The use of high-flow nasal cannulae is an increasingly popular alternative to nasal continuous positive airway pressure (CPAP) for noninvasive respiratory support of very preterm infants (gestational ...age, <32 weeks) after extubation. However, data on the efficacy or safety of such cannulae in this population are lacking.
In this multicenter, randomized, noninferiority trial, we assigned 303 very preterm infants to receive treatment with either high-flow nasal cannulae (5 to 6 liters per minute) or nasal CPAP (7 cm of water) after extubation. The primary outcome was treatment failure within 7 days. Noninferiority was determined by calculating the absolute difference in the risk of the primary outcome; the margin of noninferiority was 20 percentage points. Infants in whom treatment with high-flow nasal cannulae failed could be treated with nasal CPAP; infants in whom nasal CPAP failed were reintubated.
The use of high-flow nasal cannulae was noninferior to the use of nasal CPAP, with treatment failure occurring in 52 of 152 infants (34.2%) in the nasal-cannulae group and in 39 of 151 infants (25.8%) in the CPAP group (risk difference, 8.4 percentage points; 95% confidence interval, -1.9 to 18.7). Almost half the infants in whom treatment with high-flow nasal cannulae failed were successfully treated with CPAP without reintubation. The incidence of nasal trauma was significantly lower in the nasal-cannulae group than in the CPAP group (P=0.01), but there were no significant differences in rates of serious adverse events or other complications.
Although the result for the primary outcome was close to the margin of noninferiority, the efficacy of high-flow nasal cannulae was similar to that of CPAP as respiratory support for very preterm infants after extubation. (Funded by the National Health and Medical Research Council; Australian New Zealand Clinical Trials Network number, ACTRN12610000166077.).
Objective To determine whether postextubation respiratory support via heated, humidified, high-flow nasal cannulae (HHHFNC) results in a greater proportion of infants younger than 32 weeks' gestation ...being successfully extubated after a period of endotracheal positive pressure ventilation compared with conventional nasal continuous positive airway pressure (NCPAP). Study design We randomly assigned preterm ventilated infants to Vapotherm HHHFNC or NCPAP after extubation. The primary outcome, extubation failure, was defined by prespecified failure criteria in the 7 days after extubation. Results A total of 132 ventilated infants younger than 32 weeks' gestation were randomized to receive either HHHFNC (n = 67) or NCPAP (n = 65). Extubation failure occurred in 15 (22%) of the HHHFNC group compared with 22 (34%) of the NCPAP group. There was no difference in the number of infants reintubated in the first week. Treatment with HHHFNC reduced the nasal trauma score 3.1 (SD 7.2) versus NCPAP 11.8 (SD 10.7), P < .001. Conclusions HHHFNC and NCPAP produced similar rates of extubation failure.
Treatment with nasal high-flow therapy has efficacy similar to that of nasal continuous positive airway pressure (CPAP) when used as postextubation support in neonates. The efficacy of high-flow ...therapy as the primary means of respiratory support for preterm infants with respiratory distress has not been proved.
In this international, multicenter, randomized, noninferiority trial, we assigned 564 preterm infants (gestational age, ≥28 weeks 0 days) with early respiratory distress who had not received surfactant replacement to treatment with either nasal high-flow therapy or nasal CPAP. The primary outcome was treatment failure within 72 hours after randomization. Noninferiority was determined by calculating the absolute difference in the risk of the primary outcome; the chosen margin of noninferiority was 10 percentage points. Infants in whom high-flow therapy failed could receive rescue CPAP; infants in whom CPAP failed were intubated and mechanically ventilated.
Trial recruitment stopped early at the recommendation of the independent data and safety monitoring committee because of a significant difference in the primary outcome between treatment groups. Treatment failure occurred in 71 of 278 infants (25.5%) in the high-flow group and in 38 of 286 infants (13.3%) in the CPAP group (risk difference, 12.3 percentage points; 95% confidence interval CI, 5.8 to 18.7; P<0.001). The rate of intubation within 72 hours did not differ significantly between the high-flow and CPAP groups (15.5% and 11.5%, respectively; risk difference, 3.9 percentage points; 95% CI, -1.7 to 9.6; P=0.17), nor did the rate of adverse events.
When used as primary support for preterm infants with respiratory distress, high-flow therapy resulted in a significantly higher rate of treatment failure than did CPAP. (Funded by the National Health and Medical Research Council and others; Australian New Zealand Clinical Trials Registry number, ACTRN12613000303741 .).
Data from clinical trials support the use of continuous positive airway pressure (CPAP) for initial respiratory management in preterm infants, but there is concern regarding the potential failure of ...CPAP support. We aimed to examine the incidence and explore the outcomes of CPAP failure in Australian and New Zealand Neonatal Network data from 2007 to 2013.
Data from inborn preterm infants managed on CPAP from the outset were analyzed in 2 gestational age ranges (25-28 and 29-32 completed weeks). Outcomes after CPAP failure (need for intubation <72 hours) were compared with those succeeding on CPAP using adjusted odds ratios (AORs).
Within the cohort of 19 103 infants, 11 684 were initially managed on CPAP. Failure of CPAP occurred in 863 (43%) of 1989 infants commencing on CPAP at 25-28 weeks' gestation and 2061 (21%) of 9695 at 29-32 weeks. CPAP failure was associated with a substantially higher rate of pneumothorax, and a heightened risk of death, bronchopulmonary dysplasia (BPD) and other morbidities compared with those managed successfully on CPAP. The incidence of death or BPD was also increased: (25-28 weeks: 39% vs 20%, AOR 2.30, 99% confidence interval 1.71-3.10; 29-32 weeks: 12% vs 3.1%, AOR 3.62 2.76-4.74). The CPAP failure group had longer durations of respiratory support and hospitalization.
CPAP failure in preterm infants is associated with increased risk of mortality and major morbidities, including BPD. Strategies to promote successful CPAP application should be pursued vigorously.
Clinicians aim to extubate preterm infants as early as possible, to minimize the risks of mechanical ventilation. Extubation is often unsuccessful owing to lung disease or inadequate respiratory ...drive.
To conduct a systematic review and meta-analysis of interventions to improve rates of successful extubation in preterm infants.
Searches were undertaken in PubMed and The Cochrane Library.
The review was conducted using the methods of the Cochrane Collaboration and Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Studies were included if they were randomized clinical trials published in English, enrolled intubated preterm infants (born <37 weeks' gestation), and reported 1 or both of the primary outcomes.
One thousand three hundred seventy-nine titles were screened independently by 2 investigators to assess need for full-text review. Disagreements were resolved via consensus of all authors. Where no Cochrane Review existed for an intervention, or not all identified studies were included, a new pooled analysis was performed.
Primary outcomes were treatment failure or reintubation within 7 days of extubation.
Fifty studies were eligible for inclusion. Continuous positive airway pressure reduced extubation failure in comparison with head-box oxygen (risk ratio RR, 0.59; 95% CI, 0.48-0.72; number needed to treat NNT, 6; 95% CI, 3-9). Nasal intermittent positive pressure ventilation was superior to continuous positive airway pressure in preventing extubation failure (RR, 0.70; 95% CI, 0.60-0.81; NNT, 8; 95% CI, 5-13). High-flow nasal cannula therapy and continuous positive airway pressure had similar efficacy (RR, 1.11; 95% CI, 0.84-1.47). Methylxanthines reduced extubation failure (RR, 0.48; 95% CI, 0.32-0.71; NNT, 4; 95% CI, 2-7) compared with placebo or no treatment. Corticosteroids (RR, 0.18; 95% CI, 0.04-0.97; NNT, 12; 95% CI, 6-100) and chest physiotherapy (RR, 0.32; 95% CI, 0.13-0.82; NNT, 15; 95% CI, 7-50) both reduced extubation failure rates but were associated with significant adverse effects. Doxapram did not aid successful extubation (RR, 0.80; 95% CI, 0.22-2.97).
Preterm infants should be extubated to noninvasive respiratory support. Caffeine should be used routinely, while corticosteroids should be used judiciously, weighing up the competing risks of bronchopulmonary dysplasia and neurodevelopmental harm.
Very preterm infants often require respiratory support and are therefore exposed to an increased risk of bronchopulmonary dysplasia (chronic lung disease) and later neurodevelopmental disability. ...Caffeine is widely used to prevent and treat apnea (temporal cessation of breathing) associated with prematurity and facilitate extubation. Though widely recognized dosage regimes have been used for decades, higher doses have been suggested to further improve neonatal outcomes. However, observational studies suggest that higher doses may be associated with harm.
To determine the effects of higher versus standard doses of caffeine on mortality and major neurodevelopmental disability in preterm infants with (or at risk of) apnea, or peri-extubation.
We searched CENTRAL, MEDLINE, Embase, CINAHL, the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP), and clinicaltrials.gov in May 2022. The reference lists of relevant articles were also checked to identify additional studies.
We included randomized (RCTs), quasi-RCTs and cluster-RCTs, comparing high-dose to standard-dose strategies in preterm infants. High-dose strategies were defined as a high-loading dose (more than 20 mg of caffeine citrate/kg) or a high-maintenance dose (more than 10 mg of caffeine citrate/kg/day). Standard-dose strategies were defined as a standard-loading dose (20 mg or less of caffeine citrate/kg) or a standard-maintenance dose (10 mg or less of caffeine citrate/kg/day). We specified three additional comparisons according to the indication for commencing caffeine: 1) prevention trials, i.e. preterm infants born at less than 34 weeks' gestation, who are at risk for apnea; 2) treatment trials, i.e. preterm infants born at less than 37 weeks' gestation, with signs of apnea; 3) extubation trials: preterm infants born at less than 34 weeks' gestation, prior to planned extubation.
We used standard methodological procedures expected by Cochrane. We evaluated treatment effects using a fixed-effect model with risk ratio (RR) for categorical data and mean, standard deviation (SD), and mean difference (MD) for continuous data. MAIN RESULTS: We included seven trials enrolling 894 very preterm infants (reported in Comparison 1, i.e. any indication). Two studies included infants for apnea prevention (Comparison 2), four studies for apnea treatment (Comparison 3) and two for extubation management (Comparison 4); in one study, indication for caffeine administration was both apnea treatment and extubation management (reported in Comparison 1, Comparison 3 and Comparison 4). In the high-dose groups, loading and maintenance caffeine doses ranged from 30 mg/kg to 80 mg/kg, and 12 mg/kg to 30 mg/kg, respectively; in the standard-dose groups, loading and maintenance caffeine doses ranged from 6 mg/kg to 25 mg/kg, and 3 mg/kg to 10 mg/kg, respectively. Two studies had three study groups: infants were randomized in three different doses (two of them matched our definition of high dose and one matched our definition of standard dose); high-dose caffeine and standard-dose caffeine were compared to theophylline administration (the latter is included in a separate review). Six of the seven included studies compared high-loading and high-maintenance dose to standard-loading and standard-maintenance dose, whereas in one study standard-loading dose and high-maintenance dose was compared to standard-loading dose and standard-maintenance dose. High-dose caffeine strategies (administration for any indication) may have little or no effect on mortality prior to hospital discharge (risk ratio (RR) 0.86, 95% confidence of interval (CI) 0.53 to 1.38; risk difference (RD) -0.01, 95% CI -0.05 to 0.03; I² for RR and RD = 0%; 5 studies, 723 participants; low-certainty evidence). Only one study enrolling 74 infants reported major neurodevelopmental disability in children aged three to five years (RR 0.79, 95% CI 0.51 to 1.24; RD -0.15, 95% CI -0.42 to 0.13; 46 participants; very low-certainty evidence). No studies reported the outcome mortality or major neurodevelopmental disability in children aged 18 to 24 months and 3 to 5 years. Five studies reported bronchopulmonary dysplasia at 36 weeks' postmenstrual age (RR 0.75, 95% CI 0.60 to 0.94; RD -0.08, 95% CI -0.15 to -0.02; number needed to benefit (NNTB) = 13; I² for RR and RD = 0%; 723 participants; moderate-certainty evidence). High-dose caffeine strategies may have little or no effect on side effects (RR 1.66, 95% CI 0.86 to 3.23; RD 0.03, 95% CI -0.01 to 0.07; I² for RR and RD = 0%; 5 studies, 593 participants; low-certainty evidence). The evidence is very uncertain for duration of hospital stay (data reported in three studies could not be pooled in meta-analysis because outcomes were expressed as medians and interquartile ranges) and seizures (RR 1.42, 95% CI 0.79 to 2.53; RD 0.14, 95% CI -0.09 to 0.36; 1 study, 74 participants; very low-certainty evidence). We identified three ongoing trials conducted in China, Egypt, and New Zealand.
High-dose caffeine strategies in preterm infants may have little or no effect on reducing mortality prior to hospital discharge or side effects. We are very uncertain whether high-dose caffeine strategies improves major neurodevelopmental disability, duration of hospital stay or seizures. No studies reported the outcome mortality or major neurodevelopmental disability in children aged 18 to 24 months and 3 to 5 years. High-dose caffeine strategies probably reduce the rate of bronchopulmonary dysplasia. Recently completed and future trials should report long-term neurodevelopmental outcome of children exposed to different caffeine dosing strategies in the neonatal period. Data from extremely preterm infants are needed, as this population is exposed to the highest risk for mortality and morbidity. However, caution is required when administering high doses in the first hours of life, when the risk for intracranial bleeding is highest. Observational studies might provide useful information regarding potential harms of the highest doses.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is rarely fatal in children and young people (CYP, <18 years old), but quantifying the risk of death is challenging because CYP ...are often infected with SARS-CoV-2 exhibiting no or minimal symptoms. To distinguish between CYP who died as a result of SARS-CoV-2 infection and those who died of another cause but were coincidentally infected with the virus, we undertook a clinical review of all CYP deaths with a positive SARS-CoV-2 test from March 2020 to February 2021. The predominant SARS-CoV-2 variants were wild-type and Alpha. Here we show that, of 12,023,568 CYP living in England, 3,105 died, including 61 who were positive for SARS-CoV-2. Of these deaths, 25 were due to SARS-CoV-2 infection (mortality rate, two per million), including 22 due to coronavirus disease 2019-the clinical disease associated with SARS-CoV-2 infection-and 3 were due to pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2. In total, 99.995% of CYP with a positive SARS-CoV-2 test survived. CYP older than 10 years, Asian and Black ethnic backgrounds and comorbidities were over-represented in SARS-CoV-2-related deaths compared with other CYP deaths. These results are important for guiding decisions on shielding and vaccinating children. New variants might have different mortality risks and should be evaluated in a similar way.
In the absence of effective interventions to prevent preterm births, improved survival of infants who are born at the biological limits of viability has relied on advances in perinatal care over the ...past 50 years. Except for extremely preterm infants with suboptimal perinatal care or major antenatal events that cause severe respiratory failure at birth, most extremely preterm infants now survive, but they often develop chronic lung dysfunction termed bronchopulmonary dysplasia (BPD; also known as chronic lung disease). Despite major efforts to minimize injurious but often life-saving postnatal interventions (such as oxygen, mechanical ventilation and corticosteroids), BPD remains the most frequent complication of extreme preterm birth. BPD is now recognized as the result of an aberrant reparative response to both antenatal injury and repetitive postnatal injury to the developing lungs. Consequently, lung development is markedly impaired, which leads to persistent airway and pulmonary vascular disease that can affect adult lung function. Greater insights into the pathobiology of BPD will provide a better understanding of disease mechanisms and lung repair and regeneration, which will enable the discovery of novel therapeutic targets. In parallel, clinical and translational studies that improve the classification of disease phenotypes and enable early identification of at-risk preterm infants should improve trial design and individualized care to enhance outcomes in preterm infants.
Background
Globally, the majority of newborns requiring resuscitation at birth are full term or late-preterm infants. These infants typically have their umbilical cord clamped early (ECC) before ...moving to a resuscitation platform, losing the potential support of the placental circulation. Physiologically based cord clamping (PBCC) is clamping the umbilical cord after establishing lung aeration and holds promise as a readily available means of improving early newborn outcomes. In mechanically ventilated lambs, PBCC improved cardiovascular stability and reduced hypoxia. We hypothesised that PBCC compared to ECC would result in higher heart rate (HR) in infants needing resuscitation, without compromising safety.
Methods and findings
Between 4 July 2018 and 18 May 2021, infants born at ≥32
+0
weeks’ gestation with a paediatrician called to attend were enrolled in a parallel-arm randomised trial at 2 Australian perinatal centres. Following initial stimulation, infants requiring further resuscitation were randomised within 60 seconds of birth using a smartphone-accessible web link. The intervention (PBCC) was to establish lung aeration, either via positive pressure ventilation (PPV) or effective spontaneous breathing, prior to cord clamping. The comparator was early cord clamping (ECC) prior to resuscitation. The primary outcome was mean HR between 60 to 120 seconds after birth, measured using 3-lead electrocardiogram, extracted from video recordings blinded to group allocation. Nonrandomised infants had deferred cord clamping (DCC) ≥120 seconds in the observational study arm.
Among 508 at-risk infants enrolled, 123 were randomised (
n =
63 to PBCC,
n
= 60 to ECC). Median (interquartile range, IQR) for gestational age was 39.9 (38.3 to 40.7) weeks in PBCC infants and 39.6 (38.4 to 40.4) weeks in ECC infants. Approximately 49% and 50% of the PBCC and ECC infants were female, respectively. Five infants (PBCC = 2, ECC = 3, 4% total) had missing primary outcome data. Cord clamping occurred at a median (IQR) of 136 (126 to 150) seconds in the PBCC arm and 37 (27 to 51) seconds in the ECC arm. Mean HR between 60 to 120 seconds after birth was 154 bpm (beats per minute) for PBCC versus 158 bpm for ECC (adjusted mean difference −6 bpm, 95% confidence interval (CI) −17 to 5 bpm,
P
= 0.39). Among 31 secondary outcomes, postpartum haemorrhage ≥500 ml occurred in 34% and 32% of mothers in the PBCC and ECC arms, respectively. Two hundred ninety-five nonrandomised infants (55% female) with median (IQR) gestational age of 39.6 (38.6 to 40.6) weeks received DCC. Data from these infants was used to create percentile charts of expected HR and oxygen saturation in vigorous infants receiving DCC. The trial was limited by the small number of infants requiring prolonged or advanced resuscitation. PBCC may provide other important benefits we did not measure, including improved maternal–infant bonding and higher iron stores.
Conclusions
In this study, we observed that PBCC resulted in similar mean HR compared to infants receiving ECC. The findings suggest that for infants ≥32
+0
weeks’ gestation who receive brief, effective resuscitation at closely monitored births, PBCC does not provide additional benefit over ECC (performed after initial drying and stimulation) in terms of key physiological markers of transition. PBCC was feasible using a simple, low-cost strategy at both cesarean and vaginal births. The percentile charts of HR and oxygen saturation may guide clinicians monitoring the transition of at-risk infants who receive DCC.
Trial registration
Australian New Zealand Clinical Trials Registry (ANZCTR)
ACTRN12618000621213
.
The goal was to define reference ranges for pulse oxygen saturation (Spo(2)) values in the first 10 minutes after birth for infants who received no medical intervention in the delivery room.
Infants ...were eligible if a member of the research team was available to record Spo(2) immediately after birth. Infants were excluded if they received supplemental oxygen or any type of assisted ventilation. Spo(2) was measured with a sensor applied to the right hand or wrist as soon as possible after birth; data were collected every 2 seconds.
We studied 468 infants and recorded 61650 Spo(2) data points. The infants had a mean + or - SD gestational age of 38 + or - 4 weeks and birth weight of 2970 + or - 918 g. For all 468 infants, the 3rd, 10th, 50th, 90th, and 97th percentile values at 1 minute were 29%, 39%, 66%, 87%, and 92%, respectively, those at 2 minutes were 34%, 46%, 73%, 91%, and 95%, and those at 5 minutes were 59%, 73%, 89%, 97%, and 98%. It took a median of 7.9 minutes (interquartile range: 5.0-10 minutes) to reach a Spo(2) value of >90%. Spo(2) values for preterm infants increased more slowly than those for term infants. We present percentile charts for all infants, term infants of > or = 37 weeks, preterm infants of 32 to 36 weeks, and extremely preterm infants of <32 weeks.
These data represent reference ranges for Spo(2) in the first 10 minutes after birth for preterm and term infants.
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