Summary
Goal To check the speculation that non-invasive excessive frequency oscillatory air flow (NHFOV) is extra efficacious than nasal steady optimistic airway strain (NCPAP) in decreasing invasive mechanical air flow as major respiratory assist for very preterm infants with respiratory misery syndrome.
Design A multicentre, randomised managed trial.
Setting Twenty tertiary neonatal intensive care models in China.
Members 342 extraordinarily preterm infants (gestational age between 24 weeks +0 day and 28 weeks +6 days) with respiratory misery syndrome had been enrolled within the research between August 2022 and August 2024.
Interventions Members had been randomly allotted to obtain NCPAP or NHFOV as major respiratory assist for respiratory misery syndrome.
Essential end result measures The first end result was therapy failure, outlined as the necessity for invasive mechanical air flow inside 72 hours after delivery.
Outcomes Remedy failure inside 72 hours occurred in 27 of` 170 infants (15.9%) within the NHFOV group and 48 of 172 infants (27.9%) within the NCPAP group (threat distinction −12.0 proportion factors, 95% confidence interval −20.7 to −3.4; P=0.007). Remedy failure inside seven days was additionally decrease within the NHFOV group (−12.5 proportion factors, 95% confidence interval −21.9 to −3.2; P=0.008) in contrast with the NCPAP group. All noticed associations remained vital after sensitivity evaluation together with research websites and antenatal steroid use. No vital variations had been present in every other secondary outcomes between the 2 teams.
Conclusions NHFOV appeared superior to NCPAP in decreasing the necessity for intubation when used as a major respiratory assist technique in extraordinarily preterm infants. Each methods didn’t present vital variations in neonatal opposed occasions.
Introduction
Respiratory misery syndrome is a number one reason for respiratory failure in extraordinarily preterm infants (≤28 weeks of gestational age).1 Tracheal intubation and invasive mechanical air flow have considerably improved the survival charges of those infants.2 Nevertheless, extended invasive mechanical air flow is related to an elevated threat of ventilator induced lung damage, which might result in bronchopulmonary dysplasia.3 Consequently, European consensus tips suggest nasal steady optimistic airway strain (NCPAP) as the popular first line respiratory assist technique for respiratory misery syndrome.4 Nevertheless, cumulative proof has urged that as much as 40% of extraordinarily preterm infants are susceptible to a excessive threat of NCPAP failure due to chest wall collapse and poor diaphragmatic power.56
Non-invasive excessive frequency oscillatory air flow (NHFOV) applies a steady distending strain with energetic oscillations superimposed on spontaneous tidal respiration, enabling carbon dioxide elimination and alveolar recruitment with out requiring synchronisation.7 Though surfactant and NCPAP stay first line remedies for respiratory misery syndrome, rising proof reveals that early hypercapnia happens in a major minority of those infants, significantly these with chest wall immaturity or delayed surfactant administration.8 NHFOV might present twin physiological benefits over NCPAP by sustaining lung recruitment whereas actively clearing carbon dioxide via oscillatory fuel mixing—a mechanism significantly helpful for non-uniformly diseased lungs.9 Due to these potential benefits, NHFOV has seen rising adoption, particularly in sure European international locations.10 When used as assist after extubation, NHFOV reduces reintubation charges in contrast with NCPAP.11 Nevertheless, its efficacy as major respiratory assist for respiratory misery syndrome in preterm infants stays unproven.
A number of randomised managed trials evaluating NHFOV and NCPAP have reported inconsistent findings about their effectiveness in managing respiratory misery syndrome.12131415 To deal with this hole, we performed a multicentre randomised managed trial to check the effectiveness of NHFOV and NCPAP as major respiratory assist in extraordinarily preterm infants with respiratory misery syndrome. We hypothesised that NHFOV could be more practical than NCPAP in decreasing therapy failure inside 72 hours after delivery in a homogeneous inhabitants of Chinese language extraordinarily preterm infants.
Strategies
Examine design
This multicentre, randomised managed superiority trial was performed throughout 20 tertiary neonatal intensive care models in 13 provinces, autonomous areas, and municipalities in China from August 2022 to August 2024 (supplementary eTable 1). The research was permitted by the ethics committee of the Kids’s Hospital of Chongqing Medical College (No 2019.161) and was registered at ClinicalTrials.gov (NCT05141435). The trial protocol was beforehand revealed, offering full particulars of the strategies.16 All authors reviewed the protocol and ensured adherence all through the trial. Knowledgeable consent was obtained from dad and mom or guardians antenatally or upon admission to the neonatal intensive care unit, and information had been anonymised in accordance with related native rules. The trial was performed in compliance with CONSORT (consolidated requirements of reporting trials) tips.17 Sufferers or the general public weren’t concerned within the design, or conduct, or reporting, or dissemination plans of our analysis.
Examine individuals
Newborns had been enrolled in the event that they met all the following standards: gestational age between 24 weeks +0 day and 28 weeks +6 days; prognosis of respiratory misery syndrome and prerandomisation assist with NCPAP set at 6 cm H2O of optimistic finish expiratory strain (after supply room stabilisation at 6-8 cm H2O per native tips) with a fraction of impressed oxygen (FiO2) >0.25 to keep up a goal peripheral oxygen saturation (SpO2) of 89-94%; lower than two hours after delivery on the time of enrolment; and knowledgeable parental consent obtained earlier than randomisation. Infants had been excluded within the presence of any of the next: intubation at delivery for any motive; main congenital malformations or recognized complicated congenital coronary heart illness; and switch out of the neonatal intensive care unit earlier than randomisation.
Randomisation and masking
Eligible newborns had been randomly assigned to obtain NCPAP or NHFOV upon assembly all inclusion standards. Easy randomisation was carried out utilizing a pc generated random quantity sequence, which was securely posted on a devoted, password protected web site accessible 24/7. Randomisation was centrally managed by the web site, making certain allocation concealment from investigators. Infants had been stratified based on centre. Crossover between research arms was not permitted all through the research interval to keep up protocol integrity.
Owing to the character of the intervention with the distinct traits of the air flow modalities, masking of care givers was not possible, and masking of sufferers was not relevant. Nevertheless, end result assessors had been masked to the therapy allocation to minimise ascertainment bias. Consequence information had been recorded by investigators who weren’t a part of the neonatal intensive care unit workers and who reviewed affected person recordsdata with masked therapy assignments. A devoted assessor was designated for every recruiting neonatal intensive care unit to make sure unbiased analysis.
Examine process
Within the supply room, all eligible infants who had been spontaneously respiration acquired NCPAP stabilisation at 6–8 cm H2O and had been transferred to the neonatal intensive care unit with steady NCPAP assist. After admission to the neonatal intensive care unit, all enrolled infants had been maintained on standardised NCPAP at 6 cm H2O for no less than half-hour earlier than randomisation to determine uniform baseline respiratory assist circumstances.
Steady circulation gadgets (Comen NV8, China; Mindray NB350, China; supplementary eTable 2) had been used to supply NCPAP. Newborns randomised to the NCPAP group had been began on a optimistic finish expiratory strain of 6 cm H2O, with changes as much as a most of 10 cm H2O based on oxygenation (in increments of 1 cm H2O). The FiO2 was began at 25%, with changes as much as a most of 40% (in increments of 5%) to keep up a preductal SpO2 goal of 89-94%.
NHFOV was delivered utilizing piston or membrane oscillators able to energetic expiration, together with the Fabian-III (Acutronic, Switzerland), SLE 5000 (SLE (UK)) and Leoni+ (Löwenstein Medical, Germany; supplementary eTable 2). Newborns randomised to NHFOV had been began with the next parameters: imply airway strain 6 cm H2O (adjustable in 1 cm H2O increments inside a spread of 6–10 cm H2O based on oxygenation); frequency 10 Hz (modifiable in 1 Hz increments inside a spread of 8–12 Hz); inspiratory time 50% (1:1 ratio)18; amplitude 15 cm H2O (modifiable in 5 cm H2O increments inside a spread of 15–30 cm H2O).
NCPAP and NHFOV had been administered utilizing the identical brief binasal prongs as a result of these characterize the usual of care within the taking part neonatal intensive care models and provide the bottom resistance and minimal leakage.1920 Prong measurement was chosen primarily based on the diameter of the nares, making certain the most effective match—the most important prongs that match the nares with out inflicting blanching of the encircling tissues. To minimise air leaks, particular consideration was given to supportive measures, together with the usage of pacifiers and optimum positioning. Ventilatory parameters had been managed and weaned as outlined within the trial protocol.16 Instructed preliminary and most settings for respiratory assist had been offered to the research websites. To make sure protocol adherence, a devoted coaching programme was deployed to disseminate this ventilatory administration coverage to all taking part neonatal intensive care models.
Caffeine administration
Prophylactic caffeine therapy (caffeine citrate injection, Chiesi Prescribed drugs, Parma, Italy) was administered throughout the first 24 hours after delivery.4 The preliminary loading dose was 20 mg/kg, adopted by a upkeep dose of 5 mg/kg per day. Caffeine therapy was discontinued as soon as apnea resolved or when the toddler reached 36 weeks of corrected gestational age.
Surfactant therapy
Surfactant therapy (Curosurf, Chiesi Prescribed drugs) was administered at a dose of 200 mg/kg if FiO2 >30% on optimistic finish expiratory strain or imply airway strain≥6 cm H2O was required to keep up a goal SpO2 of 89-94% utilizing the much less invasive surfactant administration method.4 A repeat dose of surfactant of 100 mg/kg was administered if crucial. Surfactant doses got at 6-12 hour intervals, with a most of 4 doses permitted.
Different remedies
Antibiotics are incessantly began in newborns with respiratory misery syndrome till sepsis is excluded. Fluid therapy begins at roughly 70-80 mL/kg/day, with subsequent changes individualised primarily based on fluid stability, weight adjustments, and serum electrolyte ranges. Cardiac ultrasound ought to be carried out throughout the first three days of life to judge cardiac morphology, pulmonary pressures, and patent ductus arteriosus. If a haemodynamically vital patent ductus arteriosus is recognized, it’s handled with ibuprofen: an preliminary dose of 10 mg/kg adopted by two 5 mg/kg doses at 24 hour intervals, sometimes administered orally. Ought to the haemodynamically vital patent ductus arteriosus fail to shut after two programs of ibuprofen and considerably compromise cardiopulmonary operate, surgical ligation is taken into account.
Major end result
The first end result was respiratory assist failure, outlined by the necessity for invasive mechanical air flow inside 72 hours after delivery. Respiratory assist failure was thought-about current if any of the next standards had been met: extreme respiratory acidosis, outlined as partial strain of CO2 >60 mm Hg with pH <7.2 for at the very least one hour; hypoxia refractory to check intervention, outlined as SpO2 <90% regardless of FiO2 ≥0.4 and most allowable pressures throughout the assigned research arm, persisting for at the very least one hour after surfactant administration; extreme apnea, outlined as recurrent apnea (greater than three episodes per hour) related to a coronary heart charge <100/min or a single apnea episode requiring bag masks air flow; and pressing intubation as decided by the attending doctor.
Secondary outcomes
Prespecified secondary outcomes included causes for therapy failure, the necessity for invasive mechanical air flow inside seven days after delivery, different problems like problems of prematurity akin to surfactant therapy, length of supplemental oxygen, bronchopulmonary dysplasia outlined in 2019,21 intraventricular haemorrhage,22 necrotising enterocolitis,23 retinopathy of prematurity,24 and haemodynamically vital patent ductus arteriosus.25
Security outcomes
Critical opposed occasions had been outlined as pneumothorax or different air leaks occurring throughout the assigned therapy and demise in hospital. Moreover, thick secretions inflicting an airway obstruction and grade III-IV nasal damage.26
Statistical evaluation
Based mostly on the outcomes of a latest multicentre research, the estimated threat of therapy failure with NCPAP in extraordinarily preterm infants with respiratory misery syndrome was 30%, with a 20% discount anticipated for infants receiving NHFOV.12 To make sure sufficient statistical energy with a comparatively conservative estimate, we aimed to detect a 15% absolute distinction within the charge of respiratory assist failure between teams. With a significance degree (α) of 0.05 and 90% energy, a pattern measurement of 170 newborns per group was required, resulting in a complete enrolment goal of at the very least 340.
Outcomes had been analysed on an intention-to-treat foundation. For dichotomous outcomes, the chance distinction in proportion factors with a 95% confidence interval was calculated between research arms. For steady outcomes, the imply distinction with a 95% confidence interval or the Hodges-Lehmann median distinction with interquartile vary was reported, as applicable. Comparisons had been carried out utilizing Scholar’s t check for parametric steady variables, Mann-Whitney U check for non-parametric steady variables, and χ2 check for dichotomous variables, respectively. A two tailed P worth <0.05 was thought-about statistically vital. All statistical analyses had been performed in R software program (model 4.4.2).
Affected person and public involvement
No dad and mom had been concerned in setting the analysis query or the end result measures, nor had been they concerned in growing plans for recruitment, design, or implementation of the research. No sufferers had been requested to advise on interpretation or writing up of outcomes. It was not the coverage of the concerned establishments to incorporate dad and mom or members of the general public in planning or choice making processes on the time when the research was deliberate, submitted to moral committees and funding businesses, and began.
Outcomes
Examine inhabitants
From August 2022 to August 2024, 20 websites screened 684 infants. Of those, 360 met the eligibility standards and consent was offered by dad and mom or guardians. This consent was withdrawn earlier than randomisation for 18 newborns, leaving 342 preterm infants to proceed to randomisation. These infants acquired routine medical care, and their trial information had been destroyed in accordance with moral tips. Consequently, information from 342 newborns had been included within the last evaluation (fig 1). Baseline traits had been properly balanced between the 2 teams aside from medical threat index for infants II rating (P=0.05) and PaO2 earlier than enrolment (P=0.02), which is considerably greater within the NHFOV group (desk 1). The interim evaluation didn’t reveal any security issues, and the trial was accomplished with out main opposed occasions, discontinuation, or protocol modifications.
Baseline traits in NHFOV and NCPAP teams*
Major end result
Remedy failure inside 72 hours after delivery occurred in 27 of 170 infants (15.9%) within the NHFOV group and 48 of 172 (27.9%) within the NCPAP group (threat distinction −12.0 proportion factors, 95% confidence interval −20.7 to −3.4; P=0.007; desk 2). The explanations for therapy failure inside 72 hours after supply didn’t differ considerably between the NHFOV and NCPAP teams, with hypoxia reported as the most typical motive (70.4%, 19/27 v 66.7%, 32/48), adopted by apnea (14.8%, 4/27 v 18.8%, 9/48), respiratory acidosis (7.4%, 2/27 v 8.3%, 4/48), and pressing want for intubation (7.4%, 2/27 v 6.2%, 3/48; fig 2), respectively. Nevertheless, these with reported hypoxia appeared to have borderline discount in threat within the NHFOV group in contrast with the NCPAP group (−7.4 proportion factors, 95% confidence interval −14.9 to 0.1; P=0.05; desk 2). Moreover, NHFOV offered higher oxygenation at 24 hours after intervention (supplementary eTable 3). To account for baseline distinction between the 2 teams, we additionally carried out a sensitivity evaluation by moreover adjusting for medical threat index for infants II rating, PaO2, research websites, and use of antenatal steroid individually in all examined associations, and the importance was not attenuated (supplementary eTables 4 and 5).
Comparability of threat distinction between NHFOV and NCPAP in therapy failure inside 72 hours after delivery amongst extraordinarily preterm infants
Pie chart displaying causes for therapy failure inside first 72 hours in NHFOV (n=27) and NCPAP (n=48) teams. NCPAP=nasal steady optimistic airway strain; NHFOV=non-invasive excessive frequency oscillatory air flow
Secondary outcomes
Remedy failure inside seven days after delivery was reported in 36 of 170 infants (21.2%) within the NHFOV group and 58 of 172 (33.7%) within the NCPAP group (threat distinction −12.5 proportion factors, 95% confidence interval −21.9 to −3.2; P=0.008; desk 3). Moreover, no vital variations had been noticed between teams in surfactant administration, bronchopulmonary dysplasia incidence, bronchopulmonary dysplasia and mortality composite, length of research intervention, length of supplemental oxygen, and extrapulmonary outcomes (intraventricular haemorrhage, necrotising enterocolitis, retinopathy of prematurity, and haemodynamically vital patent ductus arteriosus; desk 3).
Secondary outcomes and security outcomes
Security outcomes
No vital variations had been noticed between teams for severe opposed occasions, together with charges of grade III-IV nasal damage, air leaks, demise in hospital, and thick secretions inflicting an airway obstruction (desk 3).
Dialogue
Principal findings
On this multicentre randomised managed trial, we discovered that NHFOV considerably decreased the necessity for invasive mechanical air flow inside 72 hours and inside seven days after delivery in contrast with NCPAP when utilized as the first strategy to respiratory misery syndrome in extraordinarily preterm infants. Moreover, there was no distinction between the teams in different respiratory and extra-respiratory secondary outcomes and opposed occasions.
Comparability with different research
Our findings ought to be contextualised inside earlier randomised managed trials evaluating NHFOV with NCPAP as major therapy for respiratory misery syndrome. Though Malakian and colleagues13 reported no vital discount in intubation charges with NHFOV versus NCPAP, their research inhabitants differed critically from ours: it included extra mature infants and had a smaller pattern measurement. Iranpour and colleagues14 confirmed a lot decrease intubation charges with NHFOV versus NCPAP in infants of comparable gestational age to Malakian et al’s cohort. Nevertheless, their research inhabitants encompassed infants with respiratory misery syndrome of various severity, together with these with extreme respiratory failure requiring FiO2 >0.6 at enrolment. Zhu and colleagues12 likewise reported that NHFOV considerably decreased intubation charges in preterm infants with reasonable to extreme respiratory misery syndrome in contrast with NCPAP. In a small randomised managed trial of infants weighing <1250 g after steady optimistic airway strain failure, Mukerji and colleagues27 in contrast NHFOV with biphasic steady optimistic airway strain and recognized a non-significant pattern in the direction of fewer intubations with NHFOV. Additional proof supporting NHFOV’s efficacy comes from Rüegger and colleagues,28 who discovered that NHFOV considerably decreased desaturation episodes and bradycardic occasions in very preterm infants in contrast with NCPAP. In distinction, Klotz and colleagues,29 in a small crossover trial of a comparable inhabitants, detected no vital enchancment in carbon dioxide clearance with NHFOV; nevertheless, the research was underpowered to judge medical outcomes akin to intubation charge. In a big multicentre, randomized managed trial, Zhu and colleagues15 confirmed that NHFOV considerably decreased therapy failure charges in contrast with NCPAP in preterm infants with gestational age <30 weeks and people with very low delivery weight. Taken collectively, these information recommend that NHFOV might mitigate the necessity for invasive mechanical air flow, significantly in infants of decrease gestational age or with extra extreme respiratory failure.
Though NHFOV considerably decreased intubation charges in contrast with NCPAP, we discovered no between group distinction in bronchopulmonary dysplasia incidence. This null discovering requires nuanced interpretation for 3 causes. Firstly, bronchopulmonary dysplasia pathogenesis includes multifactorial processes, together with mechanisms unbiased of ventilator induced damage.30 Secondly, our trial was underpowered for bronchopulmonary dysplasia as a secondary end result. Thirdly, we noticed a clinically significant, although non-significant, discount in bronchopulmonary dysplasia with NHFOV, suggesting potential lung protecting results that warrant analysis in bigger trials.
In prespecified security analyses, NHFOV and NCPAP confirmed comparable opposed occasion charges, reinforcing the medical feasibility of NHFOV as a respiratory assist modality for very preterm infants. This discovering is especially noteworthy provided that the excessive amplitude oscillations inherent to NHFOV may theoretically enhance the chance of problems akin to air leaks, secretion induced airway obstruction, or extreme (grade III-IV) nasal trauma. Our outcomes align with the security profile reported within the NASONE trial,9 offering additional proof that NHFOV doesn’t considerably enhance barotrauma threat—even at greater imply airway strain—when utilized below rigorous monitoring and applicable affected person choice. Nonetheless, we emphasise the necessity for individualised imply airway strain titration, as optimum strain settings might range relying on the underlying pathophysiology (eg, respiratory misery syndrome versus meconium aspiration syndrome). These observations recommend that earlier issues about NHFOV related barotrauma might have been overstated, offered clinicians adhere to standardised protocols for actual time adjustment and complication prevention.
Medical implications
This multicentre randomised managed trial is a big scale research evaluating NHFOV with NCPAP as major respiratory assist for respiratory misery syndrome in extraordinarily preterm infants. Our findings corroborate and lengthen the conclusions of two latest meta-analyses,3132 and supply new insights into NHFOV’s potential use in managing respiratory misery syndrome on this weak inhabitants.
The outcomes advance our present understanding by displaying that NHFOV is possible and probably advantageous as a major respiratory therapy for very preterm infants—a inhabitants notably underrepresented in earlier trials. This aligns with, and strengthens, earlier proof from retrospective research.333435 Importantly, our research design addressed a key historic limitation in evaluating NHFOV and NCPAP: variability in utilized airway pressures. By sustaining comparable strain ranges between modalities, we enabled a extra direct and clinically significant comparability.
Strengths and limitations
This research possesses a number of key strengths: enrolment of a big cohort of extraordinarily preterm infants; implementation of a rigorous, physiology focused protocol with standardised ventilatory administration; and execution throughout a longtime neonatal intensive care unit community the place all clinicians underwent protocol particular coaching. Taking part neonatologists included main educational consultants from the Chinese language Medical Physician Affiliation and the Chinese language Society of Perinatal Drugs, making certain technical proficiency and strict adherence to the research protocol. These options bolster the inner validity and medical applicability of our findings for comparable populations.
Nonetheless, a number of limitations ought to be acknowledged. Clinician masking was unfeasible owing to the inherently distinct interventions, which can have launched choice, efficiency, or detection bias. To deal with this, we used masked end result assessments and adhered to predefined goal standards. Though the much less invasive surfactant administration method decreased intubation dangers in contrast with INSURE (intubate-surfactant-extubate), most therapy failures stemmed from procedural problems (eg, derecruitment and uneven surfactant distribution36) relatively than respiratory modality efficacy. Moreover, though our protocol allowed clinician directed surfactant redosing at 6-12 hour intervals primarily based on respiratory parameters, latest pharmacokinetic proof suggests this strategy might require refinement.37
Our research targeted solely on the continual circulation steady optimistic airway strain machine and didn’t embrace the bubble steady optimistic airway strain system. Though bubble steady optimistic airway strain is extensively obtainable and usually inexpensive globally, its exclusion might restrict the generalisability and applicability of our findings to settings the place it stays the first system. Moreover, the usage of binasal prongs (to make sure consistency throughout facilities) precluded analysis of probably much less traumatic masks interfaces—a important comparability for future research, significantly relating to extended functions. Our cohort included comparatively few infants with gestational age <26 weeks (41/342, 12%), leaving the generalisability of outcomes to this subgroup unsure. Lastly, whereas our findings are sturdy for Chinese language extraordinarily preterm infants, broader exterior validity necessitates validation in additional numerous populations throughout various gestational ages and medical settings.
Conclusions
This randomised medical trial discovered that NHFOV considerably decreased the necessity for invasive mechanical air flow inside 72 hours and inside seven days after delivery in contrast with NCPAP when utilized as the first strategy to respiratory misery syndrome in extraordinarily preterm infants. Each respiratory assist methods had been equally protected.
What’s already recognized on this subject
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Earlier retrospective research and small scale observational trials urged that non-invasive excessive frequency oscillatory air flow (NHFOV) could also be superior to nasal steady optimistic airway strain (NCPAP) as a major respiratory therapy for preterm infants with respiratory misery syndrome
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Subsequent randomised managed trials evaluating NHFOV and NCPAP have yielded inconsistent findings for his or her efficacy to handle respiratory misery syndrome
What this research provides
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This randomised medical trial discovered that NHFOV considerably decreased the necessity for invasive mechanical air flow inside 72 hours and 7 days after delivery in contrast with NCPAP when utilized as the first strategy to respiratory misery syndrome in extraordinarily preterm infants
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Each respiratory assist methods had been discovered to be equally protected