MANUSCRIPT CITATION

Kidman AM, Manley BJ, Boland RA, et al. Higher versus lower nasal continuous positive airway pressure for extubation of extremely preterm infants in Australia (ÉCLAT): a multicentre, randomised, superiority trial. Lancet Child Adolesc Health. 2023 Dec;7(12):844-851. https://doi.org/10.1016/S2352-4642(23)00235-3. Epub 2023 Oct 27. PMID: 38240784.

REVIEWED BY:

Dr. Rashida Javed, Dr. Harsha Gowda
Neonatal intensive care unit, University Hospitals Birmingham, Birmingham, UK
Corresponding author: R Javed, Neonatal intensive care unit, Birmingham Heartlands Hospital, B9 5SS, UK.

TYPE OF INVESTIGATION

Treatment

QUESTION

In extreme preterm infants <28-week gestation (P) who were receiving mechanical ventilation after birth, extubation to a higher nCPAP of 9-11cmH2O (I) compared with standard nCPAP of 6-8cmH2O (C) reduces the risk of extubation failure (O) within 7 days (T)?

METHODS

Design: Multicenter randomized, parallel group, open label, superiority trial.

Allocation: Infants were randomly assigned to receive one of two nCPAP levels using Research Electronic Data Capture tool, stratified according to centre and gestation (22-25 completed weeks or 26-27 completed weeks).

Blinding: Unblinded

Follow-up period: Seven days for extubation failure as a primary outcome. 36 weeks postmenstrual age for secondary outcome BPD defined as a requirement for supplemental oxygen or respiratory support or nasal high flow ³2L/min. Data were collected until death, first hospital discharge or until 52 weeks postmenstrual age, whichever occurred first for secondary outcomes and adverse events.

Setting: Three tertiary perinatal centres in Australia

Patients: 139 infants were randomly assigned

Inclusion criteria:

• • • • Infants born less than 28 weeks gestation.
      • Receiving mechanical ventilation via endotracheal tube.
      • Being extubated for the first time to nCPAP.
      • Must have received previous treatment with exogenous surfactant and caffeine.

Exclusion criteria:

• • • • Extubation to mode of respiratory support other than nCPAP.
      • Known major congenital anomaly that might affect breathing.
      • Ongoing intensive care not being provided.

Intervention: Higher nCPAP of 10cmH₂O (range 9-11cmH₂O) vs standard nCPAP of 7cmH₂O (range 6-8cmH₂O) after extubation. Infants remained in allocated nCPAP setting range for the first 24 hours post extubation. After 24 hours, nCPAP could be either altered within the range or weaned below the range (or stopped) at the discretion of the clinical team, but could not exceed 11cmH₂O in higher nCPAP group and 8cmH₂O in standard nCPAP group in first 7 days post extubation.

Outcomes:

Primary outcome:

Extubation failure within 7 days after extubation.

Extubation failure was defined as an infant receiving maximum permitted nCPAP level (higher nCPAP group 11cmH2O or standard nCPAP group 8cmH2O) and meeting at least one of the following criteria:

 1) FiO2 0·20 or more above the FiO2 before extubation

2) pH less than 7·20 and partial pressure of CO2 more than 60 mmHg on an arterial or capillary blood gas sample

3) More than one apnoeic episode requiring intermittent positive- pressure ventilation within a 24 h period, or six or more apnoeic episodes requiring stimulation within six consecutive hours

 4) An urgent need for re- intubation and mechanical ventilation, as determined by the treating team.

Secondary outcomes:

• • Bronchopulmonary dysplasia
  • Duration of mechanical ventilation
  • Duration of any respiratory support
  • Duration of oxygen supplementation
  • Length of hospital admission in days
  • Necrotizing enterocolitis Bells stage II or greater
  • Severe intraventricular haemorrhage (grade III or IV)
  • Retinopathy of prematurity
  • Death before hospital discharge

Analysis and Sample Size: Rate of extubation failure within 7 days in extreme preterm infants was estimated at 55%. To detect a reduction in extubation failure from 55% to 35% with 80% power and two-tailed alpha error of 0.05, a sample size of 93 infants in each group (total 186 infants). The trial was ended before the anticipated sample size reached because of pauses in recruitment due to COVID-19 pandemic.

All analyses were done on an intention-to-treat basis, and infants remained in their assigned group for all outcomes. For each of the primary and dichotomous secondary outcomes, authors calculated the risk difference between the groups, estimated a 95% CI using the Wallenstein method with continuity correction, and estimated a p value using the Fisher exact test.

• • For the primary outcome the number needed to treat was calculated as 1 divided by the risk difference.
  • To compare continuous secondary outcomes, authors used the parametric test (t-test) or non-parametric test (Wilcoxon rank-sum test) as appropriate.
  • 483 infants were born less than 28 weeks, only 139 infants were enrolled and randomly assigned, 70 to high CPAP group and 69 to standard CPAP group.

Patient follow-up: Of the 139 infants enrolled, 138 were analysed for the primary outcome.

MAIN RESULTS:

Maternal and infant demographics were similar between the groups. Antenatal corticosteroid exposure of 94% (130 infants). Most infants were born by caesarian section 63%, 75% were white mothers and 51% infants were female. The mean gestation age was 25.7 weeks and mean birth weight was 777 grams. 49% infants were born before 26 weeks gestation. The median age of extubation was 4 days (IQR 1-8).

For primary outcome: extubation failure occurred in 24 (35%) of 69 infants in the higher nCPAP group and 39 (57%) of 69 infants in the standard nCPAP groups (risk difference -21.7%, 95% CI -38.5% to -3.7%). The number needed to treat was 5. Extubation failure was less common with higher CPAP in both gestational age subgroups, and most likely to occur during first 72 hours in both groups. The most common reason of extubation failure in the standard nCPAP group was increase in supplemental oxygen. (Table 1)

For secondary outcome: There was no significant between-group difference in the rate of secondary or serious adverse events. (Table 2,3)

Table 1:

Primary Outcome
	Higher nCPAP 10cmH2O (n=69)	Standard nCAP 7cmH2O (n=69)	Risk differences, percentage points (95% CI)
Extubation failure within 7 days	24 (35%)	39 (57%)	-21.7 (-38.5 to -3.7)
Extubation failure within 7 days stratified by gestational age subgroups
22-25 completed weeks gestation	18/32 (56%)	25/36 (69%)	-13.2 (-37.6 to 12.4)
26-27 completed weeks gestation	6/37 (16%)	14/33 (42%)	-26.2 (-47.7 to -2.1)

Table 2:

Secondary and other outcomes
	Higher nCPAP 10cmH2O (n=69)	Standard nCPAP 7cmH2O (n=69)	Risk differences, percentage points (95% CI) or p value
Extubation failure 0-24 h	18 (26%)	14 (20%)	5.8 (-9.6 to 20.9)
Extubation failure 25-72 h	6 (9%)	13 (19%)	-10.1 (-22.5 to 2.8)
Extubation failure 73-168 h	0	12 (17%)	-17.4 (-29.6 to -6.6)
Positive blood culture at time of failure	7 of 24 (29%)	5 of 39 (13%)	16.3 (-6.3 to 40.4)
Duration of mechanical ventilation after random assignment, days	13 (7-21)	18 (8-26)	p=0.41
Duration of non-invasive respiratory support after random assignment, days	64 (53-78)	66 (55-94)	p=0.31
Duration of oxygen therapy, days	79 (61-105)	86 (68-110)	p=0.35
Treatment with postnatal corticosteroids after random assignment	13 (19%)	18 (26%)	-7.2 (-22.1 to 8.1)
Bronchopulmonary dysplasia	59 (89%)	57 (89%)	0.3 (-9.3 to 12.4)
Length of total hospital stay, days	110 (90-136%)	117 (99-149)	p=0.14

Table 3:

Adverse events
	Higher nCPAP 10cmH2O (n=69)	Standard nCPAP 7cmH2O (n=69)	Risk differences, percentage points (95% CI)
Adverse events within primary outcome period
Death	2 (3%)	1 (1%)	1.4 (-5.3 to 10.0)
Pneumothorax	1 (1%)	1 (1%)	0.0 (-7.8 to -7.8)
Spontaneous intestinal perforation	2 (3%)	1 (1%)	1.4 (-5.3 to 10.0)
Adverse events any time during hospital stay
Death before hospital discharge	3 (4%)	5 (7%)	-2.9 (-12.0 to 6.3)
Pneumothorax	2 (3%)	1 (1%)	1.4 ( -5.3 to 10.0)
Pulmonary interstitial emphysema	6 (9%)	4 (6%)	2.9 ( -7.1 to 12.7)
Spontaneous intestinal perforation	4 (6%)	3 (4%)	1.4 (-7.2 to 10.0)
Necrotizing enterocolitis	6 (9%)	3 (4%)	4.3 (-5.3 to 14.0)
Retinopathy of prematurity	13/66 (20%)	11/64 (17%)	2.5 (-12.3 to 17.0)

CONCLUSION 

The authors concluded significant reduction in extubation failure with the use of higher nCPAP of 10cmH2O compared with standard nCPAP of 7cmH2O without increasing rates of adverse effects among infants less than 28-week gestation after receiving exogenous surfactant and caffeine

COMMENTARY

Despite advances in non-invasive respiratory support, extremely preterm infants experience extubation failure frequently which can be associated with morbidity and mortality¹. The increased risk of extubation failure is due to lung immaturity, poor chest compliance and immature respiratory drive².

 

Nasal continuous positive airway pressure (nCPAP) or high flow have been the mainstay of post extubation respiratory support³. Following extubation, nCPAP settings vary between centers. Higher set nCPAP levels post extubation may help to maintain end expiratory lung volume and reduce atelectasis. But, a small pilot RCT by Kitsommart et al in 2013 comparing high vs low nCPAP pressures showed no difference in extubation failure rates⁴.

 

In the ECLAT study, extubating infants less than 28-week gestation to a higher nCPAP of 10cmH₂O reduced extubation failure (35% – 24/69 infants) compared to standard nCPAP group (57% – 39/69 infants) with risk difference of -21.7%, 95% CI -38.5% to -3.7%. The number needed to treat was 5 infants meaning five infants needed to receive higher nCPAP to standard nCPAP to prevent one additional extubation failure. Stratification for gestational age subgroups (22-25 and 26-27 completed weeks) also showed a lower extubation failure rate in the nCPAP group receiving higher pressures, especially in the more mature subgroup. However, the study was underpowered for subgroup analysis. The secondary outcomes showed no significant differences between groups which was also underpowered. The most common adverse events, such as pneumothorax, pulmonary interstitial emphysema, spontaneous intestinal perforation, and death were similar in both groups. All infants had exogenous surfactant prior to recruitment which might had contributed to minimal incidence of pneumothorax in higher nCPAP group.

 

13(19%) infants in standard nCPAP group and 2(3%) in higher nCPAP deviated from protocol to increased nCPAP level above the prescribed level. All these infants were eventually re-intubated within the primary outcome period. Recruitment ceased at 74% of planned sample size due to recurrent pauses during COVID-19 pandemic.  Other limitations are clinicians were not blinded and actual distending pressure in alveoli was not measured. Also, there were no standardized criteria for readiness for extubation.

 

Inspite of above limitations, it is a well-designed randomized control trial showing benefits of higher nCPAP reducing extubation failure. Buzzella et al did randomized control trial in 93 infants of less than 30 weeks gestational age to a higher nCPAP of 7-9 cmH₂O or a lower nCPAP of 4-6 cmH₂O and found a significant reduction in extubation failure in higher nCPAP group⁵. But in the ECLAT trial, a much higher nCPAP was used and more immature infants were included. All the extubation failure in higher nCPAP group occurred in first 72hours and nil between 73-168 hours compared to 12 in standard nCPAP group. Probably this suggests the importance of high alveoli end expiratory pressure after extubation to prevent later atelectasis and extubation failure.

 

To conclude, the ECLAT study provides evidence for the use of higher nCPAP in infants less than 28 weeks’ gestation to reduce extubation failure compared to standard nCPAP. There was no difference in BPD rates observed, so the benefit of higher nCPAP (9-11 cmH2O) is questionable. Further large RCT adequately powered to compare BPD rates is required to better evaluate the safety and efficacy of higher post-extubation nCPAP levels on outcomes of greater importance to clinicians and families.

 

References:

1. Razak A, Shah PS, Ye XY, Mukerji A. Post‐extubation use of non‐invasive respiratory support in preterm infants: a network meta‐analysis. Cochrane Database Syst Rev. 2021;2021(10):CD014509. Published 2021 Oct 25.

2. Kidman AM, Manley BJ, Boland RA, Davis PG, Bhatia R. Predictors and outcomes of extubation failure in extremely preterm infants. J Paediatr Child Health. 2021;57(6):913–9.

3. Awanti, Srinivas & Pol, Ramesh & Katti, Arun. (2023). A randomized controlled trial to compare the success rates and efficacy of high flow nasal cannulae versus nasal continuous positive airway pressure in post extubation period in neonates. International Journal of Contemporary Pediatrics. 10. 510-513. 10.18203/2349-3291.ijcp20230728.

4. Kitsommart R, MHSc AK, Al-Saleem N. Levels of nasal CPAP applied during the immediate post- extubation phase. A Randomized Controlled Pilot Trial2013;3:9.

5. Buzzella B, Claure N, D’Ugard C, Bancalari E. A randomized controlled trial of two nasal continuous positive airway pressure levels after extubation in preterm infants. J Pediatr 2014; 164: 46–51.