Presión positiva continua de las vías respiratorias (del inglés CPAP) para la dificultad respiratoria en recién nacidos prematuros
Resumen
Antecedentes
La dificultad respiratoria, en particular el síndrome de dificultad respiratoria (SDR), es la causa más importante de morbilidad y mortalidad en los recién nacidos prematuros. En los recién nacidos con insuficiencia respiratoria progresiva, la ventilación con presión positiva intermitente (VPPI) con surfactante es el tratamiento estándar, pero es invasivo, lo que puede provocar lesiones en las vías respiratorias y los pulmones. La presión positiva continua de las vías respiratorias (del inglés CPAP) se ha utilizado para la prevención y el tratamiento de la dificultad respiratoria, así como para la prevención de la apnea, y en la desconexión de la VPPI. Su uso para el tratamiento del SDR puede reducir la necesidad de VPPI y sus secuelas.
Objetivos
Determinar el efecto de la presión de distensión continua en forma de CPAP sobre la necesidad de VPPI y la morbilidad asociada en recién nacidos prematuros que respiran espontáneamente con dificultad respiratoria.
Métodos de búsqueda
Se utilizó la estrategia estándar del Grupo Cochrane de Neonatología (Cochrane Neonatal Group) para buscar en CENTRAL (2020, número 6); Ovid MEDLINE y Epub Ahead of Print, In‐Process & Other Non‐Indexed Citations, Daily and Versions; y CINAHL el 30 de junio de 2020. También se buscaron ensayos controlados aleatorizados (ECA) y cuasialeatorizados en bases de datos de ensayos clínicos y en las listas de referencias de artículos obtenidos.
Criterios de selección
Fueron elegibles todos los ensayos aleatorizados o cuasialeatorizados en recién nacidos prematuros con dificultad respiratoria. Las intervenciones fueron CPAP por mascarilla, cánula nasal, tubo nasofaríngeo o tubo endotraqueal, en comparación con respiración espontánea con oxígeno suplementario, según fuera necesario.
Obtención y análisis de los datos
Se utilizaron los métodos estándar de Cochrane y de su Grupo de Revisión de Neonatología, incluida la evaluación independiente del riesgo de sesgo y la extracción de datos por dos autores de la revisión. Se utilizaron los criterios GRADE para evaluar la certeza de la evidencia.
Los análisis de subgrupos se planificaron sobre la en función del peso al nacer (mayor o menor de 1000 ó 1500 g), la edad gestacional (grupos divididos en aproximadamente 28 y 32 semanas), el momento de la aplicación (temprano versus tardío en el curso de la dificultad respiratoria), la presión aplicada (alta versus baja) y el contexto del ensayo (terciario en comparación con hospitales no terciarios; altos ingresos en comparación con bajos ingresos)
Resultados principales
Se incluyeron cinco estudios con 322 lactantes; dos estudios utilizaron CPAP con mascarilla facial, dos estudios utilizaron CPAP nasal y un estudio utilizó CPAP endotraqueal y presión negativa continua en un número pequeño de lactantes menos enfermos. En esta actualización se incluyó un ensayo nuevo.
La CPAP se asoció con un menor riesgo de fracaso del tratamiento (muerte o uso de ventilación asistida) (riesgo relativo [RR] típico 0,64; intervalo de confianza [IC] del 95%: 0,50 a 0,82; diferencia de riesgos [DR] típica ‐0,19; IC del 95%: ‐0,28 a ‐0,09; número necesario a tratar para lograr un desenlace beneficioso adicional [NNTB] 6; IC del 95%: 4 a 11; I2 = 50%; cinco estudios, 322 lactantes; evidencia de certeza muy baja), un menor uso de la ventilación asistida (RR típico 0,72; IC del 95%: 0,54 a 0,96; DR típica ‐0,13; IC del 95%: ‐0,25 a ‐0,02; NNTB 8; IC del 95%: 4 a 50; I2 = 55%; evidencia de certeza muy baja) y una menor mortalidad general (RR típico 0,53; IC del 95%: 0,34 a 0,83; DR típica ‐0,11; IC del 95%: ‐0,18 a ‐0,04; NNTB 9; IC del 95%: 2 a 13; I2 = 0%; cinco estudios, 322 lactantes; evidencia de certeza moderada). El uso de la CPAP se asocia con un aumento en el riesgo de neumotórax (RR típico 2,48; IC del 95%: 1,16 a 5,30; DR típica 0,09; IC del 95%: 0,02 a 0,16; número necesario a tratar para un desenlace perjudicial adicional [NNTD] 11; IC del 95%: 7 a 50; I2 = 0%; cuatro estudios; 274 lactantes; evidencia de certeza baja). No hubo evidencia de una diferencia en la displasia broncopulmonar, definida como dependencia del oxígeno a los 28 días (RR 1,04; IC del 95%: 0,35 a 3,13; I2 = 0%; dos estudios, 209 lactantes; evidencia de certeza muy baja). Los ensayos no notificaron sobre el uso de surfactante, hemorragia intraventricular, retinopatía del prematuro, enterocolitis necrosante ni desenlaces del desarrollo neurológico en la infancia.
Conclusiones de los autores
En los recién nacidos prematuros con dificultad respiratoria, la aplicación de la CPAP se asocia con una reducción de la insuficiencia respiratoria, el uso de la ventilación mecánica, mortalidad y un aumento de la tasa de neumotórax en comparación con la respiración espontánea con oxígeno suplementario a demanda. Tres de cinco de estos ensayos se realizaron en los años setenta. Por lo tanto, la aplicabilidad de estos resultados en la práctica actual no está clara. Es preciso considerar la posibilidad de realizar más estudios en contextos de escasos recursos y realizar estudios de investigación para determinar el nivel de presión más adecuado.
PICO
Resumen en términos sencillos
Presión positiva continua de las vías respiratorias para la dificultad respiratoria en recién nacidos prematuros
Pregunta de revisión: se quería saber si el uso de la presión positiva continua de las vías respiratorias (del inglés CPAP) en comparación con solo oxígeno reduciría de forma segura la muerte o el uso de la ventilación mecánica en los recién nacidos prematuros con dificultades respiratorias.
Antecedentes: las dificultades respiratorias debidas a la inmadurez de los pulmones son la causa más frecuente de muerte en los recién nacidos prematuros. Estas dificultades respiratorias suelen ser leves al poco tiempo de nacer y empeoran durante las primeras horas o días de vida. La atención habitual de los recién nacidos ligeramente enfermos consiste en la administración de oxígeno. Se puede administrar a través de una máscara, una sonda colocada en la nariz o a través de una campana (un casco de metacrilato con un flujo de oxígeno y aire). Los recién nacidos más enfermos requieren un ventilador mecánico, que respira por el recién nacido a través de un tubo insertado en los pulmones (tubo endotraqueal). Sin embargo, los ventiladores, aunque pueden salvar vidas, pueden dañar los pulmones, especialmente los inmaduros. En los recién nacidos prematuros este daño se conoce como displasia broncopulmonar (DBP). Una complicación de la ventilación es el colapso del pulmón (neumotórax), donde el aire se escapa del pulmón a través de un orificio en el espacio entre el pulmón y la pleura (su cubierta).
La CPAP es una forma relativamente simple de proporcionar asistencia respiratoria a un recién nacido que puede reducir el daño pulmonar. Este método se basa en que el recién nacido continúe respirando. Se aplica una presión continua por medio de una sonda en las fosas nasales (cánula binasal), una mascarilla que cubre sólo la nariz (mascarilla nasal), una mascarilla facial o por un tubo colocado en los pulmones (tubo endotraqueal). Esto abre las vías respiratorias del recién nacido y facilita la respiración.
La presión negativa continua (PNC) es una alternativa a la CPAP. El cuerpo del recién nacido se coloca en una cámara que expande los pulmones y facilita la respiración. La PNC es engorrosa y la CPAP la ha reemplazado. En esta actualización de la revisión no se han incluido estudios de PCN.
Fechas de la búsqueda: la búsqueda se realizó el 30 de junio de 2020.
Características de los estudios: se incluyeron cinco ensayos que reclutaron 322 recién nacidos.
Tres estudios se realizaron en la década de 1970, uno en 2007 y otro en 2020 en un contexto de bajos recursos. Pocos de los recién nacidos, de haber alguno, pesaban menos de 1000 g al nacer. Todos los estudios notificaron sobre si la CPAP redujo la muerte o el fracaso del tratamiento (que incluyó la muerte o la ventilación). Cuatro estudios notificaron sobre si la CPAP redujo el uso de los ventiladores.
Resultados clave: se encontró que cerca de la mitad de los recién nacidos que recibieron sólo oxígeno complementario tuvieron un fracaso del tratamiento (murieron o recibieron ventilación), de tal manera que si 1000 recién nacidos fueran tratados, 519 fracasarían en el tratamiento. La CPAP redujo esta cifra a un tercio, de tal manera que si se trataran 1000 recién nacidos, 332 presentarían fracaso del tratamiento o entre 259 y 425 por 1000. Sin embargo, debido al riesgo de sesgo, a las diferencias entre los estudios y al pequeño tamaño muestral y al contexto (hace más de 40 años de la realización de tres estudios), hay muy poca certeza sobre este efecto. Tampoco hay certeza acerca de si se redujo la ventilación sola. Es probable que la muerte se reduzca de 235 por 1000 a entre 80 por 1000 y 195 por 1000.
El neumotórax puede ser más frecuente con la CPAP. No hubo información suficiente para mostrar si hubo una diferencia en la tasa de DBP. No hay información sobre otras complicaciones importantes ni sobre si hay alguna diferencia más adelante en la infancia.
Authors' conclusions
Summary of findings
| CPAP compared to supplemental oxygen for respiratory distress in preterm infants | ||||||
| Patient or population: respiratory distress in preterm infants | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with supplemental oxygen | Risk with CPAP | |||||
| Treatment failure (death or use of additional ventilatory support) | Study population | RR 0.64 | 322 (5 RCTs) | ⊕⊝⊝⊝ | Downgraded for lack of blinding because need of additional ventilatory support is a subjective outcome. | |
| 519 per 1000 | 332 per 1000 | |||||
| Use of assisted ventilation | Study population | RR 0.72 | 233 (3 RCTs) | ⊕⊝⊝⊝ | Downgraded for lack of blinding because need of additional ventilatory support is a subjective outcome. | |
| 492 per 1000 | 354 per 1000 | |||||
| Mortality | Study population | RR 0.53 | 322 (5 RCTs) | ⊕⊕⊕⊝ | Not downgraded for lack of blinding because mortality is considered an objective outcome. | |
| 235 per 1000 | 124 per 1000 | |||||
| Pneumothorax occurring after allocation | Study population | RR 2.91 | 270 (4 RCTs) | ⊕⊕⊝⊝ | Not downgraded for lack of blinding because pneumothorax is considered an objective outcome. | |
| 58 per 1000 | 150 per 1000 | |||||
| Bronchopulmonary dysplasia (oxygen dependency at 28 days) | Study population | RR 1.04 | 209 (2 RCTs) | ⊕⊝⊝⊝ | Not downgraded for lack of blinding because bronchopulmonary dysplasia is considered an objective outcome. | |
| 56 per 1000 | 58 per 1000 | |||||
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; CPAP: continuous positive airway pressure; RCT: randomised controlled trial; RR: risk ratio. | ||||||
| GRADE Working Group grades of evidence | ||||||
| aDowngraded one level due to lack of blinding of the intervention for a subjective outcome. | ||||||
Background
Description of the condition
Respiratory failure due to pulmonary disease, particularly respiratory distress syndrome (RDS), is the most important cause of morbidity and mortality in preterm infants (Manuck 2016; WHO 2012). Most causes of respiratory distress present in a similar manner, which makes precise diagnosis difficult. Intermittent positive pressure ventilation (IPPV) with surfactant treatment is the standard treatment for RDS. The major difficulty with IPPV is that it is invasive and contributes to airway and lung injury, including the development of bronchopulmonary dysplasia (BPD). Surfactant has brought some amelioration to this problem (Soll 1998).
Description of the intervention
Therapy for respiratory distress traditionally consisted of oxygen given via headbox, low‐flow nasal prong or cannula, or face mask. Infants with severe disease received IPPV. Continuous distending pressure (CDP) either as a continuous positive airway pressure (CPAP) or continuous negative pressure (CNP) pressure 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 was first proposed for the treatment of RDS as early as 1971 as a means of reducing the need for IPPV and hence its sequelae (Gregory 1971). CPAP has the potential to reduce the overall cost of care through the avoidance of IPPV and use of surfactant.
CPAP is applied via face mask, nasal mask, nasopharyngeal tube or nasal prongs, using a conventional ventilator, bubble circuit or CPAP driver. CNP is applied externally to the thorax using a negative pressure chamber with the seal around the neck; it produces lung distension as a result of negative intrathoracic pressure.
Initially both CPAP and CNP were used in preterm infants (Srikasibhandha 1974), but due to its ease of use, CPAP has become widely used and it is now recommended by the World Health Organization (WHO) as a form of respiratory support for neonates with respiratory disorders (WHO 2015). Therefore, this review focused on CPAP.
How the intervention might work
Infants with reduced surfactant have low functional residual lung capacity and this results in increased work of breathing and collapse of the terminal airways. This further increases ventilation‐perfusion mismatch (Woodrum 1972). CPAP provides a distending pressure which results in better lung volumes (Richardson 1978) and improvement of ventilation‐perfusion mismatch. It may have other benefits including stretching of the Herring Breuer reflex (Martin 1977), which may improve respiratory drive and result in more regular breathing (Elgellab 2001). CPAP is generally applied at pressures between 4 cmH2O and 6 cmH2O but the use of pressures of up to 8 cmH2O have also been reported (Mukerji 2019). Higher pressure might result in overdistension which affects gaseous exchange and might damage the terminal airway resulting in air leak. However, the optimum CPAP level is uncertain and may vary with age and stage in the course of the disease.
CPAP might not be as effective in extremely preterm infants who not only have a deficiency in surfactant but also have reduced numbers and maturity of the terminal airways.
Why it is important to do this review
CPAP is widely used in high‐ and middle‐income countries and has been recommended by WHO to improve outcomes of newborn preterm infants with respiratory distress (WHO 2015). Therefore, a formal evaluation is important.
Several systematic reviews have examined the effects of CDP, particularly when given as CPAP. Subramaniam 2016 looked at prophylactic CPAP applied to preterm infants immediately after birth, Davis 2003 studied the effects of CPAP on infants immediately after extubation from IPPV and De Paoli 2008 looked at devices and pressure sources for applying CPAP. Ho 2004 examined the timing of initiation of CDP in preterm infants with respiratory distress.
A formal evaluation of the use of CPAP is required to assess its role in preterm infants with established respiratory distress and to determine which methods of application are appropriate.
A systematic review on this subject was previously published (Bancalari 1992), but further trials have been performed since then.
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.
Methods
Criteria for considering studies for this review
Types of studies
Randomised or quasi‐randomised studies.
Types of participants
Preterm infants (less than 37 weeks of gestation) with respiratory failure becoming evident soon after birth.
Types of interventions
Intervention
CPAP by mask, nasal prong, nasopharyngeal tube or endotracheal tube in spontaneously breathing infants
Comparison
Spontaneous breathing with the addition of supplemental oxygen if necessary, delivered by headbox or low‐flow nasal cannula (supplemental oxygen alone).
We excluded infants receiving IPPV beyond the initial resuscitation period and excluded trials examining the effect of CPAP compared with another intervention such as nasal intermittent positive pressure or high‐flow nasal cannula.
For this update, we excluded trials using CNP.
Types of outcome measures
Primary outcomes
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Treatment failure (death or respiratory failure as measured by use of any additional assisted ventilation, blood gas criteria or transfer to a neonatal intensive care unit (NICU)).
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Use of assisted ventilation.
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Respiratory failure by blood gas criteria.
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Transfer to a NICU.
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Mortality at 28 days and at hospital discharge.
At the 2008 update, review authors modified the definition of treatment failure and added the two additional outcomes of transfer to a NICU and respiratory failure by blood gas criteria.
Secondary outcomes
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Pulmonary morbidity as judged by pulmonary air leak (any air leak, gross air leak including pneumothorax), duration of oxygen therapy, BPD (respiratory support or oxygen therapy (or both) at 28 days' and at 36 weeks' postmenstrual age).
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Use of surfactant.
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Other morbidities such as intraventricular haemorrhage, cystic brain lesions on ultrasound, retinopathy of prematurity, necrotising enterocolitis and duration of hospital stay.
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Neurodevelopment in childhood (death or severe disability (as defined by authors), severe disability, any disability, cerebral palsy).
At the 2009 update, review authors defined prespecified neurodevelopmental outcomes in childhood.
Search methods for identification of studies
Electronic searches
All Cochrane CPAP review searches were updated simultaneously in October 2017. We ran a sensitive search using only CPAP intervention terms, and we used a beginning search date of 1 January 2007 in order to comprehensively search for all reviews. See Appendix 1 for search details for this search.
On 30 June 2020, we updated the search using Cochrane Neonatal's current search practices (see Differences between protocol and review). We conducted a comprehensive search including: Cochrane Central Register of Controlled Trials (CENTRAL 2020, Issue 6) in the Cochrane Library; Ovid MEDLINE and Epub Ahead of Print, In‐Process & Other Non‐Indexed Citations, Daily and Versions (2017 to 30 June 2020) and CINAHL (2017 to 30 June 2020). We have included the search strategies for each database in Appendix 2. We applied no language restrictions.
We searched clinical trial registries for ongoing or recently completed trials (ISRCTN registry; www.isrctn.com/). The World Health Organization's International Clinical Trials Registry Platform (ICTRP) and the U.S. National Library of Medicine's ClinicalTrials.gov were searched via Cochrane CENTRAL.
For reviews published prior to 2017, see previous search strategies in Appendix 3.
Searching other resources
We searched the reference lists of any articles selected for inclusion in this review in order to identify additional relevant articles.
Data collection and analysis
We used the standard methods of the Cochrane Neonatal Review Group.
Selection of studies
We included all randomised and quasi‐randomised controlled trials fulfilling the selection criteria. Review authors reviewed the results of the search and separately selected studies for inclusion. We resolved disagreements by discussion.
Data extraction and management
The original data extraction and assessment of bias was done by JJH and the late DHS (see Acknowledgements). For this update, two review authors (JJH and PS) separately repeated data extraction, assessment and coding all data for each study as well as assessment of risk of bias. We replaced any standard error of the mean with the corresponding standard deviation and resolved disagreements by discussion. For each study, one review author entered final data into Review Manager 5 and a second review author checked the data (Review Manager 2014).
We performed statistical analyses using Review Manager 5 software and analysed categorical data using risk ratio (RR), risk difference (RD) and the number needed to treat for an additional beneficial outcome (NNTB) or the number needed to treat for an additional harmful outcome (NNTH) (Review Manager 2014). We analysed continuous data using mean difference (MD). We reported the 95% confidence interval (CI) on all estimates and used a fixed‐effect model for meta‐analysis. If we had encountered outcomes using different scales (e.g. for neurodevelopmental assessment) we would have used standardised mean difference.
Assessment of risk of bias in included studies
Two review authors (JJH and PS) independently assessed the risk of bias (low, high or unclear) of all included trials using the Cochrane 'Risk of bias' tool for the following domains (Higgins 2017).
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Sequence generation (selection bias).
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Allocation concealment (selection bias).
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Blinding of participants and personnel (performance bias).
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Blinding of outcome assessment (detection bias).
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Incomplete outcome data (attrition bias).
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Selective reporting (reporting bias).
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Any other bias.
Any disagreements were resolved by discussion or by a third assessor (PD). See Appendix 4 for a more detailed description of risk of bias for each domain.
Measures of treatment effect
We presented dichotomous data as a typical RR with 95% CIs, and continuous data as MD with 95% CIs.
Unit of analysis issues
We did not include crossover studies because we considered this design unsuitable for this question. We planned to include eligible cluster randomised controlled trials adjusting for clustering effects using the methods recommended in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2017).
Dealing with missing data
We attempted to contact authors for any missing data. Belenky provided data for preterm infants. We did not attempt to impute missing data (Belenky 1976).
Assessment of heterogeneity
We assessed statistical heterogeneity in each meta‐analysis using the I2 statistic. We regarded heterogeneity as probably not important if the I2 statistic was less than 40%, moderate if between 40% and 60% and substantial if greater than 60% (Deeks 2011).
Assessment of reporting biases
We planned to construct funnel plots of the primary outcomes if we identified sufficient numbers of included studies (10 or more).
Data synthesis
We carried out statistical analysis using Review Manager 5 (Review Manager 2014). We used a fixed‐effect meta‐analysis for combining data when it was reasonable to assume that studies were examining the same intervention and we determined that trial populations and methods used were similar.
Certainty of the evidence
We used the GRADE approach, as outlined in the GRADE Handbook to assess the certainty of the evidence for the following (clinically relevant) outcomes: treatment failure, use of assisted ventilation, mortality, pulmonary air leak, BPD and neurodevelopment in childhood (Schünemann 2013).
Two review authors independently assessed the certainty of the evidence for each of the outcomes above. We considered evidence from randomised controlled trials as high certainty but downgraded the evidence one level for serious (or two levels for very serious) limitations based upon the following: design (risk of bias), consistency across studies, directness of the evidence, precision of estimates and presence of publication bias. We used GRADEpro GDT to create a 'Summary of findings' table to report the certainty of the evidence.
The GRADE approach results in an assessment of the certainty of a body of evidence in one of four grades.
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High: we are very confident that the true effect lies close to that of the estimate of the effect.
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Moderate: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
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Low: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
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Very low: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
Subgroup analysis and investigation of heterogeneity
We examined the treatment effects of individual trials and heterogeneity between trials by inspecting the forest plots and quantifying the impact of heterogeneity using the I2 statistic. If we detected statistical heterogeneity, we explored possible causes using prespecified subgroup analyses. We planned subgroup analyses on the basis of birthweight (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), applied pressure (high versus low pressure) and trial setting (tertiary compared with non‐tertiary hospitals and high‐, middle‐ and low‐income settings).
Sensitivity analysis
We performed sensitivity analyses to test the following decisions: inclusion of quasi‐random studies (Rhodes 1973) and inclusion of a study which included some infants on CNP (Durbin 1976). Since the study by Belenky 1976 included only a subset of those randomised to each group, potentially disrupting the randomisation, we tested our decision to include this study.
Results
Description of studies
Results of the search
The 2008 update identified one new trial (Buckmaster 2007) and excluded two. In 2009, we identified three new trials and excluded them all (Colnaghi 2008; Morley 2008; Rojas 2009). In the 2015 update, we identified another four trials, which we excluded (Dunn 2011; Finer 2010; Sandri 2010; Tapia 2012). In 2020, we included one new study (Mwatha 2020). We excluded two CNP trials that we had previously included in the review (Fanaroff 1973; Samuels 1996; see Ho 2015). We also excluded four studies identified through searching (Afjeh 2017; Badiee 2013; Celik 2018; Heiring 2015). We listed reasons for exclusion in the Characteristics of excluded studies table. Figure 1 summaries the search.
Study flow diagram: review update. RCT: randomised controlled trial.
Included studies
We included five studies involving 322 infants and provide details of these studies in the Characteristics of included studies table (Belenky 1976; Buckmaster 2007; Durbin 1976; Mwatha 2020; Rhodes 1973). Four studies were conducted in high‐income settings and one in a low‐resource setting (Tanzania) (Mwatha 2020). Entry criteria for participants were based on a clinical diagnosis of respiratory failure and spontaneous breathing at a fraction of inspired oxygen (FiO2) that ranged from 0.3 to 0.95. The mean age at study entry varied from 10 hours up to 149 hours. Mwatha 2020 used the Silverman‐Anderson score and the age at recruitment was not reported.
Buckmaster 2007 included neonates with respiratory distress not due to cardiac disease. Study authors supplied data for preterm infants. All infants had respiratory failure thought to be due to RDS, but it is not possible to exclude other conditions, in particular, meconium aspiration in eight infants with meconium‐stained amniotic fluid. The study was performed in Australian non‐tertiary hospitals.
Antenatal steroids were administered to 35% of eligible infants in Buckmaster 2007 and 40% in Mwatha 2020. The other studies did not mention rates of antenatal steroid exposure. Some of the participants in Buckmaster 2007 may have received surfactant after transfer to a NICU, but this was not recorded. Mwatha 2020 was conducted in a setting that did not have access to surfactant. The other trials did not report use of surfactant and were all conducted in the presurfactant era.
Two studies used face mask CPAP (Belenky 1976; Rhodes 1973), and two used nasal CPAP (Buckmaster 2007; Mwatha 2020). The other study used negative pressure for less severe illness (three infants) and endotracheal CPAP when more severe (eight infants) (Durbin 1976). We decided to include this study since 73% of the infants received CPAP. We tested this decision by sensitivity analysis.
There were few, if any, infants below 1000 g bodyweight. Two studies performed a subgroup analysis of mortality for very low‐birthweight infants (Belenky 1976; Rhodes 1973). Buckmaster 2007 stratified for gestations of 31 weeks to 33 weeks and 34 weeks to 36 weeks.
Belenky 1976 included both spontaneously breathing infants on face mask CPAP and ventilated infants on face mask or endotracheal IPPV with PEEP. Only infants who were spontaneously breathing at trial entry were eligible for this review. For spontaneously breathing infants the only outcome available from the published report was the use of IPPV. We obtained further information on spontaneously breathing infants from the study authors. However, data for subgroups by birthweight were not available.
None of the studies reported neurodevelopmental outcomes.
Excluded studies
We excluded 14 studies and provided details in the Characteristics of excluded studies table. For this update, we excluded two previously included studies because the intervention was CNP (Fanaroff 1973; Samuels 1996). Two additional studies were excluded in this update (Badiee 2013; Heiring 2015). Badiee 2013 included preterm infants requiring respiratory support at five minutes of age to compare very early CPAP initiated at five minutes of age with early CPAP initiated at 30 minutes of age. Heiring 2015 randomised infants stable on CPAP at four to seven days of age to continue CPAP or be weaned to low‐flow oxygen. Because the infants did not have respiratory distress, they did not meet our inclusion criteria
Tooley 2003 included infants of 25 weeks' gestation to 28 weeks' gestation who were intubated at birth, given a single dose of surfactant, then randomly assigned at about one hour of age to extubation, to nasal CPAP or to continued conventional IPPV. No criteria for the diagnosis of RDS were given. Swyer 1973 was a randomised comparison of three CDP methods, but included no control (supportive care) treatment group. Pieper 2003 was performed in a middle income setting. Participants were extremely low birthweight babies 750 g to 1000 g or 26 weeks' gestation to 28 weeks' gestation who had no access to intensive care. The study was not randomised (Pieper 2003). We excluded one study that measured no clinical outcomes (Colnaghi 2008). Morley 2008 randomly assigned preterm infants at 25 weeks' gestation to 28 weeks' gestation with respiratory distress at five minutes of age to nasal CPAP or mechanical ventilation. There was no control group allocated to supportive care. One study included infants born from 27 weeks' gestation to 31 weeks' gestation who had respiratory distress within the first hour of life randomly assigned to receive surfactant followed by nasal CPAP or nasal CPAP alone (Rojas 2009). There was no control group with supportive care. Dunn 2011 examined three interventions, prophylactic surfactant, intubation‐surfactant‐extubation and nasal CPAP, for preterm infants at 26 weeks to 29 weeks immediately after birth. Sandri 2010 randomly assigned infants to prophylactic surfactant plus nasal CPAP or nasal CPAP alone immediately after birth, whereas infants in Finer 2010 received CPAP alone or surfactant plus mechanical ventilation as a prophylactic strategy. Tapia 2012 examined prophylactic CPAP compared with supportive care, which included headbox or low‐flow nasal cannula oxygen when indicated.
Studies awaiting classification
There are no studies awaiting classification.
Ongoing studies
We found one ongoing study that started in January 2020.
Risk of bias in included studies
We provided details of the risk of bias for each study in the Characteristics of included studies table. A graphical summary of our judgements is shown in Figure 2 and Figure 3.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Allocation
Four studies used random allocation (Belenky 1976; Buckmaster 2007; Durbin 1976; Mwatha 2020). One used off‐site computer‐generated random sequence and allocation (Buckmaster 2007), two used sealed envelopes, but did not report the method of generation of a random sequence (Durbin 1976; Mwatha 2020). One study used alternate allocation without allocation concealment (Rhodes 1973), Belenky 1976 used random card selection.
Blinding
Blinding of treatment or outcome assessment was not feasible during hospitalisation for any study. Although studies used fixed criteria for treatment failure, the lack of blinding could affect the judgement of the clinician. However, we judged risk of bias due to lack of blinding to be low for the outcomes mortality, air leak, intraventricular haemorrhage, necrotising enterocolitis and BPD.
Incomplete outcome data
Three studies stated how many were randomly assigned (Buckmaster 2007; Durbin 1976; Mwatha 2020). These studies analysed all infants. Two studies stated only the numbers analysed, and it is not possible to tell how many exclusions were made after randomisation (Belenky 1976; Rhodes 1973).
Selective reporting
No trial protocols were available. However, all expected outcomes were reported for all the included studies.
Other potential sources of bias
Belenky 1976 included infants who were not spontaneously breathing at trial entry. The authors provided data for those spontaneously breathing. Although the authors stated that there was no significant difference between the groups for the number of infants on ventilation at baseline, we judged the inclusion of only this subset of infants as a potential source of bias since this might potentially disrupt the random sequence.
Effects of interventions
Five trials, including 322 infants, met eligibility criteria (Belenky 1976; Buckmaster 2007; Durbin 1976; Mwatha 2020; Rhodes 1973).
Continuous positive airway pressure versus supplemental oxygen
Treatment failure (death or respiratory failure measured by use of any additional ventilation, blood gas criteria or transfer to a neonatal intensive care unit) (Outcome 1.1)
All trials reported treatment failure as death or respiratory failure defined by the need for additional ventilation, one trial measured treatment failure as death or respiratory failure by blood gas criteria (Buckmaster 2007), and one trial as death or transfer to a NICU (Buckmaster 2007). In two trials, failure defined by use of mechanical ventilation was significantly reduced in the CPAP group (Buckmaster 2007; Rhodes 1973). The meta‐analysis of all five trials showed a reduction in treatment failure defined as death or need for additional ventilation in the CPAP group compared with the supplemental oxygen group (typical RR 0.64 95% CI 0.50 to 0.82; typical RD –0.19, 95% CI –0.28 to –0.09; NNTB 6, 95% CI 4 to 11; I2 = 50%; 322 infants; very low‐certainty evidence; Analysis 1.1.1). Treatment failure defined by death or blood gas criteria was significantly reduced in the one trial that measured this (RR 0.53, 95% CI 0.32 to 0.90; RD –0.18, 95% CI –0.32 to –0.04; NNTB 6, 95% CI 4 to 25; Analysis 1.1.2) (Buckmaster 2007). Treatment failure defined by transfer to a NICU was significantly reduced in the one trial that measured this (RR 0.49, 95% CI 0.30 to 0.78; RD –0.24, 95% CI –0.38 to –0.10; NNTB 5, 95% CI 3 to 10; Analysis 1.1.3) (Buckmaster 2007). See Analysis 1.1; Figure 4.
Forest plot of comparison: 1 Continuous positive airway pressure (CPAP) versus supplemental oxygen, outcome: 1.1 Treatment failure (by death and use of additional ventilatory assistance, by blood gas criteria or by transfer to a neonatal intensive care unit).
Subgroup analysis (Outcome 1.2 to 1.3)
There were no data available to perform subgroup analysis by birthweight or gestation. Four studies reported time of application of the intervention. Two initiated the intervention in the first 24 hours. For Belenky 1976, the mean age of application of the intervention was between 10 and 17 hours of life (depending on the birthweight subgroups) and for Rhodes 1973 it was between 10 and 13 hours. Buckmaster 2007 reported the mean time of application of the intervention was 120 to 149 hours and for Durbin 1976 was 28 to 30 hours. On subgroup analysis by time of application (less than 24 hours versus 24 hours or greater) there was no difference between the subgroups (test for subgroup differences P = 0.94, I2 = 0%; Analysis 1.2). Three studies were performed in a tertiary care NICU, one study was performed in a tertiary hospital without NICU and one study was performed in a non‐tertiary NICU. There was no difference between the subgroups by level of care (test for subgroup differences P = 0.42, I2 = 0%; Analysis 1.3). There was no difference on subgroup analysis by resource setting (P = 0.09, I2 = 31%; Analysis 1.4).
Use of assisted ventilation (Outcome 1.5)
Three studies reported use of additional ventilatory assistance. One trial showed a statistically significant difference in the use of IPPV (Buckmaster 2007), and two trials did not (Belenky 1976; Durbin 1976). The meta‐analysis showed reduced use of IPPV in the CPAP group (RR 0.72, 95% CI 0.54 to 0.96; RD –0.13, 95% CI –0.25 to –0.02; NNTB 7, 95% CI 4 to 50; 233 infants; I2 = 55%; very low‐certainty evidence; Analysis 1.5; Figure 5).
Forest plot of comparison: 1 Continuous positive airway pressure (CPAP) versus supplemental oxygen, outcome: 1.5 Use of assisted ventilation.
Respiratory failure by blood gas criteria (Outcome 1.6)
One study reported respiratory failure by blood gas criteria (Buckmaster 2007). Since there were no deaths in this study, respiratory failure by blood gas criteria yielded the same outcome as treatment failure (death or blood gas criteria), that is, a reduction in respiratory failure (RR 0.53, 95% CI 0.32 to 0.90; RD –0.18, 95% CI –0.32 to –0.04; NNTB 6, 95% CI 4 to 25; Analysis 1.6).
Transfer to a neonatal intensive care unit (Outcome 1.7)
Buckmaster 2007 reported transfer to a NICU. This was reduced in the CPAP group (RR 0.49, 95% CI 0.30 to 0.78; RD –0.24, 95% CI –0.38 to –0.10; NNTB 5, 95% CI 3 to 10; Analysis 1.7).
Mortality at 28 days and at hospital discharge (Outcomes 1.8 and 1.9)
All five trials reported mortality. The definition of mortality was unclear in Belenky 1976 and Rhodes 1973 although mortality to discharge was implied. Mwatha 2020 reported mortality to discharge, Durbin 1976 reported mortality to discharge and 28 days, and no infant died in Buckmaster 2007. Belenky 1976 found a significant reduction (RR 0.38, 95% CI 0.14 to 0.99), but the other trials found no evidence of a difference between groups. The meta‐analysis of all five trials showed a probable reduction in 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 5 to 25; 322 infants; I2 = 0%; moderate‐certainty evidence; Analysis 1.8; Figure 6). Two trials reported mortality by birth weight less than 1500 g or 1500 g and above (Belenky 1976; Rhodes 1973). For infants 1500 g or greater at birth, mortality was reduced in the CPAP group (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 to 13; 60 infants; I2 = 0%). For the 32 infants in the two trials with birth weight of less than 1500 g, there was no evidence of a difference in mortality (RR 0.67, 95% CI 0.38 to 1.20, I2 = 26%; test for subgroup differences P = 0.20; I2 = 53%; Analysis 1.9).
Forest plot of comparison: 1 Continuous positive airway pressure (CPAP) versus supplemental oxygen, outcome: 1.8 Mortality.
Pulmonary morbidity (Outcomes 1.10 to 1.13)
Four trials reported the rate of pneumothorax during hospital admission (Belenky 1976; Buckmaster 2007; Durbin 1976; Rhodes 1973). Although no individual trial showed a significant increase, the meta‐analysis found an increase in the rate of pneumothorax in the CPAP group (typical RR 2.91, 95% CI 1.38 to 6.13; typical RD 0.11, 95% CI 0.04 to 0.19; NNTH 11, 95% CI 6 to 25; I2 = 0%; 274 infants; low‐certainty evidence; Analysis 1.11). Four trials reported the presence of pneumothorax after trial entry, and overall there was an increase in the CPAP group (typical RR 2.48, 95% CI 1.16 to 5.03; typical RD 0.09, 95% CI 0.02 to 0.16; NNTB 11, 95% CI 7 to 50; I2 = 0%; 270 infants; low‐certainty evidence; Analysis 1.12). There was no evidence of a difference between treatment and control groups in the duration of oxygen therapy for the one trial that reported this (MD 0.20 days, 95% CI –2.47 to 2.87; 24 infants; Analysis 1.10) (Durbin 1976), or in rates of BPD at 28 days (RR 1.04, 95% CI 0.35 to 3.13; 2 trials, 209 infants; very low‐certainty evidence; Analysis 1.13) (Belenky 1976; Buckmaster 2007). Mwatha 2020 reported duration of treatment and duration of stay as medians and range and found no difference. Although not a prespecified outcome, Mwatha 2020 also reported the incidence of nasal trauma. This occurred in 10/25 infants in the CPAP group and 1/23 in the oxygen therapy group (RR 9.20, 95% CI 1.28 to 66.37; 48 infants; data not shown).
Use of surfactant
Three trials were performed in the presurfactant era (Belenky 1976; Durbin 1976; Rhodes 1973). Although some infants in Buckmaster 2007 might have received surfactant after admission to the NICU, this was not reported. The study by Mwatha 2020 was in a setting where surfactant was not available.
Intraventricular haemorrhage and cystic brain lesions
None of the trials reported intraventricular haemorrhage and cystic brain lesions.
Retinopathy of prematurity
None of the trials reported retinopathy of prematurity.
Necrotising enterocolitis
None of the trials reported necrotising enterocolitis.
Neurodevelopment in childhood
None of the trials reported neurodevelopment in childhood.
Sensitivity analyses
Sensitivity analyses, which excluded the study using quasi‐random patient allocation (Rhodes 1973), and the study whose only infants eligible for inclusion in this review were those who were breathing spontaneously at trial entry (Belenky 1976), did not yield substantially different results. We also performed sensitivity analysis to test our decision of including Durbin 1976 who allocated fewer ill participants to CNP.
Discussion
Summary of main results
We found very low‐certainty evidence that CPAP compared with supplemental oxygen reduced treatment failure in preterm infants, whether it was defined as the combined outcome of mortality with the need for IPPV, deterioration of blood gas parameters or need for admission to a NICU. We found moderate‐certainty evidence that CPAP reduced mortality and very low‐certainty evidence for a reduction in the need for additional ventilatory support. There was an increase in any pneumothorax and pneumothorax appearing after the start of the intervention (low‐certainty evidence). Based on very low‐certainty evidence, we do not know whether there was any effect on BPD at 28 days and there were no data in BPD at 36 weeks' postmenstrual age. There were no data on adverse events such as intraventricular haemorrhage, periventricular leukomalacia and necrotising enterocolitis, or on long‐term neurodevelopmental outcomes.
Overall completeness and applicability of evidence
For several reasons, the results of this review, which included mainly trials carried out in the 1970s, have limited application to current neonatal care. In the 1970s, antenatal corticosteroid use was uncommon and surfactant treatment was not available. The mean birthweight of infants in the studies reviewed was between 1700 g and 2000 g, with two trials excluding infants weighing less than 1000 g (Belenky 1976; Durbin 1976). Two trials applied CPAP by face mask (Belenky 1976; Rhodes 1973), and this has been reported to be associated with adverse effects (Pape 1976). Currently, the nasal route is the standard way of delivering CPAP (Ramaswamy 2020), and differences in efficacy have been shown between devices delivering nasal CPAP (De Paoli 2008). The intervention in early trials was initiated later than would be current practice (Morley 2008; Narendran 2003; Tooley 2003), with mean age at entry greater between 10 and 149 hours. Earlier CPAP is more effective in preventing intubation for IPPV than later CPAP in infants with RDS (Ho 2004). All trials provided outcomes only up to discharge from the NICU.
This review is historically important because it establishes the role of CPAP in preterm infants with respiratory distress. In addition, the results are currently relevant in settings where access to intensive care is not immediately available, such as in level 2 hospitals or in low‐ and middle‐income settings where intensive care is limited. However, conditions today in low‐ and middle‐income countries are unlike those of the studies from the 1970s included in this review. Today there is some availability, even if limited, of antenatal steroids, surfactant and ventilators. CPAP is an inexpensive therapy; therefore, randomised trials in low‐ and middle‐income countries where resources are scarce seem appropriate and have been recommended (Martin 2014). This update includes one study performed in a low‐income country. The study did not achieve its calculated sample size and was unable to show whether CPAP improved mortality in this setting. The reduced mortality seen in our meta‐analysis makes randomisation to headbox oxygen or other forms of oxygen therapy (compared with CPAP) difficult, which might mean that future studies in resource‐poor settings would be difficult to perform. In addition, the conduct of such studies in resource‐poor settings is difficult. Mwatha 2020 failed to achieve the calculated sample size. This problem is also well illustrated by the trial of Pieper 2003. Loss of equipoise by the clinical staff at participating South African centres led to cessation of randomisation and allocation of infants to CPAP based on availability of this form of care.
Quality of the evidence
The overall certainty of evidence was moderate to very low. Subjective outcomes, such as treatment failure, were downgraded for lack of blinding and some outcomes were downgraded for inconsistency. All outcomes were downgraded for indirectness because most of the evidence was derived from trials performed in the presurfactant era. We also downgraded all outcomes for imprecision because of the small study samples which, even after synthesis, did not meet the optimal information size. We judged the evidence for the primary outcome, treatment failure, to be of very‐low certainty. We downgraded for risk of bias (lack of blinding of a subjective outcome), inconsistency, applicability (data from presurfactant era) and evidence was derived from only four small studies. This also applied to the primary outcome, use of ventilation. However, for the outcome mortality, we judged this to be moderate‐certainty evidence because there were no serious concerns about risk of bias or inconsistency. The secondary outcomes were judged low (pneumothorax after trial allocation) and very low (BPD at 28 days)
Potential biases in the review process
We made several judgements during the review process. First, we made a post hoc decision to limit this version of the review to include only CPAP trials. This was because of lack of interest in CNP for preterm infants. This decision resulted in the exclusion of two studies (Fanaroff 1973; Samuels 1996), one of which provided the only neurodevelopmental outcomes available across all trials involving the use of CDP in the preterm infant. The exclusion of these trials has resulted in slightly broader CIs but effect estimates have not changed substantially. The only remarkable changes seen were for use of ventilatory assistance in which heterogeneity went from low (I2 = 16%) to moderate (I2 = 55%). We also made judgements about inclusion of individual studies. From the Belenky 1976 trial, we included only spontaneously breathing infants and group allocation to CPAP or control was not stratified for this characteristic, and this could lead to imbalance by disrupting the randomisation process. Indeed, an effect of an imbalance is suggested by the greater birthweight of the group allocated to CPAP. Removal of this trial as part of a sensitivity analysis did not substantially alter the results. We also made a judgement to include Durbin 1976. In this study, 73% of the intervention group received CPAP, the remainder received CNP. Removal of this study did not substantially alter the results. One further trial used alternate unconcealed allocation. Removal of this trial also did not substantially alter the results (Rhodes 1973).
Study flow diagram: review update. RCT: randomised controlled trial.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Forest plot of comparison: 1 Continuous positive airway pressure (CPAP) versus supplemental oxygen, outcome: 1.1 Treatment failure (by death and use of additional ventilatory assistance, by blood gas criteria or by transfer to a neonatal intensive care unit).
Forest plot of comparison: 1 Continuous positive airway pressure (CPAP) versus supplemental oxygen, outcome: 1.5 Use of assisted ventilation.
Forest plot of comparison: 1 Continuous positive airway pressure (CPAP) versus supplemental oxygen, outcome: 1.8 Mortality.
Comparison 1: Continuous positive airway pressure (CPAP) versus supplemental oxygen, Outcome 1: Treatment failure (by death and use of additional ventilatory assistance, by blood gas criteria or by transfer to a neonatal intensive care unit)
Comparison 1: Continuous positive airway pressure (CPAP) versus supplemental oxygen, Outcome 2: Treatment failure (death or use of additional ventilatory support by early or late application of CPAP)
Comparison 1: Continuous positive airway pressure (CPAP) versus supplemental oxygen, Outcome 3: Treatment failure (death or additional ventilatory support by level of care (tertiary vs non‐tertiary))
Comparison 1: Continuous positive airway pressure (CPAP) versus supplemental oxygen, Outcome 4: Treatment failure (death or use of assisted ventilation) by resource setting
Comparison 1: Continuous positive airway pressure (CPAP) versus supplemental oxygen, Outcome 5: Use of assisted ventilation
Comparison 1: Continuous positive airway pressure (CPAP) versus supplemental oxygen, Outcome 6: Respiratory failure by blood gas criteria
Comparison 1: Continuous positive airway pressure (CPAP) versus supplemental oxygen, Outcome 7: Transfer to a NICU
Comparison 1: Continuous positive airway pressure (CPAP) versus supplemental oxygen, Outcome 8: Mortality
Comparison 1: Continuous positive airway pressure (CPAP) versus supplemental oxygen, Outcome 9: Mortality by birthweight
Comparison 1: Continuous positive airway pressure (CPAP) versus supplemental oxygen, Outcome 10: Duration of supplemental oxygen
Comparison 1: Continuous positive airway pressure (CPAP) versus supplemental oxygen, Outcome 11: Any pneumothorax
Comparison 1: Continuous positive airway pressure (CPAP) versus supplemental oxygen, Outcome 12: Pneumothorax occurring after allocation
Comparison 1: Continuous positive airway pressure (CPAP) versus supplemental oxygen, Outcome 13: Bronchopulmonary dysplasia at 28 days
| CPAP compared to supplemental oxygen for respiratory distress in preterm infants | ||||||
| Patient or population: respiratory distress in preterm infants | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with supplemental oxygen | Risk with CPAP | |||||
| Treatment failure (death or use of additional ventilatory support) | Study population | RR 0.64 | 322 (5 RCTs) | ⊕⊝⊝⊝ | Downgraded for lack of blinding because need of additional ventilatory support is a subjective outcome. | |
| 519 per 1000 | 332 per 1000 | |||||
| Use of assisted ventilation | Study population | RR 0.72 | 233 (3 RCTs) | ⊕⊝⊝⊝ | Downgraded for lack of blinding because need of additional ventilatory support is a subjective outcome. | |
| 492 per 1000 | 354 per 1000 | |||||
| Mortality | Study population | RR 0.53 | 322 (5 RCTs) | ⊕⊕⊕⊝ | Not downgraded for lack of blinding because mortality is considered an objective outcome. | |
| 235 per 1000 | 124 per 1000 | |||||
| Pneumothorax occurring after allocation | Study population | RR 2.91 | 270 (4 RCTs) | ⊕⊕⊝⊝ | Not downgraded for lack of blinding because pneumothorax is considered an objective outcome. | |
| 58 per 1000 | 150 per 1000 | |||||
| Bronchopulmonary dysplasia (oxygen dependency at 28 days) | Study population | RR 1.04 | 209 (2 RCTs) | ⊕⊝⊝⊝ | Not downgraded for lack of blinding because bronchopulmonary dysplasia is considered an objective outcome. | |
| 56 per 1000 | 58 per 1000 | |||||
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; CPAP: continuous positive airway pressure; RCT: randomised controlled trial; RR: risk ratio. | ||||||
| GRADE Working Group grades of evidence | ||||||
| aDowngraded one level due to lack of blinding of the intervention for a subjective outcome. | ||||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1.1 Treatment failure (by death and use of additional ventilatory assistance, by blood gas criteria or by transfer to a neonatal intensive care unit) Show forest plot | 5 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 1.1.1 Death or use of additional ventilatory assistance | 5 | 322 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.64 [0.50, 0.82] |
| 1.1.2 Death or respiratory failure by blood gas criteria | 1 | 158 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.53 [0.32, 0.90] |
| 1.1.3 Death or transfer to a neonatal intensive care unit (NICU) | 1 | 158 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.49 [0.30, 0.78] |
| 1.2 Treatment failure (death or use of additional ventilatory support by early or late application of CPAP) Show forest plot | 4 | 274 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.67 [0.51, 0.87] |
| 1.2.1 Early application < 24 hours | 2 | 92 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.66 [0.49, 0.90] |
| 1.2.2 Later application ≥ 24 hours | 2 | 182 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.68 [0.44, 1.04] |
| 1.3 Treatment failure (death or additional ventilatory support by level of care (tertiary vs non‐tertiary)) Show forest plot | 5 | 325 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.68 [0.53, 0.87] |
| 1.3.1 Tertiary care with NICU | 3 | 119 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.79 [0.59, 1.05] |
| 1.3.2 Non‐tertiary care | 1 | 158 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.54 [0.31, 0.92] |
| 1.3.3 Tertiary hospital without NICU | 1 | 48 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.61 [0.31, 1.23] |
| 1.4 Treatment failure (death or use of assisted ventilation) by resource setting Show forest plot | 5 | 325 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.68 [0.53, 0.87] |
| 1.4.1 Low‐resource setting | 1 | 48 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.61 [0.31, 1.23] |
| 1.4.2 High‐resource setting | 4 | 277 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.69 [0.53, 0.90] |
| 1.5 Use of assisted ventilation Show forest plot | 3 | 233 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.72 [0.54, 0.96] |
| 1.6 Respiratory failure by blood gas criteria Show forest plot | 1 | 158 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.53 [0.32, 0.90] |
| 1.7 Transfer to a NICU Show forest plot | 1 | 158 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.49 [0.30, 0.78] |
| 1.8 Mortality Show forest plot | 5 | 322 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.53 [0.34, 0.83] |
| 1.9 Mortality by birthweight Show forest plot | 2 | 92 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.47 [0.27, 0.82] |
| 1.9.1 > 1500 g | 2 | 60 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.24 [0.07, 0.84] |
| 1.9.2 ≤ 1500 g | 2 | 32 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.67 [0.38, 1.20] |
| 1.10 Duration of supplemental oxygen Show forest plot | 1 | 24 | Mean Difference (IV, Fixed, 95% CI) | 0.20 [‐2.47, 2.87] |
| 1.11 Any pneumothorax Show forest plot | 4 | 274 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.91 [1.38, 6.13] |
| 1.12 Pneumothorax occurring after allocation Show forest plot | 4 | 270 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.48 [1.16, 5.30] |
| 1.13 Bronchopulmonary dysplasia at 28 days Show forest plot | 2 | 209 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.04 [0.35, 3.13] |
