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DOI: 10.1542/peds.2010-0922; originally published online January 24, 2011;2011;127;300Pediatrics

Jucille Meneses, Vineet Bhandari, Joao Guilherme Alves and Delia HerrmannControlled Trial

Noninvasive Ventilation for Respiratory Distress Syndrome: A Randomized

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Noninvasive Ventilation for Respiratory DistressSyndrome: A Randomized Controlled Trial

WHATS KNOWN ON THIS SUBJECT: Nasal continuous positiveairway pressure (NCPAP) has been the initial respiratory supportfor many preterm infants with respiratory distress syndrome (RDS).Nasal intermittent positive-pressure ventilation (NIPPV) seems toincrease the benecial effects of NCPAP by combining it withventilatory inations.

WHAT THIS STUDY ADDS: This study suggests that NIPPV, as anintial respiratory support for preterm infants with RDS, isfeasible and safe and may have benecial effects, whencompared with NCPAP.

abstractCONTEXT: Strategies for reducing exposure to endotracheal ventilation through the use of early noninvasive ventilation has proven to besafe and effective, but the option with the greatest benets needs to bedetermined.

OBJECTIVE: To determine, in infants with respiratory distress syn-drome, if early nasal intermittent positive-pressure ventilation (NIPPV)compared with nasal continuous positive airway pressure (NCPAP)decreases the need for mechanical ventilation.

PATIENTS AND METHODS: In this single-center, randomized controlled trial, infants (gestational ages 26 to 33 6 7 weeks) with respiratory distress syndrome were randomly assigned to receive early NIPPV orNCPAP. Surfactant was administered as rescue therapy. The primaryoutcome was the need for mechanical ventilation within the rst 72hours of life.

RESULTS: A total of 200 infants, 100 in each arm, were randomly as-signed. Rates of the primary outcome did not differ signicantly between the NIPPV (25%) and NCPAP (34%) groups (relative risk [RR]: 0.71[95% condence interval (CI): 0.481.14]). In posthoc analysis, from 24 to 72 hours of life, signicantly more infants in the NIPPV group re-mained extubated compared with those in the NCPAP groups (10 vs

22%; RR: 0.45 [95% CI: 0.22 0.91]). This difference was also noted in thegroup of infants who received surfactant therapy, NIPPV (10.9%), andNCPAP (27.1%) (RR: 0.40 [95% CI: 0.18 0.86]).

CONCLUSIONS: Early NIPPV did not decrease the need for mechanicalventilation compared with NCPAP, overall, in the rst 72 hours of life.However, further studies to assess the potential benets of noninva-sive ventilation are warranted, especially for the most vulnerable orpreterm infants. Pediatrics 2011;127:300307

AUTHORS: Jucille Meneses, MD, DM, a Vineet Bhandari,MD, DM,b Joao Guilherme Alves, MD, DM,a and DeliaHerrmann, MD, DMc

a Department of Pediatrics, Instituto de Medicina Integral Prof Fernando Figueira (IMIP), Recife, Brazil; b Department of Pediatrics, Yale University School of Medicine, New Haven,Connecticut; and c Department of Pediatrics, University of Alagoas, Maceio, Brazil

KEY WORDSrespiratory distress syndrome, preterm infant, noninvasiveventilation

ABBREVIATIONSETTendotracheal tubeMVmechanical ventilationBPDbronchopulmonary dysplasiaNCPAPnasal continuous positive airway pressureRDSrespiratory distress syndromePPVpositive-pressure ventilationNIPPVnasal intermittent positive-pressure ventilationSNIPPVsynchronized nasal intermittent positive-pressureventilationRCTrandomized controlled trialBWbirth weightPDApatent ductus arteriosusRRrelative riskCIcondence interval

This trial has been registered at www.clinicaltrials.gov (identi-er NCT00821119).

www.pediatrics.org/cgi/doi/10.1542/peds.2010-0922

doi:10.1542/peds.2010-0922

Accepted for publication Nov 17, 2010

Address correspondence to Jucille Meneses, MD, MS, Rua DomJose Lopes 955, Apt 1801, PE 51021-370, Recife, Brazil. E-mail: [email protected]

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

Copyright 2011 by the American Academy of Pediatrics

FINANCIAL DISCLOSURE: The authors have indicated they have no nancial relationships relevant to this article to disclose.

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Noninvasive ventilation, ventilatorysupport that does not use an invasivearticial airway such as an endotra-cheal tube (ETT), has been increasinglyused to reduce mechanical ventilation(MV) in preterm infants and subse-

quently lower the incidence of bron-chopulmonary dysplasia (BPD). 1,2

Nasal continuous positive airwaypressure (NCPAP) has been the initialrespiratory support for preterm in-fants with respiratory distress syn-drome (RDS) and has become an established practice in many centers. 3,4

Studies have revealed benecial ef-fects when combining early surfactant treatment by transient intubation (theintubation, surfactant treatment, andextubation [INSURE] approach) fol-lowed by NCPAP to further reduce therisk of invasive ventilation 5 8 whiledemonstrating a trend toward a lowerincidence of BPD. 79 However, not all in-fants who are given early NCPAP can besuccessfully managed, and studieshave revealed failure rates that rangefrom 25% to 50%, 2,8,10 12 which has en-couraged the use of nasal intermittentpositive-pressure ventilation (NIPPV) to reduce these failure rates.

NIPPV is noninvasive ventilation that in-creases the benecial effects of NCPAPby combining it with ventilatory inations and, therefore, decreasing theneed for ETT ventilation. 13,14 It can beused in a synchronized (SNIPPV) ornonsynchronized manner to supple-ment the infants own breathing ef-

forts.15

Kiciman et al16

found reduced thoracoabdominal motion asynchronyduring SNIPPV when compared withNCPAP. Aghai et al17 revealed thatSNIPPV decreases the work of breath-ing in preterm infants. SNIPPV in-creased tidal volume and minute vol-ume when compared with NCPAP. 18

Trialshave found that NIPPV decreases the rate of extubation failure, withoutadverse gastrointestinal complica-

tions, in preterm infants when com-pared with NCPAP. 19 21

Theinitiation of MV in the rst days of apreterm infant is a major factor forBPD and ventilator-associated morbid-ities. 22,23 Two randomized controlled

trials (RCTs) have revealed that earlyNIPPV reduced the need for endotra-cheal intubation within the rst 72hours of life when compared withNCPAP. Kugelman et al24 found a signi-cant difference in the total cohort (11of 43 [25%] in the NIPPV group and 20of 41 [49%) in the NCPAP group; P .04) and a similar trend in infants witha birth weight (BW) of 1500 g (6 of 19[31%] and 13 of 21 [62%], respectively;

P .06). They also reported that fail-ure of NIPPV was associated withlower BW. Subsequently, Sai SunilKishore et al 25 demonstrated that theneed for MV at 48 hours was signi-cantly less among the infants in theNIPPV group (13.5% vs 35.9%).

We conducted a single-center, pro-spective RCT using standardized proto-cols for intubation and surfactant therapy. The primary outcome of the

study was to assess the need for intu-bation within the rst 72 hours of lifeafter random assignment to earlyNIPPV or NCPAP.

METHODS

Subjects

This single-center RCT was conductedfrom August 2007 to September 2009at the Instituto de Medicina IntegralProf Fernando Figueira in an inborn tertiary NICU and approved by the insti- tutional research ethics committee.Preterm infants were eligible if gestational age was 26 to 33 6 7 weeks and there was clinical evidence of respiratory distress. Small for gestational agewas classied according to Alexanderet al. 26 Parental written informed con-sent was required before delivery of the potentially eligible infants. Infantswere excluded for any of the following

reasons: major congenital anomalies;presence of cardiovascular instability;intubation at admission to the NICU;consent notprovided or refused; or un-availability of a ventilator. Infants wereresuscitated according to Neonatal Re-

suscitation Program guidelines. 27

Study Intervention

Randomization was performed byusing random-number, computer-generated protocol, and sequentiallynumbered sealed opaque envelopes that contained the group assignmentswere prepared. Infants from multiplebirths were randomly assigned indi-vidually. When the infant was admitted

to the NICU and had fullled the entrycriteria, the envelope was opened and the allocated treatment, NCPAP orNIPPV, was started immediately.

We used a time-cycled, pressure-limited, and continuous-ow neonatalventilator (Inter Neo, Intermed Inc, SaoPaulo, Brazil) for infants assigned to the NIPPV group, in the nonsynchro-nized mode. The initial settings were:frequency of 20 to 30 breaths per

minute, peak inspiratory pressure of 15 to 20 cm H2 O, peak end expiratorypressure of 4 to 6 cm H 2 O, inspiratory time of 0.4 to 0.5 seconds, and a owrate of 8 to 10 L/minute. Infants ran-domly assigned to the NCPAP groupwere initiated on a pressure of 5 to 6cm H2 O and a ow of 8 to 10 L/minuteby an underwater seal (Bubble CPAPsystem [Intermed Inc]). Short binasalprongs were used, and settings were

adjusted to target a pulse oxygen sat-uration between 88% to 92%.

The diagnosis and severity of RDS werebased on clinical signs along with Kerosand Makinensradiologic classication. 28

Infants were maintained in their allo-cated treatment at least during therst 72 hours, because crossover wasnot allowed. Surfactant (Curosurf [Chiesi Pharmaceuticals, Parma, It-aly]) was administered, 100 mg/kg per

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dose, as a rescue treatment by theINSURE (intubation, surfactant treat-ment, and extubation) approach if in-fants needed invasive MV or if theywere on noninvasive ventilation thatrequired a fraction of inspired oxygen

of 0.50 to maintain the targeted sat-uration of 88%to92%.Wegaveasec-ond dose if the infants needed a fraction of inspired oxygen of 0.40 tomaintain the targeted saturation. If in-fants were intubated for surfactant in the rst 72 hours, they were extubated to their allocated mode. Subjects wereweaned from NIPPV or NCPAP accord-ing to our standard nursery practice.After 72 hours of life, infants in the

NIPPVgroup could be weaned to NCPAPand later to nasal cannula. Infants in the NCPAP group were also weaned tonasal cannula. Prophylactic methyl-xanthines were used in all infants.

Primary and Secondary Outcomes

The primary outcome was to assess the need for intubation within the rst72 hours of life in the 2 groups. Thecriteria for failure were met by at

least 1 of the following: pH 7.20and Pa CO2 60 mm Hg; recurrent ap-nea with 3 episodes per hour asso-ciated with bradycardia; a singleepisode of apnea that required bag-and-mask ventilation; and a Pa O2

50 mm Hg with a fraction of inspiredoxygen of 0.5.

The secondary outcomes concerningrespiratory support were total duration on ETT ventilation, total duration

on NCPAP, total duration on supple-mental oxygen, incidence of pneumothorax, and BPD. BPD was dened ac-cording to the National Institutes of Health consensus denition. 29 Otheroutcomes included incidence of patentductus arteriosus (PDA), necrotizingenterocolitis, intraventricular hemor-rhage grades 3 and 4, retinopathy of prematurity stage 3, time to fullfeeds, and length of hospital stay. PDA

was conrmed by echocardiography,and intraventricular hemorrhage wasdened by using the Papile classication.30 Necrotizing enterocolitis wasclassied according to Bells classi-cation, as modied by Kliegman and

Walsh, 31 at stage II or greater. Retinop-athy of prematurity was dened ac-cording to the international classication of retinopathy of prematurity. 32

Full feeds were dened as feeds thatreached 130 to 150 mL/kg per day.

Statistical Analysis

On the basis of previous data from ourNICU, 40% to 45% of our preterm in-fants administered early NCPAP and

rescue surfactant treatment for RDSneeded intubation and MV within therst 72 hours of life. We estimated a20% absolute reduction in the need touse ETTventilation with theearly use of NIPPV. A sample size of 100 infants pergroup was calculated with a power of 80% and an error rate of 5%.

Categorical variables were comparedby using 2 or Fishers test, as needed.Students t test was used for continu-

ous variables with a normal distribution, and for skewed distribution,Mann-Whitneys test was used. Theanalysis was performed according to the intention-to-treat principle.

RESULTS

In total, 423 infants were assessed foreligibility and 223 were excluded. Of these infants, 64 were excluded be-cause of clinical conditions that didnotmeet the eligibility criteria. Consentwas not obtained for 82 eligible infants(the mother was admitted in labor and there was a lack of time before deliv-ery,the consent form was not found, or the study members were not awareof the admission or were unable toreach the parents in the appropriate time). Fourteen parents refused con-sent, and 63 infants were eligible butdid not get randomly assigned be-

cause there was no ventilator avail-able in the NICU and, hence, wereplaced on bubble CPAP. As a result, 100infants were randomly assigned to earlyNCPAP and 100 to early NIPPV (Fig 1).

Table 1 lists the demographic and clin-ical characteristics of both groups.The high proportion of small for gestational age (40.5%) is reective of a low-income population with a high incidenceof pregnancy-induced hypertension(36%). Infants who received PPV in thedelivery room were equally distributedamong the groups (NCPAP, 35%; NIPPV,32%). Eighteen (9%) all the infantswere intubated for resuscitation and then extubated on admission to theNICU; 10 were randomly assigned toNCPAP and 8 to NIPPV.

The rates of the primary outcome didnot differ signicantly between theNIPPV and NCPAP groups (relative risk[RR]: 0.71 [95% condence interval(CI): 0.48 1.14]) ( Table 2) orin the sub-group of infants who received surfactant therapy ( Table 3) .

In the posthoc subgroup analysis of

the primary outcome, a signicant dif-ference was found between the NIPPVand NCPAP groups during the periodfrom 24 to 72 hours (RR: 0.45 [95% CI:0.22 0.91]), which was also present in the group of infants who received sur-factant, NIPPV, and NCPAP (RR: 0.40[95% CI: 0.18 0.86]).

Infants with a BW of 1000 g had asignicantly decreased failure rate in the NIPPV group when compared with

those in the NCPAP group ( P .03), butno difference between the groups wasfound in infants with a BW of 1000 g(P .65).

In the NCPAP group, 36 infants nevergot intubated and 30 never got surfactant; 18 (18%) never got intubated orreceived surfactant. In the NIPPVgroup, 42 never got intubated and 27never received surfactant; 19 (19%)never gotintubatedor received surfac-

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tant. We found no difference between the groups.

In this study, noninvasive ventilationfailed for 59 infants in the rst 72hours, and it failed for 27 (45.7%) of them in the rst 24 hours. PPV wasgiven to 9 of 27 (33.3%) infants (by self-inating bag and mask for 3 infantsand with an ETT for the other 6 infants).

These 6 infants were extubated in thedelivery room after recovery and thenadmitted to the NICU; 3 infants wererandomly assigned to the CPAP groupand 3 to the NIPPV group. All 27 infantsreceived surfactant therapy, 19 (70%)required 2 doses, 18 (65%) had RDSclassied as moderate, and the mean time to ETT intubation was 12.3 6.8

hours, which suggests an initiallymore severe form of respiratory dis-ease. Five of the 27 infants (18.5%) hadearly sepsis.

In the NIPPV group (n 100), noninva-sive ventilation failed for 25 infants in

the rst 72 hours, and 75 infants wereable to be weaned to NCPAP. However,33 of 75 (44%) infants later needed MVat median day of life 13. A total of 58infants needed MV in the NIPPV group,45 (77%) because of recurrent/signi-cant apneic episodes.

In the NCPAP group ( n 100), noninva-sive ventilation failed for 34 infants in the rst 72 hours, and 66 infants wereable stay on NCPAP. However, 30 of 66

(45%) infants later needed MV at me-dian day of life 12. A total of 64 infantsin the NCPAP group needed MV, 55(86%) because of recurrent apnea thatdid not respond to a trial of NIPPV.

The overall rate of BPD was the same inboth groups ( Table 2) . Of the 20 infantswith BPD in the NCPAP group, 16 sur-vived (80%), whereas in the NIPPVgroup, 18 of 22 infants with BPD sur-vived (85.7%); this result was not sig-

nicantly different ( P .88). In thisstudy, 4 of 80 (5%) infants in the NCPAPgroup and 9 of 83 (10.8%) infants in theNIPPV group had moderate or severeBPD, but this was not signicant ( P .16). In the NCPAP group, 57 of 74 (77%)survived with no BPD, which was simi-lar to results for the NIPPV group (61 of 78 [78%]; P .86).

No signicant differences were notedbetween the 2 treatment groups for

the other secondary respiratory out-comes ( Table 2 ). All other clinical out-comes were not different among the 2 treatment groups ( Table 4 ).

DISCUSSION

In this single-center randomized trial,we found a reduced need for ETT intu-bation and MV overall within the rst72 hours in the NIPPV group (25%)when compared with NCPAP (34%)

Assessed for eligibility ( N = 423)

Excluded ( n = 223)

Did not meet inclusion criteria ( n = 64)

Parents declined to participate ( n = 14)

Consent not obtained ( n = 82)

Had consent but ventilator unavailable ( n = 63)

Randomly assigned (n = 200)

Allocated to NCPAP ( n = 100)

Received allocated intervention ( n = 100)

Lost to follow-up ( n = 0)

Allocated to NIPPV ( n = 100)

Received allocated intervention ( n = 100)

Lost to follow-up ( n = 0)

Analyzed ( n = 100) Analyzed ( n = 100)

E n r o

l l m e n

t

A l l o c a t

i o n

F o l

l o w - u p

A n a

l y s i s

FIGURE 1Flowchart of the participants.

TABLE 1 Demographic and Clinical Data in the Study Groups

Characteristic NCPAP ( N 100) NIPPV (N 100)

Pregnancy-induced hypertension, n (%) 37 (37) 35 (35)Antenatal steroids, any, n (%) 76 (76) 72 (72)Cesarean deliveries, n (%) 59 (59) 50 (50)Multiple births, n (%) 16 (16) 17 (17)Male gender, n (%) 49 (49) 51 (51)Delivery-room resuscitation (need for PPV), n (%) 35 (35) 32 (32)Apgar score at 1 min, median (IQR) 7 (29) 7 (29)Apgar score at 5 min, median (IQR) 8 (410) 8 (510)Gestational age, mean SD, wk 30.1 2.3 29 1.6BW, mean SD, g 1151 289 1112 252SGA, n (%) 42 (42) 39 (39)RDS, n (%)

Mild 77 (77) 78 (78)Moderate 23 (23) 22 (22)

None of the differences between groups were signicant. IQR indicates interquartile range; SGA, small for gestational age(below the 10th centile).

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(not signicant). Although this ndingcould mean that there was actually nodifference with the 2 approaches, the

effect could have been masked be-cause of sample size or affected byother factors (see below). In an at-

tempt to better understand the rea-sons for success/failure using thenasal-ventilation approach over therst 72 hours, we conducted a posthocsubgroup analysis. During the periodfrom 24 to 72 hours, a signicant de-

crease was found in the NIPPV groupwhen compared with infants randomlyassigned to NCPAP. This nding wassimilar in the group of infants who re-quired surfactant.

In this cohort of 59 infants for whomnoninvasive ventilation failed in therst 72 hours of life, it failed for 27(47.5%) of them in the rst 24 hours.The rst 24 hours of life is a crucialperiod for preterm infants with RDS,

and most ofthemwillrespond torespi-ratory support and surfactant therapy.Yet, 20% of preterm infants are con-sidered poor responders. 33,34 In addition, there is a group of sick infantswith major risk factors such as: resus-citation in the delivery room, severeform of respiratory disease, presenceof chorioamnionitis, and early sepsis.These factors may Contribute to amore progressive respiratory failure

that requires invasive MV. 35,36 The 27infants for whom noninvasive ventilation failed in the rst 24 hours had initially a more severe respiratorycourse because they required moreaggressive care in the delivery roomand more respiratory support anddoses of surfactant and, subsequently,had an early need for ETT ventilationand MV. It is possible that such infantsare more prone to early atelectasis,

which could not be overcome by in-creased ventilator settings, which re-sults in failure of NIPPV and reintuba- tion, as was recently suggested. 13

In a recent RCT, Moretti et al 37 demon-strated that more infants were suc-cessfully extubated to SNIPPV whencompared with NCPAP (94% vs 61%).The main causes of extubation failurein the NCPAP group were respiratoryacidosis and apneic episodes adding

TABLE 2 Respiratory Support and BPD Outcome in the Study Groups

Outcome NCPAP(N 100)

NIPPV(N 100)

RR With NIPPV(95% CI)

AdjustedP

Failure of NIV at 72 h, n (%) 34 (34) 25 (25) 0.70 (0.481.14) .16Failure of NIV in the rst 24 h, n (%) 12 (12) 15 (15) 1.25 (0.612.53) .53Failure of NIV at 2448 h, n (%) 12 (12) 5 (5) 0.41 (0.151.13) .08Failure of NIV at 4872 h, n (%) 10 (10) 5 (5) 0.50 (0.171.41) .19

Failure of NIV at 2472 h, n (%) 22 (22) 10 (10) 0.45 (0.220.91) .02Failure of NIV, n /N (%)Infants 1000 g 9/37 (24) 11/38 (29) 1.19 (0.552.53) .65Infants 1000 g 25/63 (39) 14/62 (22) 0.56 (0.320.98) .04

Need for MV, n (%) 64 (64) 58 (58) 0.90 (0.721.13) .38Total time on MV, median (IQR), d 5 (138) 7 (173) .14Total time of NCPAP, mean SD, d 9.4 8.9 9.6 6.8 .65Total time of nasal cannula, mean SD, d 6.1 7 6.8 0.4 .46Total time of oxygen, mean SD, d 20.4 16 23.6 22.6 .97BPD, n /N (%)a 20/80 (25) 22/83 (26.5) 1.06 (0.621.78) .82

Milda 16/80 (20) 13/83 (15.6) 0.78 (0.401.52) .46Moderate a 1/80 (1.2 ) 3 /83 (7 .2 ) 2 .89 (0.3027 .2) .32Severe a 3/80 (3.7 ) 6 /83 (7 .2 ) 1 .90 (0.497.40) .34

NIV indicates noninvasive ventilation; IQR, interquartile range.a Denominator survivors to 36 weeks postmenstrual age.

TABLE 3 Respiratory Support and BPD Outcome in the Study Groups of Infants Who ReceivedSurfactant

Outcome NCPAP (N 70) NIPPV (N 70) RR With NIPPV(95% CI)

AdjustedP

Failure of NIV at 72 h, n (%) 31 (44.2) 23 (31.5) 0.71 (0.461.09) .11Failure of NIV in the rst 24 h, n (%) 12 (17.1) 15 (20.5) 1.19 (0.602.37) .60Failure of NIV at 2448 h, n (%) 11 (15.7) 4 (5.4) 0.34 (0.111.04) .05Failure of NIV at 4872 h, n (%) 8 (11.4) 4 (5.4) 0.48 (0.151.54) .22Failure of NIV at 2472 h, n (%) 19 (27.1) 8 (10.9) 0.40 (0.180.86) .01Dose of surfactant, median (IQR) 1 (12) 1 (12) .29Surfactant rescue doses, n (%) 29 (41.4) 24 (32.8) 0.79 (0.511.22) .29Time of surfactant, median (IQR), h 3 (136) 3 (144) .82BPD, n /N (%)a 15/55 (27.3) 19 /60 (31.7) 1.16 (0 .652.05) .60

NIV indicates noninvasive ventilation; IQR, interquartile range.a Denominator survivors to 36 weeks postmenstrual age.

TABLE 4 Neonatal Outcomes in the Study Groups

Outcome NCPAP(N 100)

NIPPV(N 100)

RR With NIPPV(95% CI)

AdjustedP

Pneumothorax, n (%) 5 (5) 3 (3) 0.60 (0.142.44) .47PDA, n (%) 29 (29) 25 (25) 0.86 (0.541.36) .52PDA, indomethacin, n (%) 24 (24) 16 (16) 0.66 (0.371.17) .16PDA, ligation, n (%) 6 (6) 4 (4) 0.66 (0.190.29) .51NEC, n (%) 9 (9) 5 (5) 0.55 (0.191.50) .27IVH, grades 3 and 4, n /N (%)a 6/75 (8) 6/73 (8.2) 1.02 (0.343.00) .96

ROP stage 3, n /N (%)b

8/71 (11.2) 10/64 (15.6) 1.38 (0.583.20) .45Time to full feeds, mean SD, d 18.3 8.1 17.9 9.9 .49Duration of hospitalization, mean SD, d 53.9 19 .15 55.9 20.5 .45Survival to discharge, n (%) 74 (74) 78 (78) 1.05 (0.901.23) .50Survival with no BPD, n /N (%) 57/74 (77) 61/78 (78) 1.01 (0.851.20) .86

NEC indicates necrotizing enterocolitis; IVH, intraventricular hemorrhage; ROP, retinopathy of prematurity.a Denominator infants submitted to cranial ultrasound scans.b Denominator infants submitted to examination by ophthalmologist.

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up to 75% of the cases, which were notpresent in the SNIPPV group. The authors suggested that the most important effect of SNIPPV might be that of stimulating breathing. We believe that the results of our subgroup analysis,

during the period from 24 to 72 hours,provide clinically relevant information,because during the rst few days of life and especially after the rst 24hours, when the preterm infant is re-solving RDS, this apparent advantageof NIPPV over NCPAP in stimulatingbreathing to avoid apnea and hyper-capnia could play an important role inavoiding failure of noninvasive ventilation. In addition, we speculate that the

relative success of NIPPV over NCPAPafter 24 hours could be a result of im-proved pulmonary mechanics, whichresults in better alveolar recruitment,after elimination of those infants withworse lung function in the rst 24hours.

Another interesting result was thatamong infants with a BW of 1000 g,NIPPV failure was signicantly lowerwhen compared with NCPAP, which in-

dicates a more effective approach inreducing the need forETT ventilation in this subgroup of patients. For thisgroup of infants, we speculate that im-proved pulmonary mechanics causedby their relatively larger size contrib-uted to better alveolar recruitment.However, caution needs to be maintained when interpreting these re-sults, because the number of infantswithaBWof 1000 g, and especially of

750 g, was small.A lower incidence of BPD in infants treated initially with NCPAP when com-pared with MV has been reported. 22,23

However, 2 multicenter RCTs have notfound a decrease in BPDwhen compar-ing these 2 ventilatory strategies. TheContinuous Positive Airway Pressureor Intubation at Birth (COIN) trial found the outcome of oxygen dependency at28 days of age lower in the NCPAP

group, although this was not seen at36weeks postmenstrual age. 38 The morerecent Surfactant, Positive Pressureand Pulse Oximetry Randomized Trial(SUPPORT) revealed no difference in the primary outcome of death or BPD

between infants assigned to earlyNCPAP or early surfactant and MV. 39

Bhandari et al evaluated SNIPPV andsurfactant therapy, compared withcontinued ETT MV, and found a signi-cantly lower primary outcome of BPD/death in the SNIPPV group. 40 From arecent trial, Ramanathan et al 41 alsoreported a signicant reduction inphysiologic and clinical BPD in theNIPPV group. Results of these studies

suggest that NIPPV seems to be fea-sible and effective and results in alower incidence of BPD when com-pared with MV.

The impact of NCPAP compared withSNIPPV on the incidence of BPD wasevaluated in a large retrospectivestudy in infants with a birthweightequaling 1250 g. In the subgroup of those born at 500 to 750 g, SNIPPV wasassociated with a signicant lower in-

cidence of BPD ( P .01), as well as thecomposite outcome BPD/death ( P .01), when compared with NCPAP. 42

Kugelman et al 24 also found a substan- tial decrease in the incidence of BPD in the NIPPV group among the subgroupof infants born at 1500 g (5% vs 33%;P .04) when compared with NCPAP.As we pointed out previously, 43 in addition to the lower rate of ETT found in the NIPPV group in this study, higher

tolerance to initial ventilatory settingsand early extubation from MV mighthave helped decrease the incidence of BPD in this group.

We did not nd a difference in the inci-dence or severity of BPD or the com-bined outcome of survival without BPDfor infants in the NIPPV versus NCPAPgroups. An important nding was that there were no gastrointestinal compli-cations. The incidence of necrotizing

enterocolitis as well as the time to fullfeeds was the same in both groups.Other authors have reported the samendings, which emphasizes the safetyof NIPPV.24,25,4042

This study has some limitations. Therst limitation concerns potential se-lection bias; consent was not obtainedfor 82 infants, which accounts for 20%of the eligible infants. This result issimilar to that of the Surfactant Posi- tive Airway Pressure and Pulse Oxime- try Randomized Trial, in which the authors found that 5 families needed to be antenatally identied andscreened for every 1 infant enrolledsuccessfully in the study. 39 In thisstudy, 63 infants (15% of the eligiblepopulation) were excluded becauseof the unavailability of a ventilator(ventilators were used for both MVand NIPPV), which became a practi-cal limitation to provide NIPPV.

Another limitation of this single-centerstudy was that the difference found infailure of noninvasive ventilation in theNCPAP arm (34%) was lower than that

used for the calculation of our samplesize (40%45%), which was based onour historical rate. We believe thatmultiple factors contributed this dif-ference: exclusion of infants of 26weeks gestation; increased antenatalsteroid use; earlier administration of surfactant; and enhanced use of NCPAP over time. Per our study de-sign, we allowed crossover of infants to other modes of respiratory sup-

port after 72 hours. It is possible thata longer duration of NIPPV in the rstpostnatal week may have additionalbenets.

The strengths of the study include theRCT design and the use of consistentstandardized protocols established inour NICU. Given that the majority of theNICUs do not have access to SNIPPV, the use of NIPPV and bubble CPAP isclinically relevant.

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CONCLUSIONS

Our study results suggest that NIPPV isfeasible and safe and may have bene-cial effects when compared with NC-

PAP, especially for infants with a BW of 1000 g. Further multicenter RCTs

with adequate power, targeted to in-fants witha BWof 1000 g, are needed to assess if NIPPV and/or NCPAP as the

rst (soon after birth) or primary (ie,after a brief intubation and early sur-factant administration) mode of nonin-vasive respiratory support can affectBPD and long-term outcomes.

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DOI: 10.1542/peds.2010-0922; originally published online January 24, 2011;2011;127;300Pediatrics

Jucille Meneses, Vineet Bhandari, Joao Guilherme Alves and Delia HerrmannControlled Trial

Noninvasive Ventilation for Respiratory Distress Syndrome: A Randomized

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