DÄ internationalArchive11/2019Non-Invasive Ventilation in Neonatology

Review article

Non-Invasive Ventilation in Neonatology

Dtsch Arztebl Int 2019; 116(11): 177-83; DOI: 10.3238/arztebl.2019.0177

Behnke, J; Lemyre, B; Czernik, C; Zimmer, K; Ehrhardt, H; Waitz, M

Background: Invasive mechanical ventilation (IMV) has been replaced by early continuous positive airway pressure (CPAP) in the treatment of respiratory distress syndrome (RDS) in preterm infants aiming to reduce the rate of bronchopulmonary dysplasia (BPD). Subsequently, modern non-invasive ventilation strategies (NIV) were introduced into clinical practice with limited evidence of effects on pulmonary and neurodevelopmental outcomes.

Methods: We performed a selective literature search in PubMed including randomized controlled trials (RCT) (n ≥ 200) and meta-analyses published in the field of NIV in neonatology and follow-up studies focusing on long term pulmonary and neurodevelopmental outcomes.

Results: Individual studies do not show a significant risk reduction for the combined endpoint death or BPD in preterm infants caused by early CPAP in RDS when compared to primary intubation. One meta-analysis comparing four studies found CPAP significantly reduces the risk of BPD or death (relative risk: 0.91; 95% confidence interval [0.84;0.99]). Nasal intermittent positive pressure ventilation (NIPPV) as a primary ventilation strategy reduces the rate of intubations in infants with RDS (RR: 0.78 [0.64;0.94]) when compared to CPAP but does not affect the rate of BPD (RR: 0.78 [0.58;1.06]).

Conclusion: Early CPAP reduces the need for IMV and the risk of BPD or death in preterm infants with RDS. NIPPV may offer advantages over CPAP regarding intubation rates. Networking-based follow-up programs are required to assess the effect of NIV on long term pulmonary and neurodevelopmental outcomes.

LNSLNS

For years, invasive mechanical ventilation (IMV) was the primary treatment of very low birth weight infants (VLBWI) with respiratory distress syndrome (RDS). RDS is caused by a primary surfactant deficiency of the immature lungs and leads to a reduced compliance of the respiratory system and progressive hypoxic respiratory failure if untreated (1). Although lifesaving, IMV is an important risk factor in the development of bronchopulmonary dysplasia (BPD) (2). BPD is characterized histologically by impaired alveolar and vascular lung development and clinically defined clinically as the need for oxygen and or respiratory support at 36 weeks postmenstrual age (2, 3). More than 20% of preterm infants with a gestational age (GA) <32 weeks in Germany are affected by the disease (4).

The diagnosis of BPD is associated with neurological sequelae (i.e. cerebral palsy, visual and hearing impairment, mental and motor developmental delay), as well as chronic respiratory problems in childhood and adolescence including asthma-like symptoms and frequent wheezing episodes (5, 6). Affected infants require comprehensive medical follow-up and treatment after hospital discharge with frequent hospital readmissions, visits to the doctor’s office, home oxygen therapy, treatment for pulmonary hypertension and specific immunization requirements (7).

Despite advances in neonatal pulmonology, such as antenatal corticosteroids and surfactant administration, the incidence of BPD has not changed significantly over the last decade (e1). To alleviate the harmful effects of IMV on the immature lungs (i.e. volu- and barotrauma, inflammatory mediated alveolar and vascular destruction resulting in progressive impaired gas exchange), nasal CPAP has been introduced as a noninvasive ventilation (NIV) strategy in neonatal care. CPAP significantly reduced the need for IMV, but failure rates of almost 50% have prompted neonatologists to seek more effective NIV modalities (8, 9). Nasal intermittent positive pressure ventilation (NIPPV) and heated humidified high flow nasal cannulae (HHHFNC) have emerged and are now used in both pediatrics and adult intensive care medicine (10, 11, e2).

In this review, we discuss and summarize the current evidence of the available NIV modes in neonatology, their indications, mechanisms of action and effects on important short and long term morbidities associated with the use of NIV. The review is based on a selective literature search in PubMed.

Effects and Clinical Application of Different NIV Modes in Neonates

Nasal CPAP—nasal continuous positive airway pressure

Since CPAP was first used clinically in preterm infants in 1971 (e3), various effects on respiratory mechanics have been reported with its use (eBox 1). Nasal CPAP devices deliver constant positive pressure (PEEP) to the neonatal lungs using different nasal interfaces (Figures 1 and 2). PEEP counteracts the collapsing lung properties, maintains functional residual capacity and facilitates gas exchange (1).

nCPAP- Mechanism of action and potential side effects (e11, e12)
nCPAP- Mechanism of action and potential side effects (e11, e12)
eBox 1
nCPAP- Mechanism of action and potential side effects (e11, e12)

Several randomized controlled trials (RCT) assessed the efficacy and safety of early nasal CPAP in VLBWI in the surfactant and antenatal corticosteroid era (Table 1, eBox 2). Although the study designs and thresholds for respiratory interventions (i.e. criteria for intubation and surfactant administration) vary among the trials, two basic treatment strategies were compared:

  • infants were randomized either to early nasal CPAP (variable set pressure levels of 5–8cmH2O) with selective intubation if prespecified CPAP failure criteria were met (i.e. oxygen requirements, apnea and hypoxemic events, respiratory acidosis) or
  • were primarily intubated in the delivery room and exposed to a short or a longer course of IMV.
Selected RCTs on nCPAP with selective or prophylactic surfactant administration vs. IMV with or without surfactant application (including INSURE)
Selected RCTs on nCPAP with selective or prophylactic surfactant administration vs. IMV with or without surfactant application (including INSURE)
Table 1
Selected RCTs on nCPAP with selective or prophylactic surfactant administration vs. IMV with or without surfactant application (including INSURE)
Effects of antenatal systemic corticosteroids on the preterm lung and side effects (e13–e15)
Effects of antenatal systemic corticosteroids on the preterm lung and side effects (e13–e15)
eBox 2
Effects of antenatal systemic corticosteroids on the preterm lung and side effects (e13–e15)

The results of the trials demonstrate that the use of early CPAP significantly reduced the need for IMV and surfactant administration as compared to primary intubation in the delivery room. However, none of the individual trials was able to show a significant reduction in the rate of BPD or death (8, 9, 1215) (Table 1).

A meta-analysis of 4 trials confirmed a small, but significant reduction in the combined outcome of BPD or death (relative risk [RR]: 0.91, 95% confidence interval [0.84;0.99], number needed to treat [NNT]: 25) (16). However, BPD alone (RR 0.91 [0.79;1.04]) and death alone (RR 0.88 [0.68;1.14]) were not significantly affected by the CPAP intervention. The incidence of CPAP failure within the first week of life ranged from 46.0–51.2% (8, 9, 12). CPAP failure was ultimately linked with some degree of IMV, which may have diminished the possible lung protective treatment effects of CPAP among the trials.

NIPPV—nasal intermittent positive pressure ventilation

NIPPV has emerged as an alternative strategy to nasal CPAP (1, e2, e4). NIPPV delivers time-cycled positive pressure ventilation above a PEEP level in the absence of an endotracheal tube. Currently, two NIPPV delivery systems are available: bilevel-NIPPV and conventional mechanical ventilator-driven NIPPV (CMV-NIPPV). Bilevel-NIPPV provides two alternating PEEP levels on which the infant breathes spontaneously. In contrast, CMV-NIPPV uses higher peak inspiratory pressures and shorter inspiratory times (eFigure 1) (17, e5). The interfaces to support NIPPV are identical to those that deliver CPAP (Figure 1).

Interfaces for nCPAP application
Interfaces for nCPAP application
Figure 1
Interfaces for nCPAP application
Time and Pressure Cycling during Bilevel-NIPPV versus CMV-NIPPV Different pressure wave types during (A) bilevel-NIPPV and (B) CMV-NIPPV PIP, peak inspiratory pressure; PEEP, positive end-expiratory pressure Adapted from Waitz et al. Clin Perinatol 2016 (e19)
Time and Pressure Cycling during Bilevel-NIPPV versus CMV-NIPPV Different pressure wave types during (A) bilevel-NIPPV and (B) CMV-NIPPV PIP, peak inspiratory pressure; PEEP, positive end-expiratory pressure Adapted from Waitz et al. Clin Perinatol 2016 (e19)
eFigure 1
Time and Pressure Cycling during Bilevel-NIPPV versus CMV-NIPPV Different pressure wave types during (A) bilevel-NIPPV and (B) CMV-NIPPV PIP, peak inspiratory pressure; PEEP, positive end-expiratory pressure Adapted from Waitz et al. Clin Perinatol 2016 (e19)

NIPPV can be applied in a synchronized mode with different trigger systems (i.e. pneumatic capsule to detect abdominal movement or flow-trigger). Effects mediated during NIPPV are summarized in eBox 3. NIPPV can be used in different clinical scenarios.

  • “Primary or early” mode of ventilation refers to its use within the first six hours of life.
  • NIPPV as “post extubation” refers to its use after a longer period (usually >24 hours) of IMV.
NIPPV- Mechanism of action and potential side effects (e2, e16)
NIPPV- Mechanism of action and potential side effects (e2, e16)
eBox 3
NIPPV- Mechanism of action and potential side effects (e2, e16)

Evidence for the use of NIPPV mainly derives from small, single-center trials that differ substantially in the ventilators used (bilevel-NIPPV, CMV-NIPPV), the settings (i.e. respiratory rate, pressures, inspiratory times), the patient population and the mode of synchronization, if applied. A recent Cochrane meta-analysis including RCT and quasi RCT found a significantly lower rate of respiratory failure (RR: 0.65 [0.51;0.82]) and need for intubation within the first week of life (RR: 0.78 [0.64;0.94]) in infants treated with primary NIPPV as compared to CPAP (18) (Table 2).

Results of meta-analyses on NIPPV vs. nCPAP as primary respiratory support and post-extubation
Results of meta-analyses on NIPPV vs. nCPAP as primary respiratory support and post-extubation
Table 2
Results of meta-analyses on NIPPV vs. nCPAP as primary respiratory support and post-extubation

NIPPV as post-extubation mode of ventilation resulted in a significantly lower rate of respiratory failure (RR: 0.71 [0.61;0.82]) and reintubation rates (RR: 0.76 [0.65;0.88]) when compared to nasal CPAP in another Cochrane meta-analysis (19). Data on other important outcome measures (BPD, mortality, necrotizing enterocolitis, intraventricular hemorrhage, retinopathy of prematurity) remained unaffected by the NIPPV intervention in the CPAP and the NIPPV group in both meta-analyses (Table 2).

HHHFNC—heated humidified high flow nasal cannula

The function of HHHFNC is to deliver heated and humidified gas at flow rates > 1l/min through small binasal prongs (eFigure 2). Several mechanisms of action and clinical effects of this method have been reported (eBox 4) (20, e6). Importantly and in contrast to nasal CPAP, HHHFNC creates a flow-related, variable distending pressure that is unmeasurable in clinical practice, delivered to the infants’ upper airway and lungs. Because of the pragmatic setup, easy handling and cost-effectiveness, the use of HHHFNC is rapidly increasing (21). However, evidence for the use of HHHFNC as primary respiratory support for RDS or post-extubation is limited and predominantly restricted to non-inferiority trial settings with nasal CPAP being the comparative measure (Table 3).

Preterm infant with nCPAP and binasal prongs (bonnet)
Preterm infant with nCPAP and binasal prongs (bonnet)
Figure 2
Preterm infant with nCPAP and binasal prongs (bonnet)
Selected RCTs on HHHFNC vs. CPAP/NIPPV as primary respiratory support or post extubation
Selected RCTs on HHHFNC vs. CPAP/NIPPV as primary respiratory support or post extubation
Table 3
Selected RCTs on HHHFNC vs. CPAP/NIPPV as primary respiratory support or post extubation
HHHFNC- Mechanism of action and potential side effects (20, e6)
HHHFNC- Mechanism of action and potential side effects (20, e6)
eBox 4
HHHFNC- Mechanism of action and potential side effects (20, e6)
Preterm infant with HHHFNC
Preterm infant with HHHFNC
eFigure 2
Preterm infant with HHHFNC

Manley et al. randomized preterm infants to HHHFNC or nasal CPAP after extubation (22). The primary outcome “treatment failure within seven days” occurred in 34.2% in the HHHFNC group and in 25.8% of the CPAP group (risk difference: 8.4%, [–1.9; 18.7]). Based on a chosen non-inferiority margin of 20% the authors concluded that HHHFNC is non-inferior to nasal CPAP after extubation. Of note, almost 50% of infants that failed on HHHFNC in this trial were rescued with nasal CPAP, leaving concerns regarding the non-inferiority conclusion. Two recent non-inferiority RCT assessed HHHFNC versus nasal CPAP as primary respiratory support in preterm infants with RDS (GA >28 weeks) defining a more restrictive margin of non-inferiority (5% and 10%, respectively) (23, 24). Enrollment was stopped early in both trials owing to a significant difference in the primary outcome “treatment failure within 72h” between the HHHFNC and the CPAP group (25.5% vs. 13.3%, risk difference: 12.3%, [5.8; 18.7], p<0.001 and 26.3% vs. 7.9%, risk difference: 18.4% [9.7; 27.1], p<0.001), both studies favoring CPAP. While the rate of intubation did not differ between the groups in the intention-to-treat analysis in both studies, respectively 39% and 91% of subjects assigned to the HHHFNC group received rescue CPAP and were subsequently saved from intubation. Another comparable non-inferiority trial, however, found non-significant failure rates between HHHFNC and CPAP/Bilevel-NIPPV when used as primary mode of ventilation (25) (Table 3).

According to a recent meta-analysis, HHHFNC as primary mode or post extubation does not significantly affect the rate of BPD or other short term neonatal morbidities, except for significantly less nasal trauma in comparison to nasal CPAP (e7, e8). However, only few subjects were <28 weeks GA in most of the trials and study results confirm inferiority of HHHFNC compared to nasal CPAP when used as primary mode of ventilation in preterm infants with RDS.

Long Term Pulmonary and Neurodevelopmental Outcomes Associated with NIV

Advances in perinatal care, i.e.

  • antenatal corticosteroids,
  • improved fetal monitoring,
  • caffeine therapy
  • surfactant therapy,
  • enhanced nutrition,
  • and gentle ventilation strategies

have contributed to improved rates of survival, especially in the very immature population between 22+0 and 24+6 weeks GA (survival rate of 30% in 2000–2003 and 36% in 2008–2011, analysis of US data) (26). In Germany, the number of preterm infants born before 28 weeks GA increased by 65% between 2001 and 2010 (27).

Since the risk of BPD is inversely proportional to GA and birthweight, it is not surprising that the incidence of BPD has increased over time by shifting the demographics to earlier GA (28). Of note, the rates of BPD reported in the NIV studies differ substantially since the definition of BPD and the study population is often diverse (5).

Few prospective long-term follow-up studies on the effect of NIV on pulmonary and neurodevelopmental outcomes in preterm infants have been published. Respiratory follow-up from the SUPPORT study showed fewer episodes of wheezing (28.9% vs. 36.5%, p<0.05) and fewer physician visits for breathing problems (68.0 vs. 72.9%, p<0.05) in the CPAP group as compared to the IMV + surfactant group at 18–22 months corrected age (29). Doyle and colleagues recently presented 8 year follow-up data on lung function of surviving infants with ≤ 28 weeks GA and compared cohorts with similar baseline demographics from three different time periods (1991–1992 vs. 1997 vs. 2005) (30). Besides a substantial increase in CPAP duration over time the authors found a higher rate of BPD and significantly reduced expiratory flow rates in the 2005 study cohort as compared to the 1991–1992 study population. However, these data should be interpreted with caution. First, the 8-year survival rate of the 1991–1992 cohort was 53% vs. 65% in the 2005 study group, therefore a trade-off effect for the outcome lung function cannot be excluded since the causes of mortality were not reported in the study. Second, the authors found a significant decrease in the use of postnatal steroids (40% in 1991–1992 vs. 23% in 2005), a treatment strategy that reduces the rate of BPD but may also adversely affect neurodevelopmental outcomes (31) (eBox 5).

Effects of postnatal systemic corticosteroids on the preterm lung and side effects (31, e17, e18)
Effects of postnatal systemic corticosteroids on the preterm lung and side effects (31, e17, e18)
eBox 5
Effects of postnatal systemic corticosteroids on the preterm lung and side effects (31, e17, e18)

The SUPPORT study group did not find significant differences in the composite outcome of death or neurodevelopmental impairment between the CPAP and the IMV + surfactant group at 18–22 months corrected age (32). Importantly, 10.9 % of infants in the CPAP group and 9.1% in the IMV group had neurodevelopmental impairments (defined as any of the following: a cognitive composite score on the Bayley Scale of Infants and Toddler Development III of less than 70, a Gross Motor Function Classification System score of 2 or higher, moderate or severe cerebral palsy, hearing impairment, or bilateral visual impairment).

Lack of systematic follow up data from other representative RCTs (e.g. COIN-trial, CURPAP-study (8, 13) emphasizes the need for an adequate long term neurological and pulmonary follow up and interdisciplinary treatment of these high risk infants.

Trends and Future Perspectives in Neonatal NIV

Acknowledging the evidence for the use of early CPAP, the European Consensus Guidelines currently recommend prophylactic CPAP and early selective surfactant administration over primary intubation in spontaneously breathing preterm infants (33). The results of a survey study in the US (26 participating network centers) suggest a decreasing number of VLBWI being on IMV and an increased use of NIPPV modes from 2002 to 2012 (14% to 37%) (34).

There is growing evidence that frequent fluctuations in arterial oxygen saturation are associated with the development of retinopathy of prematurity and a higher risk of late death and neurological disabilities at 18 months corrected age in VLBWI (35, 36).

Utility and duration of NIV have been further extended by caregivers to prevent and treat symptoms of apnea of prematurity (e9, e10). This opens further research questions on the effect of prolonged NIV support on neonatal morbidities, as well as the upcoming and challenging questions about the appropriate weaning strategies from NIV (37).

Newer methods, such as neurally adjusted ventilator assist (NAVA) or the use of nasal high frequency oscillatory ventilation (nHFOV) are promising innovations for NIV in preterm infants. To date, only results of small single-center trials are available with promising data on effective synchronization during neutrally adjusted NIV and a reduced need for IMV with the use of nHFOV as compared to nasal CPAP in preterm infants with moderate/severe RDS (38, 39).

In the context of initial stabilization on NIV, the role of noninvasive surfactant application becomes more important, especially how its use may further contribute to improved outcomes in VLBWI (40).

Conclusion

Based on best evidence, nasal CPAP is the gold standard NIV mode. NIPPV is an alternative to nasal CPAP as primary or post-extubation respiratory support in preterm infants with RDS. With its advantages of easy handling, less nasal trauma and improved infant-parent bonding, HHHFNC therapy is now almost universally employed in neonatal intensive care but may not be suitable in VLBWI infants with surfactant-deficiency and severe acute pulmonary dysfunction. Effects of NIV on the rate of BPD are small but promising and warrant ongoing research in the field of NIV. Long-term neurodevelopmental and pulmonary outcomes require a prospective, ideally neonatal network–based follow-up program.

Conflict of interest statement
The authors declare that no conflict of interest exists.

Manuscript received on 29 May 2018; revised version accepted on 21 January 2019

Corresponding author
Dr. med. Markus Waitz, MD
Abteilung Allgemeine Pädiatrie & Neonatologie
Zentrum für Kinderheilkunde und Jugendmedizin
Justus-Liebig-Universität Gießen
Feulgenstr. 10–12
35392 Gießen, Germany
markus.waitz@paediat.med.uni-giessen.de

Supplementary material

For eReferences please refer to:
www.aerzteblatt-internatioanl.de/ref1119

eBoxes, eFigures:
www.aerzteblatt-international.de/19m0177

1.
Owen LS, Manley BJ, Davis PG, Doyle LW: The evolution of modern respiratory care for preterm infants. Lancet 2017; 389: 1649–59 CrossRef
2.
Jobe AH, Bancalari E: Bronchopulmonary dysplasia. Am J Respir Crit Care Med 2001; 163: 1723–9 CrossRef MEDLINE
3.
Shahzad T, Radajewski S, Chao CM, Bellusci S, Ehrhardt H: Pathogenesis of bronchopulmonary dysplasia: when inflammation meets organ development. Mol Cell Pediatr 2016; 3: 23 CrossRefMEDLINE PubMed Central
4.
Gortner L, Misselwitz B, Milligan D, et al.: Rates of bronchopulmonary dysplasia in very preterm neonates in Europe: results from the MOSAIC cohort. Neonatology 2011; 99: 112–7 CrossRef MEDLINE
5.
Ehrenkranz RA, Walsh MC, Vohr BR, et al.: Validation of the National Institutes of Health consensus definition of bronchopulmonary dysplasia. Pediatrics 2005; 116: 1353–60 CrossRef MEDLINE
6.
Jaakkola JJK, Ahmed P, Ieromnimon A, et al.: Preterm delivery and asthma: a systematic review and meta-analysis. J Allergy Clin Immunol 2006; 118: 823–30 CrossRef MEDLINE
7.
Álvarez-Fuente M, Arruza L, Muro M, et al.: The economic impact of prematurity and bronchopulmonary dysplasia. Eur J Pediatr 2017; 176: 1587–93 CrossRef MEDLINE
8.
Morley CJ, Davis PG, Doyle LW, Brion LP, Hascoet JM, Carlin JB: Nasal CPAP or intubation at birth for very preterm infants. N Engl J Med 2008; 358: 700–8 CrossRef MEDLINE
9.
Finer NN, Carlo WA, Walsh MC, et al.: Early CPAP versus surfactant in extremely preterm infants. N Engl J Med 2010; 362: 1970–9 CrossRefMEDLINE PubMed Central
10.
Roberts CT, Hodgson KA: Nasal high flow treatment in preterm infants. Matern Health Neonatol Perinatol 2017; 3: 15 CrossRef MEDLINE PubMed Central
11.
Westhoff M, Schonhofer B, Neumann P, et al.: Noninvasive mechanical ventilation in acute respiratory failure. Pneumologie 2015; 69: 719–56 MEDLINE
12.
Dunn MS, Kaempf J, de Klerk A, et al.: Randomized trial comparing 3 approaches to the initial respiratory management of preterm neonates. Pediatrics 2011; 128: e1069–76 CrossRef MEDLINE
13.
Sandri F, Plavka R, Ancora G, et al.: Prophylactic or early selective surfactant combined with nCPAP in very preterm infants. Pediatrics 2010; 125: e1402–9 CrossRef MEDLINE
14.
Tapia JL, Urzua S, Bancalari A, et al.: Randomized trial of early bubble continuous positive airway pressure for very low birth weight infants. J Pediatr 2012; 161: 75–80.e1 CrossRef MEDLINE
15.
Rojas MA, Lozano JM, Rojas MX, et al.: Very early surfactant without mandatory ventilation in premature infants treated with early continuous positive airway pressure: a randomized, controlled trial. Pediatrics 2009; 123: 137–42 CrossRef MEDLINE
16.
Schmolzer GM, Kumar M, Pichler G, Aziz K, O‘Reilly M, Cheung PY: Non-invasive versus invasive respiratory support in preterm infants at birth: systematic review and meta-analysis. BMJ 2013; 347: f5980 CrossRef MEDLINE PubMed Central
17.
Roberts CT, Davis PG, Owen LS: Neonatal non-invasive respiratory support: synchronised NIPPV, non-synchronised NIPPV or bi-level CPAP: what is the evidence in 2013? Neonatology 2013; 104: 203–9 CrossRef MEDLINE
18.
Lemyre B, Laughon M, Bose C, Davis PG: 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 CrossRef
19.
Lemyre B, Davis PG, de Paoli AG, Kirpalani H: 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 CrossRef
20.
Manley BJ, Dold SK, Davis PG, Roehr CC: High-flow nasal cannulae for respiratory support of preterm infants: a review of the evidence. Neonatology 2012; 102: 300–8 CrossRef MEDLINE
21.
Schmid F, Olbertz DM, Ballmann M: The use of high-flow nasal cannula (HFNC) as respiratory support in neonatal and pediatric intensive care units in Germany—a nationwide survey. Respir Med 2017; 131: 210–4 CrossRef
22.
Manley BJ, Owen LS, Doyle LW, et al.: High-flow nasal cannulae in very preterm infants after extubation. N Engl J Med 2013; 369: 1425–33 CrossRef
23.
Roberts CT, Owen LS, Manley BJ, et al.: Nasal high-flow therapy for primary respiratory support in preterm infants. N Engl J Med 2016; 375: 1142–51 CrossRef MEDLINE
24.
Murki S, Singh J, Khant C, et al.: High-flow nasal cannula versus nasal continuous positive airway pressure for primary respiratory support in preterm infants with respiratory distress: a randomized controlled trial. Neonatology 2018; 113: 235–41 CrossRef MEDLINE
25.
Lavizzari A, Colnaghi M, Ciuffini F, et al.: Heated, humidified high-flow nasal cannula vs nasal continuous positive airway pressure for respiratory distress syndrome of prematurity: a randomized clinical noninferiority trial. JAMA Pediatr 2016 CrossRef
26.
Younge N, Goldstein RF, Bann CM, et al.: Survival and neurodevelopmental outcomes among periviable infants. N Engl J Med 2017; 376: 617–28 CrossRef MEDLINE
27.
Schleußner E: The prevention, diagnosis and treatment of premature labor. Dtsch Arztebl Int 2013; 110: 227–36 CrossRef
28.
van Marter LJ: Epidemiology of bronchopulmonary dysplasia. Semin Fetal Neonatal Med 2009; 14: 358–66 CrossRef MEDLINE
29.
Stevens TP, Finer NN, Carlo WA, et al.: Respiratory outcomes of the surfactant
positive pressure and oximetry randomized trial (SUPPORT). J Pediatr 2014; 165: 240–9.e4 CrossRef MEDLINE
30.
Doyle LW, Ranganathan S, Cheong JLY: Ventilation in preterm infants and lung function at 8 years. N Engl J Med 2017; 377: 1601–2 CrossRef
31.
Doyle LW, Ehrenkranz RA, Halliday HL: Late (7 days) postnatal corticosteroids for chronic lung disease in preterm infants. Cochrane Database Syst Rev 2014; 5: CD001145 CrossRef
32.
Vaucher YE, Peralta-Carcelen M, Finer NN, et al.: Neurodevelopmental outcomes in the early CPAP and pulse oximetry trial. N Engl J Med 2012; 367: 2495–504 CrossRef MEDLINE
33.
Sweet DG, Carnielli V, Greisen G, et al.: European consensus guidelines on the management of respiratory distress syndrome – 2016 update. Neonatology 2017; 111: 107–25 CrossRef MEDLINE
34.
Stoll BJ, Hansen NI, Bell EF, et al.: Trends in care practices, morbidity, and mortality of extremely preterm neonates, 1993–2012. JAMA 2015; 314: 1039–51 CrossRef MEDLINE
35.
Di Fiore JM, Bloom JN, Orge F, et al.: A higher incidence of intermittent hypoxemic episodes is associated with severe retinopathy of prematurity. J Pediatr 2010; 157: 69–73 CrossRef MEDLINE
36.
Poets CF, Roberts RS, Schmidt B, et al.: Association between intermittent hypoxemia or bradycardia and late death or disability in extremely preterm infants. JAMA 2015; 314: 595–603 CrossRef MEDLINE
37.
Bamat N, Jensen EA, Kirpalani H: Duration of continuous positive airway pressure in premature infants. Semin Fetal Neonatal Med 2016; 21: 189–95 CrossRef MEDLINE
38.
Firestone KS, Beck J, Stein H: Neurally adjusted ventilatory assist for noninvasive support in neonates. Clin Perinatol 2016; 43: 707–24 CrossRef MEDLINE
39.
Mukerji A, Dunn M: High-frequency ventilation as a mode of noninvasive respiratory support. Clin Perinatol 2016; 43: 725–40 CrossRef MEDLINE
40.
Kribs A: Minimally invasive surfactant therapy and noninvasive respiratory support. Clin Perinatol 2016; 43: 755–71 CrossRef MEDLINE
e1.
Jensen EA, Schmidt B: Epidemiology of bronchopulmonary dysplasia. Birth Defects Res Part A Clin Mol Teratol 2014; 100: 145–57 CrossRef MEDLINE
e2.
Owen LS, Manley BJ: Nasal intermittent positive pressure ventilation in preterm infants: equipment, evidence, and synchronization. Semin Fetal Neonatal Med 2016; 21: 146–53 CrossRef MEDLINE
e3.
Gregory GA, Kitterman JA, Phibbs RH, Tooley WH, Hamilton WK: Treatment of the idiopathic respiratory-distress syndrome with continuous positive airway pressure. N Engl J Med 1971; 284: 1333–40 CrossRef MEDLINE
e4.
Courtney SE, Barrington KJ: Continuous positive airway pressure and noninvasive ventilation. Clin Perinatol 2007; 34: 73–92, vi CrossRef MEDLINE
e5.
Millar D, Lemyre B, Kirpalani H, Chiu A, Yoder BA, Roberts RS: A comparison of bilevel and ventilator-delivered non-invasive respiratory support. Arch Dis Child Fetal Neonatal Ed 2016; 101: F21–5 CrossRef MEDLINE
e6.
Dysart K, Miller TL, Wolfson MR, Shaffer TH: Research in high flow therapy: mechanisms of action. Respir Med 2009; 103: 1400–5 CrossRef MEDLINE
e7.
Collins CL, Barfield C, Horne RSC, Davis PG: A comparison of nasal trauma in preterm infants extubated to either heated humidified high-flow nasal cannulae or nasal continuous positive airway pressure. Eur J Pediatr 2014; 173: 181–6 CrossRef MEDLINE
e8.
Wilkinson D, Andersen C, O‘Donnell CP, De Paoli AG, Manley BJ: High flow nasal cannula for respiratory support in preterm infants. Cochrane Database Syst Rev 2016; 2: CD006405 MEDLINE
e9.
Rüegger C, Hegglin M, Adams M, Bucher HU: Population based trends in mortality, morbidity and treatment for very preterm- and very low birth weight infants over 12 years. BMC Pediatr 2012; 12: 17 CrossRef MEDLINE PubMed Central
e10.
Gizzi C, Montecchia F, Panetta V, et al.: Is synchronised NIPPV more effective than NIPPV and NCPAP in treating apnoea of prematurity (AOP)? A randomised cross-over trial. Arch Dis Child Fetal Neonatal Ed 2015; 100: F17–23.
e11.
Diblasi RM: Nasal continuous positive airway pressure (CPAP) for the respiratory care of the newborn infant. Respir Care 2009; 54: 1209–35 MEDLINE
e12.
Gupta S, Donn SM: Continuous positive airway pressure: physiology and comparison of devices. Semin Fetal Neonatal Med 2016; 21: 204–11 CrossRef MEDLINE
e13.
Vyas J, Kotecha S: Effects of antenatal and postnatal corticosteroids on the preterm lung. Arch Dis Child Fetal Neonatal Ed 1997; 77: F147–50 CrossRef MEDLINE PubMed Central
e14.
Roberts D, Brown J, Medley N, Dalziel SR: Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database Syst Rev 2017; 3: CD004454 MEDLINE
e15.
Carlo WA, McDonald SA, Fanaroff AA, et al.: Association of antenatal corticosteroids with mortality and neurodevelopmental outcomes among infants born at 22 to 25 weeks’ gestation. JAMA 2011; 306: 2348 CrossRef MEDLINE PubMed Central
e16.
Lampland AL, Meyers PA, Worwa CT, Swanson EC, Mammel MC: Gas exchange and lung inflammation using nasal intermittent positive-pressure ventilation versus synchronized intermittent mandatory ventilation in piglets with saline lavage-induced lung injury: an observational study. Crit Care Med 2008; 36: 183–7 CrossRef MEDLINE
e17.
Rhen T, Cidlowski JA: Antiinflammatory action of glucocortiods— new mechanisms for old drugs. N Engl J Med 2005; 353: 1711–23 CrossRef MEDLINE
e18.
Doyle LW, Cheong JL, Ehrenkranz RA, Halliday HL: Early (< 8 days) systemic postnatal corticosteroids for prevention of bronchopulmonary dysplasia in preterm infants. Cochrane Database Syst Rev 2017; 10: CD001146 MEDLINE
e19.
Waitz M, Mense L, Kirpalani H, Lemyre B: Nasal intermittent positive pressure ventilation for preterm neonates: synchronized or not? Clin Perinatol 2016; 43: 799–816 CrossRef MEDLINE
Department of General Pediatrics & Neonatology, Center for Pediatrics and Youth Medicine, Justus Liebig University of Giessen: Dr. med. Judith Behnke, MD; Prof. Dr. med. Klaus-Peter Zimmer, MD; PD Dr. med. Harald Ehrhardt, MD; Dr. med. Markus Waitz, MD
Division of Neonatology, Children’s Hospital of Eastern Ontario, Ottawa, Canada:
Dr. med. Brigitte Lemyre, MD
Department of Neonatology, Charité—Universitätsmedizin Berlin, Berlin: PD Dr. med. Christoph Czernik, MD
Member of the German Lung Research Center (DZL), Giessen: Dr. med. Judith Behnke, MD;
PD Dr. med. Harald Ehrhardt, MD
Interfaces for nCPAP application
Interfaces for nCPAP application
Figure 1
Interfaces for nCPAP application
Preterm infant with nCPAP and binasal prongs (bonnet)
Preterm infant with nCPAP and binasal prongs (bonnet)
Figure 2
Preterm infant with nCPAP and binasal prongs (bonnet)
Key messages
Selected RCTs on nCPAP with selective or prophylactic surfactant administration vs. IMV with or without surfactant application (including INSURE)
Selected RCTs on nCPAP with selective or prophylactic surfactant administration vs. IMV with or without surfactant application (including INSURE)
Table 1
Selected RCTs on nCPAP with selective or prophylactic surfactant administration vs. IMV with or without surfactant application (including INSURE)
Results of meta-analyses on NIPPV vs. nCPAP as primary respiratory support and post-extubation
Results of meta-analyses on NIPPV vs. nCPAP as primary respiratory support and post-extubation
Table 2
Results of meta-analyses on NIPPV vs. nCPAP as primary respiratory support and post-extubation
Selected RCTs on HHHFNC vs. CPAP/NIPPV as primary respiratory support or post extubation
Selected RCTs on HHHFNC vs. CPAP/NIPPV as primary respiratory support or post extubation
Table 3
Selected RCTs on HHHFNC vs. CPAP/NIPPV as primary respiratory support or post extubation
nCPAP- Mechanism of action and potential side effects (e11, e12)
nCPAP- Mechanism of action and potential side effects (e11, e12)
eBox 1
nCPAP- Mechanism of action and potential side effects (e11, e12)
Effects of antenatal systemic corticosteroids on the preterm lung and side effects (e13–e15)
Effects of antenatal systemic corticosteroids on the preterm lung and side effects (e13–e15)
eBox 2
Effects of antenatal systemic corticosteroids on the preterm lung and side effects (e13–e15)
NIPPV- Mechanism of action and potential side effects (e2, e16)
NIPPV- Mechanism of action and potential side effects (e2, e16)
eBox 3
NIPPV- Mechanism of action and potential side effects (e2, e16)
HHHFNC- Mechanism of action and potential side effects (20, e6)
HHHFNC- Mechanism of action and potential side effects (20, e6)
eBox 4
HHHFNC- Mechanism of action and potential side effects (20, e6)
Effects of postnatal systemic corticosteroids on the preterm lung and side effects (31, e17, e18)
Effects of postnatal systemic corticosteroids on the preterm lung and side effects (31, e17, e18)
eBox 5
Effects of postnatal systemic corticosteroids on the preterm lung and side effects (31, e17, e18)
Time and Pressure Cycling during Bilevel-NIPPV versus CMV-NIPPV Different pressure wave types during (A) bilevel-NIPPV and (B) CMV-NIPPV PIP, peak inspiratory pressure; PEEP, positive end-expiratory pressure Adapted from Waitz et al. Clin Perinatol 2016 (e19)
Time and Pressure Cycling during Bilevel-NIPPV versus CMV-NIPPV Different pressure wave types during (A) bilevel-NIPPV and (B) CMV-NIPPV PIP, peak inspiratory pressure; PEEP, positive end-expiratory pressure Adapted from Waitz et al. Clin Perinatol 2016 (e19)
eFigure 1
Time and Pressure Cycling during Bilevel-NIPPV versus CMV-NIPPV Different pressure wave types during (A) bilevel-NIPPV and (B) CMV-NIPPV PIP, peak inspiratory pressure; PEEP, positive end-expiratory pressure Adapted from Waitz et al. Clin Perinatol 2016 (e19)
Preterm infant with HHHFNC
Preterm infant with HHHFNC
eFigure 2
Preterm infant with HHHFNC
1.Owen LS, Manley BJ, Davis PG, Doyle LW: The evolution of modern respiratory care for preterm infants. Lancet 2017; 389: 1649–59 CrossRef
2.Jobe AH, Bancalari E: Bronchopulmonary dysplasia. Am J Respir Crit Care Med 2001; 163: 1723–9 CrossRef MEDLINE
3.Shahzad T, Radajewski S, Chao CM, Bellusci S, Ehrhardt H: Pathogenesis of bronchopulmonary dysplasia: when inflammation meets organ development. Mol Cell Pediatr 2016; 3: 23 CrossRefMEDLINE PubMed Central
4.Gortner L, Misselwitz B, Milligan D, et al.: Rates of bronchopulmonary dysplasia in very preterm neonates in Europe: results from the MOSAIC cohort. Neonatology 2011; 99: 112–7 CrossRef MEDLINE
5.Ehrenkranz RA, Walsh MC, Vohr BR, et al.: Validation of the National Institutes of Health consensus definition of bronchopulmonary dysplasia. Pediatrics 2005; 116: 1353–60 CrossRef MEDLINE
6.Jaakkola JJK, Ahmed P, Ieromnimon A, et al.: Preterm delivery and asthma: a systematic review and meta-analysis. J Allergy Clin Immunol 2006; 118: 823–30 CrossRef MEDLINE
7.Álvarez-Fuente M, Arruza L, Muro M, et al.: The economic impact of prematurity and bronchopulmonary dysplasia. Eur J Pediatr 2017; 176: 1587–93 CrossRef MEDLINE
8.Morley CJ, Davis PG, Doyle LW, Brion LP, Hascoet JM, Carlin JB: Nasal CPAP or intubation at birth for very preterm infants. N Engl J Med 2008; 358: 700–8 CrossRef MEDLINE
9.Finer NN, Carlo WA, Walsh MC, et al.: Early CPAP versus surfactant in extremely preterm infants. N Engl J Med 2010; 362: 1970–9 CrossRefMEDLINE PubMed Central
10. Roberts CT, Hodgson KA: Nasal high flow treatment in preterm infants. Matern Health Neonatol Perinatol 2017; 3: 15 CrossRef MEDLINE PubMed Central
11.Westhoff M, Schonhofer B, Neumann P, et al.: Noninvasive mechanical ventilation in acute respiratory failure. Pneumologie 2015; 69: 719–56 MEDLINE
12.Dunn MS, Kaempf J, de Klerk A, et al.: Randomized trial comparing 3 approaches to the initial respiratory management of preterm neonates. Pediatrics 2011; 128: e1069–76 CrossRef MEDLINE
13.Sandri F, Plavka R, Ancora G, et al.: Prophylactic or early selective surfactant combined with nCPAP in very preterm infants. Pediatrics 2010; 125: e1402–9 CrossRef MEDLINE
14. Tapia JL, Urzua S, Bancalari A, et al.: Randomized trial of early bubble continuous positive airway pressure for very low birth weight infants. J Pediatr 2012; 161: 75–80.e1 CrossRef MEDLINE
15.Rojas MA, Lozano JM, Rojas MX, et al.: Very early surfactant without mandatory ventilation in premature infants treated with early continuous positive airway pressure: a randomized, controlled trial. Pediatrics 2009; 123: 137–42 CrossRef MEDLINE
16.Schmolzer GM, Kumar M, Pichler G, Aziz K, O‘Reilly M, Cheung PY: Non-invasive versus invasive respiratory support in preterm infants at birth: systematic review and meta-analysis. BMJ 2013; 347: f5980 CrossRef MEDLINE PubMed Central
17.Roberts CT, Davis PG, Owen LS: Neonatal non-invasive respiratory support: synchronised NIPPV, non-synchronised NIPPV or bi-level CPAP: what is the evidence in 2013? Neonatology 2013; 104: 203–9 CrossRef MEDLINE
18.Lemyre B, Laughon M, Bose C, Davis PG: 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 CrossRef
19.Lemyre B, Davis PG, de Paoli AG, Kirpalani H: 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 CrossRef
20.Manley BJ, Dold SK, Davis PG, Roehr CC: High-flow nasal cannulae for respiratory support of preterm infants: a review of the evidence. Neonatology 2012; 102: 300–8 CrossRef MEDLINE
21.Schmid F, Olbertz DM, Ballmann M: The use of high-flow nasal cannula (HFNC) as respiratory support in neonatal and pediatric intensive care units in Germany—a nationwide survey. Respir Med 2017; 131: 210–4 CrossRef
22.Manley BJ, Owen LS, Doyle LW, et al.: High-flow nasal cannulae in very preterm infants after extubation. N Engl J Med 2013; 369: 1425–33 CrossRef
23.Roberts CT, Owen LS, Manley BJ, et al.: Nasal high-flow therapy for primary respiratory support in preterm infants. N Engl J Med 2016; 375: 1142–51 CrossRef MEDLINE
24.Murki S, Singh J, Khant C, et al.: High-flow nasal cannula versus nasal continuous positive airway pressure for primary respiratory support in preterm infants with respiratory distress: a randomized controlled trial. Neonatology 2018; 113: 235–41 CrossRef MEDLINE
25.Lavizzari A, Colnaghi M, Ciuffini F, et al.: Heated, humidified high-flow nasal cannula vs nasal continuous positive airway pressure for respiratory distress syndrome of prematurity: a randomized clinical noninferiority trial. JAMA Pediatr 2016 CrossRef
26.Younge N, Goldstein RF, Bann CM, et al.: Survival and neurodevelopmental outcomes among periviable infants. N Engl J Med 2017; 376: 617–28 CrossRef MEDLINE
27.Schleußner E: The prevention, diagnosis and treatment of premature labor. Dtsch Arztebl Int 2013; 110: 227–36 CrossRef
28.van Marter LJ: Epidemiology of bronchopulmonary dysplasia. Semin Fetal Neonatal Med 2009; 14: 358–66 CrossRef MEDLINE
29.Stevens TP, Finer NN, Carlo WA, et al.: Respiratory outcomes of the surfactant
positive pressure and oximetry randomized trial (SUPPORT). J Pediatr 2014; 165: 240–9.e4 CrossRef MEDLINE
30.Doyle LW, Ranganathan S, Cheong JLY: Ventilation in preterm infants and lung function at 8 years. N Engl J Med 2017; 377: 1601–2 CrossRef
31.Doyle LW, Ehrenkranz RA, Halliday HL: Late (7 days) postnatal corticosteroids for chronic lung disease in preterm infants. Cochrane Database Syst Rev 2014; 5: CD001145 CrossRef
32. Vaucher YE, Peralta-Carcelen M, Finer NN, et al.: Neurodevelopmental outcomes in the early CPAP and pulse oximetry trial. N Engl J Med 2012; 367: 2495–504 CrossRef MEDLINE
33.Sweet DG, Carnielli V, Greisen G, et al.: European consensus guidelines on the management of respiratory distress syndrome – 2016 update. Neonatology 2017; 111: 107–25 CrossRef MEDLINE
34.Stoll BJ, Hansen NI, Bell EF, et al.: Trends in care practices, morbidity, and mortality of extremely preterm neonates, 1993–2012. JAMA 2015; 314: 1039–51 CrossRef MEDLINE
35.Di Fiore JM, Bloom JN, Orge F, et al.: A higher incidence of intermittent hypoxemic episodes is associated with severe retinopathy of prematurity. J Pediatr 2010; 157: 69–73 CrossRef MEDLINE
36.Poets CF, Roberts RS, Schmidt B, et al.: Association between intermittent hypoxemia or bradycardia and late death or disability in extremely preterm infants. JAMA 2015; 314: 595–603 CrossRef MEDLINE
37.Bamat N, Jensen EA, Kirpalani H: Duration of continuous positive airway pressure in premature infants. Semin Fetal Neonatal Med 2016; 21: 189–95 CrossRef MEDLINE
38.Firestone KS, Beck J, Stein H: Neurally adjusted ventilatory assist for noninvasive support in neonates. Clin Perinatol 2016; 43: 707–24 CrossRef MEDLINE
39.Mukerji A, Dunn M: High-frequency ventilation as a mode of noninvasive respiratory support. Clin Perinatol 2016; 43: 725–40 CrossRef MEDLINE
40.Kribs A: Minimally invasive surfactant therapy and noninvasive respiratory support. Clin Perinatol 2016; 43: 755–71 CrossRef MEDLINE
e1.Jensen EA, Schmidt B: Epidemiology of bronchopulmonary dysplasia. Birth Defects Res Part A Clin Mol Teratol 2014; 100: 145–57 CrossRef MEDLINE
e2.Owen LS, Manley BJ: Nasal intermittent positive pressure ventilation in preterm infants: equipment, evidence, and synchronization. Semin Fetal Neonatal Med 2016; 21: 146–53 CrossRef MEDLINE
e3.Gregory GA, Kitterman JA, Phibbs RH, Tooley WH, Hamilton WK: Treatment of the idiopathic respiratory-distress syndrome with continuous positive airway pressure. N Engl J Med 1971; 284: 1333–40 CrossRef MEDLINE
e4.Courtney SE, Barrington KJ: Continuous positive airway pressure and noninvasive ventilation. Clin Perinatol 2007; 34: 73–92, vi CrossRef MEDLINE
e5.Millar D, Lemyre B, Kirpalani H, Chiu A, Yoder BA, Roberts RS: A comparison of bilevel and ventilator-delivered non-invasive respiratory support. Arch Dis Child Fetal Neonatal Ed 2016; 101: F21–5 CrossRef MEDLINE
e6.Dysart K, Miller TL, Wolfson MR, Shaffer TH: Research in high flow therapy: mechanisms of action. Respir Med 2009; 103: 1400–5 CrossRef MEDLINE
e7.Collins CL, Barfield C, Horne RSC, Davis PG: A comparison of nasal trauma in preterm infants extubated to either heated humidified high-flow nasal cannulae or nasal continuous positive airway pressure. Eur J Pediatr 2014; 173: 181–6 CrossRef MEDLINE
e8.Wilkinson D, Andersen C, O‘Donnell CP, De Paoli AG, Manley BJ: High flow nasal cannula for respiratory support in preterm infants. Cochrane Database Syst Rev 2016; 2: CD006405 MEDLINE
e9.Rüegger C, Hegglin M, Adams M, Bucher HU: Population based trends in mortality, morbidity and treatment for very preterm- and very low birth weight infants over 12 years. BMC Pediatr 2012; 12: 17 CrossRef MEDLINE PubMed Central
e10. Gizzi C, Montecchia F, Panetta V, et al.: Is synchronised NIPPV more effective than NIPPV and NCPAP in treating apnoea of prematurity (AOP)? A randomised cross-over trial. Arch Dis Child Fetal Neonatal Ed 2015; 100: F17–23.
e11.Diblasi RM: Nasal continuous positive airway pressure (CPAP) for the respiratory care of the newborn infant. Respir Care 2009; 54: 1209–35 MEDLINE
e12. Gupta S, Donn SM: Continuous positive airway pressure: physiology and comparison of devices. Semin Fetal Neonatal Med 2016; 21: 204–11 CrossRef MEDLINE
e13.Vyas J, Kotecha S: Effects of antenatal and postnatal corticosteroids on the preterm lung. Arch Dis Child Fetal Neonatal Ed 1997; 77: F147–50 CrossRef MEDLINE PubMed Central
e14.Roberts D, Brown J, Medley N, Dalziel SR: Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database Syst Rev 2017; 3: CD004454 MEDLINE
e15.Carlo WA, McDonald SA, Fanaroff AA, et al.: Association of antenatal corticosteroids with mortality and neurodevelopmental outcomes among infants born at 22 to 25 weeks’ gestation. JAMA 2011; 306: 2348 CrossRef MEDLINE PubMed Central
e16.Lampland AL, Meyers PA, Worwa CT, Swanson EC, Mammel MC: Gas exchange and lung inflammation using nasal intermittent positive-pressure ventilation versus synchronized intermittent mandatory ventilation in piglets with saline lavage-induced lung injury: an observational study. Crit Care Med 2008; 36: 183–7 CrossRef MEDLINE
e17.Rhen T, Cidlowski JA: Antiinflammatory action of glucocortiods— new mechanisms for old drugs. N Engl J Med 2005; 353: 1711–23 CrossRef MEDLINE
e18.Doyle LW, Cheong JL, Ehrenkranz RA, Halliday HL: Early (< 8 days) systemic postnatal corticosteroids for prevention of bronchopulmonary dysplasia in preterm infants. Cochrane Database Syst Rev 2017; 10: CD001146 MEDLINE
e19.Waitz M, Mense L, Kirpalani H, Lemyre B: Nasal intermittent positive pressure ventilation for preterm neonates: synchronized or not? Clin Perinatol 2016; 43: 799–816 CrossRef MEDLINE