Advertisement

Nasal Intermittent Positive Pressure Ventilation for Neonatal Respiratory Distress Syndrome

  • Christoph M. Rüegger
    Correspondence
    Corresponding author.
    Affiliations
    Newborn Research, Department of Neonatology, University Hospital Zurich, University of Zurich, Frauenklinikstrasse 10, Zurich 8091, Switzerland
    Search for articles by this author
  • Louise S. Owen
    Affiliations
    Newborn Research Centre and Neonatal Services, The Royal Women's Hospital, Melbourne, Australia

    Department of Obstetrics and Gynaecology, The University of Melbourne, Melbourne, Australia

    Clinical Sciences, Murdoch Children’s Research Institute, Melbourne, Australia
    Search for articles by this author
  • Peter G. Davis
    Affiliations
    Newborn Research Centre and Neonatal Services, The Royal Women's Hospital, Melbourne, Australia

    Department of Obstetrics and Gynaecology, The University of Melbourne, Melbourne, Australia

    Clinical Sciences, Murdoch Children’s Research Institute, Melbourne, Australia
    Search for articles by this author
Open AccessPublished:October 02, 2021DOI:https://doi.org/10.1016/j.clp.2021.07.004

      Keywords

      Key points

      • Two device types have typically been used to deliver NIPPV: ventilators and flow-drivers, both devices can incorporate the option to synchronize pressure changes with spontaneous breathing.
      • Ventilator-generated NIPPV is traditionally set up to deliver NIPPV with settings mimicking settings used during endotracheal ventilation.
      • Flow-driver-generated NIPPV may also be set up in this manner, albeit with lower peak pressures, but it is more typically used with settings reflective of bilevel CPAP.
      • Overall, NIPPV is superior to CPAP as primary and postextubation support for the prevention of respiratory failure in preterm infants, especially when ventilator-generated, synchronized NIPPV is used.
      • Ventilator-generated, synchronized NIPPV as either primary or postextubation support in preterm infants may reduce the risk of bronchopulmonary dysplasia, but is not associated with a decrease in mortality.

      Introduction

      In the past, preterm infants with signs of moderate or severe respiratory distress were intubated and mechanically ventilated. This invasive approach resulted in inflammation of the lungs in the short-term and impaired development and scarring known as bronchopulmonary dysplasia (BPD) in the long-term.
      • Baraldi E.
      • Filippone M.
      Chronic lung disease after premature birth.
      Efforts to decrease rates of BPD in the surfactant/antenatal steroid era have led to an increased use of noninvasive respiratory support for even the most immature infants.
      • Doyle L.W.
      • Carse E.
      • Adams A.-M.
      • et al.
      Ventilation in extremely preterm infants and respiratory function at 8 years.
      Prophylactic nasal continuous positive airway pressure (CPAP), started soon after birth, is now recommended for spontaneously breathing very preterm or very low-birth-weight infants with respiratory distress syndrome (RDS).
      • Subramaniam P.
      • Ho J.J.
      • Davis P.G.
      Prophylactic nasal continuous positive airway pressure for preventing morbidity and mortality in very preterm infants.
      Prophylactic CPAP reduces the need for mechanical ventilation and surfactant administration, and lowers the rates of both BPD alone and the combined outcome of death or BPD when compared with immediate endotracheal ventilation.
      • Subramaniam P.
      • Ho J.J.
      • Davis P.G.
      Prophylactic nasal continuous positive airway pressure for preventing morbidity and mortality in very preterm infants.
      Despite the physiologic and clinical benefits, CPAP failure rates remain at approximately 50% in the first week of life in extremely preterm newborns at highest risk for developing BPD.
      • Dargaville P.A.
      • Aiyappan A.
      • Paoli A.G.D.
      • et al.
      Continuous positive airway pressure failure in preterm infants: incidence, predictors and consequences.
      SUPPORT Study Group of the Eunice Kennedy Shriver NICHD Neonatal Research Network
      Target ranges of oxygen saturation in extremely preterm infants.
      • Morley C.J.
      • Davis P.G.
      • Doyle L.W.
      • et al.
      Nasal CPAP or intubation at birth for very preterm infants.
      • Sandri F.
      • Plavka R.
      • Ancora G.
      • et al.
      Prophylactic or early selective surfactant combined with nCPAP in very preterm infants.
      CPAP failure is associated with a substantial increase in important adverse outcomes including air leak, BPD, intraventricular hemorrhage, and death.
      • Dargaville P.A.
      • Gerber A.
      • Johansson S.
      • et al.
      Incidence and outcome of CPAP failure in preterm infants.
      As a result, methods to augment the effectiveness of CPAP have gained interest.
      • Owen L.S.
      • Morley C.J.
      • Davis P.G.
      Neonatal nasal intermittent positive pressure ventilation: a survey of practice in England.
      Noninvasive intermittent positive pressure ventilation (NIPPV) applied at the nose has become a well-established therapy for preterm infants.
      • Kieran E.A.
      • Walsh H.
      • O’Donnell C.P.F.
      Survey of nasal continuous positive airways pressure (NCPAP) and nasal intermittent positive pressure ventilation (NIPPV) use in Irish newborn nurseries.
      Despite its frequent use, uncertainty remains regarding the precise terminology, the appropriate clinical indications, the different devices and techniques used to generate NIPPV, and the level of benefit they provide. These differences complicate the interpretation of the available evidence.
      • Lemyre B.
      • Laughon M.
      • Bose C.
      • et al.
      Early nasal intermittent positive pressure ventilation (NIPPV) versus early nasal continuous positive airway pressure (NCPAP) for preterm infants.
      ,
      • Lemyre B.
      • Davis P.G.
      • Paoli A.G.D.
      • et al.
      Nasal intermittent positive pressure ventilation (NIPPV) versus nasal continuous positive airway pressure (NCPAP) for preterm neonates after extubation.
      In this review, we address these uncertainties, with a particular focus on NIPPV as primary and postextubation respiratory support for preterm infants with RDS. For both indications, we summarize the current evidence from randomized controlled trials (RCTs) comparing NIPPV with CPAP.

      Nasal intermittent positive pressure ventilation

      Terminology

      NIPPV is a form of noninvasive respiratory support that combines a continuous positive end-expiratory airway pressure (PEEP) with intermittent higher pressures delivered by a nasal mask or nasal prongs. The terminology surrounding NIPPV is confusing. There are many alternative pressure generating devices, interfaces, and settings available. In addition, some devices allow synchronization with the infant’s own breathing efforts. The most common abbreviations include nsNIPPV (nonsynchronized NIPPV), sNIPPV (synchronized NIPPV), BiPAP (biphasic CPAP), bilevel CPAP, and bilevel NIPPV.
      Although all these modes are considered forms of NIPPV, 2 main NIPPV modalities must be distinguished: traditional NIPPV, with settings designed to mimic ventilator settings, typically generated using a ventilator, or alternatively settings that are more reflective of bilevel CPAP, typically generated using flow-drivers. There are devices of both types which have the capacity to synchronize pressure changes with spontaneous breathing (Table 1).
      Table 1Characteristics of ‘traditional’ NIPPV and bilevel CPAP
      • Waitz M.
      • Mense L.
      • Kirpalani H.
      • et al.
      Nasal intermittent positive pressure ventilation for preterm neonates synchronized or not?.
      ,
      • Owen L.S.
      • Manley B.J.
      Nasal intermittent positive pressure ventilation in preterm infants: Equipment, evidence, and synchronization.
      ,
      • Ekhaguere O.
      • Patel S.
      • Kirpalani H.
      Nasal intermittent mandatory ventilation versus nasal continuous positive airway pressure before and after invasive ventilatory support.
      ‘Traditional’ NIPPVBilevel CPAP
      DeviceMostly ventilator, can be flow-driver with lower peak pressure settingsFlow-driver
      PrincipleMimics timings and settings used during endotracheal ventilationIndependent breathing on two PEEP levels
      InterfaceShort binasal prongs, nasal masks, nasopharyngeal tubesShort binasal prongs, nasal masks
      Maximum pressureSimilar to endotracheal ventilation, usually ≤25 cm H2O11–15 cm H2O, depending on operating mode
      Infant Flow SiPAP (Vyaire Medical, Mettawa, Il, USA): theoretic maximum at 11 cm H2O if nonsynchronized and at 15 cm H2O if synchronized, although delivered pressures are often well below these maximums.9,19
      Peak and PEEP pressure difference≥5 cm H2O≤4 cm H2O
      High pressure delivery rateVariable (10–60 per min)Low (10–30 per min)
      High pressure durationShort (<0.5 s)Long (0.5–1 s)
      SynchronizationPossible, available with some ventilatorsPossible, usually not intended, available with some devices
      Method of synchronizationPneumatic capsule (eg, Graseby), flow sensor, pressure sensor, neurally adjusted ventilator assist (NAVA)Pneumatic capsule (eg, Graseby)
      • Miedema M.
      • Burg P.S.
      • Beuger S.
      • et al.
      Effect of nasal continuous and biphasic positive airway pressure on lung volume in preterm infants.
      Pressure curves
      a Infant Flow SiPAP (Vyaire Medical, Mettawa, Il, USA): theoretic maximum at 11 cm H2O if nonsynchronized and at 15 cm H2O if synchronized, although delivered pressures are often well below these maximums.
      • Owen L.S.
      • Morley C.J.
      • Davis P.G.
      Neonatal nasal intermittent positive pressure ventilation: a survey of practice in England.
      ,
      • Owen L.S.
      • Morley C.J.
      • Davis P.G.
      Effects of synchronisation during SiPAP-generated nasal intermittent positive pressure ventilation (NIPPV) in preterm infants.

      Pressure and Volume Delivery

      The lower pressure level (PEEP) during NIPPV offers the same physiologic benefits as CPAP, that is, stabilization of the upper airways and the compliant preterm chest wall and prevention of end-expiratory alveolar collapse. This maintains functional residual capacity and reduces ventilation-perfusion mismatch, which improves oxygenation and work of breathing. The intermittent pressure peaks increase the mean airway pressure (MAP) above the PEEP level, potentially further recruiting the lung, which may improve functional residual capacity more efficiently than CPAP alone.
      • Owen L.S.
      • Morley C.J.
      • Davis P.G.
      Do the pressure changes of neonatal non-synchronised NIPPV (NS nasal intermittent positive pressure ventilation) confer advantages over cpap, or are high CPAP pressures as effective?.
      Because of large and variable leaks around the nose and mouth, the transmission of applied NIPPV pressures to the lung is substantially attenuated.
      • Schmölzer G.M.
      • Dawson J.A.
      • Kamlin C.O.F.
      • et al.
      Airway obstruction and gas leak during mask ventilation of preterm infants in the delivery room.
      ,
      • Owen L.S.
      • Morley C.J.
      • Davis P.G.
      Pressure variation during ventilator generated nasal intermittent positive pressure ventilation in preterm infants.
      Moreover, observational studies demonstrate that the majority of nonsynchronized pressure peaks occur during spontaneous expiration and do not contribute to tidal volume.
      • Owen L.S.
      • Morley C.J.
      • Dawson J.A.
      • et al.
      Effects of non-synchronised nasal intermittent positive pressure ventilation on spontaneous breathing in preterm infants.
      When the pressure rises coincided with spontaneous inspiration, only a 15% increase in relative tidal volume was noted. During apneic episodes, pressure peaks resulted in measurable tidal volumes only 5% of the time, and produced tidal volumes a quarter of those seen during spontaneous breathing. Higher peak inspiratory pressures did not increase the likelihood of a visible chest inflation, suggesting that higher set pressures may not provide additional respiratory assistance during apnoea.
      • Owen L.S.
      • Morley C.J.
      • Dawson J.A.
      • et al.
      Effects of non-synchronised nasal intermittent positive pressure ventilation on spontaneous breathing in preterm infants.
      Whether nonsynchronized NIPPV confers any benefit over CPAP when the PEEP during CPAP is matched to the generated MAP during NIPPV is still a matter of debate. A small crossover study including 10 infants on nonsynchronized NIPPV and CPAP delivered at the same MAP found minimal differences in short-term outcomes, suggesting that any advantage of nonsynchronized NIPPV may arise from a higher MAP rather than from the effect of the intermittent pressure peaks themselves.
      • Owen L.S.
      • Morley C.J.
      • Davis P.G.
      Do the pressure changes of neonatal non-synchronised NIPPV (NS nasal intermittent positive pressure ventilation) confer advantages over cpap, or are high CPAP pressures as effective?.

      Synchronization

      Observations of low pressure and volume delivery during nonsynchronized NIPPV suggest support may be more effective if inflations are synchronized with the infant’s own inspiratory efforts. Synchronization may be achieved by airway flow detection, which ensures that the glottis is open before pressure is applied.
      • Dimitriou G.
      • Greenough A.
      • Laubscher B.
      • et al.
      Comparison of airway pressure-triggered and airflow-triggered ventilation in very immature infants.
      However, this is challenging because of air leakage around the prongs and masks and from the open mouth. Graseby capsules are unaffected by air leak, but may be affected by movement artifact; however, they are the most commonly used method for NIPPV synchronization.
      • Waitz M.
      • Mense L.
      • Kirpalani H.
      • et al.
      Nasal intermittent positive pressure ventilation for preterm neonates synchronized or not?.
      These cheap, lightweight, and disposable capsules are noninvasively attached to the anterior abdominal wall below the xiphoid process; they consist of a small, flat balloon filled with air, which is sensitive to pressure variations. The balloon connects to a pressure transducer capable of detecting the beginning of the diaphragmatic contraction, which enables the synchronization of the pressure peak. Although the accuracy of the Graseby capsule is affected by its position, method of fixation, and movement artifacts, it produces reliable signals that rapidly trigger the set pressure peak with most spontaneous breaths.
      • Owen L.S.
      • Morley C.J.
      • Davis P.G.
      Effects of synchronisation during SiPAP-generated nasal intermittent positive pressure ventilation (NIPPV) in preterm infants.
      • Stern D.J.
      • Weisner M.D.
      • Courtney S.E.
      Synchronized neonatal non-invasive ventilation-a pilot study: the graseby capsule with bi-level NCPAP.
      • Chang H.-Y.
      • Claure N.
      • D’Ugard C.
      • et al.
      Effects of synchronization during nasal ventilation in clinically stable preterm infants.
      Other potential synchronization methods include neurally adjusted ventilatory assist, currently available with the Servo-n ventilator (Maquet, Solna, Sweden) and respiratory inductance plethysmography.
      • Owen L.S.
      • Manley B.J.
      Nasal intermittent positive pressure ventilation in preterm infants: Equipment, evidence, and synchronization.

      Safety

      Although there were initial concerns regarding an increased risk of gastrointestinal side effects with NIPPV, recent evidence suggests that NIPPV is a safe therapy in preterm infants.
      • Garland J.S.
      • Nelson D.B.
      • Rice T.
      • et al.
      Increased risk of gastrointestinal perforations in neonates mechanically ventilated with either face mask or nasal prongs.
      This has been confirmed by 2 systematic reviews of the Cochrane Collaboration on NIPPV for initial support of neonatal RDS and for preterm infants after extubation.
      • Lemyre B.
      • Laughon M.
      • Bose C.
      • et al.
      Early nasal intermittent positive pressure ventilation (NIPPV) versus early nasal continuous positive airway pressure (NCPAP) for preterm infants.
      ,
      • Lemyre B.
      • Davis P.G.
      • Paoli A.G.D.
      • et al.
      Nasal intermittent positive pressure ventilation (NIPPV) versus nasal continuous positive airway pressure (NCPAP) for preterm neonates after extubation.
      Both reviews reported no significant differences between the NIPPV and CPAP groups in rates of feeding intolerance, gastrointestinal perforation, necrotizing enterocolitis, or air leak. The incidence of nasal injury through tight-fitting binasal prongs has not been assessed systematically for infants receiving NIPPV. Since the risk of nasal injury, and the strategies to prevent it are considered the same for NIPPV and CPAP, use of nasal masks, rotating nasal interfaces, and nasal barrier dressings may be equally effective in reducing nasal injury during NIPPV.
      • Imbulana D.I.
      • Manley B.J.
      • Dawson J.A.
      • et al.
      Nasal injury in preterm infants receiving non-invasive respiratory support: a systematic review.

      Clinical evidence

      The majority of clinical trials in preterm infants have compared NIPPV with CPAP as either the primary mode of treatment for neonatal RDS, or after extubation. Of these trials, Kirpalani’s NIPPV Trial dominates the literature.
      • Kirpalani H.
      • Millar D.
      • Lemyre B.
      • et al.
      A trial comparing noninvasive ventilation strategies in preterm infants.
      This large, pragmatic trial differs from the smaller studies in that it recruited a heterogeneous study population and permitted a variety of devices to deliver NIPPV, including some that delivered synchronized pressure changes. Although pragmatic, the considerable degree of methodological and clinical heterogeneity makes interpretation of pooled trial results difficult. To evaluate the impact of these variations, we begin with a review of Kirpalani’s NIPPV Trial and its substudies, and provide updated meta-analyses of trials comparing NIPPV with CPAP as primary or postextubation support for neonatal RDS.

      Kirpalani’s Nasal Intermittent Positive Pressure Ventilation Trial

      This large randomized, controlled, multicenter trial conducted between 2007 and 2011 hypothesized that NIPPV would reduce the risk of BPD in extremely low-birth-weight infants by minimizing the duration of endotracheal intubation.
      • Kirpalani H.
      • Millar D.
      • Lemyre B.
      • et al.
      A trial comparing noninvasive ventilation strategies in preterm infants.
      Infants with a birth weight of less than 1000 g and a gestational age of less than 30 weeks, eligible for noninvasive support within the first 28 days of life, were randomly assigned to 1 of 2 forms of noninvasive respiratory support, NIPPV or CPAP. Initial settings for respiratory support were provided, but not mandated and clinicians could individualize care. No NIPPV delivery devices were specified, NIPPV synchronization was permitted but not mandated. The primary outcome was a composite of death or moderate/severe BPD according to National Institutes of Health criteria.
      • Jobe A.H.
      • Bancalari E.
      Bronchopulmonary dysplasia.
      Three preplanned subgroup analyses were performed according to birth weight, prior intubation status (intubated or nonintubated before randomization), and the form of the intervention used in the NIPPV group (synchronized or nonsynchronized).
      A total of 1009 infants with a mean gestational age of 26 weeks and a mean birth weight of 800 g were enrolled. The primary outcome, death or BPD occurred in 38.4% (191 of 497 infants) randomized to NIPPV and in 36.7% (180 of 490) randomized to CPAP (adjusted odds ratio, 1.09; 95% confidence interval [CI], 0.83–1.43; P = .56). There were no significant differences between NIPPV and CPAP in the individual components of death or BPD, in other prespecified secondary outcomes including potential adverse effects of treatment, or in the subgroup analyses according to birth weight, prior intubation status, or synchronization.
      In the years following the publication of Kirpalani’s NIPPV Trial results, 2 secondary analyses have been published with the following aims: (1) to examine whether important outcomes differed in infants who received ventilator-generated or flow-driver-generated NIPPV, and (2) to compare noninvasive ventilation failure rates in intubation-naïve extremely low-birth-weight infants randomized to NIPPV or CPAP.
      • Millar D.
      • Lemyre B.
      • Kirpalani H.
      • et al.
      A comparison of bilevel and ventilator-delivered non-invasive respiratory support.
      ,
      • Bourque S.L.
      • Roberts R.S.
      • Wright C.J.
      • et al.
      Nasal intermittent positive pressure ventilation versus nasal continuous positive airway pressure to prevent primary noninvasive ventilation failure in extremely low Birthweight infants.

      Substudy 1: ventilator-generated versus flow-driver-generated nasal intermittent positive pressure ventilation

      This nonrandomized comparison from Kirpalani’s NIPPV Trial provides outcome data on the 497 infants in the NIPPV group.
      • Millar D.
      • Lemyre B.
      • Kirpalani H.
      • et al.
      A comparison of bilevel and ventilator-delivered non-invasive respiratory support.
      NIPPV could be delivered by a ventilator or a flow-driver device based on unit preference, practice, and device availability. Irrespective of the device, traditional NIPPV settings or bilevel CPAP settings could be used. In the NIPPV group, 215 infants received ventilator-generated NIPPV and 241 received flow-driver-generated NIPPV. Forty-one infants, in whom both devices had been used, were excluded. The composite outcome, death or BPD at 36 weeks was 39% in the ventilator-generated NIPPV group and 37% in the flow-driver-generated NIPPV group (adjusted odds ratio, 0.88; 95% CI, 0.57–1.35; P = .56). Although rates of BPD were not significantly different between groups (adjusted odds ratio, 0.64; 95% CI, 0.41–1.02; P = .061), more deaths occurred before 36 weeks gestational age in the flow-driver-generated NIPPV group (2.3% vs 9.4%; adjusted odds ratio, 5.01; 95% CI, 1.74–14.4; P = .003).

      Substudy 2: nasal intermittent positive pressure ventilation versus continuous positive airway pressure in intubation-naïve infants

      The second substudy compared the rate of ‘failure of noninvasive support’ in infants who were never intubated before enrollment and randomization.
      • Bourque S.L.
      • Roberts R.S.
      • Wright C.J.
      • et al.
      Nasal intermittent positive pressure ventilation versus nasal continuous positive airway pressure to prevent primary noninvasive ventilation failure in extremely low Birthweight infants.
      As opposed to the original trial and substudy 1, the primary outcome was defined as failure of noninvasive respiratory support requiring endotracheal intubation at any time in the first 7 days after randomization. Of the 1009 extremely low-birth-weight infants initially enrolled in the NIPPV trial, 142 had not been intubated before randomization. Of those, 27.5% in the NIPPV group and 30.1% in the CPAP group were subsequently intubated (relative risk, 0.91; 95% CI, 0.54–1.53). The combined outcome of death or BPD at 36 weeks postmenstrual age was not different between groups (19.7% vs 16.7%; risk ratio, 1.18; 95% CI, 0.58–2.40). There was no significant difference in rates of air leak.

      What do the results of Kirpalani’s nasal intermittent positive pressure ventilation trial and its substudies mean?

      In contrast with the results obtained from the pooled analysis of smaller trials that favored the use of NIPPV in preterm infants, Kirpalani’s NIPPV trial and its substudies found no significant benefit of NIPPV with respect to the risk of death or survival without BPD.
      • Lemyre B.
      • Laughon M.
      • Bose C.
      • et al.
      Early nasal intermittent positive pressure ventilation (NIPPV) versus early nasal continuous positive airway pressure (NCPAP) for preterm infants.
      ,
      • Lemyre B.
      • Davis P.G.
      • Paoli A.G.D.
      • et al.
      Nasal intermittent positive pressure ventilation (NIPPV) versus nasal continuous positive airway pressure (NCPAP) for preterm neonates after extubation.
      ,
      • Meneses J.
      • Bhandari V.
      • Alves J.G.
      Nasal intermittent positive-pressure ventilation vs nasal continuous positive airway pressure for preterm infants with respiratory distress syndrome: a systematic review and meta-analysis.
      • Ramaswamy V.V.
      • Bandyopadhyay T.
      • Nanda D.
      • et al.
      Efficacy of noninvasive respiratory support modes as postextubation respiratory support in preterm neonates: A systematic review and network meta-analysis.
      • Ramaswamy V.V.
      • More K.
      • Roehr C.C.
      • et al.
      Efficacy of noninvasive respiratory support modes for primary respiratory support in preterm neonates with respiratory distress syndrome: Systematic review and network meta-analysis.
      There may be several reasons for the differences in findings. First, more immature infants were included in Kirpalani’s NIPPV trial (Tables 2 and 3); failure of noninvasive support is more prevalent in extremely preterm infants and is associated with a marked increase in the rate of adverse outcomes, including death and BPD.
      • Dargaville P.A.
      • Aiyappan A.
      • Paoli A.G.D.
      • et al.
      Continuous positive airway pressure failure in preterm infants: incidence, predictors and consequences.
      ,
      • Dargaville P.A.
      • Gerber A.
      • Johansson S.
      • et al.
      Incidence and outcome of CPAP failure in preterm infants.
      In such a high-risk population with RDS due to surfactant-deficient lungs, collapsing airways and poor muscle strength, a number of infants may still be inadequately supported with NIPPV despite the modest increase in MAP provided by additional positive pressure breaths. Second, the pragmatic trial design did not specify the ventilator device, settings, or use of synchronization. In the NIPPV group, approximately half of infants received flow-driver-generated NIPPV, typically set to deliver modest peak pressures, lower than pressures set during ventilator-generated NIPPV. Indeed, mortality was higher in infants who mostly received flow-driver-generated NIPPV, possibly due to a higher reintubation rate compared with infants receiving ventilator-generated NIPPV (adjusted rate ratio for number of reintubations, 1.23; 95% CI, 1.02–1.49).
      • Millar D.
      • Lemyre B.
      • Kirpalani H.
      • et al.
      A comparison of bilevel and ventilator-delivered non-invasive respiratory support.
      Moreover, a subgroup analysis by synchronization rather than by device revealed that ventilator-generated NIPPV was mostly applied in a nonsynchronized manner, and synchronization was more often used during flow-driver-generated NIPPV (suggesting that traditional NIPPV settings with short high-pressure durations were still commonly used during flow-driver-generated NIPPV, cf. Table 1). Both combinations of device and technique may be associated with a lack of effective pressure transmission to the lungs, and may contribute to the finding of no significant benefit of NIPPV.
      Table 2Trials comparing NIPPV with CPAP for primary respiratory support (by device and synchronization)
      Mean GA
      GA, gestational age.
      at Birth [wk]
      SurfactantDevice
      1: Bear Infant Ventilator CUB 750 (Ackrad Laboratories, Cranford, NJ, USA). 2: Drager Babylog 8000 (Drager Medical Inc, Lubeck, Germany). 3: VIP Bird-R Sterling (Vyaire Medical, Il, USA). 4: Continuous flow ventilator, not specified. 5: SLE 2000 (Specialised Laboratory Equipment, Croydon, UK). 6. Neoport E100 M (DRE Medical, Louisville, KY, USA). 7: Inspiration 5i ventilator (eVent Medical Ltd, Ireland). 8: BiPAP device, not specified. 9: Infant Flow SiPAP System (Vyaire Medical, Il, USA). 10: Fabian (Acutronic Medical Systems AG, Hirzel, Switzerland). 11: Avea CVS Ventilator (Vyaire Medical, Il, USA).
      NIPPVCPAP
      Set Peak Pressure [cm H2O]High Pressure Duration [s]High Pressure Delivery Rate [per minute]PEEP
      PEEP, positive end expiratory pressure.
      [cm H2O]
      PEEP
      PEEP, positive end expiratory pressure.
      [cm H2O]
      1.1.1 Ventilator-generated, nonsynchronized NIPPV
       Bisceglia et al,
      • Bisceglia M.
      • Belcastro A.
      • Poerio V.
      • et al.
      A comparison of nasal intermittent versus continuous positive pressure delivery for the treatment of moderate respiratory syndrome in preterm infants.
      2007
      NDA
      NDA, no data available.
      No114–20NDA
      NDA, no data available.
      404–64–6
       Sai Sunil Kishore et al,
      • Kishore M.S.S.
      • Dutta S.
      • Kumar P.
      Early nasal intermittent positive pressure ventilation versus continuous positive airway pressure for respiratory distress syndrome.
      2009
      30.8Mixed2, 315–260.30–0.3550–605–65–7
       Meneses et al,
      • Meneses J.
      • Bhandari V.
      • Alves J.G.
      • et al.
      Noninvasive ventilation for respiratory distress syndrome: a randomized controlled trial.
      2011
      29.6No415–200.40–0.5020–304–65–6
       Armanian et al,
      • Armanian A.-M.
      • Badiee Z.
      • Heidari G.
      • et al.
      Initial treatment of respiratory distress syndrome with nasal intermittent mandatory ventilation versus nasal continuous positive airway pressure: a randomized controlled trial.
      2014
      30.0No416–200.4040–505–65–6
       Oncel et al,
      • Oncel M.Y.
      • Arayici S.
      • Uras N.
      • et al.
      Nasal continuous positive airway pressure versus nasal intermittent positive-pressure ventilation within the minimally invasive surfactant therapy approach in preterm infants: a randomised controlled trial.
      2015
      Trials not yet included in the corresponding meta-analysis of the Cochrane Collaboration.
      29.2No515–20NDA
      NDA, no data available.
      20–305–65–6
       Sabzehei et al,
      • Sabzehei M.K.
      • Basiri B.
      • Shokouhi M.
      • et al.
      A comparative study of treatment response of respiratory distress syndrome in preterm infants: early nasal intermittent positive pressure ventilation versus early nasal continuous positive airway pressure.
      2018
      Trials not yet included in the corresponding meta-analysis of the Cochrane Collaboration.
      30.1Yes414–200.30–0.3530–505–65–6
       Skariah & Lewis,
      • Skariah T.A.
      • Lewis L.E.
      Early nasal intermittent positive pressure ventilation (NIPPV) versus nasal continuous positive airway pressure (NCPAP) for respiratory distress syndrome (RDS) in infants of 28-36 weeks gestational age: a randomized controlled trial.
      2019
      Trials not yet included in the corresponding meta-analysis of the Cochrane Collaboration.
      31.8No211–180.36–0.4018–303–53–5
      1.1.2 Ventilator-generated, synchronized NIPPV
       Kugelman et al,
      • Kugelman A.
      • Feferkorn I.
      • Riskin A.
      • et al.
      Nasal intermittent mandatory ventilation versus nasal continuous positive airway pressure for respiratory distress syndrome: a randomized, controlled, prospective study.
      2007
      30.9No514–220.3012–306–76–7
       Salama et al,
      • Salama G.S.A.
      • Ayyash F.F.
      • Al-Rabadi A.J.
      • et al.
      Nasal-imv versus nasal-CPAP as an initial mode of respiratory support for premature infants with RDS: a prospective randomized clinical trial.
      2015
      31.2Mixed65–120.30–0.5015–184–66
       Dursun et al,
      • Dursun M.
      • Uslu S.
      • Bulbul A.
      • et al.
      Comparison of early nasal intermittent positive pressure ventilation and nasal continuous positive airway pressure in preterm infants with respiratory distress syndrome.
      2019
      Trials not yet included in the corresponding meta-analysis of the Cochrane Collaboration.
      29.3No516–240.4030–406–86–8
       Gharehbaghi et al,
      • Gharehbaghi M.M.
      • Hosseini M.B.
      • Eivazi G.
      • et al.
      Comparing the efficacy of nasal continuous positive airway pressure and nasal intermittent positive pressure ventilation in early management of respiratory distress syndrome in preterm infants.
      2019
      Trials not yet included in the corresponding meta-analysis of the Cochrane Collaboration.
      30.1No718–200.35–0.4030–405–65–6
      1.1.3 Flow-driver-generated, nonsynchronized NIPPV
       Kong et al,
      • Kong L.-K.
      • Kong X.-Y.
      • Li L.-H.
      • et al.
      Comparative study on application of duo positive airway pressure and continuous positive airway pressure in preterm neonates with respiratory distress syndrome.
      2012
      Trials not yet included in the corresponding meta-analysis of the Cochrane Collaboration.
      32.9No812–150.35–0.5020–304–64–6
       Aguiar et al,
      • Aguiar T.
      • Macedo I.
      • Voutsen O.
      • et al.
      Nasal bilevel versus continuous positive airway pressure in preterm infants: a randomized controlled trial.
      2015
      Trials not yet included in the corresponding meta-analysis of the Cochrane Collaboration.
      31.0No9821066–8
       Sadeghnia et al,
      • Sadeghnia A.
      • Barekateyn B.
      • Badiei Z.
      • et al.
      Analysis and comparison of the effects of N-BiPAP and Bubble-CPAP in treatment of preterm newborns with the weight of below 1500 grams affiliated with respiratory distress syndrome: a randomised clinical trial.
      2016
      Trials not yet included in the corresponding meta-analysis of the Cochrane Collaboration.
      29.9No1080.503046
      1.1.4 Flow-driver-generated, synchronized NIPPV
       Lista et al,
      • Lista G.
      • Castoldi F.
      • Fontana P.
      • et al.
      Nasal continuous positive airway pressure (CPAP) versus bi-level nasal CPAP in preterm babies with respiratory distress syndrome: a randomised control trial.
      2010
      30.3Yes980.50–0.70304.56
       Wood et al,
      • Wood F.
      • Gupta S.
      • Tin W.
      • et al.
      G170 randomised controlled trial of synchronised intermittent positive airway pressure (SiPAPTM) versus continuous positive airway pressure (CPAP) as a primary mode of respiratory support in preterm infants with respiratory distress syndrome.
      2013
      29.8No96–90.3104–64–6
      1.1.5 Mixed methods
       Ramanathan et al,
      • Ramanathan R.
      • Sekar K.C.
      • Rasmussen M.
      • et al.
      Nasal intermittent positive pressure ventilation after surfactant treatment for respiratory distress syndrome in preterm infants <30 weeks’ gestation: a randomized, controlled trial.
      2012
      27.8Yes9, 1115–200.5030–4055–8
       Kirpalani et al,
      • Kirpalani H.
      • Millar D.
      • Lemyre B.
      • et al.
      A trial comparing noninvasive ventilation strategies in preterm infants.
      2013
      26.2No2, 3, 9≤18
      Suggested initiating and maximal settings.
      0.30–0.50
      Suggested initiating and maximal settings.
      10–40
      Suggested initiating and maximal settings.
      5–8
      Suggested initiating and maximal settings.
      5–8
      Suggested initiating and maximal settings.
      a GA, gestational age.
      b PEEP, positive end expiratory pressure.
      c NDA, no data available.
      d Suggested initiating and maximal settings.
      e Trials not yet included in the corresponding meta-analysis of the Cochrane Collaboration.
      f 1: Bear Infant Ventilator CUB 750 (Ackrad Laboratories, Cranford, NJ, USA). 2: Drager Babylog 8000 (Drager Medical Inc, Lubeck, Germany). 3: VIP Bird-R Sterling (Vyaire Medical, Il, USA). 4: Continuous flow ventilator, not specified. 5: SLE 2000 (Specialised Laboratory Equipment, Croydon, UK). 6. Neoport E100 M (DRE Medical, Louisville, KY, USA). 7: Inspiration 5i ventilator (eVent Medical Ltd, Ireland). 8: BiPAP device, not specified. 9: Infant Flow SiPAP System (Vyaire Medical, Il, USA). 10: Fabian (Acutronic Medical Systems AG, Hirzel, Switzerland). 11: Avea CVS Ventilator (Vyaire Medical, Il, USA).
      Table 3Trials comparing NIPPV with CPAP for postextubation support (by device and synchronization)
      Mean GA
      GA, gestational age.
      at Birth [wk]
      Device
      1: Bear Infant Ventilator CUB 750 (Ackrad Laboratories, Cranford, NJ, USA). 2: Drager Babylog 8000 (Drager Medical Inc, Lubeck, Germany). 3. Neoport E100 M (DRE medical, Louisville, KY, USA). 4. Inter 3/5/5plus (Intermed, Sao Paulo, Brazil). 5: Continuous flow ventilator, not specified. 6. Infantstar 500/950 (Infrasonics, San Diego, CA, USA). 7. Giulia (Ginevri, Rome, Italy). 8. Comen nv8 (Comen Medical, Shenzen, China). 9: Infant Flow SiPAP System (Vyaire Medical, Il, USA). 10: VIP Bird-R Sterling (Vyaire Medical, Il, USA).
      NIPPVCPAP
      Set Peak Pressure [cm H2O]High Pressure Duration [s]High Pressure Delivery Rate [per minute]PEEP
      PEEP, positive end expiratory pressure.
      [cm H2O]
      PEEP
      PEEP, positive end expiratory pressure.
      [cm H2O]
      1.2.1 Ventilator-generated, nonsynchronized NIPPV
       Khorana et al,
      • Khorana M.
      • Paradeevisut H.
      • Sangtawesin V.
      • et al.
      A randomized trial of non-synchronized Nasopharyngeal Intermittent Mandatory Ventilation (nsNIMV) vs. Nasal Continuous Positive Airway Pressure (NCPAP) in the prevention of extubation failure in pre-term < 1,500 grams.
      2008
      NDA
      NDA, no data available.
      1Pre-ext
      pre-ext, pre-extubation settings.
      Pre-ext
      pre-ext, pre-extubation settings.
      Pre-ext
      pre-ext, pre-extubation settings.
      Pre-ext
      pre-ext, pre-extubation settings.
      Pre-ext
      pre-ext, pre-extubation settings.
       Kahramaner et al,
      • Kahramaner Z.
      • Erdemir A.
      • Turkoglu E.
      • et al.
      Unsynchronized nasal intermittent positive pressure versus nasal continuous positive airway pressure in preterm infants after extubation.
      2014
      28.82Pre-ext
      pre-ext, pre-extubation settings.
       +2
      NDA
      NDA, no data available.
      2566
       Jasani et al,
      • Jasani B.
      • Nanavati R.
      • Kabra N.
      • et al.
      Comparison of non-synchronized nasal intermittent positive pressure ventilation versus nasal continuous positive airway pressure as post-extubation respiratory support in preterm infants with respiratory distress syndrome: a randomized controlled trial.
      2016
      30.71Pre-ext
      pre-ext, pre-extubation settings.
       +4
      NDA
      NDA, no data available.
      Pre-ext
      pre-ext, pre-extubation settings.
      ≤55–6
       Komatsu et al,
      • Komatsu D.F.R.
      • Diniz E.M.
      • Ferraro A.A.
      • et al.
      Randomized controlled trial comparing nasal intermittent positive pressure ventilation and nasal continuous positive airway pressure in premature infants after tracheal extubation.
      2016
      Trials not yet included in the corresponding meta-analysis of the Cochrane Collaboration.
      30.8316NDA
      NDA, no data available.
      1266
       Ribeiro et al,
      • Ribeiro S.
      • Fontes M.
      • Bhandari V.
      • et al.
      Noninvasive ventilation in newborns ≤1,500 g after tracheal extubation: randomized clinical trial.
      2017
      Trials not yet included in the corresponding meta-analysis of the Cochrane Collaboration.
      29.6414–160.30–0.3512–184–64–5
       Estay et al,
      • Estay A.S.
      • Mariani G.L.
      • Alvarez C.A.
      • et al.
      Randomized controlled trial of nonsynchronized nasal intermittent positive pressure ventilation versus nasal CPAP after extubation of VLBW infants.
      2020
      Trials not yet included in the corresponding meta-analysis of the Cochrane Collaboration.
      27.9512–180.45–0.60205–65–6
      1.2.2 Ventilator-generated, synchronized NIPPV
       Friedlich et al,
      • Friedlich P.
      • Lecart C.
      • Posen R.
      • et al.
      A randomized trial of nasopharyngeal-synchronized intermittent mandatory ventilation versus nasopharyngeal continuous positive airway pressure in very low birth weight infants after extubation.
      1999
      27.86Pre-ext
      pre-ext, pre-extubation settings.
      0.60104–64–6
       Barrington et al,
      • Barrington K.J.
      • Bull D.
      • Finer N.N.
      Randomized trial of nasal synchronized intermittent mandatory ventilation compared with continuous positive airway pressure after extubation of very low birth weight infants.
      2001
      26.1616NDA
      NDA, no data available.
      1266
       Khalaf et al,
      • Khalaf M.N.
      • Brodsky N.
      • Hurley J.
      • et al.
      A prospective randomized, controlled trial comparing synchronized nasal intermittent positive pressure ventilation versus nasal continuous positive airway pressure as modes of extubation.
      2001
      28.06Pre-ext
      pre-ext, pre-extubation settings.
       +2 – +4
      NDA
      NDA, no data available.
      Pre-ext
      pre-ext, pre-extubation settings.
      ≤54–6
       Moretti et al,
      • Moretti C.
      • Gizzi C.
      • Papoff P.
      • et al.
      Comparing the effects of nasal synchronized intermittent positive pressure ventilation (nSIPPV) and nasal continuous positive airway pressure (nCPAP) after extubation in very low birth weight infants.
      2008
      27.0710–20NDA
      NDA, no data available.
      Pre-ext
      pre-ext, pre-extubation settings.
      3–53–5
       Gao et al,
      • Gao W.-W.
      • Tan S.-Z.
      • Chen Y.-B.
      • et al.
      Randomized trail of nasal synchronized intermittent mandatory ventilation compared with nasal continuous positive airway pressure in preterm infants with respiratory distress syndrome.
      2010
      32.5520NDA
      NDA, no data available.
      4054–8
       Ding et al,
      • Ding F.
      • Zhang J.
      • Zhang W.
      • et al.
      Clinical study of different modes of non-invasive ventilation treatment in preterm infants with respiratory distress syndrome after extubation.
      2020
      Trials not yet included in the corresponding meta-analysis of the Cochrane Collaboration.
      29.8815–25NDA
      NDA, no data available.
      15–504–66
      1.2.3 Flow-driver-generated, nonsynchronized NIPPV
       O’Brien et al,
      • O’Brien K.
      • Campbell C.
      • Brown L.
      • et al.
      Infant flow biphasic nasal continuous positive airway pressure (BP- NCPAP) vs. infant flow NCPAP for the facilitation of extubation in infants’ ≤1,250 grams: a randomized controlled trial.
      2012
      27.498–101205–75–7
       Victor et al,
      • Victor S.
      • Roberts S.A.
      • Mitchell S.
      • et al.
      Biphasic positive airway pressure or continuous positive airway pressure: a randomized trial.
      2016
      Trials not yet included in the corresponding meta-analysis of the Cochrane Collaboration.
      27.39813046
      1.2.4 Mixed methods
       Kirpalani et al,
      • Kirpalani H.
      • Millar D.
      • Lemyre B.
      • et al.
      A trial comparing noninvasive ventilation strategies in preterm infants.
      2013
      26.22, 9, 10≤18
      Suggested initiating and maximal settings.
      0.30–0.50
      Suggested initiating and maximal settings.
      10–40
      Suggested initiating and maximal settings.
      5–8
      Suggested initiating and maximal settings.
      5–8
      Suggested initiating and maximal settings.
      a GA, gestational age.
      b PEEP, positive end expiratory pressure.
      c NDA, no data available.
      d pre-ext, pre-extubation settings.
      e Suggested initiating and maximal settings.
      f Trials not yet included in the corresponding meta-analysis of the Cochrane Collaboration.
      g 1: Bear Infant Ventilator CUB 750 (Ackrad Laboratories, Cranford, NJ, USA). 2: Drager Babylog 8000 (Drager Medical Inc, Lubeck, Germany). 3. Neoport E100 M (DRE medical, Louisville, KY, USA). 4. Inter 3/5/5plus (Intermed, Sao Paulo, Brazil). 5: Continuous flow ventilator, not specified. 6. Infantstar 500/950 (Infrasonics, San Diego, CA, USA). 7. Giulia (Ginevri, Rome, Italy). 8. Comen nv8 (Comen Medical, Shenzen, China). 9: Infant Flow SiPAP System (Vyaire Medical, Il, USA). 10: VIP Bird-R Sterling (Vyaire Medical, Il, USA).

      Meta-Analyses of Trials Comparing Nasal Intermittent Positive Pressure Ventilation with Continuous Positive Airway Pressure

      The updated meta-analyses were performed using RevMan, version 5.4.
      Centre TCCNC
      Nordic Cochrane centre, the Cochrane collaboration. Review Manager (RevMan) [Computer program]. Version 5.3. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration,.
      Relevant studies were identified by searching PubMed, The Cochrane Library, and the reference lists of included articles. Studies were included if they were RCTs that enrolled preterm infants (born <37 weeks’ gestation), compared any form of NIPPV with CPAP, and reported the primary outcome. Four subgroup analyses included whether NIPPV was delivered by a ventilator or by a flow-driver-device and whether pressure changes were synchronized with spontaneous breathing or not. No differentiation was made between the type of settings (traditional NIPPV vs bilevel CPAP) applied in each trial. A fixed-effect model was used to pool data of included trials.

      Primary respiratory support

      This meta-analysis aimed to compare the efficacy of NIPPV versus CPAP when used as primary respiratory support in preterm infants with RDS who were less than 6 hours old. We defined the primary outcome as respiratory failure leading to additional ventilatory support during the first week of life. An early and brief period of endotracheal ventilation for an INSURE (intubate—surfactant administration—extubate) procedure was not considered as respiratory failure.
      We pooled data from 18 trials and 1900 infants (see Table 2). We added data from 8 newly published trials comprising 850 infants to the existing meta-analysis of the Cochrane Collaboration.
      • Lemyre B.
      • Laughon M.
      • Bose C.
      • et al.
      Early nasal intermittent positive pressure ventilation (NIPPV) versus early nasal continuous positive airway pressure (NCPAP) for preterm infants.
      In 11 trials, ventilator-generated NIPPV with variable peak pressures of 12 to 26 cm H2O were used. Five trials used flow-driver-generated support with peak pressures of 8 to 15 cm H2O. Two trials, including Kirpalani’s NIPPV trial used mixed methods: both ventilator-generated and flow-driver-generated NIPPV, with or without synchronization, and with variable pressure settings. None of the included studies attempted to match the PEEP in the CPAP group with the generated MAP in the NIPPV group.
      Six individual trials reported a significant reduction in rates of respiratory failure during the first week of life in infants managed with NIPPV. Twelve showed no significant difference, and none showed a significant benefit for CPAP. Pooled data from all 18 trials demonstrated a clinically important, 37% relative reduction in the risk of respiratory failure with NIPPV (Fig. 1). This beneficial effect was most obvious in the trials using ventilator-generated NIPPV (combined subgroups 1.1.1 and 1.1.2: RR 0.60; 95% CI, 0.48–0.76), and was greatest when synchronization was used (subgroup 1.1.2), with 7 infants needing to be treated with ventilator-generated, synchronized NIPPV to prevent one respiratory failure. Flow-driver devices provided a smaller (subgroup 1.1.3) and nonsignificant effect (subgroup 1.1.4) on the risk of respiratory failure (combined subgroups 1.1.3 and 1.1.4: RR 0.70; 95% CI, 0.49–1.01). These findings are consistent with those of the corresponding 2016 Cochrane Review.
      • Lemyre B.
      • Laughon M.
      • Bose C.
      • et al.
      Early nasal intermittent positive pressure ventilation (NIPPV) versus early nasal continuous positive airway pressure (NCPAP) for preterm infants.
      Figure thumbnail gr1
      Fig. 1Forest plot of trials comparing NIPPV versus CPAP for primary respiratory support (by device and synchronization).

      Postextubation respiratory support

      This meta-analysis evaluated the efficacy of NIPPV versus CPAP when used as postextubation respiratory support for preterm infants. We defined the primary outcome as respiratory failure leading to additional ventilatory support during the week postextubation.
      Fifteen trials enrolling 2444 infants were included (see Table 3). Data from 5 trials published between 2016 and 2020 enrolling 1013 infants were added to the existing meta-analysis of the Cochrane Collaboration.
      • Lemyre B.
      • Davis P.G.
      • Paoli A.G.D.
      • et al.
      Nasal intermittent positive pressure ventilation (NIPPV) versus nasal continuous positive airway pressure (NCPAP) for preterm neonates after extubation.
      Twelve trials used ventilator-generated NIPPV, 2 trials delivered flow-driver-generated NIPPV, the final study being the Kirpalani mixed methods study.
      Overall, infants extubated to NIPPV had a 22% relative risk reduction for respiratory failure within the first week postextubation compared with those managed with CPAP (Fig. 2). Extubation of 12 infants to NIPPV would prevent one case of extubation failure. Again, this benefit was greatest in trials using ventilator-generated NIPPV (combined subgroups 1.2.1 and 1.2.2: RR 0.51; 95% CI, 0.40–0.65) and was strongest when ventilator-generated, synchronized NIPPV was used (subgroup 1.2.2). On average, only 3 infants would need to be extubated to ventilator-generated, synchronized NIPPV to prevent one case of postextubation failure. No beneficial effect was found for flow-driver devices (subgroup 1.2.3).
      Figure thumbnail gr2
      Fig. 2Forest plot of trials comparing NIPPV versus CPAP for postextubation support (by device and synchronization).

      Mortality

      Results from 17 trials enrolling 1834 infants could be pooled for this analysis. Overall and within subgroups, no difference in mortality was noted when NIPPV was compared with CPAP as primary respiratory support for preterm infants with neonatal RDS (Table 4). After extubation, no significant reduction in mortality was found in the meta-analysis of 10 trials and 2178 infants, and no significant difference was detected when mortality was examined by device or synchronization for either primary or postextubation support.
      Table 4Meta-analysis of trials comparing NIPPV with CPAP for primary and postextubation support
      Number of TrialsNIPPVCPAPRisk Ratio (95% CI)
      DeathsTotalDeathsTotal
      Primary respiratory support
       Ventilator-generated, nonsynchronized NIPPV740390494100.83 (0.57–1.20)
       Ventilator-generated, synchronized NIPPV4214531440.76 (0.17–3.30)
       Flow-driver-generated, nonsynchronized NIPPV2614681440.75 (0.28–1.99)
       Flow-driver-generated, synchronized NIPPV20802800.20 (0.01–4.08)
       Mixed methods2414851470.78 (0.21–2.83)
       Total1752909679250.79 (0.57–1.09)
      Postextubation care
       Ventilator-generated, nonsynchronized NIPPV517238272610.61 (0.35–1.06)
       Ventilator-generated, synchronized NIPPV25727710.70 (0.23–2.11)
       Flow-driver-generated, nonsynchronized NIPPV221337223390.96 (0.54–1.71)
       Flow-driver-generated, synchronized NIPPV0
       Mixed methods135430414300.85 (0.55–1.31)
       Total107810779711010.80 (0.60–1.06)
      Outcome: Mortality during study period.
      These findings contrast the results of the respective meta-analysis of the Cochrane Collaboration on NIPPV versus CPAP for preterm neonates after extubation, where a small difference in mortality between treatment groups was reported, favoring NIPPV (RR 0.69; 95% CI, 0.48–0.99).
      • Lemyre B.
      • Davis P.G.
      • Paoli A.G.D.
      • et al.
      Nasal intermittent positive pressure ventilation (NIPPV) versus nasal continuous positive airway pressure (NCPAP) for preterm neonates after extubation.

      Bronchopulmonary dysplasia

      Fourteen of the 18 trials (1534 infants) evaluating NIPPV versus CPAP as primary respiratory support reported BPD at 36 weeks’ corrected gestational age. We noted a 28% relative reduction in the risk of BPD with NIPPV (Table 5). However, this overall difference was fully attributable to the reduction in BPD seen in studies using ventilator-generated, synchronized NIPPV. None of the other subanalyses showed a significant difference in the rate of BPD between groups. In the meta-analysis of the Cochrane Collaboration on NIPPV as primary respiratory support for preterm infants, no reduction in BPD was observed in any of the subgroups.
      • Lemyre B.
      • Laughon M.
      • Bose C.
      • et al.
      Early nasal intermittent positive pressure ventilation (NIPPV) versus early nasal continuous positive airway pressure (NCPAP) for preterm infants.
      Table 5Meta-analysis of trials comparing NIPPV with CPAP for primary and postextubation support
      Number of TrialsNIPPVCPAPRisk Ratio (95% CI)
      BPDTotalBPDTotal
      Primary Respiratory Support
       Ventilator-generated, nonsynchronized NIPPV432257432560.73 (0.48–1.11)
       Ventilator-generated, synchronized NIPPV49145241440.37 (0.18–0.78)
       Flow-driver-generated, nonsynchronized NIPPV2914671441.27 (0.48–3.32)
       Flow-driver-generated, synchronized NIPPV25807800.71 (0.24–2.13)
       Mixed methods228140341420.85 (0.54–2.72)
       Total14837681157660.72 (0.56–0.93)
      Postextubation care
       Ventilator-generated, nonsynchronized NIPPV452209582290.91 (0.66–1.27)
       Ventilator-generated, synchronized NIPPV430133451280.63 (0.44–0.91)
       Flow-driver-generated, nonsynchronized NIPPV21533281653270.92 (0.79–1.08)
       Flow-driver-generated, synchronized NIPPV0
       Mixed methods11443941433800.97 (0.81–1.17)
       Total11379106441110640.91 (0.81–1.01)
      Outcome: Bronchopulmonary dysplasia
      After extubation, meta-analysis of 11 studies enrolling 2128 infants revealed a borderline lower rate of BPD when infants were randomized to NIPPV compared with infants randomized to CPAP (see Table 5). Once again, within subgroups, only ventilator-generated, synchronized NIPPV was associated with a reduction in BPD. In the corresponding meta-analysis of the Cochrane Collaboration, both ventilator-generated (RR 0.69; 95% CI, 0.50–0.95) and synchronized NIPPV (RR 0.64; 95% CI, 0.44–0.95) were associated with a reduction in BPD.

      Summary

      There is clear evidence that NIPPV is superior to CPAP as primary and postextubation respiratory support for the prevention of respiratory failure in preterm infants with RDS. For both indications, ventilator-generated, synchronized NIPPV is most effective to prevent respiratory failure. Results show no reduction in mortality overall or within subgroups, irrespective of whether primary or postextubation NIPPV support is delivered. Longer-term pulmonary benefits include a reduction in BPD, but only with ventilator-generated, synchronized NIPPV. Implementation of this evidence may be hampered by the limited availability of ventilators able to deliver synchronized pressure changes. There is little evidence of harm during NIPPV generated by any device or delivered in any mode, with no reported increase in abdominal adverse events.
      In view of the high heterogeneity among trials included in our meta-analyses, results may not be generalizable and must be interpreted with caution. It is important for clinicians to understand that not all modes of noninvasive support are the same, and variations in the applied strategy may not provide the same level of benefit. Superiority of ventilator-generated NIPPV over flow-driver-generated NIPPV is explained by higher peak pressures used during ventilator-generated NIPPV. If MAPs were matched across all devices and all modes, there may be little difference between CPAP, flow-driver-generated NIPPV, and ventilator-generated NIPPV.
      Additional data from adequately powered RCTs are warranted to determine the benefits of NIPPV in smaller and more immature infants. A particular focus should be placed on clinically relevant outcomes such as death, BPD, and long-term respiratory function following prolonged NIPPV use. Moreover, the role of synchronized NIPPV as primary respiratory support starting directly after birth in the delivery room deserves further attention.

      Best practices

      • NIPPV is preferable over CPAP as primary and post-extubation respiratory support in preterm infants with RDS.
      • For both indications, ventilator-generated, synchronized NIPPV should be used to prevent respiratory failure.
      • Ventilator-generated, synchronized NIPPV may reduce the risk of bronchopulmonary dysplasia when used as either primary or post-extubation support in preterm infants, but is not associated with a decrease in mortality.

      Clinics care points

      • Not all modes of NIPPV are the same, and variations in the applied strategy may affect the level of benefit.
      • During nonsynchronized NIPPV, most pressure peaks occur during spontaneous expiration and do not contribute to tidal volume.
      • Any advantage of nonsynchronized NIPPV may arise from a higher mean airway pressure rather than from the effect of the intermittent pressure peaks themselves.
      • Synchronization of the positive pressure peaks with the infant’s own breathing efforts results in a more effective pressure and volume delivery.
      • Superiority of ventilator-generated NIPPV over flow-driver-generated NIPPV is explained by higher peak pressures used during ventilator-generated NIPPV.
      • There is little evidence of harm during NIPPV generated by any device or delivered in any mode.

      Disclosure

      The authors have nothing to disclose.

      References

        • Baraldi E.
        • Filippone M.
        Chronic lung disease after premature birth.
        N Engl J Med. 2007; 357: 1946-1955
        • Doyle L.W.
        • Carse E.
        • Adams A.-M.
        • et al.
        Ventilation in extremely preterm infants and respiratory function at 8 years.
        N Engl J Med. 2017; 377: 329-337
        • Subramaniam P.
        • Ho J.J.
        • Davis P.G.
        Prophylactic nasal continuous positive airway pressure for preventing morbidity and mortality in very preterm infants.
        Cochrane Database Syst Rev. 2016; 6 (CD001243)
        • Dargaville P.A.
        • Aiyappan A.
        • Paoli A.G.D.
        • et al.
        Continuous positive airway pressure failure in preterm infants: incidence, predictors and consequences.
        Neonatology. 2013; 104: 8-14
        • SUPPORT Study Group of the Eunice Kennedy Shriver NICHD Neonatal Research Network
        Target ranges of oxygen saturation in extremely preterm infants.
        N Engl J Med. 2010; 362: 1959-1969
        • Morley C.J.
        • Davis P.G.
        • Doyle L.W.
        • et al.
        Nasal CPAP or intubation at birth for very preterm infants.
        N Engl J Med. 2008; 358: 700-708
        • Sandri F.
        • Plavka R.
        • Ancora G.
        • et al.
        Prophylactic or early selective surfactant combined with nCPAP in very preterm infants.
        Pediatrics. 2010; 125: e1402-e1409
        • Dargaville P.A.
        • Gerber A.
        • Johansson S.
        • et al.
        Incidence and outcome of CPAP failure in preterm infants.
        Pediatrics. 2016; 138: e20153985
        • Owen L.S.
        • Morley C.J.
        • Davis P.G.
        Neonatal nasal intermittent positive pressure ventilation: a survey of practice in England.
        Arch Dis Child Fetal Neonatal Ed. 2008; 93: F148
        • Kieran E.A.
        • Walsh H.
        • O’Donnell C.P.F.
        Survey of nasal continuous positive airways pressure (NCPAP) and nasal intermittent positive pressure ventilation (NIPPV) use in Irish newborn nurseries.
        Arch Dis Child Fetal Neonatal Ed. 2011; 96: F156
        • Lemyre B.
        • Laughon M.
        • Bose C.
        • et al.
        Early nasal intermittent positive pressure ventilation (NIPPV) versus early nasal continuous positive airway pressure (NCPAP) for preterm infants.
        Cochrane Database Syst Rev. 2016; 12 (CD005384)
        • Lemyre B.
        • Davis P.G.
        • Paoli A.G.D.
        • et al.
        Nasal intermittent positive pressure ventilation (NIPPV) versus nasal continuous positive airway pressure (NCPAP) for preterm neonates after extubation.
        Cochrane Database Syst Rev. 2017; 2 (CD003212)
        • Owen L.S.
        • Morley C.J.
        • Davis P.G.
        Do the pressure changes of neonatal non-synchronised NIPPV (NS nasal intermittent positive pressure ventilation) confer advantages over cpap, or are high CPAP pressures as effective?.
        Pediatr Res. 2011; 70: 16
        • Schmölzer G.M.
        • Dawson J.A.
        • Kamlin C.O.F.
        • et al.
        Airway obstruction and gas leak during mask ventilation of preterm infants in the delivery room.
        Arch Dis Child Fetal Neonatal Ed. 2011; 96: F254
        • Owen L.S.
        • Morley C.J.
        • Davis P.G.
        Pressure variation during ventilator generated nasal intermittent positive pressure ventilation in preterm infants.
        Arch Dis Child Fetal Neonatal Ed. 2010; 95: F359
        • Owen L.S.
        • Morley C.J.
        • Dawson J.A.
        • et al.
        Effects of non-synchronised nasal intermittent positive pressure ventilation on spontaneous breathing in preterm infants.
        Arch Dis Child Fetal Neonatal Ed. 2011; 96: F422
        • Dimitriou G.
        • Greenough A.
        • Laubscher B.
        • et al.
        Comparison of airway pressure-triggered and airflow-triggered ventilation in very immature infants.
        Acta Paediatr. 1998; 87: 1256-1260
        • Waitz M.
        • Mense L.
        • Kirpalani H.
        • et al.
        Nasal intermittent positive pressure ventilation for preterm neonates synchronized or not?.
        Clin Perinatol. 2016; 43: 799-816
        • Owen L.S.
        • Morley C.J.
        • Davis P.G.
        Effects of synchronisation during SiPAP-generated nasal intermittent positive pressure ventilation (NIPPV) in preterm infants.
        Arch Dis Child Fetal Neonatal Ed. 2015; 100: F24
        • Stern D.J.
        • Weisner M.D.
        • Courtney S.E.
        Synchronized neonatal non-invasive ventilation-a pilot study: the graseby capsule with bi-level NCPAP.
        Pediatr Pulm. 2014; 49: 659-664
        • Chang H.-Y.
        • Claure N.
        • D’Ugard C.
        • et al.
        Effects of synchronization during nasal ventilation in clinically stable preterm infants.
        Pediatr Res. 2011; 69: 84-89
        • Owen L.S.
        • Manley B.J.
        Nasal intermittent positive pressure ventilation in preterm infants: Equipment, evidence, and synchronization.
        Semin Fetal Neonatal Med. 2016; 21: 146-153
        • Garland J.S.
        • Nelson D.B.
        • Rice T.
        • et al.
        Increased risk of gastrointestinal perforations in neonates mechanically ventilated with either face mask or nasal prongs.
        Pediatrics. 1985; 76: 406-410
        • Imbulana D.I.
        • Manley B.J.
        • Dawson J.A.
        • et al.
        Nasal injury in preterm infants receiving non-invasive respiratory support: a systematic review.
        Arch Dis Child Fetal Neonatal Ed. 2018; 103: F29
        • Kirpalani H.
        • Millar D.
        • Lemyre B.
        • et al.
        A trial comparing noninvasive ventilation strategies in preterm infants.
        N Engl J Med. 2013; 369: 611-620
        • Jobe A.H.
        • Bancalari E.
        Bronchopulmonary dysplasia.
        Am J Resp Crit Care. 2012; 163: 1723-1729
        • Millar D.
        • Lemyre B.
        • Kirpalani H.
        • et al.
        A comparison of bilevel and ventilator-delivered non-invasive respiratory support.
        Arch Dis Child Fetal Neonatal Ed. 2016; 101: 21
        • Bourque S.L.
        • Roberts R.S.
        • Wright C.J.
        • et al.
        Nasal intermittent positive pressure ventilation versus nasal continuous positive airway pressure to prevent primary noninvasive ventilation failure in extremely low Birthweight infants.
        J Pediatr. 2019; 216: 218-221.e1
        • Meneses J.
        • Bhandari V.
        • Alves J.G.
        Nasal intermittent positive-pressure ventilation vs nasal continuous positive airway pressure for preterm infants with respiratory distress syndrome: a systematic review and meta-analysis.
        Arch Pediat Adol Med. 2012; 166: 372-376
        • Ramaswamy V.V.
        • Bandyopadhyay T.
        • Nanda D.
        • et al.
        Efficacy of noninvasive respiratory support modes as postextubation respiratory support in preterm neonates: A systematic review and network meta-analysis.
        Pediatric Pulmonology. 2020; 55: 2924-2939
        • Ramaswamy V.V.
        • More K.
        • Roehr C.C.
        • et al.
        Efficacy of noninvasive respiratory support modes for primary respiratory support in preterm neonates with respiratory distress syndrome: Systematic review and network meta-analysis.
        Pediatric Pulmonology. 2020; 55: 2940-2963
        • Centre TCCNC
        Nordic Cochrane centre, the Cochrane collaboration. Review Manager (RevMan) [Computer program]. Version 5.3. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration,.
        2014
        • Ekhaguere O.
        • Patel S.
        • Kirpalani H.
        Nasal intermittent mandatory ventilation versus nasal continuous positive airway pressure before and after invasive ventilatory support.
        Clin Perinatol. 2019; 46: 517-536
        • Miedema M.
        • Burg P.S.
        • Beuger S.
        • et al.
        Effect of nasal continuous and biphasic positive airway pressure on lung volume in preterm infants.
        J Pediatr. 2013; 162: 691-697
        • Bisceglia M.
        • Belcastro A.
        • Poerio V.
        • et al.
        A comparison of nasal intermittent versus continuous positive pressure delivery for the treatment of moderate respiratory syndrome in preterm infants.
        Minerva Pediatr. 2007; 59: 91-95
        • Kishore M.S.S.
        • Dutta S.
        • Kumar P.
        Early nasal intermittent positive pressure ventilation versus continuous positive airway pressure for respiratory distress syndrome.
        Acta Paediatr. 2009; 98: 1412-1415
        • Meneses J.
        • Bhandari V.
        • Alves J.G.
        • et al.
        Noninvasive ventilation for respiratory distress syndrome: a randomized controlled trial.
        Pediatrics. 2011; 127: 300-307
        • Armanian A.-M.
        • Badiee Z.
        • Heidari G.
        • et al.
        Initial treatment of respiratory distress syndrome with nasal intermittent mandatory ventilation versus nasal continuous positive airway pressure: a randomized controlled trial.
        Int J Prev Med. 2014; 5: 1543-1551
        • Oncel M.Y.
        • Arayici S.
        • Uras N.
        • et al.
        Nasal continuous positive airway pressure versus nasal intermittent positive-pressure ventilation within the minimally invasive surfactant therapy approach in preterm infants: a randomised controlled trial.
        Arch Dis Child Fetal Neonatal Ed. 2015; 101: F323-F328
        • Sabzehei M.K.
        • Basiri B.
        • Shokouhi M.
        • et al.
        A comparative study of treatment response of respiratory distress syndrome in preterm infants: early nasal intermittent positive pressure ventilation versus early nasal continuous positive airway pressure.
        Int J Pediatr. 2018; 6: 8339-8346
        • Skariah T.A.
        • Lewis L.E.
        Early nasal intermittent positive pressure ventilation (NIPPV) versus nasal continuous positive airway pressure (NCPAP) for respiratory distress syndrome (RDS) in infants of 28-36 weeks gestational age: a randomized controlled trial.
        Iranian J Neonatal. 2019; 10: 1-8
        • Kugelman A.
        • Feferkorn I.
        • Riskin A.
        • et al.
        Nasal intermittent mandatory ventilation versus nasal continuous positive airway pressure for respiratory distress syndrome: a randomized, controlled, prospective study.
        J Pediatr. 2007; 150: 521-526.e1
        • Salama G.S.A.
        • Ayyash F.F.
        • Al-Rabadi A.J.
        • et al.
        Nasal-imv versus nasal-CPAP as an initial mode of respiratory support for premature infants with RDS: a prospective randomized clinical trial.
        Rawal Med J. 2015; 40: 197-202
        • Dursun M.
        • Uslu S.
        • Bulbul A.
        • et al.
        Comparison of early nasal intermittent positive pressure ventilation and nasal continuous positive airway pressure in preterm infants with respiratory distress syndrome.
        J Trop Pediatr. 2018; 65: 352-360
        • Gharehbaghi M.M.
        • Hosseini M.B.
        • Eivazi G.
        • et al.
        Comparing the efficacy of nasal continuous positive airway pressure and nasal intermittent positive pressure ventilation in early management of respiratory distress syndrome in preterm infants.
        Oman Med J. 2019; 34: 99-104
        • Kong L.-K.
        • Kong X.-Y.
        • Li L.-H.
        • et al.
        Comparative study on application of duo positive airway pressure and continuous positive airway pressure in preterm neonates with respiratory distress syndrome.
        Zhongguo Dang Dai Er Ke Za Zhi. 2012; 14: 888-892
        • Aguiar T.
        • Macedo I.
        • Voutsen O.
        • et al.
        Nasal bilevel versus continuous positive airway pressure in preterm infants: a randomized controlled trial.
        J Clin Trials. 2015; 5 (2167–0870)
        • Sadeghnia A.
        • Barekateyn B.
        • Badiei Z.
        • et al.
        Analysis and comparison of the effects of N-BiPAP and Bubble-CPAP in treatment of preterm newborns with the weight of below 1500 grams affiliated with respiratory distress syndrome: a randomised clinical trial.
        Adv Biomed Res. 2016; 5: 3
        • Lista G.
        • Castoldi F.
        • Fontana P.
        • et al.
        Nasal continuous positive airway pressure (CPAP) versus bi-level nasal CPAP in preterm babies with respiratory distress syndrome: a randomised control trial.
        Arch Dis Child Fetal Neonatal Ed. 2010; 95: F85
        • Wood F.
        • Gupta S.
        • Tin W.
        • et al.
        G170 randomised controlled trial of synchronised intermittent positive airway pressure (SiPAPTM) versus continuous positive airway pressure (CPAP) as a primary mode of respiratory support in preterm infants with respiratory distress syndrome.
        Arch Dis Child. 2013; 98: A78
        • Ramanathan R.
        • Sekar K.C.
        • Rasmussen M.
        • et al.
        Nasal intermittent positive pressure ventilation after surfactant treatment for respiratory distress syndrome in preterm infants <30 weeks’ gestation: a randomized, controlled trial.
        J Perinatol. 2012; 32: 336-343
        • Khorana M.
        • Paradeevisut H.
        • Sangtawesin V.
        • et al.
        A randomized trial of non-synchronized Nasopharyngeal Intermittent Mandatory Ventilation (nsNIMV) vs. Nasal Continuous Positive Airway Pressure (NCPAP) in the prevention of extubation failure in pre-term < 1,500 grams.
        J Med Assoc Thai. 2008; 91: S136-S142
        • Kahramaner Z.
        • Erdemir A.
        • Turkoglu E.
        • et al.
        Unsynchronized nasal intermittent positive pressure versus nasal continuous positive airway pressure in preterm infants after extubation.
        J Matern Fetal Neonatal Med. 2013; 27: 926-929
        • Jasani B.
        • Nanavati R.
        • Kabra N.
        • et al.
        Comparison of non-synchronized nasal intermittent positive pressure ventilation versus nasal continuous positive airway pressure as post-extubation respiratory support in preterm infants with respiratory distress syndrome: a randomized controlled trial.
        J Matern Fetal Neonatal Med. 2015; 29: 1546-1551
        • Komatsu D.F.R.
        • Diniz E.M.
        • Ferraro A.A.
        • et al.
        Randomized controlled trial comparing nasal intermittent positive pressure ventilation and nasal continuous positive airway pressure in premature infants after tracheal extubation.
        Rev Assoc Med Bras (1992). 2016; 62: 568-574
        • Ribeiro S.
        • Fontes M.
        • Bhandari V.
        • et al.
        Noninvasive ventilation in newborns ≤1,500 g after tracheal extubation: randomized clinical trial.
        Am J Perinat. 2017; 34: 1190-1198
        • Estay A.S.
        • Mariani G.L.
        • Alvarez C.A.
        • et al.
        Randomized controlled trial of nonsynchronized nasal intermittent positive pressure ventilation versus nasal CPAP after extubation of VLBW infants.
        Neonatology. 2020; 117: 193-199
        • Friedlich P.
        • Lecart C.
        • Posen R.
        • et al.
        A randomized trial of nasopharyngeal-synchronized intermittent mandatory ventilation versus nasopharyngeal continuous positive airway pressure in very low birth weight infants after extubation.
        J Perinatol. 1999; 19: 413-418
        • Barrington K.J.
        • Bull D.
        • Finer N.N.
        Randomized trial of nasal synchronized intermittent mandatory ventilation compared with continuous positive airway pressure after extubation of very low birth weight infants.
        Pediatrics. 2001; 107: 638-641
        • Khalaf M.N.
        • Brodsky N.
        • Hurley J.
        • et al.
        A prospective randomized, controlled trial comparing synchronized nasal intermittent positive pressure ventilation versus nasal continuous positive airway pressure as modes of extubation.
        Pediatrics. 2001; 108: 13-17
        • Moretti C.
        • Gizzi C.
        • Papoff P.
        • et al.
        Comparing the effects of nasal synchronized intermittent positive pressure ventilation (nSIPPV) and nasal continuous positive airway pressure (nCPAP) after extubation in very low birth weight infants.
        Early Hum Dev. 1999; 56: 167-177
        • Gao W.-W.
        • Tan S.-Z.
        • Chen Y.-B.
        • et al.
        Randomized trail of nasal synchronized intermittent mandatory ventilation compared with nasal continuous positive airway pressure in preterm infants with respiratory distress syndrome.
        Zhongguo Dang Dai Er Ke Za Zhi. 2010; 12: 524-526
        • Ding F.
        • Zhang J.
        • Zhang W.
        • et al.
        Clinical study of different modes of non-invasive ventilation treatment in preterm infants with respiratory distress syndrome after extubation.
        Front Pediatr. 2020; 8: 63
        • O’Brien K.
        • Campbell C.
        • Brown L.
        • et al.
        Infant flow biphasic nasal continuous positive airway pressure (BP- NCPAP) vs. infant flow NCPAP for the facilitation of extubation in infants’ ≤1,250 grams: a randomized controlled trial.
        BMC Pediatr. 2012; 12: 43
        • Victor S.
        • Roberts S.A.
        • Mitchell S.
        • et al.
        Biphasic positive airway pressure or continuous positive airway pressure: a randomized trial.
        Pediatrics. 2016; 138: e20154095