Non-invasive versus invasive respiratory support in preterm infants at birth: systematic review and meta-analysis

The systematic review by Schmolzer et al (1) on nasal continuous positive airway pressure (CPAP) versus invasive ventilation as initial respiratory support in very preterm infants examines one of the most pertinent issues in neonatology. Observational studies indicate that mechanical ventilation is one of the biggest risk factors for the development of bronchopulmonary dysplasia (BPD). (2) We were therefore surprised to find that in the present review avoiding ventilation and using nasal CPAP as initial mode for respiratory support in extremely preterm neonates resulted only in a modest reduction in the risk of BPD or death at 36 weeks (relative risk 0.91, 95% CI: 0.84 to 0.99). Twenty-five neonates need to be given nasal CPAP instead of endotracheal ventilation in order to prevent 1 extra BPD. We feel the following considerations have a potential bearing on the interpretation of this review:

1.  The systematic review classifies those neonates who received prophylactic surfactant and were quickly extubated to nasal CPAP (within minutes or an hour at the most) under the "intubation group". However, these neonates are clearly different from those who remained on mechanical ventilation for many hours. For instance, the premise of Sandri et al's CURPAP trial (3) was actually to compare prophylactic surfactant followed by CPAP as against CPAP alone. In other words, the trial proposed to evaluate if adding prophylactic surfactant improved the efficacy of early CPAP. The infants classified in the “intubation group” of CURPAP trial were mostly extubated within 1 hour whereas neonates in the “intubation group” of SUPPORT and COIN trial received mechanical ventilation for much longer periods (mean duration 27.7± 1.1 days in SUPPORT (4) and median duration 4 days (IQR 1-14) in COIN trials. (5)) Likewise, Dunn et al (6) randomized participating neonates in three groups, which the systematic review has merged into two. The ventilation group and prophylactic surfactant followed by CPAP groups have been merged together. This apparent misclassification may underestimate the efficacy of CPAP in lowering the risk for BPD as some infants who have actually experienced the benefits of CPAP except for few minutes of ventilation have been ‘wrongly’ grouped along with the neonates who have been ventilated for days.  If a meta-analysis is conducted after excluding study by Sandri et al and excluding ‘prophylactic surfactant-CPAP’ group from study by Dunn et al, pooled estimates for risk of CLD or death at 36 weeks become more favourable for nasal CPAP (relative risk: 0.89; 95% CI: 0.81-0.97) with number needed to treat of 19.  
2. The benefits of nasal CPAP in the review are less dramatic than the observations of earlier investigators like Avery (2) due to other reasons as well. Use of antenatal steroids has become nearly universal and there has been increasing awareness about the importance of gentle, better synchronized, volume targeted ventilatory modes with evidence based strategies such as permissive hypercapnoea and early weaning. These lung-protective strategies have possibly made BPD less common even in the “intubation” group. Also, nasal CPAP may have its own limitations in this extremely low gestational group with its poor respiratory drive, excessive chest wall compliance and vulnerability to nasal injury. 
3. Despite demonstrating only a modest reduction in the risk for BPD or death, the use of CPAP has been shown to substantially reduce the need for surfactant (RR 0.40 [0.23 to 0.70], NNT 2 [1 to 4]) and mechanical ventilation ( RR 0.56 [0.32 to 0.97], NNT 3 [1,100]). (1) These are meaningful clinical benefits, especially in resource-poor settings and have important implications for neonatal physicians and policy makers.

We feel that the ‘nasal CPAP movement’ has made one of biggest impacts in improving pulmonary outcomes of preterm neonates and only a modest benefit indicated in the current systematic review should be interpreted cautiously.

References

1.            Schmölzer GM, Kumar M, Pichler G, Aziz K, O’Reilly M, Cheung P-Y. Non-invasive versus invasive respiratory support in preterm infants at birth: systematic review and meta-analysis. BMJ. 2013;347:f5980.

2.            Avery ME, Tooley WH, Keller JB, Hurd SS, Bryan MH, Cotton RB, et al. Is chronic lung disease in low birth weight infants preventable? A survey of eight centers. Pediatrics. 1987 Jan;79(1):26–30.

3.            Sandri F, Plavka R, Ancora G, Simeoni U, Stranak Z, Martinelli S, et al. Prophylactic or early selective surfactant combined with nCPAP in very preterm infants. Pediatrics. 2010 Jun;125(6):e1402–1409.

4.            SUPPORT Study Group of the Eunice Kennedy Shriver NICHD Neonatal Research Network, Finer NN, Carlo WA, Walsh MC, Rich W, Gantz MG, et al. Early CPAP versus surfactant in extremely preterm infants. N Engl J Med. 2010 May 27;362(21):1970–9.

5.            Morley CJ, Davis PG, Doyle LW, Brion LP, Hascoet J-M, Carlin JB, et al. Nasal CPAP or intubation at birth for very preterm infants. N Engl J Med. 2008 Feb 14;358(7):700–8.

6.            Dunn MS, Kaempf J, de Klerk A, de Klerk R, Reilly M, Howard D, et al. Randomized trial comparing 3 approaches to the initial respiratory management of preterm neonates. Pediatrics. 2011 Nov;128(5):e1069–1076.

7.            Rojas MA, Lozano JM, Rojas MX, Laughon M, Bose CL, Rondon MA, et al. Very early surfactant without mandatory ventilation in premature infants treated with early continuous positive airway pressure: a randomized, controlled trial. Pediatrics. 2009 Jan;123(1):137–42.

8.            Thomson MA. Early Nasal Continuous Positive Airways Pressure (nCPAP) with Prophylactic Surfactant for Neonates at Risk of RDS. The IFDAS Multi-Centre Randomised Trial.PAS abstract 2002.2204.