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A randomised controlled trial of flow driver and bubble continuous positive airway pressure in preterm infants in a resource-limited setting
  1. P Mazmanyan1,
  2. K Mellor2,
  3. C J Doré3,
  4. N Modi4
  1. 1Scientific Research Centre of Maternal and Child Health, Yerev, Armenia
  2. 2BirthLink, London, UK
  3. 3Medical Research Council Clinical Trials Unit at University College London, London, UK
  4. 4Department of Medicine, Section of Neonatal Medicine, Chelsea & Westminster Campus, Imperial College London, London, UK
  1. Correspondence to Dr Pavel Mazmanyan, Scientific Research Centre of Maternal and Child Health Protection, Yerevan 0002, Armenia; pavelart{at}gmail.com

Abstract

Objectives The variable-flow flow driver (FD; EME) and continuous-flow bubble (Fisher-Paykel) continuous positive airway pressure (CPAP) systems are widely used. As these differ in cost and technical requirements, determining comparative efficacy is important particularly where resources are limited.

Design We performed a randomised, controlled, equivalence trial of CPAP systems. We specified the margin of equivalence as 2 days. We analysed binary variables by logistical regression adjusted for gestation, and log transformed continuous variables by multiple linear regression adjusted for gestation, sex and antenatal steroids.

Setting A neonatal unit with no blood gas analyser or surfactant availability and limited X-ray and laboratory facilities

Patients Neonates <37 weeks of gestation.

Interventions We provided CPAP at delivery followed by randomisation to FD or bubble (B).

Outcomes Primary outcome included total days receiving CPAP; secondary outcomes included days receiving CPAP, supplemental oxygen, ventilation, death, pneumothorax and nasal excoriation.

Results We randomised 125 infants (B 66, FD 59). Differences in infant outcomes on B and FD were not statistically significant. The median (range) for CPAP days for survivors was B 0.8 (0.04 to 17.5), FD 0.5 (0.04 to 5.3). B:FD (95% CI) ratios were CPAP days 1.3 (0.9 to 2.1), CPAP plus supplementary oxygen days 1.2 (0.7 to 1.9). B:FD (95% CI) ORs were death 2.3 (0.2 to 28), ventilation 2.1 (0.5 to 9), nasal excoriation 1.2 (0.2 to 8) and pneumothorax 2.4 (0.2 to 26).

Conclusions In a resource-limited setting we found B CPAP equivalent to FD CPAP in the total number of days receiving CPAP within a margin of 2 days.

Trial registration number ISRCTN22578364.

  • Infant preterm
  • Infant newborn
  • continuous positive airway pressure
  • ventilation
  • low and middle income country

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What is already known on this topic

  • Bubble continuous positive airway pressure (CPAP) is a relatively simple health technology that can be delivered safely in low-income and middle-income countries.

  • The majority of studies of CPAP in low-income and middle-income countries are case-series describing implementation, safety and cost-effectiveness.

What this study adds

  • This study adds to the small number of randomised controlled trials of CPAP in low-income and middle-income countries.

  • Bubble is equivalent to flow driver within a margin of 2 CPAP days; safety benefits from flow driver CPAP cannot be excluded.

  • It is possible to conduct a randomised evaluation of an important neonatal intervention without specific funding in a resource-limited setting.

Introduction

Continuous positive airway pressure (CPAP) is widely used to provide respiratory support for preterm neonates and has become established as an alternative to routine intubation and ventilation. Nasal CPAP increases functional residual capacity and improves oxygenation, reduces airway resistance and lessens the incidence of apnoea. Where resources are limited CPAP may be of particular importance. Since its introduction, >30 years ago, CPAP devices have proliferated and currently there are a large number of delivery systems.

Two devices widely used for the administration of continuous CPAP are the flow driver (FD) and bubble systems. The FD is in established use in the developed world and there has been renewed interest in bubble CPAP systems. The systems differ substantially in cost with bubble CPAP considerably cheaper. Bubble CPAP is simple in concept and involves expiration against a pressure generated by bubbling gas under water. The airway distending pressure is a function of the depth of the expiratory tubing under water. A basic CPAP circuit requires a gas flow source and humidification, nasal prongs, tubing and a water container.

In order to be adopted as a standard of care it is necessary to demonstrate that bubble CPAP and FD CPAP have equivalent efficacy. The demonstration of equivalent efficacy would be an important step towards improving healthcare and outcomes for vulnerable infants worldwide and of particular benefit in low-income and middle-income settings.

Methods

We conducted a single centre, prospective, randomised controlled equivalence trial at the Neonatal Unit of the Research Center Maternal and Child Health Protection, Yerevan, Armenia. The neonatal unit admits approximately 140 preterm babies and ventilates around 35 infants each year. Surfactant is unavailable; at the time of the trial the neonatal unit had no access to blood gas analyser and limited X-ray and laboratory facilities.

All infants born <37 weeks of gestational age, with the exception of those with major life-threatening congenital malformations, were considered eligible. Written parent consent was obtained prior to enrolment. Infants received CPAP 4–6 cm at delivery by mask followed by FD or bubble CPAP according to randomisation. The randomisation allocation sequence, stratified by infant sex and antenatal steroid exposure, was generated by PM. Randomisation allocation concealment was achieved by the use of sealed opaque envelopes. Consecutively numbered envelopes were opened from one of four bundles: (1) boy, received antenatal steroids; (2) boy, did not receive antenatal steroids; (3) girl, received antenatal steroids and (4) girl, did not receive antenatal steroids. We considered antenatal steroids ‘received’ if the mother had treatment at least 4 h prior to delivery. Neonatal unit staff received training from KM and PM prior to the start of the trial in the setup of CPAP systems and in the evaluation of infants.

The primary outcome was total days receiving CPAP in survivors; secondary outcomes were total days receiving CPAP and supplemental oxygen, ventilation, death, pneumothorax, nasal excoriation, periventricular haemorrhage, periventricular leucomalacia, retinopathy of prematurity and necrotising enterocolitis.

We estimated that 64 babies per group were required to demonstrate equivalence ±2 days for total days receiving CPAP (two-sided test; 80% power; 5% significance level; assuming SD of 4 days). We analysed binary variables by logistical regression adjusted for gestation, and log-transformed continuous variables by multiple linear regression adjusted for gestation, sex and antenatal steroids. We performed a subgroup analysis including babies born ≤32 weeks of gestational age as they are at higher risk.

Study interventions

Every anticipated preterm delivery was notified to the neonatal staff. Information about antenatal steroids and gestational age was obtained from the obstetric staff. In the delivery room, all infants received CPAP 4–6 cm H2O applied by mask (NeoPuff Infant Resuscitator, Fisher-Paykel, Auckland, New Zealand). Positive pressure breaths with air were administered if the heart rate dropped <100/min; if the heart rate remained <100/min after 30 s of positive pressure ventilation 100% oxygen was started. Other aspects of the resuscitation were performed according to the American Academy of Paediatrics Neonatal Resuscitation Program guidelines. Intubation was performed if there was failure to respond to positive pressure ventilation, with continuing cyanosis or bradycardia, need for chest compressions or need to administer medications. Study procedures are shown in figure 1.

Figure 1

Trial procedures. CPAP, continuous positive airway pressure.

After admission to the neonatal unit infants from both groups were placed on CPAP commencing at 6 cm H2O. Short binasal prongs were used for FD CPAP and pliable long anatomically curved prongs for bubble CPAP. The CPAP pressure was reduced to 4 cm H2O if SaO2 >88% with FiO2 <0.3. The preductal saturation was continuously monitored by pulse-oximetеr. CPAP was stopped when SaO2 >88 with FiO2 <0.21. If the respiratory rate rose >60/min with recessions or apnoea and bradycardia, CPAP was recommenced. Criteria for CPAP failure and indications for intubation were SaO2 <88% with FiO2 >0.6. Parameters for mechanical ventilation were the lowest peak inspiratory pressure to maintain good chest wall movement, inspiratory time 0.4 s, FiO2 to maintain SpO2 88%–92% with a positive end expiratory pressure  of 5 cm H2O. Infants were extubated when SaO2 >88 and FiO2 <0.4. The ventilator rate was never reduced below 20/min. Methylxanthine treatment was not used. Patent ductus arteriosus was managed conservatively; routine echocardiography and prophylactic treatment were not undertaken. All infants received a cranial ultrasound scan at discharge.

Results

One hundred and twenty-five infants were randomised (bubble 66, FD 59; figure 2). The baseline characteristics of the two randomised groups are shown in table 1. Over half the participants were boys and approximately one-third had received a complete course of antenatal steroids. Outcomes for the two randomised groups are shown in table 2. Differences in infant outcomes on bubble and FD CPAP were not statistically significant. The median (range) for days on CPAP for survivors were bubble 0.8 (0.04 to 17.5), FD 0.5 (0.04 to 5.3). Bubble:FD ratios (95% CI) were CPAP days 1.3 (0.9 to 2.1) and CPAP plus supplementary oxygen days 1.2 (0.7 to 1.9). Bubble:FD ORs (95% CI ) were death 2.3 (0.2 to 28), ventilation 2.1 (0.5 to 9), nasal excoriation 1.2 (0.2 to 8) and pneumothorax 2.4 (0.2 to 26). Four infants died, one in the FD group and three in the Bubble groups; the cause of death in the former was respiratory failure and this baby also developed a pneumothorax; the causes in the latter were respiratory failure (also with a pneumothorax), presumed sepsis with severe sclerema, and congenital pneumonia confirmed at autopsy.

Table 1

Baseline characteristics

Table 2

Outcomes

Figure 2

Trial flow diagram. CPAP, continuous positive airway pressure. IFD, infant flow driver.

The baseline characteristics of the 53 infants born at a gestational age ≤32 weeks are shown in table 3. Outcomes for the two groups are shown in table 4. In this higher risk subgroup all ratios or ORs for outcomes in infants on bubble CPAP were increased but the differences were not statistically significant.

Table 3

Baseline characteristics if gestational age ≤32 weeks

Table 4

Outcomes if gestational age ≤32 weeks

Infants in the bubble group were more likely to have needed resuscitation at birth (50% vs 20%). However, conclusions did not alter when we refitted the regression models for the continuous primary outcome, CPAP days, including whether or not the infant was resuscitated at birth.

Discussion

In this randomised controlled equivalence trial carried out in a resource-limited setting, we have shown that bubble is equivalent to FD CPAP within a margin of 2 days. We chose an equivalence trial as the question we wanted to address was whether clinicians could be reassured that it is reasonable to use either FD or bubble CPAP. In an equivalence trial, the statistical test aims at showing that two treatments are ‘reasonably equivalent’ where ‘reasonably equivalent’ is clearly defined in clinically meaningful terms. Adverse outcomes were more frequent in the bubble group, although no differences achieved statistical significance. The strengths of our study include a preregistered protocol and rigorous study design. We stratified randomisation by sex and antenatal steroid exposure to ensure that the composition of the two randomised groups was balanced for these two important prognostic factors. We included stratifying variables and gestational age when performing the statistical analysis. As blinding of treatments of respiratory support is not possible, to minimise ascertainment bias we employed a clear flow diagram for trial procedures with data collation carried out by a single observer (PM) who was not directly involved in delivering CPAP. A limitation is that there was insufficient power to address differences in secondary outcomes with precision.

There have been previous evaluations of CPAP such as the postextubation trial by Gupta et al,1 but few in resource-limited settings. Walk et al2 describe an observational study of bubble CPAP in 77 Malawian children aged 1 week to 14 years; they conclude that it can be implemented in an African hospital with high-risk patients and limited resources and is well accepted by staff and patients. Similarly, McAdams et al3 describe the successful implementation of bubble CPAP in a rural Ugandan neonatal unit. We used short binasal prongs as these have been shown to be more effective than single prongs4 and as with other studies conducted in resource-limited settings, we found that CPAP techniques were readily accepted and effectively delivered by medical and nursing staff. Chen et al5 performed an economic evaluation to determine the cost-effectiveness of a low-cost bubble CPAP device and suggest that in a Malawian setting bubble CPAP is a highly cost-effective strategy especially for very low birthweight infants, and infants with respiratory distress syndrome or sepsis. Martin et al6 conducted a systematic review of the safety and efficacy of bubble CPAP in neonatal care in low-income and middle-income countries. The majority of studies were case series but they identified four randomised trials, two conducted in India (N=30 and N=114),7 ,8 one in Iran (N=50)9 and one in South America (N=256).10 They found no evidence of survival benefit from bubble CPAP in low-income and middle-income countries, but conclude that though the reported studies are limited by poor study design and quality, bubble CPAP appears to be safe and to reduce the need for mechanical ventilation.

We have shown that it is possible to conduct a randomised evaluation of an important neonatal intervention without specific funding in a resource-limited setting. Our study adds to accumulating evidence that bubble CPAP is a relatively simple health technology that can be delivered safely in low-income and middle-income countries. We recommend that every opportunity is taken to conduct objective evaluations in order to provide a robust evidence-base for newborn critical care globally.

Acknowledgments

We thank BirthLInk UK for providing the CPAP systems.

References

Footnotes

  • Contributors The study was designed by NM, PM and CJD and delivered by KM and PM; data analysis was by CJD; the manuscript was written by NM, with contributions from all authors; all authors approved the final version submitted.

  • Competing interests In the last 5 years NM has held research grants awarded by the National Institute of Health Research, Wellcome Trust, Action Medical Research, Child Growth Foundation, Department of Health, Westminster Medical School Research Trust, Healthcare Quality Improvement Partnership, HCA International, and Bliss. In the last 5 years CJD has held research grants awarded by the National Institute of Health Research, Arthritis Research UK, NHS Blood & Transplant, Medical Research Council, Michael J Fox Foundation, and Wellcome Trust. KM is founder and director of BirthLInk UK.

  • Ethics approval Institutional Review Board for clinical studies, American University of Armenia.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement Data are held by CD and available on request to the corresponding author with the agreement of all authors.

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