Sustained inflations versus UK standard inflations during initial resuscitation of prematurely born infants in the delivery room: a study protocol for a randomised controlled trial

Seventy-five percent of infants born at < 34 weeks of gestational age require resuscitation including positive pressure ventilation and/or endotracheal intubation at delivery [1]. Current UK guidelines recommend initial resuscitation using five inflations of 2–3 s duration with peak inflation pressures of 20–25 cmH₂O [2]. It has been shown, however, that despite resuscitation training, clinicians in both simulated and real resuscitation scenarios do not deliver the recommended duration of the inflations [3, 4]. This, combined with leaks around the facemask often as large as 50% or greater, contributes to low expired tidal volumes during resuscitation [5]. Indeed, during resuscitation by facemask or endotracheal tube, tidal volumes and end tidal carbon dioxide (ETCO₂) levels remained low until a respiratory effort was made coinciding with a mechanical inflation (an active inflation) [3, 6]. Analysis of data collected during the resuscitation of infants born at < 34 weeks of gestational age who received inflations of 1–3 s in duration demonstrated that active inflations occurred sooner with longer inflation times [7].

There is evidence that sustained inflations (≥5 s) may be of benefit. In preterm rabbits, a sustained inflation of 20 s compared to a shorter inflation or no inflation before mechanical ventilation was commenced was associated with a more rapid establishment of a functional residual capacity; 90% of lung aeration was achieved within the first 14 s [8, 9]. Preterm lambs who received a 60-s sustained inflation followed by mechanical ventilation compared to those who received ventilation alone (tidal volumes of 7 mL/kg delivered at a rate of 60 bpm) had increased pulmonary blood flow, more stable cerebral oxygen delivery and better compliance during subsequent ventilation [10]. Comparison of five repeated 3-s inflations to a 20-s sustained inflation in asphyxiated lambs delivered near term showed that the sustained inflation provoked an earlier rise in heart rate, improved gas exchange and improved lung compliance during subsequent ventilation [11]. Another study in lambs, however, showed that a 30-s sustained inflation compared to no sustained inflation led to more cerebral vascular leakage and potential perturbation of blood–brain barrier function [12]. In all of the above studies, the lambs were sedated during resuscitation, whereas infants are not and indeed their respiratory efforts can make an important contribution to gas exchange [3, 6].

There have been several studies of sustained inflations in infants. Early studies in term infants born after elective Caesarean section demonstrated that a 5-s inflation produced a larger inflation volume than a 1-s inflation and also was more efficient at establishing a functional residual capacity [13, 14]. A study of infants born at < 32 weeks of gestational age demonstrated that those who were resuscitated with a sustained inflation compared to a historical cohort resuscitated without a sustained inflation were less likely to be intubated (51% vs 76%, p < 0.0001) and had lower durations of mechanical ventilation (5 vs 11 days, p < 0.008) and supplementary oxygen therapy (21 vs 31 days, p = 0.016) [15]. They were also less likely to receive postnatal steroids (25% vs 10%, p = 0.01) and had a lower incidence of bronchopulmonary dysplasia (BPD) (7% vs 25%, p = 0.04) [15]. Another study compared infants born at < 34 weeks of gestational age who received a 15-s sustained inflation to a historical cohort who received recurrent inflations at 60 breaths per minute. The sustained inflation group had a lower need for intubation (6% vs 21%, p < 0.01) and a shorter duration of ventilation (9.1 vs 13.8 days, p < 0.001) [16]. The findings of both studies [15, 16], however, should be interpreted with caution as other changes in perinatal care may have influenced the outcomes. In infants born at 25–33 weeks, a 10-s sustained inflation delivered via a nasopharyngeal tube compared to ventilation with initial inflation pressures of 30–40 cmH₂O, then 20 cmH₂O, at a rate of 60 bpm via a bag-mask device, was associated with a lower need for endotracheal intubation and mechanical ventilation, a shorter duration of total respiratory support and a lower rate of BPD. There were, however, limitations to the study, as the ‘ventilation’ group did not receive positive end expiratory pressure (PEEP) during resuscitation and were intubated and ventilated after 30 s of mask ventilation if unstable, whereas the sustained inflation group subsequently received nasal continuous positive airways pressure (CPAP) or several minutes of nasal ventilation as part of stabilization [17]. A randomised trial comparing a 15-s sustained inflation to resuscitation with inflations at 60 breaths per minute both delivered by nasopharyngeal tube, did not demonstrate significant differences in the need for mechanical ventilation. The trial, however, was stopped early due to slow recruitment [18]. In a subsequent randomised trial enrolling infants born at 25–29 weeks of gestational age, a 15-s sustained inflation followed by nasal CPAP was compared to nasal CPAP alone. A smaller proportion of the sustained inflation group required mechanical ventilation in the first 72 h after birth (53% vs 65%, p = 0.04) [19]. A further randomised trial enrolled infants born at 25–32 weeks of gestational age and randomised them to either a 15-s inflation at 25 cmH₂O or resuscitation as per the American Heart Association guidelines (positive pressure ventilation at 15–20/5 cmH₂O). A lower inspired oxygen concentration (FiO₂) 10 min after delivery was demonstrated in the sustained inflation group (0.28 vs 0.47) (p < 0.01). Among those born < 28 weeks of gestational age, there was a lower need for intubation in the group that received a sustained inflation (29% vs 63%, p = 0.05), but this was not a pre-specified analysis [20]. In contrast to those promising results in moderately or extremely prematurely born infants, in infants born at 34–36 weeks of gestational age there were no significant differences in the need for respiratory support, the incidence of neonatal intensive care unit (NICU) admission for respiratory distress or the total length of NICU stay between infants who received a 15-s sustained inflation and those who received standard resuscitation according to the American Association of Pediatrics guidelines (drying, stimulation and, if inadequate respiratory effort or a heart rate < 100 bpm, positive pressure ventilation at 40–60 inflations per minute) [21].

There have been concerns raised regarding potential adverse effects of sustained inflations, in particular relating to air leak, intraventricular haemorrhage (IVH) and patent ductus arteriosus [22, 23]. Non-significant increases in IVH in infants born at < 28 weeks of gestational age [16] and non-significant increases in pneumothorax in infants born at < 34 weeks of gestational age have been reported in those exposed to sustained inflations [19]. A meta-analysis of four small trials [24], however, showed no significant differences in rates of pneumothorax or of IVH. A subsequent study of prematurely born infants showed a non-significant decrease in pneumothorax with a 15-s sustained inflation compared to ventilation with a self-inflating bag [25]. The peak inspiratory pressures, however, used in the bag-mask ventilation were up to 40 cmH₂O, whereas those used in the sustained inflation group were 30 cmH₂O [25]. The meta-analysis [24] also reported that in the sustained inflation group there was a higher proportion of infants who required treatment (medical or surgical) for a patent ductus arteriosus (relative risk = 1.27 [95% confidence interval = 1.05–1.54]). Cerebral blood flow, as assessed by near-infrared spectroscopy, however, was more stable in preterm infants resuscitated with a sustained inflation compared to in those who were resuscitated without a sustained inflation [26‐28]. In addition, in prematurely born infants, a 5-s inflation compared to a 2-s inflation was not associated with higher levels of inflammatory cytokines (IL-6, IL-10, IL-1β, and TNF-α) in bronchoalveolar fluid [29].

Resuscitation guidelines from the USA, UK and Europe suggest that sustained inflations should be researched further [30, 31]. To date, there are no studies comparing sustained inflations to the current UK practice of the first five inflations lasting 2–3 s. In addition, there has only been one study in which a respiratory function monitor was used to assess the physiological effects of a sustained inflation. Sustained inflations were shown not to be effective in producing tidal volumes > 2.5 mL/kg or generating a functional residual capacity unless there was spontaneous respiratory effort during the inflation, but there was no comparison to other methods of resuscitation [32]. The aim of this study, therefore, is to determine whether a 15-s sustained inflation or five inflations each of 2–3 s duration is more effective at stimulating respiratory efforts in prematurely born infants. The primary outcome is the minute volume in the first minute of resuscitation and the secondary outcomes are the time to the first active inflation (inspiration occurring during an inflation) and end tidal carbon dioxide (ETCO₂) levels in the first minute.