The Diaphragmatic Initiated Ventilatory Assist (DIVA) trial: study protocol for a randomized controlled trial comparing rates of extubation failure in extremely premature infants undergoing extubation to non-invasive neurally adjusted ventilatory assist versus non-synchronized nasal intermittent positive pressure ventilation.

BACKGROUND: Invasive mechanical ventilation contributes to bronchopulmonary dysplasia (BPD), the most common complication of prematurity and the leading respiratory cause of childhood morbidity. Non-invasive ventilation (NIV) may limit invasive ventilation exposure and can be either synchronized or non-synchronized (NS). Pooled data suggest synchronized forms may be superior. Non-invasive neurally adjusted ventilatory assist (NIV-NAVA) delivers NIV synchronized to the neural signal for breathing, which is detected with a specialized catheter. The DIVA (Diaphragmatic Initiated Ventilatory Assist) trial aims to determine in infants born 240/7-276/7 weeks' gestation undergoing extubation whether NIV-NAVA compared to non-synchronized nasal intermittent positive pressure ventilation (NS-NIPPV) reduces the incidence of extubation failure within 5 days of extubation. METHODS: This is a prospective, unblinded, pragmatic, multicenter phase III randomized clinical trial. Inclusion criteria are preterm infants 24-276/7 weeks gestational age who were intubated within the first 7 days of life for at least 12 h and are undergoing extubation in the first 28 postnatal days. All sites will enter an initial run-in phase, where all infants are allocated to NIV-NAVA, and an independent technical committee assesses site performance. Subsequently, all enrolled infants are randomized to NIV-NAVA or NS-NIPPV at extubation. The primary outcome is extubation failure within 5 days of extubation, defined as any of the following: (1) rise in FiO2 at least 20% from pre-extubation for > 2 h, (2) pH ≤ 7.20 or pCO2 ≥ 70 mmHg; (3) > 1 apnea requiring positive pressure ventilation (PPV) or ≥ 6 apneas requiring stimulation within 6 h; (4) emergent intubation for cardiovascular instability or surgery. Our sample size of 478 provides 90% power to detect a 15% absolute reduction in the primary outcome. Enrolled infants will be followed for safety and secondary outcomes through 36 weeks' postmenstrual age, discharge, death, or transfer. DISCUSSION: The DIVA trial is the first large multicenter trial designed to assess the impact of NIV-NAVA on relevant clinical outcomes for preterm infants. The DIVA trial design incorporates input from clinical NAVA experts and includes innovative features, such as a run-in phase, to ensure consistent technical performance across sites. TRIAL REGISTRATION: www. CLINICALTRIALS: gov , trial identifier NCT05446272 , registered July 6, 2022.

High-flow nasal cannula (HFNC) vs continuous positive airway pressure (CPAP) vs nasal intermittent positive pressure ventilation as primary respiratory support in infants of ≥ 32 weeks gestational age (GA): study protocol for a three-arm multi-center randomized controlled trial.

BACKGROUND: Health problems in neonates with gestational age (GA) ≥ 32 weeks remain a major medical concern. Respiratory distress (RD) is one of the common reasons for admission of neonates with GA ≥ 32 weeks. Noninvasive ventilation (NIV) represents a crucial approach to treat RD, and currently, the most used NIV modes in neonatal intensive care unit include high-flow nasal cannula (HFNC), continuous positive airway pressure (CPAP), and nasal intermittent positive pressure ventilation. Although extensive evidence supports the use of NIPPV in neonates with a GA < 32 weeks, limited data exist regarding its effectiveness in neonates with GA ≥ 32 weeks. Therefore, the aim of this study is to compare the clinical efficacy of HFNC, CPAP, and NIPPV as primary NIV in neonates with GA ≥ 32 weeks who experience RD. METHODS: This trial is designed as an assessor-blinded, three-arm, multi-center, parallel, randomized controlled trial, conducted in neonates ≥ 32 weeks' GA requiring primary NIV in the first 24 h of life. The neonates will be randomly assigned to one of three groups: HFNC, CPAP or NIPPV group. The effectiveness, safety and comfort of NIV will be evaluated. The primary outcome is the occurrence of treatment failure within 72 h after enrollment. Secondary outcomes include death before discharge, surfactant treatment within 72 h after randomization, duration of both noninvasive and invasive mechanical ventilation, duration of oxygen therapy, bronchopulmonary dysplasia, time to achieve full enteral nutrition, necrotizing enterocolitis, duration of admission, cost of admission, air leak syndrome, nasal trauma, and comfort score. DISCUSSION: Currently, there is a paucity of data regarding the utilization of NIPPV in neonates with GA ≥ 32 weeks. This study will provide clinical evidence for the development of respiratory treatment strategies in neonates at GA ≥ 32 weeks with RD, with the aim of minimizing the incidence of tracheal intubation and reducing the complications associated with NIV. TRIAL REGISTRATION: Chinese Clinical Trial Registry: ChiCTR2300069192. Registered on March 9, 2023, https://www.chictr.org.cn/showproj.html?proj=171491 .

A comparison of the effect of bi-level positive airway pressure and synchronized intermittent mandatory ventilation in preterm infants with respiratory distress syndrome.

OBJECTIVE: Bi-level positive airway pressure (BiPAP) and synchronized intermittent mandatory ventilation (SIMV) can be used to achieve peak inspiratory pressure and positive end-expiratory pressure to avoid alveolar collapse and improve oxygenation in preterm infants during the treatment of respiratory distress syndrome (RDS), and there is an urgent demand for evaluating the effects and prognoses of these two ventilation modes. STUDY DESIGN: We conducted a retrospective study on preterm infants (≤32 weeks and <2500 g) from March 2015 to March 2020 with BiPAP (n = 63) and SIMV (n = 63). The primary outcomes were successful treatment and weaning within 72 h, the demand for a second pulmonary surfactant supply and the need for a second respiratory support. The secondary outcome was the incidence of complications. RESULTS: There were no significant differences (p > .05) in the primary outcomes or the incidence of complications (pneumonia, apnea, respiratory failure, air leak syndrome, persistence of patent ductus arteriosus, neonatal sepsis, necrotizing enterocolitis, retinopathy of prematurity, and intraventricular hemorrhage). There were significant differences (p < .05) in the incidence of pulmonary hemorrhage, bronchopulmonary dysplasia and IVH (≥grade II). CONCLUSIONS: Although both BiPAP and SIMV achieved good early treatment outcomes of RDS in preterm infants, BiPAP support is recommended for reducing the incidence of pulmonary hemorrhage, bronchopulmonary dysplasia and IVH (≥grade II) if infants are tolerant. Attempts should be made to prevent these complications from happening with the use of SIMV support if infants are intolerant.

Sustained Inflation Versus Intermittent Positive Pressure Ventilation for Preterm Infants at Birth: Respiratory Function and Vital Sign Measurements.

OBJECTIVE: To characterize respiratory function monitor (RFM) measurements of sustained inflations and intermittent positive pressure ventilation (IPPV) delivered noninvasively to infants in the Sustained Aeration of Infant Lungs (SAIL) trial and to compare vital sign measurements between treatment arms. STUDY DESIGN: We analyzed RFM data from SAIL participants at 5 trial sites. We assessed tidal volumes, rates of airway obstruction, and mask leak among infants allocated to sustained inflations and IPPV, and we compared pulse rate and oxygen saturation measurements between treatment groups. RESULTS: Among 70 SAIL participants (36 sustained inflations, 34 IPPV) with RFM measurements, 40 (57%) were spontaneously breathing prior to the randomized intervention. The median expiratory tidal volume of sustained inflations administered was 5.3 mL/kg (IQR 1.1-9.2). Significant mask leak occurred in 15% and airway obstruction occurred during 17% of sustained inflations. Among 34 control infants, the median expiratory tidal volume of IPPV inflations was 4.3 mL/kg (IQR 1.3-6.6). Mask leak was present in 3%, and airway obstruction was present in 17% of IPPV inflations. There were no significant differences in pulse rate or oxygen saturation measurements between groups at any point during resuscitation. CONCLUSION: Expiratory tidal volumes of sustained inflations and IPPV inflations administered in the SAIL trial were highly variable in both treatment arms. Vital sign values were similar between groups throughout resuscitation. Sustained inflation as operationalized in the SAIL trial was not superior to IPPV to promote lung aeration after birth in this study subgroup. TRIAL REGISTRATION: Clinicaltrials.gov: NCT02139800.

Repeated intermittent hypoxic stimuli to operative lung reduce hypoxemia during subsequent one-lung ventilation for thoracoscopic surgery: A randomized controlled trial.

BACKGROUND: An intervention to potentiate hypoxic pulmonary vasoconstriction may reduce intrapulmonary shunt and hypoxemia during one-lung ventilation. Previous animal studies reported that repeated intermittent hypoxic stimuli potentiated hypoxic pulmonary vasoconstriction, but no clinical study has examined the effects of this intervention on hypoxemia during one-lung ventilation. We thus performed a single-center, parallel-group, double-blind, randomized controlled trial to investigate whether repeated intermittent hypoxic stimuli to the operative lung reduce hypoxemia during the subsequent one-lung ventilation for thoracoscopic surgery. METHODS: Patients undergoing one-lung ventilation were randomized into two groups (n = 68 each). Before one-lung ventilation, in the intermittent hypoxia group, the nondependent lung was not ventilated for 2 min and then ventilated for 2 min while the dependent lung was continuously ventilated. This was repeated five times. In the continuous normoxia group, both lungs were ventilated for 20 min. We measured SpO2, PaO2, FiO2, PaCO2, SaO2, and central venous oxygen saturation during one-lung ventilation. The primary outcome was the number of patients with hypoxemia defined as a SpO2 <95% during one-lung ventilation, which was analyzed with a chi-squared test. RESULTS: Hypoxemia was less frequent in the intermittent hypoxia group than in the continuous normoxia group during OLV [6/68 (8.8%) vs 17/68 (25.0%), risk ratio (95% CI) 0.35 (0.15-0.84), p = 0.012]. The PaO2 (p = 0.008 for 30 min and 0.007 for 60 min) and PaO2/FiO2 (p = 0.008 for both) were higher 30 and 60 min after starting one-lung ventilation, and the alveolar-arterial pressure gradient (p = 0.010) and shunt index (p = 0.008) were lower 30 min after starting one-lung ventilation in the intermittent hypoxia group than in the continuous normoxia group. Postoperative adverse events did not differ significantly between groups. CONCLUSIONS: Repeated intermittent hypoxic stimuli to the operative lung seemed to potentiate hypoxic pulmonary vasoconstriction, and thus reduced hypoxemia during the subsequent one-lung ventilation.

Continuous positive airway pressure (CPAP) for respiratory distress in preterm infants.

BACKGROUND: Respiratory distress, particularly respiratory distress syndrome (RDS), is the single most important cause of morbidity and mortality in preterm infants. In infants with progressive respiratory insufficiency, intermittent positive pressure ventilation (IPPV) with surfactant has been the usual treatment, but it is invasive, potentially resulting in airway and lung injury. Continuous positive airway pressure (CPAP) has been used for the prevention and treatment of respiratory distress, as well as for the prevention of apnoea, and in weaning from IPPV. Its use in the treatment of RDS might reduce the need for IPPV and its sequelae. OBJECTIVES: To determine the effect of continuous distending pressure in the form of CPAP on the need for IPPV and associated morbidity in spontaneously breathing preterm infants with respiratory distress. SEARCH METHODS: We used the standard strategy of Cochrane Neonatal to search CENTRAL (2020, Issue 6); Ovid MEDLINE and Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Daily and Versions; and CINAHL on 30 June 2020. We also searched clinical trials databases and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials. SELECTION CRITERIA: All randomised or quasi-randomised trials of preterm infants with respiratory distress were eligible. Interventions were CPAP by mask, nasal prong, nasopharyngeal tube or endotracheal tube, compared with spontaneous breathing with supplemental oxygen as necessary. DATA COLLECTION AND ANALYSIS: We used standard methods of Cochrane and its Neonatal Review Group, including independent assessment of risk of bias and extraction of data by two review authors. We used the GRADE approach to assess the certainty of evidence. Subgroup analyses were planned on the basis of birth weight (greater than or less than 1000 g or 1500 g), gestational age (groups divided at about 28 weeks and 32 weeks), timing of application (early versus late in the course of respiratory distress), pressure applied (high versus low) and trial setting (tertiary compared with non-tertiary hospitals; high income compared with low income) MAIN RESULTS: We included five studies involving 322 infants; two studies used face mask CPAP, two studies used nasal CPAP and one study used endotracheal CPAP and continuing negative pressure for a small number of less ill babies. For this update, we included one new trial. CPAP was associated with lower risk of treatment failure (death or use of assisted ventilation) (typical risk ratio (RR) 0.64, 95% confidence interval (CI) 0.50 to 0.82; typical risk difference (RD) -0.19, 95% CI -0.28 to -0.09; number needed to treat for an additional beneficial outcome (NNTB) 6, 95% CI 4 to 11; I2 = 50%; 5 studies, 322 infants; very low-certainty evidence), lower use of ventilatory assistance (typical RR 0.72, 95% CI 0.54 to 0.96; typical RD -0.13, 95% CI -0.25 to -0.02; NNTB 8, 95% CI 4 to 50; I2 = 55%; very low-certainty evidence) and lower overall mortality (typical RR 0.53, 95% CI 0.34 to 0.83; typical RD -0.11, 95% CI -0.18 to -0.04; NNTB 9, 95% CI 2 to 13; I2 = 0%; 5 studies, 322 infants; moderate-certainty evidence). CPAP was associated with increased risk of pneumothorax (typical RR 2.48, 95% CI 1.16 to 5.30; typical RD 0.09, 95% CI 0.02 to 0.16; number needed to treat for an additional harmful outcome (NNTH) 11, 95% CI 7 to 50; I2 = 0%; 4 studies, 274 infants; low-certainty evidence). There was no evidence of a difference in bronchopulmonary dysplasia, defined as oxygen dependency at 28 days (RR 1.04, 95% CI 0.35 to 3.13; I2 = 0%; 2 studies, 209 infants; very low-certainty evidence). The trials did not report use of surfactant, intraventricular haemorrhage, retinopathy of prematurity, necrotising enterocolitis and neurodevelopment outcomes in childhood. AUTHORS' CONCLUSIONS: In preterm infants with respiratory distress, the application of CPAP is associated with reduced respiratory failure, use of mechanical ventilation and mortality and an increased rate of pneumothorax compared to spontaneous breathing with supplemental oxygen as necessary. Three out of five of these trials were conducted in the 1970s. Therefore, the applicability of these results to current practice is unclear. Further studies in resource-poor settings should be considered and research to determine the most appropriate pressure level needs to be considered.

Effect of sustained inflations and intermittent positive pressure ventilation on bronchopulmonary dysplasia or death among neonatal: A protocol for systematic review.

BACKGROUND: Sustained Inflations (SI) and Intermittent Positive Pressure Ventilation (IPPV) are two interventions to prevent Bronchopulmonary dysplasia (BPD). The aim of this study is to assess the effect of these two interventions. METHODS: The databases of PubMed, EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL) will be comprehensively searched from inception to September 2019. All RCTs and quasi-RCTs which compare the efficacy of SI vs IPPV among preterm infants are eligible. We will assess the methodological quality using the Cochrane Handbook version 5.1.0. A meta-analysis will be performed using RevMan 5.3 software and the results will be presented using risk ratios (RRs) and 95% confidence intervals (CIs). CONCLUSIONS: This study will provide strong evidence for assessing the effect of SI and IPPV on BPD or death among preterm infants. PROSPERO REGISTRATION NUMBER: CRD42019135816.

Prolonged non-invasive ventilation in extremely low birth weight preterm infants is associated with bronchopulmonary dysplasia.

AIM: To evaluate the association between the use of nasal continuous positive airway pressure (nCPAP) or nasal intermittent positive pressure ventilation (NIPPV) with the development of bronchopulmonary dysplasia (BPD). METHODS: This is a single center retrospective cohort analysis of infants born at ≤1000 grams and ≤28 weeks gestation with respiratory distress treated with nCPAP or NIPPV. Groups were compared using Student's t test or chi-square, and associations estimated by logistic regression. RESULTS: Compared to nCPAP, infants who received NIPPV had a higher incidence of moderate to severe (M-S) BPD (84.2 vs 65.5%, p = 0.044) and death or severe BPD (75.0 vs 47.6%, p = 0.003). Each day on NIPPV was associated with an increased risk of M-S BPD (OR 1.08, p < 0.001) and an increased risk of death or severe BPD (OR 1.03, p = 0.006). After adjusting for days on oxygen, ventilator days, and days on all respiratory support, the odds of developing M-S BPD increased by 4.9% for each additional week on NIPPV (CI 2.1-7.7%, p = .0001). CONCLUSION: In this cohort, use of NIPPV was associated with an increased risk for developing BPD when compared to infants receiving nCPAP, and each additional day on NIPPV carried significant increased risk for developing BPD.

Sustained inflations and avoiding mechanical ventilation to prevent death or bronchopulmonary dysplasia: a meta-analysis.

Sustained inflations and avoidance of endotracheal mechanical ventilation (eMV) are delivery room interventions aimed at preventing bronchopulmonary dysplasia (BPD). Their effectiveness is the subject of the present meta-analysis.The databases MEDLINE, EMBASE and CENTRAL were searched for randomised controlled trials (RCTs) of preterm infants that compared: 1) sustained inflations with intermittent positive-pressure ventilation; and 2) a non-intubated strategy of respiratory support with one that prescribed eMV at an earlier stage. Data extraction and analysis followed the standard methods of the Cochrane Collaboration. The primary outcome was death or BPD, defined as need for oxygen or positive pressure treatment at 36 weeks' postmenstrual age.Avoiding eMV (nine RCTs, 3486 infants) reduced the risk of death or BPD, with a risk ratio of 0.90 (95% CI 0.84-0.97) and a number needed to treat of 35. After sustained inflations (six RCTs, 854 infants), the risk ratio was 0.85 (95% CI 0.65-1.12). A current multicentre RCT of sustained inflations in very preterm infants was halted for increased early mortality in the sustained inflations arm.While strategies aimed at avoiding eMV had a small but significant impact on preventing BPD, sustained inflations had no effect and may even increase mortality in very preterm infants.

[Comparison of clinical efficacy of two noninvasive respiratory support therapies for respiratory distress syndrome in very low birth weight preterm infants].

OBJECTIVE: To compare the clinical efficacy of nasal intermittent positive pressure ventilation (NIPPV) and heated humidified high flow nasal cannula (HHHFNC) in the treatment of respiratory distress syndrome (RDS) among very low birth weight (VLBW) preterm infants. METHODS: A total of 89 very low birth weight premature infants with respiratory distress syndrome (RDS) who were randomly administered with NIPPV (n=46) and HHHFNC (n=43) as an initial respiratory support. The incidence of initial treatment failure, the usage of pulmonary surfactant (PS), the parameters of respiratory support treatment and the incidence of complications were compared between the two groups. RESULTS: There were no significant differences between the NIPPV and HHHFNC groups in the following items: the rate of intubation within 72 hours, rate of PS use, duration of invasive or non-invasive mechanical ventilation, duration of oxygen therapy, and incidence rates of severe apnea and pneumonia (P>0.05). There were also no significant differences in the incidence rates of bronchopulmonary dysplasia, necrotizing enterocolitis, retinopathy of prematurity, patent ductus arteriosus, intracranial hemorrhage, and air leak between the two group (P>0.05). The incidence rate of nose injury in the NIPPV group was higher than that in the HHHFNC group (P<0.05). CONCLUSIONS: As an initial respiratory support for very low birth weight preterm infants with RDS, HHHFNC has a similar clinical effect as NIPPV, suggesting that HHHFNC is a safe and effective clinical option as a non-invasive ventilation treatment.

Effects of Pressure-Controlleda Volume-Controlled Ventilation on Hemodynamic and Respiratory Parameters in Patients During Laparoscopic Cholecystectomy.

Many papers have been published investigating the effects of intraoperative mechanical ventilation on the incidence of intra- and postoperative respiratory complications. The potential advantages of protective pressure over volume-controlled ventilation mode during laparoscopic surgery have yet to be proven. This study included 60 patients aged between 18 and 70 with ASA score 1-3, body mass index (BMI) ≤35 kg/m2, and without prior history of chronic respiratory diseases, who were scheduled for laparoscopic cholecystectomy under general anesthesia. Patients were assigned randomly to protective pressure or volume-controlled mechanical ventilation mode. The initial results showed no significant differences in respiratory and hemodynamic parameters between the groups. Comparison of patients with BMI ≥25 showed significantly lower peak inspiratory pressure (Ppeak) at 15 (18.52 vs. 21.83 cm H2O, p=0.022), 30 (18.73 vs. 21.83 cm H2O, p=0.009) and 45 (18.94 vs. 22.667 cm H2O, p=0.010) minutes after tracheal intubation in the pressure-controlled ventilation (PCV) group. Other measured parameters were of similar characteristics. It is concluded that PCV and volume-controlled ventilation were equally effective in maintaining adequate ventilation, oxygenation and hemodynamic stability in the groups of patients observed. However, comparison of obese patients revealed some advantages of PCV which, given the present pace of change, should be additionally investigated.

Early nasal intermittent positive pressure ventilation (NIPPV) versus early nasal continuous positive airway pressure (NCPAP) for preterm infants.

BACKGROUND: Nasal continuous positive airway pressure (NCPAP) is a strategy for maintaining positive airway pressure throughout the respiratory cycle through the application of bias flow of respiratory gas to an apparatus attached to the nose. Treatment with NCPAP is associated with decreased risk of mechanical ventilation and might be effective in reducing chronic lung disease. Nasal intermittent positive pressure ventilation (NIPPV) is a form of noninvasive ventilation during which patients are exposed intermittently to higher levels of airway pressure, along with NCPAP through the same nasal device. OBJECTIVES: To examine the risks and benefits of early NIPPV versus early NCPAP alone for preterm infants at risk of or in respiratory distress within the first hours after birth.Primary endpoints are respiratory failure and the need for intubated ventilatory support during the first week of life. Secondary endpoints include chronic lung disease (CLD) (oxygen therapy at 36 weeks' postmenstrual age), air leaks, duration of respiratory support, duration of oxygen therapy, intraventricular hemorrhage, and incidence of mortality. SEARCH METHODS: We used the standard search strategy of the Cochrane Neonatal Review Group to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2015, Issue 9), MEDLINE via PubMed (1966 to September 28, 2015), Embase (1980 to September 28, 2015), and the Cumulative Index to Nursing and Allied Health Literature (CINAHL; 1982 to September 28, 2015). We also searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomized controlled trials and quasi-randomized trials. A member of the Cochrane Neonatal Review Group handsearched abstracts from the European Society of Pediatric Research (ESPR). We contacted the authors of ongoing clinical trials to ask for information. SELECTION CRITERIA: We considered all randomized and quasi-randomized controlled trials. Studies selected compared NIPPV versus NCPAP treatment, starting at birth or shortly thereafter in preterm infants (< 37 weeks' gestational age). DATA COLLECTION AND ANALYSIS: We performed data collection and analysis using the recommendations of the Cochrane Neonatal Review Group. MAIN RESULTS: Ten trials, enrolling a total of 1061 infants, met criteria for inclusion in this review. Meta-analyses of these studies showed significantly reduced risk of meeting respiratory failure criteria (typical risk ratio (RR) 0.65, 95% confidence interval (CI) 0.51 to 0.82; typical risk difference (RD) -0.09, 95% CI -0.13 to -0.04) and needing intubation (typical RR 0.78, 95% CI 0.64 to 0.94; typical RD -0.07, 95% CI -0.12 to -0.02) among infants treated with early NIPPV compared with early NCPAP. The meta-analysis did not demonstrate a reduction in the risk of CLD among infants randomized to NIPPV (typical RR 0.78, 95% CI 0.58 to 1.06). Investigators observed no evidence of harm. Review authors graded the quality of the evidence as moderate (unblinded studies). AUTHORS' CONCLUSIONS: Early NIPPV does appear to be superior to NCPAP alone for decreasing respiratory failure and the need for intubation and endotracheal tube ventilation among preterm infants with respiratory distress syndrome. Additional studies are needed to confirm these results and to assess the safety of NIPPV compared with NCPAP alone in a larger patient population.

Nasal continuous positive airway pressure versus nasal intermittent positive-pressure ventilation within the minimally invasive surfactant therapy approach in preterm infants: a randomised controlled trial.

OBJECTIVE: To compare the effectiveness of nasal continuous positive airway pressure (NCPAP) and nasal intermittent positive-pressure ventilation (NIPPV) as the initial respiratory support within the minimally invasive surfactant therapy (MIST) approach in preterm infants with respiratory distress syndrome. DESIGN: Prospective, randomised controlled study. SETTING: Tertiary neonatal intensive care unit. PATIENTS AND INTERVENTIONS: This study enrolled 200 preterm infants with a gestational age of 26-32 weeks who showed signs of respiratory distress but did not require intubation in the delivery room. Surfactant therapy was performed using the MIST approach in the patients who met the criteria for surfactant administration. MAIN OUTCOME MEASURES: The primary outcomes were a need for intubation within the first 72 h of life and a surfactant requirement. RESULTS: The infants in the study displayed similar characteristics at birth. Fewer infants in the NIPPV group required surfactant therapy (38% vs 60%; p=0.002) or invasive ventilation during the first 72 h of life (13% vs 29%; p=0.005), and NIPPV reduced the rate of moderate-to-severe bronchopulmonary dysplasia (BPD) (7% vs 16%; p=0.046). Multivariate logistic regression analysis showed that NIPPV support (OR: 0.36, 95% CI 0.17 to 0.76; p=0.008) and higher gestational age (OR: 0.76, 95% CI 0.59 to 0.98; p=0.041) reduced the need for invasive ventilation within the first 72 h of life. Surfactant requirement was also decreased with NIPPV support (OR: 0.39, 95% CI 0.22 to 0.71; p=0.002). However, there was no impact on BPD, based on the multivariate analysis. CONCLUSIONS: In infants born at 26-32 weeks' gestation, NIPPV reduced the need for invasive ventilation and the surfactant requirement within the MIST approach. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov under identifier NCT01741129.

A comparison of bilevel and ventilator-delivered non-invasive respiratory support.

OBJECTIVE: To compare the rates of death or bronchopulmonary dysplasia (BPD) in infants who received nasal intermittent positive pressure ventilation (NIPPV) delivered by a conventional mechanical ventilator (CMV) or a bilevel device. DESIGN: A preplanned non-randomised comparison of infants randomised to the NIPPV arm of the NIPPV trial. SETTING: Thirty-six tertiary neonatal units in three continents. PATIENTS: Infants <1000 g and <30 weeks gestational age at birth. INTERVENTIONS: Infants received treatment with CMV NIPPV or bilevel NIPPV, as a primary mode of respiratory support or following first extubation. RESULTS: 241 received mainly bilevel NIPPV and 215 mainly CMV NIPPV. No difference was found in death or BPD at 36 weeks corrected age (adjusted OR 0.88 (95% CI 0.57 to 1.35)). More deaths occurred in infants receiving bilevel NIPPV (9.4%) than in CMV NIPPV (2.3%) (adjusted OR 5.01: 95% CI 1.74 to 14.4). There was a corresponding but not statistically significant decrease in BPD in the bilevel NIPPV group (30% vs 37%) (adjusted OR 0.64 (95% CI 0.41 to 1.02)). No difference was observed in extubation failure or age at last extubation. A post hoc test of interaction between device type and synchronisation was not statistically significant. CONCLUSIONS: We did not observe a statistically significant difference in the composite outcome of death or BPD between infants who received mostly bilevel NIPPV compared with mostly CMV NIPPV. Differences in component outcomes of morbidity and BPD may be due to the competing nature of these outcomes or differences in baseline characteristics of infants. TRIAL REGISTRATION NUMBER: NCT00433212.

Continuous distending pressure for respiratory distress in preterm infants.

BACKGROUND: Respiratory distress syndrome (RDS) is the single most important cause of morbidity and mortality in preterm infants. In infants with progressive respiratory insufficiency, intermittent positive pressure ventilation (IPPV) with surfactant is the standard treatment for the condition, but it is invasive, potentially resulting in airway and lung injury. Continuous distending pressure (CDP) has been used for the prevention and treatment of RDS, as well as for the prevention of apnoea, and in weaning from IPPV. Its use in the treatment of RDS might reduce the need for IPPV and its sequelae. OBJECTIVES: To determine the effect of continuous distending pressure (CDP) on the need for IPPV and associated morbidity in spontaneously breathing preterm infants with respiratory distress.Subgroup analyses were planned on the basis of birth weight (> or < 1000 or 1500 g), gestational age (groups divided at about 28 weeks and 32 weeks), methods of application of CDP (i.e. CPAP and CNP), application early versus late in the course of respiratory distress and high versus low pressure CDP and application of CDP in tertiary compared with non-tertiary hospitals, with the need for sensitivity analysis determined by trial quality.At the 2008 update, the objectives were modified to include preterm infants with respiratory failure. SEARCH METHODS: We used the standard search strategy of the Neonatal Review Group. This included searches of the Oxford Database of Perinatal Trials, the Cochrane Central Register of Controlled Trials (CENTRAL, 2015 Issue 4), MEDLINE (1966 to 30 April 2015) and EMBASE (1980 to 30 April 2015) with no language restriction, as well as controlled-trials.com, clinicaltrials.gov and the International Clinical Trials Registry Platform of the World Health Organization (WHO). SELECTION CRITERIA: All random or quasi-random trials of preterm infants with respiratory distress were eligible. Interventions were continuous distending pressure including continuous positive airway pressure (CPAP) by mask, nasal prong, nasopharyngeal tube or endotracheal tube, or continuous negative pressure (CNP) via a chamber enclosing the thorax and the lower body, compared with spontaneous breathing with oxygen added as necessary. DATA COLLECTION AND ANALYSIS: We used standard methods of The Cochrane Collaboration and its Neonatal Review Group, including independent assessment of trial quality and extraction of data by each review author. MAIN RESULTS: We included six studies involving 355 infants - two using face mask CPAP, two CNP, one nasal CPAP and one both CNP (for less ill babies) and endotracheal CPAP (for sicker babies). For this update, we included no new trials.Continuous distending pressure (CDP) is associated with lower risk of treatment failure (death or use of assisted ventilation) (typical risk ratio (RR) 0.65, 95% confidence interval (CI) 0.52 to 0.81; typical risk difference (RD) -0.20, 95% CI -0.29 to -0.10; number needed to treat for an additional beneficial outcome (NNTB) 5, 95% CI 4 to 10; six studies; 355 infants), lower overall mortality (typical RR 0.52, 95% CI 0.32 to 0.87; typical RD -0.15, 95% CI -0.26 to -0.04; NNTB 7, 95% CI 4 to 25; six studies; 355 infants) and lower mortality in infants with birth weight above 1500 g (typical RR 0.24, 95% CI 0.07 to 0.84; typical RD -0.28, 95% CI -0.48 to -0.08; NNTB 4, 95% CI 2.00 to 13.00; two studies; 60 infants). Use of CDP is associated with increased risk of pneumothorax (typical RR 2.64, 95% CI 1.39 to 5.04; typical RD 0.10, 95% CI 0.04 to 0.17; number needed to treat for an additional harmful outcome (NNTH) 17, 95% CI 17.00 to 25.00; six studies; 355 infants). We found no difference in bronchopulmonary dysplasia (BPD), defined as oxygen dependency at 28 days (three studies, 260 infants), as well as no difference in outcome at nine to 14 years (one study, 37 infants). AUTHORS' CONCLUSIONS: In preterm infants with respiratory distress, the application of CDP as CPAP or CNP is associated with reduced respiratory failure and mortality and an increased rate of pneumothorax. Four out of six of these trials were done in the 1970s. Therefore, the applicability of these results to current practice is difficult to assess. Further research is required to determine the best mode of administration.

Sustained Aeration of Infant Lungs (SAIL) trial: study protocol for a randomized controlled trial.

BACKGROUND: Extremely preterm infants require assistance recruiting the lung to establish a functional residual capacity after birth. Sustained inflation (SI) combined with positive end expiratory pressure (PEEP) may be a superior method of aerating the lung compared with intermittent positive pressure ventilation (IPPV) with PEEP in extremely preterm infants. The Sustained Aeration of Infant Lungs (SAIL) trial was designed to study this question. METHODS/DESIGN: This multisite prospective randomized controlled unblinded trial will recruit 600 infants of 23 to 26 weeks gestational age who require respiratory support at birth. Infants in both arms will be treated with PEEP 5 to 7 cm H2O throughout the resuscitation. The study intervention consists of performing an initial SI (20 cm H20 for 15 seconds) followed by a second SI (25 cm H2O for 15 seconds), and then PEEP with or without IPPV, as needed. The control group will be treated with initial IPPV with PEEP. The primary outcome is the combined endpoint of bronchopulmonary dysplasia or death at 36 weeks post-menstrual age. TRIAL REGISTRATION: www.clinicaltrials.gov , Trial identifier NCT02139800 , Registered 13 May 2014.

Sustained inflation versus positive pressure ventilation at birth: a systematic review and meta-analysis.

CONTEXT: Sustained inflation (SI) has been advocated as an alternative to intermittent positive pressure ventilation (IPPV) during the resuscitation of neonates at birth, to facilitate the early development of an effective functional residual capacity, reduce atelectotrauma and improve oxygenation after the birth of preterm infants. OBJECTIVE: The primary aim was to review the available literature on the use of SI compared with IPPV at birth in preterm infants for major neonatal outcomes, including bronchopulmonary dysplasia (BPD) and death. DATA SOURCE: MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials, until 6 October 2014. STUDY SELECTION: Randomised clinical trials comparing the effects of SI with IPPV at birth in preterm infants for neonatal outcomes. DATA EXTRACTION AND SYNTHESIS: Descriptive and quantitative information was extracted; data were pooled using a random effects model. Heterogeneity was assessed using the Q statistic and I(2). RESULTS: Pooled analysis showed significant reduction in the need for mechanical ventilation within 72 h after birth (relative risk (RR) 0.87 (0.77 to 0.97), absolute risk reduction (ARR) -0.10 (-0.17 to -0.03), number needed to treat 10) in preterm infants treated with an initial SI compared with IPPV. However, significantly more infants treated with SI received treatment for patent ductus arteriosus (RR 1.27 (1.05 to 1.54), ARR 0.10 (0.03 to 0.16), number needed to harm 10). There were no differences in BPD, death at the latest follow-up and the combined outcome of death or BPD among survivors between the groups. CONCLUSIONS: Compared with IPPV, preterm infants initially treated with SI at birth required less mechanical ventilation with no improvement in the rate of BPD and/or death. The use of SI should be restricted to randomised trials until future studies demonstrate the efficacy and safety of this lung aeration manoeuvre.

Volume guarantee pressure support ventilation in extremely preterm infants and neurodevelopmental outcome at 18 months.

OBJECTIVE: Compared with pressure-controlled ventilation (PCV), volume-targeted ventilation is associated with decreased neonatal complications, including the combined outcome of death or bronchopulmonary dysplasia. However, little is known about its effect on neurodevelopmental outcome. We evaluated the hypothesis that as compared with PCV, volume-targeted ventilation reduces the risk of the combined outcome of neurodevelopmental impairment or death in very low birth weight infants. STUDY DESIGN: We studied a cohort of extremely preterm infants managed with either volume guarantee pressure support ventilation (VGPSV; n=135) or PCV (n=135). Infants were evaluated at 18 months adjusted age with a standardized neurological examination and the Bayley Scales of Infant and Toddler Development-third edition. Logistic regression models were used to evaluate the association of ventilation mode and neurodevelopmental outcome. RESULT: Rates of pulmonary interstitial emphysema (odds ratio 0.6; 95% confidence limits: 0.4, 0.8), hypotension (odds ratio: 0.7; 95% confidence limits: 0.5, 0.9) and mortality (odds ratio 0.45; 95% confidence limits: 0.22, 0.9) were lower among infants treated with VGPSV. The infants in the VGPSV group had a significantly shorter duration on mechanical ventilation compared with infants in the PCV group (log-rank test P<0.01). Seventy percent (155/221) of survivors were evaluated at 18 months adjusted age. A trend towards benefit for the combined outcome of death or neurodevelopmental impairment was seen in the VGPSV group but did not reach statistical significance (odds ratio: 0.59; 95% confidence limits: 0.32, 1.08). CONCLUSION: VGPSV was associated with a decreased risk of short-term complications but not long-term developmental impairment in this modest-sized cohort.

Factors affecting nasal intermittent positive pressure ventilation failure and impact on bronchopulmonary dysplasia in neonates.

BACKGROUND: Nasal intermittent positive pressure ventilation (NIPPV) is becoming more important as a mode of ventilation in premature neonates predisposed to development of bronchopulmonary dysplasia (BPD). To the best of our knowledge, there have been no detailed studies characterizing neonates who fail NIPPV. OBJECTIVE: To determine the differences between neonates who are successfully extubated to NIPPV and those who require re-intubation from NIPPV, and the impact of timing of NIPPV failure on BPD rates. STUDY DESIGN: This was a retrospective cohort study in which we included infants with gestational age (GA) ⩽ 28 weeks and birth weight ⩽ 1000 g. χ²-test, analysis of variance and multivariate logistic regression models were used. RESULTS: Two hundred and forty infants were studied; 180 failed NIPPV and of those, 33 (18%), 39 (22%) and 108 (60%) failed NIPPV within 0 to 6 h, ⩾ 6 to 24 h and ⩾ 24 h, respectively. Female sex and increased weight were protective against NIPPV failure (adjusted odds ratio (95% confidence interval): 0.28 (0.14 to 0.58), 0.04 (0.01 to 0.22)). Increased GA at extubation and female sex were both associated with increased time to failure (P=0.008, <0.001, respectively). Apnea was more likely the cause for failure ⩾ 24 h (P=0.015), whereas increased work of breathing/fraction of inspired oxygen requirements were more significant when NIPPV failure occurred earlier (P=0.001). Neonates who failed NIPPV within 24 h did not have any association with likelihood of developing BPD or severity of BPD, after adjusting for confounding variables. CONCLUSION: Significant differences in neonatal characteristics may help identify which neonates are more likely to fail NIPPV, and their timing of failure.

Effects of synchronized intermittent mandatory ventilation versus pressure support plus volume guarantee ventilation in the weaning phase of preterm infants*.

OBJECTIVE: To compare the effects and short-term outcomes of pressure support ventilation with volume guarantee versus synchronized intermittent mandatory ventilation in the weaning phase of very low-birth weight infants with respiratory distress syndrome. DESIGN: Randomized controlled prospective study. SETTING: Tertiary care neonatal unit. PATIENTS: A total of 60 premature infants who were less than 33 weeks' gestation and/or less than 1,500 g birth weight and received mechanical ventilation because of respiratory distress syndrome were studied. INTERVENTIONS: All infants were ventilated from the time of admission with synchronized intermittent positive pressure ventilation mode after surfactant treatment for respiratory distress syndrome and then switched to pressure support ventilation with volume guarantee or synchronized intermittent mandatory ventilation mode in the weaning phase. The ventilatory variables and neonatal outcomes were recorded in each group. MEASUREMENTS AND MAIN RESULTS: The mean peak inflation pressure was higher in synchronized intermittent mandatory ventilation group (p < 0.001) and the mean airway pressure was higher in pressure support ventilation with volume guarantee group (p = 0.03), whereas mean tidal volume and respiratory rates were similar in both groups. The prevalence of postextubation atelectasis was higher in synchronized intermittent mandatory ventilation group, but the difference was not statistically significant (p = 0.08). No differences were found in the prevalence of reintubation, patent ductus arteriosus, intraventricular hemorrhage, retinopathy of prematurity, bronchopulmonary dysplasia, and pneumothorax between the groups. CONCLUSIONS: Pressure support ventilation with volume guarantee mode may be a safe and feasible mode during the weaning phase of very low-birth weight infants on mechanical ventilation support for respiratory distress syndrome with respect to reducing the frequency of postextubation atelectasis and using less peak inflation pressure.