) at Albert Einstein Medical Center (Philadelphia, PA, USA) (born from July 2000 to January 2002) or the Newborn Special Care Unit (NBSCU) at Yale-New Haven Children s Hospital (YNHCH) (New Haven, CT, USA) (born from July 2002 to March 2005), with the following inclusion/exclusion criteria formed the study group (Table 1). The clinical parameters listed above in the exclusion criteria were at the discretion of the clinical team. Approval for this RCT was obtained from the Institutional Review Boards (IRB) of the Albert Einstein Healthcare Network and Yale University School of Medicine. Randomization was not stratified by site and was done sequentially, first at AEMC, followed by Yale University School of Medicine. There was no crossover of patients at either site. The analysis was by intention to treat. Since this was a pragmatic study to show feasibility of the primary mode of SNIPPV, detailed data were not collected on babies who met eligibility criteria, but were not enrolled. The overall number of admissions of babies Table 1 Inclusion and exclusion criteria for infants enrolled in the study Inclusion Criteria (all required) 1. <32 weeks of gestational age 2. Birth weight g 3. RDS requiring intubation and surfactant therapy within 1 h of birth. The need for intubation/surfactant was based on the following: Fi0 2 X0.4 to maintain Sa0 2 X90% Chest radiograph consistent with RDS Exclusion Criteria (any one) 1. Nasopharyngeal pathology Choanal atresia Cleft lip or palate 2. Major congenital anomalies, especially thoracic or cardiac defects 3. Clinical parameters for exclusion 90 min after initial surfactant therapy (approximately 2½ h after birth) Oxygenation index (OI ¼ [(Fi0 2 )(mean airway pressure)]/pa0 2 )>9 No indwelling arterial line More than two isotonic fluid boluses Continuous medication infusion for blood pressure support Fi0 2 >0.8 Abbreviation: RDS, respiratory distress syndrome. <32 weeks of GA and BW of 600 to 1250 g was 41 infants, with 23 having RDS at AEMC in the study period specified. Similarly, at the Yale site, the numbers were 240 and 153, respectively. Data were collected on the enrolled babies as per definitions mentioned below. Definitions. Pregnancy-induced hypertension was defined as a maternal systolic blood pressure of >140 mm Hg and a diastolic pressure of >90 mm Hg in the presence of proteinuria (>300 mg/ 24 h) and non-dependent edema. Chorioamnionitis was defined as a positive culture from the amniotic fluid. In the absence of positive cultures, the presence of organisms on gram stain, sheets of leukocytes or low glucose in the amniotic fluid in the presence of any two of the following clinical symptomatologies: maternal fever, leukocytosis, uterine tenderness, pus from the cervix, fetal tachycardia was used. RDS was defined as the presence of respiratory distress and a characteristic chest radiograph (reticulargranular pattern with air bronchograms and low lung volumes). Air leaks were documented by radiographic evidence of pneumothorax, pneumomediastinum or pulmonary interstitial emphysema. Patent ductus arteriosus (PDA) was documented by echocardiography. Intraventricular hemorrhage (IVH) was determined according to Papile s classification of blood in the germinal matrix or ventricular system with or without ventricular dilatation and parenchymal extension. 18 Periventricular leukomalacia (PVL) was defined as cerebral ultrasound findings of increased echogenicity and cystic lesions in the periventricular

3 Primary mode SNIPPV in preterm infants 699 white matter. 19 BPD was defined as the need for oxygen supplementation at 36 weeks of corrected GA in association with characteristic chest radiographic changes. 20 Sepsis was diagnosed by a positive blood culture. Necrotizing enterocolitis (NEC) was defined as Xstage 2 as per modified Bell s criteria. 21 ROP was defined as per the international classification. 22 The diagnosis of clinical gastroesophageal reflux (GER) was made, as defined previously. 23 Management of RDS. Infants in both groups were managed as per nursery standards for RDS. Initial ventilator settings of infants with RDS included peak inspiratory pressure (PIP) at 16 to 20 cm H 2 O, positive-end expiratory pressure (PEEP) at 4 to 6 cm H 2 O, an inspiratory time of 0.35 to 0.45 s, a rate of 40 to 60/min and FiO 2 adjusted to keep saturations 90 to 96%. Exogenous surfactant (Infasurf, Forest Laboratories, St Louis, MO, USA or Curosurf, Dey Inc., Napa, CA, USA or Survanta, Ross Products Divison, Abbott Laboratories, Abbott Park, IL, USA) was administered only as rescue therapy. Prophylactic surfactant therapy (in the DR) was not used at either site. Administration of surfactant required the diagnosis of RDS and an FiO 2 requirement of X0.4. Pre-medication for intubation or sedation was not routinely used at either site, as per nursery standards. All infants were started on aminophylline/ caffeine within the first 24 h of life. Randomization to the SNIPPV or CV groups was done by opening sealed, opaque envelopes with the allotment having been previously done by a computergenerated random numbers table. Randomization to one or the other group was done after birth, after consent, if the infant fulfilled the inclusion criteria. For the CV group, infants were weaned from CV and monitored by serial blood gas analyses (see below) at the discretion of the clinical team. The criteria for extubation were PIPp16 cm H 2 O, PEEPp5cm H 2 O, IMV rate 15 to 25, FiO 2 p0.35. Infants were extubated to SNIPPV (secondary mode), standard practice in our NICUs following the previous study. 8 Infants in the SNIPPV group were extubated to SNIPPV (primary mode) within 90 min after surfactant administration. We used nasopharyngeal prongs (V-SIL binasal airway, 3.0 mm outer diameter, 4 cm length attached to the infant s cheeks by a Neobar; Neotech Products Inc., Chatsworth, CA, USA) for the babies in the SNIPPV group (primary mode). Babies extubated to SNIPPV received synchronized IMV at the same rate as they were receiving before extubation, PIP was increased by 2 to 4 cm H 2 O, whereas the PEEP was kept p5cmh 2 O. FiO 2 was adjusted to maintain oxygen saturations 90 to 96% on pulse oximetry. The flow rate was kept at 8 to 10 l/min. To avoid excessive leak of pressure, attempt was made on all babies on SNIPPV to have their mouths closed (using pacifiers and/or chin-straps). All babies on SNIPPV had a largebore nasogastric tube placed, open to the atmosphere, to avoid distension of the stomach. In both groups, blood gas analyses were done at 1, 6, 24 and 48 h post-surfactant and as clinically indicated, from samples obtained from indwelling arterial lines or arterialized capillary blood obtained from a warmed heel. Ventilator settings were adjusted to maintain blood gas parameters as follows: ph 7.25 to 7.45; PaCO 2 40 to 55 mm Hg; PaO 2 50 to 80 mm Hg. Ventilator settings could be increased or decreased in the SNIPPV mode, if needed, to maintain the target blood gases. Infants were weaned to NCPAP once they had ventilator settings of PIP/PEEP 14/4 cm H 2 O, rate of p20/min and FiO 2 p0.3 with acceptable blood gas values. They were then further weaned to nasal cannula, when they were on NCPAP of 4 cm H 2 O, FiO 2 p0.3, with acceptable blood gases. Once the child was on nasal cannula flow of 1 l/min, the FiO 2 was weaned to room air while maintaining oxygen saturations 90 to 96% on pulse oximetry with acceptable blood gases. Re-intubation was performed in the presence of any of the following: a ph<7.25, PaCO 2 >60 mm Hg, a single episode of apnea needing bag and mask resuscitation; frequent (>2 to 3/h) apnea/bradycardia spells (cessation of respiration for >20 s associated with a heart rate <100/min) on therapeutic serum aminophylline/caffeine levels; frequent desaturations (<85%)X3 episodes/h not responding to increased ventilatory settings; or an increase in FiO 2 to 1.0, or a PaO 2 <50 mm Hg despite an FiO 2 of 1.0. Thus, if an infant belonging to the SNIPPV group was reintubated and then extubated, the infant would be managed with secondary mode SNIPPV, similar to what would be done for an infant in the CV group who was extubated. The CPAP kit (Argyle CPAP Nasal Cannula Kit; Sherwood Medical, St Louis, MO, USA) was used for this purpose. The size of the prongs to be used for each infant was determined by their weight as follows: small for infants 1000 to 1250 g and x-small for infants <1000 g. Any subsequent re-intubations would also be followed by extubation to secondary mode SNIPPV in both groups. Infants were monitored as per standard NICU nursing protocols. The medical management of these babies was as per the attending neonatologist. Cranial ultrasounds were done on all infants at days 1 to 3, 7 to 10, at discharge, and as indicated. Radiographs, cardiac echocardiography and sepsis evaluations were done when clinically indicated. Eye exams for ROP were performed on the infants by pediatric ophthalmologists at 4 to 6 weeks of age and repeated every 1 to 2 weeks, as indicated. Cranial ultrasounds, echocardiographic and eye examinations were interpreted by clinicians unaware of the infant s study group assignment. Discharge criteria for the infants in both groups were uniform and included the ability to maintain their temperature in a crib, apnea-free for 1 week (off aminophylline/caffeine) with a normal pneumocardiogram (the normal pneumocardiogram criterion only for babies at AEMC), accepting feeds orally and maintaining weight gain, and free from any active infection. No specific GA or

4 700 Primary mode SNIPPV in preterm infants weight limitations were used to dictate the decision to discharge any infant. Surviving infants (all for AEMC, only babies with BWp1000 g at Yale site) were invited back for neurodevelopmental assessments in the respective neonatal follow-up clinics at both institutions. Statistical analysis Our primary outcome measure was the combined outcome of BPD or death. The initial target sample size for this study had been a total of 50 patients, but was revised to 41 due to the following reasons. The patient enrollment was terminated at AEMC when the site investigator (RG) left the institution in The enrollment was terminated at Yale site in 2005 due to potential conflict with the initiation of the NIH/NICHD-sponsored SUPPORT trial. SNIPPV and CV groups were compared using Student s t-test, w 2, Mann Whitney U-test or repeated measures analyses of variance (ANOVAs), as appropriate. Statistical analyses were performed using SPSS 12.0 for Windows (SPSS Inc., Chicago, IL, USA). P<0.05 was considered statistically significant. Results Whereas 18 babies were recruited from AEMC (CV, n ¼ 8; SNIPPV, n ¼ 10), 23 were enrolled at Yale site (CV, n ¼ 13; SNIPPV, n ¼ 10). There were no significant differences in the data from AEMC and Yale site. Hence, the combined data is shown, unless specified otherwise. The maternal and infant characteristics of the groups randomized to CV or SNIPPV were similar as shown in Table 1. BW and GA were similar in both groups (Table 2). Significantly more babies in the CV group had the primary outcome of BPD/death, compared to the SNIPPV group (52 versus 20%, P ¼ 0.03; Table 2). There was no difference in the total duration of supplemental oxygen or PPV (duration of endotracheal tube ventilation or SNIPPV; Table 3). There were no differences in the blood gases (ph, pco 2,pO 2 and HCO 3 ) at 1, 6, 24 and 48 h post-surfactant in the two groups (detailed blood gas information is only available from the Yale site; data not shown). The incidence of air leaks, PDA, IVH, PVL, GER, NEC and ROP was similar in both groups (Table 3). Five of the total six babies died of respiratory failure, one of NEC at a mean age of 41.2 (±s.d., ±27.36) days. The number of babies who were re-intubated after extubation during their stay in the nursery was similar in both groups. Excluding babies who died, there were nine (45%) babies in the SNIPPV group and eight (38%) in the CV group that were reintubated (P ¼ 0.65). Surviving infants were invited back for neurodevelopmental follow-up at both sites. In accordance with center practices, only babies with BWp1000 g were followed at Yale site, whereas all babies were invited to return to AEMC for follow-up. Only two Table 2 Maternal and infant characteristics CV group (n ¼ 21) SNIPPV group (n ¼ 20) P- value Race (African-American, n, %) 10 (48) 4 (20) 0.10 Pregnancy-induced hypertension 5 (24) 5 (25) 1.0 (n, %) Chorioamnionitis (n, %) 3 (14) 4 (20) 0.70 Group B Streptococci +ve (n, %) 3 (14) 2 (10) 1.0 Antenatal antibiotics (n, %) 9 (43) 6 (30) 0.62 Antenatal steroids (n, %) 19 (90) 15 (75) 0.24 Vaginal delivery (n, %) 7 (33) 9 (45) 0.53 Birth weight (g) a 858±27 915± Gestational age (weeks) a 27.0± ± Gender (male, %) 11 (52) 11 (55) 1.00 Apgar at 5 min b 7 (6 8) 8 (6 8) 0.64 Infasurf use (n, %) 5 (24) 5 (20) 0.93 Curosurf use (n, %) 6 (29) 7 (35) 0.66 Survanta use (n, %) 10 (48) 8 (40) 0.62 Doses of surfactant a 1.2± ± Abbreviations: CV, conventional ventilation; SNIPPV, synchronized nasal intermittent positive pressure ventilation. a Mean±s.e.m. b Median (25th 75th centile). Table 3 NICU outcomes CV group (n ¼ 21) SNIPPV group (n ¼ 20) P- value BPD or deaths (n, %) 11 (52) 4 (20) 0.03 BPD (n, %) 7 (33) 2 (10) 0.04 Deaths (n, %) 4 (19) 2 (10) 0.66 Air leaks (n, %) 1 (5) 1 (5) 1.0 PDA (n, %) 3 (14) 4 (20) 0.70 IVH (n, %) 6 (29) 6 (30) 1.0 PVL (n, %) 1 (5) 2 (10) 0.61 GER (n, %) 5 (25) 2 (10) 0.41 NEC (n, %) 6 (29) 6 (30) 1.0 ROPXstage 2 (n, %) 1 (5) 3 (15) 0.34 Total duration of supplemental O ± ± (days) a Total duration of ETTPPV (days) a 16.6± ± Total Duration of SNIPPV (days) a 9.8± ± Length of stay (days) a 65.0± ± Abbreviations: BPD, bronchopulmonary dysplasia; CV, conventional ventilation; ETTPPV, endotracheal tube positive pressure ventilation; GER, gastroesophageal reflux; IVH, intraventricular hemorrhage; NEC, necrotizing enterocolitis; NICU, neonatal intensive care unit; PDA, patent ductus arteriosus; PVL, periventricular leukomalacia; ROP, retinopathy of prematurity; SNIPPV, synchronized nasal intermittent positive pressure ventilation. a Mean±s.e.m.

5 Primary mode SNIPPV in preterm infants 701 babies (one each in CV and SNIPPV groups) were excluded for neurodevelopmental follow-up at Yale site. Of the remaining survivors at both sites, data were available from 15 infants, eight in the CV group and seven in the SNIPPV group. The neurodevelopmental assessment (using Bayley Scales of Development II) 24 was performed by trained and certified personnel who were masked to the infant s group assignment. There were no statistically significant differences in the mental developmental index (MDI) (mean±s.d.; CV versus SNIPPV; 88.13±10.32 versus 81.43±17.54) or psychomotor developmental index (PDI) (88.38±11.87 versus 84.29±19.47) scores in the infants in the two groups, assessed at a median (25th to 75th centile) corrected GA of 22 (20.5 to 24) months. Discussion With increased survival of ELBW infants, there is renewed interest in minimizing the need for prolonged mechanical ventilation with the use of non-invasive ventilation, to reduce ventilator-induced trauma and oxygen toxicity. NCPAP has been advocated, 9 12 but has not achieved equivalent success in the hands of all investigators. Our attempts to use NCPAP as a primary mode of respiratory support led to limited success as infants continued to have apneic/bradycardic episodes and/or significant respiratory failure, based on clinical and blood gas parameters. Given the potential benefits of avoidance of endotracheal intubation, namely, decreased laryngeal and tracheal injury, decreased incidence and severity of BPD, and decreased nosocomial pneumonia and sepsis, 15,25,26 a decision to utilize SNIPPV as an alternative mode of ventilation was made. SNIPPV has been previously shown to be significantly better than NCPAP as a mode of extubation in recovering infants with RDS. 8 As a result of that study, 8 SNIPPV was established as the preferred method for extubation in infants recovering from RDS at our institutions. The efficacy and safety of this technique has also been reported at other sites 15,16,27 and has been shown to be effective when introduced into a NICU setting where it was previously not in use. 28,29 The primary mode of SNIPPV has been found to be feasible and effective in the larger premature infant in the acute phase of RDS. 15 In the present study, use of SNIPPV as a primary mode of ventilation in infants <32 weeks of gestation and birth weights 600 to 1250 g with RDS decreased the need for PPV. The study patients were well matched in terms of maternal demographics, BW, GA, severity of RDS (as evaluated by surfactant doses) as shown in Table 1. However, infants in the SNIPPV group had decreased BPD/ death (Table 2). There were no significant differences in the blood gases, other neonatal morbidities or MDI/PDI scores on follow-up. In the recently reported results of the COIN (CPAP or Intubation at birth) Trial (presented at Hot Topics 2006), 303 babies were randomized to the ventilation group, while 307 received NCPAP. There were no significant differences in death or BPD (using the 36 weeks PMA definition) or in any of the major morbidities in the two groups. Recently, Kiciman et al. 30 have shown that thoracoabdominal motion asynchrony decreased in neonates on nasal ventilation, and that nasal IMV decreased flow resistance through the nasal prongs and improved the stability of the chest wall, resulting in improved pulmonary mechanics. Friedlich et al. 15 have suggested that addition of a PIP above PEEP by using SNIPPV not only adds intermittent distending pressure above PEEP, but also increases flow delivery in the upper airway. Furthermore, Moretti et al. 31 found that application of SNIPPV was associated with an increase in tidal and minute volumes as compared to NCPAP in the same infant. It is also possible that SNIPPV could be creating an inadvertent PEEP that would allow further recruitment of alveoli and higher functional residual capacity. Recently, Aghai et al. 32 have reported that infants on SNIPPV have decreased work of breathing. The babies on CV were on the IMV mode, whereas the SNIPPV babies, by design were receiving synchronized ventilation. Though studies on CV have not shown any benefit with synchronization, 33 it is possible that the benefits from SNIPPV could be, in part, from synchronization. Recent reports, however, have reported success with NIPPV; 34 though, no RCT comparing synchronized versus non-synchronized NIPPV have been reported. This study has some limitations. The major limitation is the sample size. Besides the strict GA, birth weight and timing of surfactant administration criteria, too sick patients were excluded. Since this was a pragmatic study to show feasibility with a fairly novel technique in sick preterm babies, babies with severe RDS (OI>9, FiO 2 >0.8) were excluded, as per the request of the IRB at both sites. In the infants with mild-moderate RDS, major reasons for non-recruitment were the inclination of the attending neonatologists to trial NCPAP after delivery resulting in delayed intubation (and the subsequent administration of surfactant, if required, beyond 1 h after birth), and delayed/unsuccessful arterial line placements. This also hampered obtaining consents in a timely manner. Other reasons included loss of site investigators and conflict with other RCT. It took a year for the SNIPPV technique to be introduced, established and the study protocol to be approved by the IRB, before enrollment of patients at Yale site. With the long study duration and type of patient enrollment, a potential for selection bias exists. Some secondary outcomes could have been negative due to small numbers. To the best of our knowledge, however, this is the first RCT of primary mode SNIPPV in such a patient population. In conclusion, in this RCT, the primary mode SNIPPV was found to be feasible as a method of ventilation in very low birth weight infants with RDS. Recently reported results 35,36 should spur the need for this finding to be tested in an adequately powered RCT.

6 702 Primary mode SNIPPV in preterm infants Acknowledgments We thank the other attending neonatologists at AEMC and YNHCH for their support of the study. We also thank Pat Gettner, RN, Joanne Poulson, RN and Monica Konstantino, RN at YNHCH for help with patient enrollment and data collection. Finally, we are grateful to the many nurses and respiratory therapists at the two sites for their support, as well to the parents who consented for the study. VB was supported by the Einstein Society (Grant no ) and the Curosurf Study Grant Program (Dey Inc.). RGG was supported by the Advancing Newborn Medicine Grant Program (Forest Laboratories). JHN was supported by T32 HD from the NICHD of the National Institutes of Health, USA. References 1 Mathews TJ, Menacker F, MacDorman MF. Infant mortality statistics from the 2000 period linked birth/infant death data set. Natl Vital Stat Rep 2002; 50: Bancalari E, del Moral T. 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