Non-invasive versus invasive respiratory support in preterm infants at birth: systematic review and meta-analysis

ObjectivesThere is a tendency to use noninvasive ventilation (NIV) as a substitute for mechanical ventilation in preterm infants who need respiratory support. Two important modes of NIV include nasal continuous positive airway pressure (NCPAP) and nasal intermittent positive pressure ventilation (NIPPV). We sought to compare the efficacy of NCPAP and NIPPV as early respiratory support in preterm infants with respiratory distress syndrome in reducing the need for intubation, surfactant administration, and mechanical ventilation.MethodsWe conducted a randomized clinical trial. Sixty-one preterm infants with a gestational age of 28–32 weeks and a birth weight < 1500 g were randomly allocated to early NCPAP (n = 31) or NIPPV (n = 30) groups. The primary outcome was the need for intubation and mechanical ventilation in first 72 hours of life and the secondary outcome was oxygen dependency beyond day 28 post-birth.ResultsSurfactant replacement therapy was done in 15 neonates (50.0%) in the NIPPV group and 19 neonates (61.3%) in the NCPAP group, odds ratio (OR) = 1.58 (95% confidence interval (CI): 0.57–4.37; p = 0.370). Intubation and mechanical ventilation in the first 72 hours of life were needed in five cases (16.7%) in the NIPPV group and two cases (6.5%) in the NCPAP group, OR = 2.90 (95% CI: 0.51–16.27; p = 0.250). The mean duration of hospitalization was 26.2±17.4 days in the NIPPV group and 38.4±19.2 days in the NCPAP group, p = 0.009. Bronchopulmonary dysplasia (BPD) occurred in two (6.7%) neonates in the NIPPV group and eight (25.8%) neonates in the NCPAP group, p = 0.080.ConclusionsNIPPV and NCPAP are similarly effective as initial respiratory support in preterm infants in reducing the need for mechanical ventilation and occurrence of BPD. The duration of hospitalization was significantly reduced using NIPPV in our study.KeywordsNasal Continuous Positive Airway Pressure; Preterm Infants; Mechanical Ventilation; Bronchopulmonary Dysplasia; Respiratory Distress Syndrome, Newborn.

The use of nHF for primary respiratory support in preterm infants of 28 weeks' gestation or greater may result in little to no difference in death or BPD, compared with CPAP or NIPPV. nHF likely results in an increase in treatment failure within 72 hours of trial entry compared with CPAP; however, it likely does not increase the rate of mechanical ventilation. Compared with CPAP, nHF use likely results in less nasal trauma and likely a reduction in pneumothorax. As few extremely preterm infants less than 28 weeks' gestation were enrolled in the included trials, evidence is lacking for the use of nHF for primary respiratory support in this population.

Noninvasive Ventilation and Exogenous Surfactant in Times of Ever Decreasing Gestational Age: How Do We Make the Most of These Tools?

Background:: There is a growing trend toward avoidance of intubation and mechanical ventilation for preterm neonates. Noninvasive ventilation can be provided by a variety of ways including nasal cannula. Objectives:: This study was conducted to compare the efficacy and safety of Humidified high Flow Nasal Cannula (HFNC) and nasal CPAP for respiratory support after surfactant administration in preterm newborn infants with respiratory distress syndrome. Patients and Methods:: In this randomized controlled clinical trial, 85 preterm newborn infants with birth weight of 1250 - 2000 grams and gestational age of 30 - 34 weeks who received surfactant replacement therapy were enrolled. Patients were randomly allocated in two groups; NCPAP group (43 neonates) and HFNC group (42 neonates). Results:: The mean gestational age of patients was 32.07 ± 1.48 weeks in NCPAP and 32.24 ± 1.7 weeks in HFNC group and their birth weight was 1885 ± 417 and 1905 ± 464 grams in NCPAP and HFNC groups, respectively. Demographic characteristics of patients were similar in the both groups. Although the rate of re-intubation, pneumothorax, intra-ventricular hemorrhage and bronchopulmonary dysplasia were higher in NCPAP group, the differences were not statistically significant. Nasal mucosa injury was determined in 27 (62.8%) neonates in NCPAP group and 14 (33.3%) infants in HFNC group (P = 0.007). Conclusions:: In our study, HFNC was as effective as NCPAP for respiratory support in preterm infants after surfactant administration and extubation. Nasal mucosal injury rate was lower in HFNC group. It is recommended to perform future studies with larger number of patients before routine use of HFNC in post extubated preterm infants.

For preterm and very preterm infants, there is insufficient evidence to evaluate prophylactic CPAP compared to oxygen therapy and other supportive care. When compared to mechanical ventilation, prophylactic nasal CPAP in very preterm infants reduces the incidence of BPD, the combined outcome of death and BPD, and mechanical ventilation. There is probably no difference in neurodevelopmental impairment at 18 to 22 months of age. When prophylactic CPAP is compared to early CPAP, we are very uncertain about whether there is any difference between prophylactic and very early CPAP. There is no information about the effect of prophylactic or very early CPAP in late preterm infants. There is one study awaiting classification.

Eleven trials met inclusion criteria of the review. Four trials were parallel-group RCTs reporting our prespecified primary or secondary outcomes. Two trials randomized 316 infants to low versus moderate-high nasal CPAP for initial respiratory support, and two trials randomized 117 infants to low versus moderate-high nasal CPAP following endotracheal extubation. The remaining seven studies were cross-over trials reporting short-term physiological outcomes. The most common potential sources of bias were absent or unclear blinding of personnel and assessors and uncertain selective reporting. Nasal CPAP for initial respiratory support after birth and neonatal resuscitation None of the six primary outcomes prespecified for inclusion in the summary of findings was eligible for meta-analysis. No trials reported on moderate-severe neurodevelopmental impairment at 18 to 26 months. The remaining five outcomes were reported in a single trial. On the basis of this trial, we are uncertain whether low or moderate-high nasal CPAP levels improve the outcomes of: death or bronchopulmonary dysplasia (BPD) at 36 weeks' postmenstrual age (PMA) (risk ratio (RR) 1.02, 95% confidence interval (CI) 0.56 to 1.85; 1 trial, 271 participants); mortality by hospital discharge (RR 1.04, 95% CI 0.51 to 2.12; 1 trial, 271 participants); BPD at 28 days of age (RR 1.10, 95% CI 0.56 to 2.17; 1 trial, 271 participants); BPD at 36 weeks' PMA (RR 0.80, 95% CI 0.25 to 2.57; 1 trial, 271 participants), and treatment failure or need for mechanical ventilation (RR 1.00, 95% CI 0.63 to 1.57; 1 trial, 271 participants). We assessed the certainty of the evidence as very low for all five outcomes due to risk of bias, a lack of consistency across multiple studies, and imprecise effect estimates. Nasal CPAP following mechanical ventilation and endotracheal extubation One of the six primary outcomes prespecified for inclusion in the summary of findings was eligible for meta-analysis. On the basis of these data, we are uncertain whether low or moderate-high nasal CPAP levels improve the outcome of treatment failure or need for mechanical ventilation (RR 1.52, 95% CI 0.92 to 2.50; 2 trials, 117 participants; I² = 17%; risk difference 0.15, 95% CI -0.02 to 0.32; number needed to treat for an additional beneficial outcome 7, 95% CI -50 to 3). We assessed the certainty of the evidence as very low due to risk of bias, inconsistency across the studies, and imprecise effect estimates. No trials reported on moderate-severe neurodevelopmental impairment at 18 to 26 months or BPD at 28 days of age. The remaining three outcomes were reported in a single trial. On the basis of this trial, we are uncertain whether low or moderate-high nasal CPAP levels improve the outcomes of: death or BPD at 36 weeks' PMA (RR 0.87, 95% CI 0.51 to 1.49; 1 trial, 93 participants); mortality by hospital discharge (RR 2.94, 95% CI 0.12 to 70.30; 1 trial, 93 participants), and BPD at 36 weeks' PMA (RR 0.87, 95% CI 0.51 to 1.49; 1 trial, 93 participants). We assessed the certainty of the evidence as very low for all three outcomes due to risk of bias, a lack of consistency across multiple studies, and imprecise effect estimates. AUTHORS' CONCLUSIONS: There are insufficient data from randomized trials to guide nasal CPAP level selection in preterm infants, whether provided as initial respiratory support or following extubation from invasive mechanical ventilation. We are uncertain as to whether low or moderate-high nasal CPAP levels improve morbidity and mortality in preterm infants. Well-designed trials evaluating this important aspect of a commonly used neonatal therapy are needed.

Background Noninvasive respiratory support has reduced the need for invasive mechanical ventilation (MV). This may reduce the incidence of bronchopulmonary dysplasia (BPD) in preterm infants. There are many different forms of noninvasive respiratory support which include nasal continuous positive airway pressure (NCPAP), Non-invasive high-frequency oscillatory ventilation (NHFOV) and High velocity nasal insufflation (HVNI). Little is known about the hemodynamic changes that occur during NIV, particularly during the weaning phase when lung compliance has improved. Aim of the Work To evaluate the outcome of NHFOV and Hi-VNI Vapotherm in comparison to nasal CPAP as a post extubation noninvasive respiratory support in preterm neonates. 2ry aim is to assess hemodynamic changes during periods of non-invasive respiratory support including echocardiographic, cerebral blood flow and mesenteric blood flow changes. Study Design This was a randomized control prospective study at Ain Shams Children Hospital, Cairo, Egypt. conducted on 61 mechanically ventilated preterm neonates 32-36 weeks gestational age with RDS, who were on invasive ventilatory support then extubated to non-invasive mode: Group A, 21 preterm neonates extubated on NCPAP. Group B, 20 preterm neonates extubated on NHFOV and Group C, 20 preterm extubated on Hi-VNI Vapotherm. The Three groups were studied for the need for re-intubation within the first 24 hours after extubation, length of hospital stay and duration of non- invasive ventilation (NIV), Retinopathy of prematurity (ROP), air leak syndromes, Intraventricular hemorrhage (IVH), Necrotizing enterocolitis (NEC), nasal trauma, Bronchopulmonary dysplasia (BPD) and mortality. Also assessing hemodynamic changes during and after weaning of non-invasive respiratory support including echocardiography, Anterior cerebral artery resistive index (ACA) RI, Middle cerebral arteries resistive index (MCA) RI, and superior mesenteric artery resistive index (SMA) RI. Results PaCO2 was unchanged from preextubation levels after weaning in the NCPAP and NHFOV but increased significantly after weaning from vapotherm. NCPAP had the shortest length of hospital stay median (IQR) 18 while the NHFOV has the longest duration of hospital stay median (IQR) 28. NHFOV had the least failure rate10% while post extubation to Vapotherm had the highest failure rate 40%, yet this did not reach statistical significance. Significant association found between failure on vapotherm and birth weight less than or equal to 1.75 kg with OR (95% CI) of 77.00 (4.114 – 1441.049) and with p-value = 0.004. A significant higher incidence of mortality was found in vapotherm failed group as compared to the succeed group (75% vs. 0%, p = 0.03). There was significantly higher nasal trauma among NHFOV group compared to the NCPAP and Vapotherm groups (P = 0.001). NHFOV had the least mortality rate 0% while post extubation to Vapotherm had the highest mortality rate 30%, yet this did not reach statistical significance. NCPAP had the least incidence of sepsis while the vapotherm had the highest incidence (P = 0.02). No significant difference between the 3 modes of noninvasive respiratory support in the occurrence of comorbidities as NEC, IVH, ROP and BPD. By Doppler echocardiography, NHFOV showed that both RVO, SVC flow significantly increased after weaning. ACA RI significantly increased after weaning from NHFOV. Also, it showed significant increase in RVO after weaning vapotherm with no significant effect on cerebral blood flow. NCPAP didn’t have significant effect on systemic &amp; pulmonary venous return by Doppler echocardiography. Although it showed that both ACA and MCA RI significantly increased after weaning. Conclusion Overall, these findings suggest that NHFOV may be a favorable option for respiratory support in preterm infants following extubation, as it was associated with better outcomes compared to NCPAP and Vapotherm. However, further research is needed to fully understand the potential benefits and risks of each mode of noninvasive respiratory support in this population. Infants in the Hi-VNI Technology group had significantly lower nasal trauma scores than those in the NCPAP and NHFOV groups with increased failure rate in preterm infants with a birth weight less than or equal to 1.75 kgs.

Cohort studies have suggested that nasal continuous positive airways pressure (CPAP) starting in the immediate postnatal period before the onset of respiratory disease (prophylactic CPAP) may be beneficial in reducing the need for intubation and intermittent positive pressure ventilation (IPPV) and in preventing bronchopulmonary dysplasia (BPD) in preterm or low birth weight infants. To determine if prophylactic nasal CPAP started soon after birth regardless of respiratory status in the very preterm or very low birth weight infant reduces the use of IPPV and the incidence of bronchopulmonary dysplasia (BPD) without adverse effects. We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL 2016, Issue 1), MEDLINE via PubMed (1966 to 31 January 2016), EMBASE (1980 to 31 January 2016), and CINAHL (1982 to 31 January 2016). We also searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials. All trials using random or quasi-random patient allocation of very preterm infants (under 32 weeks' gestation) or less than 1500 grams at birth were eligible. We included trials if they compared prophylactic nasal CPAP started soon after birth regardless of the respiratory status of the infant with 'standard' methods of treatment such as IPPV, oxygen therapy or supportive treatment. We excluded studies where prophylactic CPAP was compared with CPAP along with other interventions. We used the standard methods of Cochrane and its Neonatal Review Group, including independent study selection, assessment of trial quality and extraction of data by two authors. Data were analysed using risk ratio (RR) and the meta-analysis was performed using a fixed-effect model. Seven trials recruiting 3123 babies were included in the meta-analysis. Four trials recruiting 765 babies compared CPAP with supportive care and three trials (2364 infants) compared CPAP with mechanical ventilation. Apart from a lack of blinding of the intervention all studies were of low risk of bias.In the comparison of CPAP with supportive care there was a reduction in failed treatment (typical risk ratio (RR) 0.66, 95% confidence interval (CI) 0.45 to 0.98; typical risk difference (RD) -0.16, 95% CI -0.34 to 0.02; 4 studies, 765 infants, very low quality evidence). There was no reduction in bronchopulmonary dysplasia (BPD) or mortality.In trials comparing CPAP with assisted ventilation with or without surfactant, CPAP resulted in a small but clinically significant reduction in the incidence of BPD at 36 weeks, (typical RR 0.89, 95% CI 0.79 to 0.99; typical RD -0.04, 95% CI -0.08 to 0.00; 3 studies, 772 infants, moderate-quality evidence); and death or BPD (typical RR 0.89, 95% CI 0.81 to 0.97; typical RD -0.05, 95% CI -0.09 to 0.01; 3 studies, 1042 infants, moderate-quality evidence). There was also a clinically important reduction in the need for mechanical ventilation (typical RR 0.50, 95% CI 0.42 to 0.59; typical RD -0.49, 95% CI -0.59 to -0.39; 2 studies, 760 infants, moderate-quality evidence); and the use of surfactant in the CPAP group (typical RR 0.54, 95% CI 0.40 to 0.73; typical RD -0.41, 95% CI -0.54 to -0.28; 3 studies, 1744 infants, moderate-quality evidence). There is insufficient evidence to evaluate prophylactic CPAP compared to oxygen therapy and other supportive care. However when compared to mechanical ventilation prophylactic nasal CPAP in very preterm infants reduces the need for mechanical ventilation and surfactant and also reduces the incidence of BPD and death or BPD.

High flow nasal cannulae (HFNC) are small, thin, tapered binasal tubes that deliver oxygen or blended oxygen/air at gas flows of more than 1 L/min. HFNC are increasingly being used as a form of non-invasive respiratory support for preterm infants. To compare the safety and efficacy of HFNC with other forms of non-invasive respiratory support in preterm infants. We used the standard search strategy of the Cochrane Neonatal Review Group to search the Cochrane Central Register of Controlled Trials (CENTRAL 2016, Issue 1), MEDLINE via PubMed (1966 to 1 January 2016), EMBASE (1980 to 1 January 2016), and CINAHL (1982 to 1 January 2016). We also searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials. Randomised or quasi-randomised trials comparing HFNC with other non-invasive forms of respiratory support in preterm infants immediately after birth or following extubation. The authors extracted and analysed data, and calculated risk ratio, risk difference and number needed to treat for an additional beneficial outcome. We identified 15 studies for inclusion in the review. The studies differed in the interventions compared (nasal continuous positive airway pressure (CPAP), nasal intermittent positive pressure ventilation (NIPPV), non-humidified HFNC, models for delivering HFNC), the gas flows used and the indications for respiratory support (primary support from soon after birth, post-extubation support, weaning from CPAP support). When used as primary respiratory support after birth compared to CPAP (4 studies, 439 infants), there were no differences in the primary outcomes of death (typical risk ratio (RR) 0.36, 95% CI 0.01 to 8.73; 4 studies, 439 infants) or chronic lung disease (CLD) (typical RR 2.07, 95% CI 0.64 to 6.64; 4 studies, 439 infants). HFNC use resulted in longer duration of respiratory support, but there were no differences in other secondary outcomes. One study (75 infants) showed no differences between HFNC and NIPPV as primary support. Following extubation (total 6 studies, 934 infants), there were no differences between HFNC and CPAP in the primary outcomes of death (typical RR 0.77, 95% CI 0.43 to 1.36; 5 studies, 896 infants) or CLD (typical RR 0.96, 95% CI 0.78 to 1.18; 5 studies, 893 infants). There was no difference in the rate of treatment failure (typical RR 1.21, 95% CI 0.95 to 1.55; 5 studies, 786 infants) or reintubation (typical RR 0.91, 95% CI 0.68 to 1.20; 6 studies, 934 infants). Infants randomised to HFNC had reduced nasal trauma (typical RR 0.64, 95% CI 0.51 to 0.79; typical risk difference (RD) -0.14, 95% CI -0.20 to -0.08; 4 studies, 645 infants). There was a small reduction in the rate of pneumothorax (typical RR 0.35, 95% CI 0.11 to 1.06; typical RD -0.02, 95% CI -0.03 to -0.00; 5 studies 896 infants) in infants treated with HFNC. Subgroup analysis found no difference in the rate of the primary outcomes between HFNC and CPAP in preterm infants in different gestational age subgroups, though there were only small numbers of extremely preterm and late preterm infants. One trial (28 infants) found similar rates of reintubation for humidified and non-humidified HFNC, and two other trials (100 infants) found no difference between different models of equipment used to deliver humidified HFNC. For infants weaning from non-invasive respiratory support (CPAP), two studies (149 infants) found that preterm infants randomised to HFNC had a reduced duration of hospitalisation compared with infants who remained on CPAP. HFNC has similar rates of efficacy to other forms of non-invasive respiratory support in preterm infants for preventing treatment failure, death and CLD. Most evidence is available for the use of HFNC as post-extubation support. Following extubation, HFNC is associated with less nasal trauma, and may be associated with reduced pneumothorax compared with nasal CPAP. Further adequately powered randomised controlled trials should be undertaken in preterm infants comparing HFNC with other forms of primary non-invasive support after birth and for weaning from non-invasive support. Further evidence is also required for evaluating the safety and efficacy of HFNC in extremely preterm and mildly preterm subgroups, and for comparing different HFNC devices.

High flow nasal cannulae (HFNC) are small, thin, tapered cannulae used to deliver oxygen or blended oxygen and air at flow rates of > 1 L/min. HFNC can be used to provide high concentrations of oxygen and may deliver positive end-expiratory pressure. To compare the safety and efficacy of HFNC with other forms of non-invasive respiratory support in preterm infants. The strategy included searches of the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2010), MEDLINE, CINAHL, EMBASE and abstracts from conference proceedings. Randomised or quasi-randomised trials comparing HFNC with other non-invasive forms of respiratory support in preterm infants immediately after birth or following extubation. Data were extracted and analysed by the authors. Relative risk, risk difference and number needed to treat were calculated. Four studies were identified for inclusion in the review. The studies differed in the interventions compared (nasal continuous positive airway pressure (CPAP), humidified HFNC, non-humidified HFNC), the flow rates provided and the indications for respiratory support. Meta-analysis and subgroup analysis were not possible. When used as primary respiratory support after birth, one trial found similar rates of treatment failure in infants treated with HFNC and nasal CPAP. Following extubation, one trial found that infants treated with HFNC had a significantly higher rate of reintubation than those treated with nasal CPAP. Another trial found similar rates of reintubation for humidified and non-humidified HFNC, and the fourth trial found no difference between two different models of equipment used to deliver humidified HFNC. There is insufficient evidence to establish the safety or effectiveness of HFNC as a form of respiratory support in preterm infants. When used following extubation, HFNC may be associated with a higher rate of reintubation than nasal CPAP. Further adequately powered randomised controlled trials should be undertaken in preterm infants comparing HFNC with nasal CPAP and with other means of respiratory support; or of support following extubation. These trials should measure clinically important outcomes.

Objective: To determine whether post-extubation respiratory support via nsNIPPV decreases the need for mechanical ventilation (MV) compared to nasal continuous positive airway pressure (NCPAP) in preterm infants with respiratory distress syndrome (RDS).Methods: In this randomized, controlled, open, prospective, single-center clinical trial, we randomly assigned preterm ventilated infants with RDS to either nsNIPPV or NCPAP after extubation. The primary outcome, extubation failure, was defined by pre-specified failure criteria in the 72 hours after extubation.Results: A total of 63 preterm ventilated infants were randomized to receive either nsNIPPV (n = 31) or NCPAP (n = 32). Extubation failure occurred in six (19.3%) of nsNIPPV group compared with nine (28.12%) of NCPAP group and was statistically not significant (p = 0.55). The duration of NIV was significantly lower in nsNIPPV group as compared to NCPAP group (40.4 ± 39.3 hours versus 111.8 ± 116.4 hours, p = 0.003). The duration of supplementary oxygen was significantly lower in nsNIPPV versus NCPAP group (84.9 ± 92.1 hours versus 190.1 ± 140.5 hours, p = 0.002). The rates of BPD in nsNIPPV group (2/29, 6.9%) were significantly lower than in NCPAP group (9/28, 32.14%) (p = 0.02).Conclusions: Compared to NCPAP, nsNIPPV appears to be a feasible mode of extubation in preterm infants with significant beneficial effects of reduced duration of NIV support, supplementary oxygen and decreased rates of BPD.

The use of continuous positive airway pressure (CPAP), first described by George Gregory in 1971 for the management of respiratory distress syndrome [1] and now used for a variety of respiratory diseases in infants remains one of the most actively investigated interventions for neonatal intensive care. Nasal CPAP (NCPAP) provides continuous distending pressure to stabilize the lung volume to prevent alveolar collapse, splint the upper airway to reduce obstructive apnea, attenuates distortion of chest wall during inspiration and increases the efficiency of the diaphragm. Several important large scale clinical trials evaluating the role of NCPAP in early respiratory management in preterm infants have been published in recent years [2–5]. Treatment with early NCPAP rather than intubation/surfactant may be associated with less respiratory morbidity by 18–22 mo corrected age [6]. NCPAP has become the primary mode of respiratory support in preterm infants to avoid intubation and mechanical ventilation and to facilitate weaning from the ventilator [7–9]. There are risks associated with NCPAP use, including pneumothorax, nasal trauma, increased abdominal distension and impeded systemic and pulmonary venous return [3, 10]. Therefore, its weaning is important when infants’ respiratory status shows improvement. However, the optimal methods and factors associated with successful wean are not well defined. A survey involving 124 Australian tertiary neonatal units showed that at least 48 % of neonatologists used gradetime-off CPAP and at least 50 % weaned the airway pressure prior to coming off NCPAP despite the paucity of evidence to support either strategy [11]. Another survey of all 58 neonatal units with intensive care cots in the Northern Region of England revealed that 66% of the units weaned by Btime off^, while the others indicated no set method [12]. Thus, an expert have commented that weaning babies from CPAP is Ba matter of trial and error to see how they manage^ [13]. The wide variation in practice undoubtedly reflects the lack of sufficient evidence from existing trials to direct neonatologists in the weaning of preterm infants from NCPAP. In this issue, Nair et al. report a pilot, feasibility study (NCT02114112) to compare the effectiveness of nasal CPAP (NCPAP) cycling with continuous NCPAP in the successful weaning of preterm infants of 25°–28 wk gestation to nasal prongs [14]. A total of 30 infants ventilated for respiratory distress syndrome (RDS) and extubated to NCPAP were randomized to NCPAP cycling or to continuous NCPAP at 4 cm of H2O. After 72 h of intervention, both groups were weaned to 1 Liter per minute (LPM) nasal prong (NP), per their neonatal intensive care unit standard practice. Successful weaning was defined when an infant continued to be on 1LPM NP for at least 72 h. The authors did not find any significant difference in rates of successful weaning between the two groups. We appreciate the efforts of the authors to study this important question of Bhow to wean^ in the most vulnerable group of extremely low gestational age neonates (ELGAN). They planned to recruit 40 subjects, but unfortunately the study was terminated early due to the introduction of a respiratory bundle quality initiative in authors’ unit to reduce the bronchopulmonary dysplasia rate. As a consequence only 30 subjects were recruited into this one-year study with 13 * Niranjan Kissoon nkissoon@cw.bc.ca

Francais en page 139 How should surfactant be used in preterm infants initially managed with nasal continuous positive airway pressure (CPAP)? Many centres providing neonatal intensive care have increased their use of CPAP as a first-line method of respiratory support for preterm infants. This practice shift started after several descriptive, as well as before/after cohort studies, suggested that avoiding intubation and mechanical ventilation may help to reduce bronchopulmonary dysplasia (BPD) (1,2). There has been concern, however, that adopting this practice might deprive some infants of the proven benefits of expeditiously administered exogenous surfactant, especially those born at the youngest gestational ages who have traditionally been provided with prophylactic treatment. Recent randomized trials comparing elective intubation and prophylactic surfactant to initial management with nasal CPAP and selective surfactant therapy, suggest that the latter approach is safe and reduces the number of infants intubated and given surfactant (3–7). In the largest of these studies, even the infants at highest risk for respiratory distress syndrome (RDS) and its associated complications (ie, those born at 24 to 25 weeks’ gestational age), appeared to fare as well, if not better, when initially managed with nasal CPAP (4). These studies suggest that application of nasal CPAP shortly after birth to very preterm infants is an acceptable alternative strategy to elective intubation and prophylactic surfactant treatment. However, the criteria for surfactant treatment of infants initially supported with nasal CPAP have been inconsistent. A short period of observation on CPAP is necessary to enable clinicians to identify infants with surfactant sufficiency or mild RDS, who may be effectively managed without endotracheal intubation and surfactant treatment. Yet, a delay in treating a newborn with significant surfactant deficiency could result in a suboptimal response and/or an increased risk of complications. Criteria for selective treatment of infants initially managed with CPAP are needed. Verder et al (8), who were early advocates of the INSURE (INtubate, SURfactant, Extubate) approach for infants with RDS, found that preterm infants with RDS initially managed with nasal CPAP had better outcomes when treated with surfactant when reaching a fraction of inspired oxygen (FiO2) of approximately 0.37 to 0.55 versus 0.57 to 0.77. A systematic review examining timing of surfactant administration to preterm infants with RDS initially managed with CPAP also found that earlier treatment was more effective (9). From this review, when a low treatment threshold (FiO2 ≤0.45) for intubation and surfactant administration in the early treatment group was used, protection from air leak and BPD was enhanced. Examining several recent, large randomized trials yields additional useful information that can be used to guide practice (3–7). The two studies that did not allow treatment with surfactant of infants initially managed with nasal CPAP, until the requirement for supplemental oxygen exceeded an FiO2 of 0.60, showed increased rates of pneumothorax compared with the group intubated and given surfactant shortly after birth (3,7). The studies in which selective treatment was provided at lower supplemental oxygen thresholds saw no increase in air leak (4–6). These observations are consistent with a previous systematic review that found that babies with or at high risk for RDS had better outcomes if surfactant was given earlier rather than later in the clinical course (10). However, the prophylactic administration of surfactant with rapid extubation to nasal CPAP for infants at risk of RDS does not appear to convey an additional advantage compared with selective treatment after a short period of nasal CPAP, as long as the threshold for treatment is not too high (5,6).

Several types of pressure sources, including underwater bubble devices, mechanical ventilators, and the Infant Flow Driver, are used for providing continuous positive airway pressure (CPAP) to preterm infants with respiratory distress. It is unclear whether the use of bubble CPAP versus other pressure sources is associated with lower rates of CPAP treatment failure, or mortality and other morbidity. OBJECTIVES: To assess the benefits and harms of bubble CPAP versus other pressure sources (mechanical ventilators or Infant Flow Driver) for reducing treatment failure and associated morbidity and mortality in newborn preterm infants with or at risk of respiratory distress. We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2023, Issue 1); MEDLINE (1946 to 6 January 2023), Embase (1974 to 6 January 2023), Maternity & Infant Care Database (1971 to 6 January 2023), and the Cumulative Index to Nursing and Allied Health Literature (1982 to 6 January 2023). We searched clinical trials databases and the reference lists of retrieved articles. We included randomised controlled trials comparing bubble CPAP with other pressure sources (mechanical ventilators or Infant Flow Driver) for the delivery of nasal CPAP to preterm infants. We used standard Cochrane methods. Two review authors separately evaluated trial quality, extracted data, and synthesised effect estimates using risk ratio (RR), risk difference (RD), and mean difference. We used the GRADE approach to assess the certainty of the evidence for effects on treatment failure, all-cause mortality, neurodevelopmental impairment, pneumothorax, moderate-severe nasal trauma, and bronchopulmonary dysplasia. We included 15 trials involving a total of 1437 infants. All trials were small (median number of participants 88). The methods used to generate the randomisation sequence and ensure allocation concealment were unclear in about half of the trial reports. Lack of measures to blind caregivers or investigators was a potential source of bias in all of the included trials. The trials took place during the past 25 years in care facilities internationally, predominantly in India (five trials) and Iran (four trials). The studied pressure sources were commercially available bubble CPAP devices versus a variety of mechanical ventilator (11 trials) or Infant Flow Driver (4 trials) devices. Meta-analyses suggest that the use of bubble CPAP compared with mechanical ventilator or Infant Flow Driver CPAP may reduce the rate of treatment failure (RR 0.76, 95% confidence interval (CI) 0.60 to 0.95; (I² = 31%); RD -0.05, 95% CI -0.10 to -0.01; number needed to treat for an additional beneficial outcome 20, 95% CI 10 to 100; 13 trials, 1230 infants; low certainty evidence). The type of pressure source may not affect mortality prior to hospital discharge (RR 0.93, 95% CI 0.64 to 1.36 (I² = 0%); RD -0.01, 95% CI -0.04 to 0.02; 10 trials, 1189 infants; low certainty evidence). No data were available on neurodevelopmental impairment. Meta-analysis suggests that the pressure source may not affect the risk of pneumothorax (RR 0.73, 95% CI 0.40 to 1.34 (I² = 0%); RD -0.01, 95% CI -0.03 to 0.01; 14 trials, 1340 infants; low certainty evidence). Bubble CPAP likely increases the risk of moderate-severe nasal injury (RR 2.29, 95% CI 1.37 to 3.82 (I² = 17%); RD 0.07, 95% CI 0.03 to 0.11; number needed to treat for an additional harmful outcome 14, 95% CI 9 to 33; 8 trials, 753 infants; moderate certainty evidence). The pressure source may not affect the risk of bronchopulmonary dysplasia (RR 0.76, 95% CI 0.53 to 1.10 (I² = 0%); RD -0.04, 95% CI -0.09 to 0.01; 7 trials, 603 infants; low certainty evidence). AUTHORS' CONCLUSIONS: Given the low level of certainty about the effects of bubble CPAP versus other pressure sources on the risk of treatment failure and most associated morbidity and mortality for preterm infants, further large, high-quality trials are needed to provide evidence of sufficient validity and applicability to inform context- and setting-relevant policy and practice.

Diaphragm-triggered non-invasive respiratory support, commonly referred to as NIV-NAVA (non-invasive neurally adjusted ventilatory assist), uses the electrical activity of the crural diaphragm to trigger the start and end of a breath. It provides variable inspiratory pressure that is proportional to an infant's changing inspiratory effort. NIV-NAVA has the potential to provide effective, non-invasive, synchronised, multilevel support and may reduce the need for invasive ventilation; however, its effects on short- and long-term outcomes, especially in the preterm infant, are unclear. To assess the effectiveness and safety of diaphragm-triggered non-invasive respiratory support in preterm infants (< 37 weeks' gestation) when compared to other non-invasive modes of respiratory support (nasal intermittent positive pressure ventilation (NIPPV); nasal continuous positive airway pressure (nCPAP); high-flow nasal cannulae (HFNC)), and to assess preterm infants with birth weight less than 1000 grams or less than 28 weeks' corrected gestation at the time of intervention as a sub-group. We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL 2019, Issue 5), MEDLINE via PubMed (1946 to 10 May 2019), Embase (1947 to 10 May 2019), and CINAHL (1982 to 10 May 2019). We also searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials (RCTs) and quasi-randomised trials. Randomised and quasi-randomised controlled trials that compared diaphragm-triggered non-invasive versus other non-invasive respiratory support in preterm infants. Two review authors independently selected trials, assessed trial quality and extracted data from included studies. We performed fixed-effect analyses and expressed treatment effects as mean difference (MD), risk ratio (RR), and risk difference (RD) with 95% confidence intervals (CIs). We used the generic inverse variance method to analyse specific outcomes for cross-over trials. We used the GRADE approach to assess the certainty of evidence. There were two small randomised controlled trials including a total of 23 infants eligible for inclusion in the review. Only one trial involving 16 infants included in the analysis reported on either of the primary outcomes of the review. This found no difference in failure of modality between NIV-NAVA and NIPPV (RR 0.33, 95% CI 0.02 to 7.14; RD -0.13, 95% CI -0.41 to 0.16; 1 study, 16 infants; heterogeneity not applicable). Both trials reported on secondary outcomes of the review, specific for cross-over trials (total 22 infants; 1 excluded due to failure of initial modality). One study involving seven infants reported a significant reduction in maximum FiO₂ with NIV-NAVA compared to NIPPV (MD -4.29, 95% CI -5.47 to -3.11; heterogeneity not applicable). There was no difference in maximum electric activity of the diaphragm (Edi) signal between modalities (MD -1.75, 95% CI -3.75 to 0.26; I² = 0%) and a significant increase in respiratory rate with NIV-NAVA compared to NIPPV (MD 7.22, 95% CI 0.21 to 14.22; I² = 72%) on a meta-analysis of two studies involving a total of 22 infants. The included studies did not report on other outcomes of interest. Due to limited data and very low certainty evidence, we were unable to determine if diaphragm-triggered non-invasive respiratory support is effective or safe in preventing respiratory failure in preterm infants. Large, adequately powered randomised controlled trials are needed to determine if diaphragm-triggered non-invasive respiratory support in preterm infants is effective or safe.