Improving Newborn Respiratory Outcomes With a Sustained Inflation: A Systematic Narrative Review of Factors Regulating Outcome in Animal and Clinical Studies

Abstract

Respiratory support is critically important for survival of newborns who fail to breathe spontaneously at birth. Although there is no internationally accepted definition of a sustained inflation (SI), it has commonly been defined as a positive pressure inflation designed to establish functional residual capacity and applied over a longer time period than normally used in standard respiratory support (SRS). Outcomes vary distinctly between studies and to date there has been no comprehensive investigation of differences in SI approach and study outcome in both pre-clinical and clinical studies. A systematic literature search was performed and, after screening, identified 17 animal studies and 17 clinical studies evaluating use of a SI in newborns compared to SRS during neonatal resuscitation. Study demographics including gestational age, SI parameters (length, repetitions, pressure, method of delivery) and study outcomes were compared. Animal studies provide mechanistic understanding of a SI on the physiology underpinning the cardiorespiratory transition at birth. In clinical studies, there is considerable difference in study quality, delivery of SIs (number, pressure, length) and timing of primary outcome evaluation which limits direct comparison between studies. The largest difference is method of delivery, where the role of a SI has been observed in intubated animals, as the inflation pressure is directly applied to the lung, bypassing the obstructed upper airway in an apnoeic state. This highlights a potential limitation in clinical use of a SI applied non-invasively. Further research is required to identify if a SI may have greater benefits in subpopulations of newborns.

Keywords: animal models; cardiorespiratory function; clinical trials; newborn respiratory outcome; resuscitation and respiratory support; sustained inflation; ventilation.

Figure 1

Summary of literature search and selection of studies included in the current synthesis of studies in animal and clinical literature evaluating the use of a sustained inflation on newborn cardiorespiratory outcome.

Figure 2

Forest plot of odds ratio and 95% confidence intervals for risk of endotracheal intubation following sustained inflation compared to standard respiratory support in clinical studies evaluated in Table 2. The timing taken into account for need for endotracheal intubation is noted for each individual study in Figure 3 except Kirpalani et al. at which is listed at 48 h following birth for consistency with other studies. Relative risk and confidence interval values were extracted from the 2020 Cochrane review where possible (45), or manually calculated (–33, 40, 41, 44). Diamonds indicate RCTs and triangles indicate non-RCT study designs. Black indicates data sets resulting in significant differences and light gray indicates data sets reporting no significant difference in risk of intubation between the sustained inflation and relative control group within individual studies.

Figure 3

Forest plot of relative risk and 95% confidence intervals for primary outcomes reported in clinical studies evaluated in Table 2. The individual studies have been ranked based on timing of primary outcome evaluation. Relative risk and confidence interval values were extracted from the 2020 Cochrane review where possible (45) or manually calculated (, –33, 40, 41, 44). Diamonds indicate RCTs and triangles indicate non-RCT study designs. Black indicates data sets resulting in significant differences and light gray indicates data sets reporting no significant difference in risk of primary outcome in SI compared to SRS. Where the primary outcome was a continuous variable, relative risk was unable to be calculated and a value has not been reported.

Figure 4

SI and subsequent respiratory ventilation protocols for the included studies (A) and SRS ventilation protocols (B). The length of the line indicates the length of the SI and the thickness of the line indicates the pressure (1 cm = 0–5 s, 2 cm = 6–10 s, 4 cm = 11–15 s, 6 cm = 16–20 s; 1 pt = 15 cmH₂O, 6 pt = 20 cmH₂O, 14 pt = 25 cmH₂O, 26 pt = 30 cmH₂O). Where multiple SIs of the same pressure were given, vertical black lines separate each SI. Black lines indicate where the SI was only given to babies noted to have insufficient respiratory effort at birth. Gray lines indicate where SI was given to all babies regardless of whether insufficient respiratory effort was noted. Following SIs, dotted lines indicate continuous positive airway pressure was used, wavy lines indicate that intermittent positive pressure ventilation was used, dashed wavy lines indicate that intermittent positive pressure ventilation was delivered via bag-mask and so it was impossible to provide PEEP. To aid interpretation of the graph, neonates who did not respond to SI and subsequent continuous positive airway pressure or intermittent positive pressure ventilation have not been included as all studies further resuscitated and intubated neonates for intermittent mechanical ventilation as required. For Harling et al. the black line indicates a 2 s inflation. For te Pas et al. PEEP was not commenced in the control group until arrival in the neonatal intensive care unit (NICU) whilst PEEP was used throughout in the SI group. For Ngan et al. subsequent to the 1st SI, the length of the second SI was determined end tidal CO₂. For El Fattah et al. four SI groups were included with various lengths and pressures of the SIs as per the graph. For Hunt and Kanaan et al. the black boxes indicate 5 × 2–3 second inflations. For Kanaan et al. ventilation protocol following SI and 5 × 3 s inflations are unclear, but it is noted that neonates were transferred to the NICU on either CPAP or NIV, so CPAP has been used in the graphs.