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Abstract
Importance A sustained inflation (SI) provided at birth might reduce bronchopulmonary dysplasia (BPD).
Objective This study aims to examine whether an SI-guided exhaled carbon dioxide (ECO2) compared with positive pressure ventilation (PPV) alone at birth decreases BPD.
Design Randomised controlled trial. Infants were randomly allocated to either SI (SI group) or PPV (PPV group).
Participants Participants of this study include infants between 23+0 and 32+6 weeks gestation with a need for PPV at birth.
Intervention Infants randomised into the SI group received an initial SI with a peak inflation pressure (PIP) of 24 cmH2O over 20 s. The second SI was guided by the amount of ECO2. If ECO2 was ≤20 mm Hg, a further SI of 20 s was delivered. If ECO2 was >20 mm Hg the second SI was 10 s. Infants randomised into the PPV group received mask PPV with an initial PIP of 24 cmH2O.
Primary outcomes Reduction in BPD defined as the need for respiratory support or supplemental oxygen at corrected gestational age of 36 weeks.
Results SI (n=76) and PPV (n=86) group had similar rates of BPD (23% vs 33%, p=0.090, not statistically significant). The duration of mechanical ventilation was significantly reduced with SI versus PPV (63 (10–246) hours versus 204 (17–562) hours, respectively (p=0.045)). No short-term harmful effects were identified from two SI lasting up to 40 s (eg, pneumothorax, intraventricular haemorrhage or patent ductus arteriosus).
Conclusion Preterm infants <33 weeks gestation receiving SI at birth had lower duration of mechanical ventilation and similar incidence of BPD compared with PPV. Using ECO2 to guide length of SI is feasible.
Trial registration number NCT01739114; Results.
- Infant
- Newborn
- Delivery room
- Neonatal Resuscitation
- Sustained Inflation, Positive Pressure Ventilation
- Respiratory Function Tests
- ExHaled Carbon Dioxide
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- Infant
- Newborn
- Delivery room
- Neonatal Resuscitation
- Sustained Inflation, Positive Pressure Ventilation
- Respiratory Function Tests
- ExHaled Carbon Dioxide
What is already known on this topic?
Exhaled carbon dioxide (ECO2) might be used as a maker of lung aeration.
Sustained inflation potentially increases the risk for the treatment of patent ductus arteriosus and increases the risk for intraventricular haemorrhage.
Sustained inflation decreases the need for intubation within the first 72 hours after birth.
What this study adds?
ECO2 can be used to guide respiratory support at birth.
No short-term harmful effects were identified from two sustained inflations lasting up to 40 s in the first minute after birth.
Introduction
International resuscitation guidelines recommend positive pressure ventilation (PPV) in the delivery room (DR) when babies fail to initiate spontaneous breathing at birth.1 However, the lungs of very preterm infants are uniquely susceptible to injury because they are structurally immature, surfactant deficient, fluid filled, not supported by a stiff chest wall and easily damaged by mechanical ventilation. This injury often leads to bronchopulmonary dysplasia (BPD)2–4; therefore, any proposed lung-protective strategy should be initiated immediately after birth.
Sustained inflations (SI) have been advocated to support development of an effective functional residual capacity to improve oxygenation. In an experimental non-breathing rabbit model, an SI of 20 s coupled with positive end-expiratory pressure (PEEP) resulted in rapid increase in functional residual capacity.5 6 Cohort studies which treated preterm infants with SI of 15 or 20 s reported significant reductions in the need for endotracheal intubation and lower incidences of BPD when compared with routine PPV alone.7–9 Recent randomised trials in preterm infants born at <32 weeks gestational age reported improved short-term outcomes (eg, decreased need for intubation in the first 72 hours and shorter duration of ventilatory support).10 11 However, a recent Cochrane review and a further meta-analysis reported no difference in BPD.12 13 SI provided at birth to preterm infants in the DR might have an additive effect in establishing adequate functional residual capacity by permitting optimal gas exchange, improving lung mechanics and reducing the need for respiratory support.5 6 However, clinicians struggle to achieve optimal lung inflation and gas exchange without damaging the lung during PPV.14 One approach might be guidance of SI or PPV by measuring the amount of exhaled carbon dioxide (ECO2), indicating to the practitioner at which point adequate gas exchange has been achieved. This approach has been recently described in animal models and term and preterm infants.15–22 Hooper et al recently reported in animal models that monitoring ECO2 during PPV identifies lung aeration.15 Finer et al described the use of colorimetric CO2 detectors to assess airway obstruction,16 which has been also recommended in the neonatal resuscitation guidelines.1 In spontaneously breathing preterm and term infants, several studies reported an ECO2 level of approximately 20 mm Hg at 1 min after birth, which continuous to rise over the next minutes.17 19 20 22 Using ECO2 to guide either peak inflation pressure (PIP) during PPV or PIP and duration during SI potentially improves respiratory outcomes in preterm infants.
The aim of our study was to examine whether SI guided by ECO2 will improve lung aeration and therefore decreases BPD. We hypothesised that preterm infants <33 weeks gestation who require breathing support at birth receiving SI (SI group) guided by ECO2 will have less incidence of BPD compared with PPV guided by ECO2 (PPV group).
Methods
This study was carried out at the Royal Alexandra Hospital (RAH), Edmonton, a tertiary perinatal centre admitting approximately 360 infants born at <33 weeks gestational age annually. The RAH Research Committee and Health Ethics Research Board, University of Alberta (Pro00034524) approved the study and the trial was registered at Clinicaltrials.gov NCT01739114. Between June 2013 and August 2014, deliveries of infants <33 weeks gestation were attended by the research team in addition to the Neonatal Resuscitation–Stabilization–Triage team (RST team) (usually a nurse, respiratory therapist, nurse practitioner and fellow and/or consultant). The research team was not involved in the clinical care of the infants.
Entry criteria
Inborn infants between 23+0 and 32+6 weeks postmenstrual age who were judged clinically to need PPV for respiratory support in the first minutes after birth.
Exclusion criteria
Infants with antenatal know congenital abnormality or condition that might have an adverse effect on breathing or ventilation (eg, congenital diaphragmatic hernia or congenital heart disease). Infants were also excluded if their parents declined to give consent to this study. In addition, if postnatal congenital abnormality or condition that might have an adverse effect on breathing or ventilation were diagnosed, these infants were excluded from the analysis (one infant was excluded with lethal respiratory congenital abnormality).
Consent
Prior to the study, both PPV and SI were routinely used during initial respiratory support in the DR. As both interventions as well as respiratory function monitoring were routinely used in the DR at the RAH, the Health Ethics Research Board, University of Alberta granted deferred consent. Written consent was sought from the parents of these infants as soon as possible after birth so acquired data could be used for research.23
Randomisation
A computer-generated randomisation scheme was used to assign the infants to treatment groups in a 1:1 ratio. Randomisation was stratified according to the gestational age (to infants 23+0 to 27+6 and 28+0 to 32+6 weeks). Infants were randomly allocated to either SI (SI group) or PPV (PPV group). A sequentially numbered, brown, sealed envelope contained a folded card box with the treatment allocation was opened by the clinical team immediately before delivery. The folded card box allocated contained the unique trial number with the treatment allocation SI group or PPV group. Twins and/or triplets were randomised as individuals.
Blinding
In the DR, there was no blinding of the RST team, as it would not be feasible to conduct a study with the delivery of different techniques of PPV without the team knowing the actual intervention. However, after admission the clinical team was not made aware of the treatment allocation. In addition, data collector and outcome assessor were both unaware of group allocation.
Data safety monitoring committee
An external safety monitoring committee reviewed the study data after 25%, 50% and 75% enrolment and recommended continuation of the trial.
Description of interventions
Intervention in both groups
One member of the RST team acted as the team leader. The team leader’s responsibilities were protocol management, guiding the intervention and observation of changes in ECO2 to adjust the delivered airway pressure and determine the length of the second SI (figure 1). All other resuscitative measures (eg, use of supplemental oxygen) were at the discretion of the clinical team guided by the team leader, following the 2010 guidelines for neonatal resuscitation.24 Resuscitation was started with air for infants >29 weeks and with 30% oxygen for infants <29 weeks gestation according to our institutional guidelines. Respiratory support was performed using appropriate size round silicone face masks (Fisher & Paykel Healthcare, Auckland, New Zealand or Laerdal, Stavanger, Norway) and a T-piece device (Giraffe Warmer;GE Health Care, Burnaby, Canada), a continuous flow, pressure-limited device with a built-in manometer and a PEEP valve. During PPV and SI, the default settings were gas flow of 8 L/min, PIP of 24 cmH2O and PEEP of 6 cmH2O. Staff members attending deliveries were trained to use the device and were familiar with both face masks.23 During PPV, respiratory rate was aimed at 40–60/min. In infants initially supported with continuous positive airway pressure (CPAP) the default pressure was a PEEP of 6 cmH2O. The clinical team was able to adjust PEEP between 6 and 8 cmH2O.
Study flow chart. NRP, Neonatal Resuscitation Program; PIP, peak inflation pressure; PPV, positive pressure ventilation; SI, sustained inflation.
DR intubation criteria were defined a priori as (1) heart rate <100/min despite adequate PPV for 60 s; (2) heart rate <60/min despite adequate PPV for 30 s (in which case chest compressions and 100% oxygen would be indicated); (3) persistent or significant apnoea requiring ongoing PPV for more than 10 min or (4) sustained fraction of inspired oxygen >40% despite PEEP of 8 cmH2O or more after 10 min of birth (criteria to administer surfactant).
Intubation criteria (A), surfactant administration (B), mechanical ventilation (C) and extubation criteria (D) were defined according to our current neonatal intensive care unit (NICU) hospital policy: (A) Intubation criteria:(1) sustained fraction of inspired oxygen >40% on maximal non-invasive respiratory support, (2)more than six apnoeas requiring stimulation over a period of 6 hours or (3) one apnoea requiring mask ventilation. (B) Surfactant administration (BLES, BLES Biochemicals at 5 mg/kg) as rescue treatment when fraction of inspired oxygen >40%. (C) Modes of mechanical ventilation were either assist control + volume guarantee or pressure support ventilation + volume guarantee. (D) Extubation was possible when they meet all of the following criteria: (1) rate on ventilator ≤40/min, (2) mean airway pressure ≤10 cmH2O and (3) fraction of inspired oxygen ≤30%.
SI group—intervention
Infants randomised into the SI group received an initial SI with PIP of 24 cmH2O over a period of 20 s. The second SI was guided by the amount of ECO2.15 If ECO2 was ≤20 mm Hg, a second SI of 20 s was delivered. However, if ECO2 was >20 mm Hg the second SI was 10 s. The ECO2 cut-off of >20 mm Hg was based on previous studies in premature and term infants, which reported an ECO2 level of approximately 20 mm Hg after 10–20 breaths.17 19 20 22 After the two SIs infants either received CPAP if adequate spontaneous breathing or if found to have apnoea or laboured breathing, PPV at a rate of 40–60/min (figure 1). In cases where infants started breathing during a SI, the SI was continued (eg, 20 s of the first SI) until assessment. Once infants were breathing spontaneously, infants were transitioned to CPAP.
PPV group intervention
Infants randomised into the PPV group received mask PPV with a ventilation rate of 40–60/min (figure 1). Once infants were breathing spontaneously, infants were transitioned to CPAP.
Monitoring systems
A respiratory profile monitor (NM3; Philips Healthcare, Electronics, Markham, Ontario, Canada) was used to continuously measure VT, airway pressures, gas flow and ECO2. Airway pressure and gas flow are measured using fixed orifice differential pressure pneumotachometer. VT was calculated by integrating the flow signal. ECO2 was measured using non-dispersive infrared absorption technique. According to the manufacturer, the accuracy for the gas flow is ±0.125 L/min and for ECO2±2 mm Hg.18
Sample size and power estimates
Our primary outcome measure was reduction in BPD defined as the need for respiratory support or supplemental oxygen at the corrected gestational age of 36 weeks.25 We hypothesised that the rate of BPD would be reduced in the SI group. A sample size of 93 (in each group) would be sufficient to detect a 40% absolute rate reduction in BPD which we considered clinically important, for example, 50% versus 30%, with 80% power and a two-tailed alpha error of 0.05. The incidence of BPD in this population at our institute at the time of trial design was 49%.
Data collection and statistical analysis
All variables were stored continuously using ‘alpha-trace digital MM’ (B.E.S.T. Medical Systems, Vienna, Austria) for subsequent analysis. Values of gas flow, VT, airway pressure and ECO2 were recorded at 200 Hz. An analysis of each SI and inflations during PPV (VT, ECO2) was performed manually for the first 60 s. All patient information were entered into a database for analysis. Secondary clinical outcomes included rate of endotracheal intubation in the DR or the NICU, duration of mechanical ventilation and non-invasive ventilation, neonatal death, air leak, patent ductus arteriosus (PDA) (medical or surgical), necrotising enterocolitis, retinopathy of prematurity, periventricular leukomalacia, abnormal cranial ultrasound (including intraventricular haemorrhage, parenchymal injury and ventriculomegaly (IVH)), air leak, surfactant administration, postnatal steroids, respiratory support or oxygen requirements at 28 days and neonatal death before discharge. The data were presented as means (±SD) for normally distributed continuous variables and as medians (IQR) when the distribution is skewed. All infants were analysed according to their group at randomisation (ie, analysis was by intention-to-treat). However, our protocol stated that randomisation will occur prior delivery, which has also been performed in previous trials.14 23 26 27 Therefore, we excluded any infants from final analysis who did not receive the intervention. The clinical characteristics and outcome parameters were compared using Student’s t-test for parametric and Mann-Whitney U test for non-parametric comparisons for continuous variables and χ2 for categorical variables. In addition, we compared the two intervention groups with the CPAP group using one-way ANOVA and two-way repeated measures ANOVA with Bonferroni post hoc analysis as appropriate. p Values were two sided and p<0.05 was considered statistically significant. Statistical analysis was performed with Stata (Intercooled 10).
Results
During the study period, a total of 249 deliveries (SI=125, PPV=120) were randomised (figure 2). Postrandomisation exclusions are presented in figure 2. Postrandomisation excluded 83 infants (SI=38 and PPV=22), which did not receive any intervention (figure 2), and further 11 in the SI group and 12 in the PPV group for various reasons presented in figure 2. Overall, 162 infants (76 and 86 in SI and PPV groups, respectively) were studied (figure 2). After stratification, the SI group had 32 infants between 23+0 to 27+6 and 44 infants at 28+0 to 32+6 weeks versus 40 infants between 23+0 to 27+6 and 46 infants at 28+0 to 32+6 weeks in the PPV group (p=0.537). Demographics were presented in table 1. There was no significant difference between the two intervention groups. There was no difference between median (IQR) years of RST team leader experience between groups with 11 (6–13) years in the SI and 11 (7–13) in the PPV group. DR outcomes were similar between both groups (table 2). In particular, no infant was intubated prior the first or second SI (table 2).
Patient flow chart. PPV, positive pressure ventilation; SI, sustained inflation.
Demographics of included infants
Delivery room outcomes
A total of 57 (78%) infants received two SI of 20 s each, 11 (15%) infants received one SI with 20 s and 1 SI with 10 s and 5 (7%) infants received only one SI with 20 s.
Primary outcomes
There was no statistical difference in the rate of BPD between the groups. The need of respiratory support or oxygen dependency at 36 weeks corrected gestational age in the SI group compared with the PPV group was 23% versus 33%, respectively (p=0.090) (table 3).
Outcomes in the NICU (until discharge)
Overall, there was no difference in death before discharge between the groups 5 (7%) in the SI group and 5 (6%) in the PPV group (p=0.840) (table 3).
Secondary clinical outcomes
Overall, hours of mechanical ventilation were significantly reduced in the SI group (table 3). No difference between incidence of PDA, necrotising enterocolitis, retinopathy of prematurity, IVH between, pneumothoraxes, intubation and/or surfactant administration in the NICU or treatment with postnatal steroids was observed (table 3).
Tidal volume and ECO2
ECO2 after the first SI increased more rapidly compared with 20 s of PPV (average rate of rise in mm Hg/s is 0.68 vs 0.49 in SI and PPV, respectively, p value <0.05). A further increase in ECO2 was observed in both groups, although the increase was slightly higher in the SI group (figure 3). Further, ECO2 values after 20 s and 40 s were significantly higher in the SI group versus the PPV group (after the first SI 14 vs10 mm Hg (p=0.04) and after the second SI 17 vs 12 mm Hg (p=0.01)). ECO2 in the SI group continued to increase suggesting better lung aeration at 60 s compared with PPV alone (figure 3).
ECO2 during SI, PPV and CPAP within the first 60 s of respiratory support. CPAP, continuous positive airway pressure; ECO2, exhaled carbon dioxide; PPV, positive pressure ventilation; SI, sustained inflation.
Discussion
This is the first randomised trial using ECO2 guidance during SI with PPV to guide respiratory support in the DR. We found no statistically significant difference between both groups in any DR or NICU outcomes. Further, no short-term or long-term harmful effects were identified from two SI lasting up to 40 s in the first minutes after birth. A previous randomised trial reported a significant reduction in moderate–serve BPD.11 The study by te Pas et al included several elements, of which the use of an SI was one. Other randomised trials, a recent meta-analysis, and a Cochrane review were unable to demonstrate a reduction in BPD with SI.10 12 13 28
Previous SI trials used a pressure-dependent approach by choosing SI with set PIPs or increasing PIPs with the second or third sustained inflation.10 28 Although these trials reported a reduction in short-term outcomes (eg, days on ventilator or less intubation within the first 72 hours after birth), neither reported differences in long-term outcomes. In the current trial, we opted to examine a time-dependent lung inflation strategy using an initial SI of 20 s. The second SI was dependent on the amount of ECO2 and lasted between 10 and 20 s. Our approach is more in line with the recent animal studies by te Pas et al5 29 which reported a minimal duration of 20 s for a SI manoeuvre to achieve complete lung aeration. We used ECO2 to assess if we achieved lung aeration. This has been recently described to be a useful tool to assess lung aeration in real time during respiratory support.15 17 18 21 30–33 A recent trial compared continuous quantitative end-tidal CO2 monitoring with clinical assessment during mask PPV in the DR.33 Infants randomised to the intervention group used end-tidal CO2 monitoring to adjust PPV based on end-tidal CO2 values. In contrast, clinical assessment was used to adjust PPV in the control arm. No difference in end-tidal CO2 levels at the end of resuscitation was found between the groups. In the current study, ECO2 monitoring was used to target duration of SI during PPV. Overall, the increase in ECO2 was moderate within the first 60 s after birth and lower compared with infants breathing spontaneously and being supported with CPAP (figure 3). This is similar to a previous report from our group demonstrating that infants who breathe spontaneously achieve lung aeration more efficiently.17 20 Our study further supports the available evidence that ECO2 can be used to guide respiratory support in the DR.
A recent study by Lista et al reported a trend to increased incidence of pneumothoraxes in infants randomised to SI compared with PPV (6% vs 1%),10 which was not observed in our study (table 3). In the current study, we delivered SI or PPV only to infants who needed respiratory support, which is different to the study by Lista et al who delivered SI or PPV even to infants spontaneously breathing.10 In addition, our gestational age range was broader and the SI procedure was different. However, our data would support that SI appears to be saved and do not increase the risk for pneumothorax.
A recent meta-analysis comparing SI versus PPV reported an increased incidence of PDA in infants receiving SI, with a number needed to harm of 10.34 We did not find any difference in the PDA rates between the two groups (table 3). The same meta-analysis also reported a higher incidence of IVH in infants receiving SI.34 Once again, our study found no difference for this outcome (table 3). Overall, there was apparent lack of harm from SI when compared with PPV in our study, which suggests safety of SI for further randomised control trials.
Strengths
Using deferred consent allowed us to enrol any potential infant, including those with high obstetric risk, urgent delivery and inadequate antenatal steroid therapy (table 1). The deferral of consent facilitated inclusion of the most acutely ill babies who may benefit most from effective lung recruitment interventions, whether PPV or SI. In addition, we were fortunate to have a trained and experienced team leader present during resuscitation, which enabled guidance of the procedures during resuscitation and adherence to both study protocol and clinical guidelines.
Limitations
The sample size of the study was calculated based on a 50% risk of the BPD in the control group, however, the observed rate (33%) in the whole study group was much lower that this estimate. Thus, the study was underpowered to detect the desired effect size. Postrandomisation exclusion resulted in less infants per group then the estimated sample size, which is a limitation of the study. Postrandomisation exclusion (27%) resulted in a lower number of included infants in the SI group and failure to achieve the number of babies required by the power analysis. Although not statistically significant, this discrepancy might have yielded different results. The timing of randomisation resulted in many postrandomisation exclusions with the potential of inadequate allocation concealment, as there were more postrandomisation exclusions in the SI treatment arm than PPV arm.
Most infants in the study (57/68, 84%) required a second SI of 20 s to achieve some lung aeration, suggesting that perhaps the ECO2 values might has limited value above standard clinical assessment. However, we believe that ECO2 has value to guide lengths or pressure needed of an SI.17 18 35
Conclusion
Using SI guided by ECO2 had similar incidence of BPD when compared with PPV. Using ECO2 to guide length of SI is feasible but requires further studies to confirm efficacy and safety of this approach. No short-term harmful effects were identified from two sustained inflations lasting up to 40 s in the first minute after birth.
Acknowledgments
We thank the parents and infants agreeing to be part of the study. We also thank the RST team at the Royal Alexandra Hospital for helping and supporting the study and the public for donating money to funding agencies who supported the study.
References
Footnotes
Contributors GMS and AYN had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Conception and design: GMS, KA, SvO, MOR, P-YC, MK. Collection and assembly of data: AYN, GMS, SvO, KA, AH-M, MOR, P-YC. Analysis and interpretation of the data: AYN, GMS, SvO, KA, AH-M, MOR, P-YC. Drafting of the article: AYN, GMS, KA, MOR, P-YC, SvO, AH-M. Critical revision of the article for important intellectual content: GMS, KA, MOR, AH-M, P-YC, SvO, AYN, MK. Final approval of the article: GMS, AYN, KA, MOR, P-YC, SvO, AH-M, MK.
Funding The study was supported by a Seed Funding Grant of the Department ofPediatrics, University of Alberta, Edmonton, Canada, and a Canadian RespiratoryHealth Professionals (CRHP) Grant, The Lung Association, Canada. MOR was supported by a Fellowship of the Molly Towell PerinatalFoundation. GMS is a recipient of the Heart and Stroke Foundation/University ofAlberta Professorship of Neonatal Resuscitation and a Heart and StrokeScholarship. No financial relationships with any organizations that might have aninterest in the submitted work in the previous 3 years; no other relationshipsor activities that could appear to have influenced the submitted work.
Competing interests None declared.
Patient consent Parental consent obtained.
Ethics approval The RAH Research Committee and Health Ethics Research Board, University of Alberta (Pro00034524).
Provenance and peer review Not commissioned; externally peer reviewed.
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