MANUSCRIPT CITATION

Jensen CF, Sellmer A, Ebbesen F, et al. Sudden vs Pressure Wean From Nasal Continuous Positive Airway Pressure in Infants Born Before 32 Weeks of Gestation: A Randomized Clinical Trial. JAMA Pediatr. 2018 Jul 23. pii: 2687936. doi: 10.1001/jamapediatrics.2018.2074. PMID: 30039171

REVIEWED BY

Islam Nour
Associate Professor of Pediatrics/Neonatology
Mansoura University Children’s Hospital
Mansoura, Egypt

Hesham Abdel-Hady
Professor of Pediatrics/Neonatology
Mansoura University Children’s Hospital
Mansoura, Egypt

TYPE OF INVESTIGATION

Treatment

QUESTION

(P) In preterm infants born before 32 weeks of gestation, receiving nCPAP at least 24 hours, (I) does sudden wean  (C) compared to pressure wean from nCPAP, (O) affect weight gain velocity (T) from randomization to postmenstrual age (PMA) 40 weeks.

METHODS

• Design: Randomized, open label, multicenter trial, 6 neonatal intensive care units in Denmark.
• Allocation: Infants were randomly assigned (1:1) with a computer-generated web-based randomization system. The randomization was stratified by study center and gestational age (<28 or 28-32 weeks) and balanced within randomly sized blocks of 2, 4, or 6 infants in each center. Twins were randomized to the same weaning strategy.
• Blinding: It was not feasible to mask caregivers and parents.
• Follow-up period: Until death or at 40 weeks PMA.
• Setting: Six NICUs in the central and north regions of Denmark between September 2012 and December 2016.
• Patients:
  • Inclusion criteria: A current PMA of 29 weeks and 0 days or older, nCPAP of 24 hours or more, nCPAP pressure of less than 8 cmH2O, oxygen requirement of less than 30% and not increasing, a respiratory rate of less than 70 breaths per minute, less than 3 episodes of bradycardias (<70 beats/minute) or desaturations (<70%) in the preceding 24 hours, and tolerate time off nCPAP during nursing procedures (up to 15 minutes).
  • Exclusion criteria: Gastrointestinal surgery, known or suspected congenital neuromuscular disease, or chromosomal anomalies or congenital malformations of the heart, lung, or gastrointestinal tract. Furthermore, infants of parents who were unable to speak or read Danish were considered ineligible.
• Intervention:
  • In the sudden wean group, discontinuation of nCPAP without a prior reduction in pressure. If the infant failed the discontinuation of the nCPAP, according to the failure criteria, nCPAP was recommenced.
  • In the pressure wean group, the nCPAP pressure was decreased by 1 cm H2O every 24 hours until a pressure of 4 cmH2O was achieved. Then the nCPAP was discontinued. If any of the failure criteria were met during the pressure reduction, the nCPAP pressure was increased. If any of the failure criteria were met after discontinuation, nCPAP was recommenced.
  • In both scenarios, a new attempt of pressure wean was at the earliest made 24 hours from the latest attempt and only when the readiness criteria were met again. A successful wean was defined as no need for recommencing nCPAP according to failure criteria for 3 days after nCPAP discontinuation.
• Outcomes:
  • Primary outcome: Weight gain velocity from randomization to PMA 40 weeks.
  • Secondary outcomes: Weight at 40 weeks PMA, weight gain velocity measured from the date of randomization to the date of a successful wean, weight at successful wean, durations of nCPAP and of oxygen supplementation, PMA at successful wean and at discharge, successful wean at the first attempt, the number of attempts to wean, bronchopulmonary dysplasia (BPD), need for supplemental oxygen at discharge from the NICU, length of stay in the NICU, and PMA at discharge.
  • Prespecified subgroup analyses by gestational age were performed.

• Analysis and Sample Size: The authors estimated the sample size on the basis of prior knowledge on weight gain velocity in preterm infants. They aimed to be able to detect a difference in weight gain velocity of 2.5 g/kg/day between the two groups. For this difference to be detected with a power of 80% and a 2-sided significance level of P= .05, a total of at least 92 infants in each group had to be recruited. However, anticipating an average cluster size of 2 and an intracluster correlation coefficient of 0.35, the adjusted sample size was 125 infants in each group. To allow for a loss to follow-up and a lack of compliance of 15%, the size of the study population was estimated to be 150 infants in each group.
• Patient follow-up: Of 611 infants screened, 372 were recruited. 185 (49.7%) were randomized to sudden wean and 187 infants (50.3%) to pressure wean. A total of 177 infants in each group completed the trial.

MAIN RESULTS:

• The demographic data and clinical characteristics were matched in the 2 groups.
• A total of 58 infants (16%) were born with a gestational age younger than 28 weeks and 296 infants (84%) were born with a gestational age between 28 and 31 weeks and 6days
• There was no difference in mean [SD] weight gain velocity from randomization to 40 weeks PMA between the 2 groups (22 [6] g/kg/day). No difference was found in any of the secondary outcomes.
• In the pressure wean group 1 infant had nasal septum necrosis. No other adverse events were observed.
• More infants born before 28 weeks of gestation were successfully weaned from nCPAP during the first attempt in the pressure wean group compared with the sudden wean group (risk difference, 31%; 95% CI, 13%-50%), but there was no difference in the weight gain velocity from the date of randomization to a PMA of 40 weeks or other secondary outcomes.
• In preterm infants 28-32 weeks of gestation, there was also no statistical significant difference between the sudden wean and pressure wean groups regarding primary or secondary outcomes.

CONCLUSIONS:

The authors conclude that both sudden wean and pressure wean from nCPAP could be considered equally good weaning strategies from nCPAP with respect to weight gain velocity and several other measures of growth and respiratory support. Pressure wean may be preferred in infants who are born before 28 weeks of gestation, as they had a higher rate of successful weaning during the first attempt.

COMMENTARY

The ideal strategy of weaning off nCPAP is not established. Premature discontinuation may lead to atelectasis, apnea and bradycardia, respiratory distress, prolonged oxygen therapy, and ultimately lung injury [1]. On the other hand, undue prolonged therapy increases the risk of nasal trauma, gastric distension, pneumothorax and agitation [2].

Previous studies showed conflicting results. Amatya et al, found that more infants in the gradual wean group were successfully weaned off nCPAP as compared with the sudden wean group, with no difference in respiratory morbidity, weight gain, days on nCPAP and length of hospital stay [3]. In contrast, Eze et al., demonstrated that weaning CPAP in very preterm infants via sprinting (gradual increasing spontaneous breathing off nCPAP) versus weaning pressure down were comparable, regarding successful weaning and the occurrence of common neonatal morbidities [4]. Jensen et al. have shown no difference in weight gain velocity from randomization to 40 weeks PMA and in secondary outcomes between preterm infants born before 32 weeks of gestation, randomized to sudden weaning versus pressure weaning from nCPAP. The discrepancy in the findings of the Jensen et al’ study and previous studies may be related to differences in gestational age and the severity of  respiratory dysfunction, as infants enrolled in Jensen et al and Amatya et al’ studies had higher gestational age [median GA 30 (29-31), mean 28.7± 1.8  weeks, respectively], compared to Eze et al [median 26.5 (23.6–30.6) weeks] and had less severe respiratory dysfunction as the need for surfactant was 36%, 20%, respectively versus 63%-73% in Eze et al study.

More infants less than 28 weeks of gestation at birth were successfully weaned from nCPAP during the first attempt in the pressure wean group compared with the sudden wean group. Similarly, Soe et al found that pressure weaning was more effective than cycling off nCPAP in infants born 24 to 27 weeks of gestation but not in infants over 28 weeks of gestation at birth [5]. This may indicate that pressure weaning is more appropriate in these infants or that they should have different readiness to wean from nCPAP criteria such as lower FiO2 requirements, lower nCPAP pressure, and older postnatal age.

This is the largest RCT to date to compare sudden wean and pressure wean of very preterm infants from CPAP. However, the results of this study should be interpreted with caution, due to some limitations such as:

• This study has adopted stability criteria for readiness to wean from nCPAP with a relatively high nCPAP pressure less than 8 cm H2O, in contrast to 4-6 cm H2O used in previous studies [3, 6]. We assume that this high pressure may not be ideal for infants born before 28 weeks of gestation;
• The authors used weight gain velocity from randomization to term-equivalent corrected gestational age as a primary outcome. However, weigh gain velocity in preterm infants is not only related to successful weaning off nCPAP but related to many other factors including initial weight percentile, sepsis, cardiovascular disease, feeding intolerance, necrotizing enterocolitis and respiratory requirements [7].

Where do we go from here? In preterm infants less than 32 weeks of gestation, sudden discontinuation and gradual pressure weaning strategies seem to be equally effective approaches for weaning from nCPAP, pressure wean may be preferred in infants who less than 28 weeks of gestation. However, future studies are warranted for refinement of readiness to wean from nCPAP criteria and to study the influence of different nCPAP weaning strategies on long-term pulmonary and neurodevelopmental outcomes.

REFERENCES

1. Jardine L, Davies MW. Withdrawal of neonatal continuous positive airway pressure: current practice in Australia. Pediatr Int 2008; 50: 572-5.
2. Abdel-Hady H, Shouman B, Nasef N. Weaning preterm infants from continuous positive airway pressure: evidence for best practice. World J Pediatr 2015: 11: 212-8.
3. Amatya S, Macomber M, Bhutada A, Rastogi D, Rastogi S. Sudden versus gradual pressure wean from Nasal CPAP in preterm infants: a randomized controlled trial. J Perinatol 2017; 37: 662-7.
4. Eze, D Murphy, V Dhar and VK Rehan, Comparison of sprinting vs non-sprinting to wean nasal continuous positive airway pressure off in very preterm infants. Journal of Perinatology 2018; 38: 164-8.
5. Soe A, Hodgkinson J, Jani B, Ducker A. Nasal continuous positive airway pressure weaning in preterm infants. Eur J Pediatr 165(suppl 1):48.
6. Todd DA, Wright A, Broom M, Chauhan M, Meskell S, Cameron C, et al. Methods of weaning preterm babies <30 weeks gestation off CPAP: a multicentre randomised controlled trial. Arch Dis Child Fetal Neonatal Ed 2012; 97: F236-40.
7. Broom M, Ying L, Wright A, Stewart A, Abdel-Latif ME, Shadbolt B, et al. CeasIng Cpap At standarD criteriA (CICADA): impact on weight gain, time to full feeds and caffeine use. Arch Dis Child Fetal Neonatal Ed 2014; 99: F423-5.