Key messages
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The differences between CPAP and theophylline in terms of treatment failure or death are very uncertain.
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Both treatments studied, CPAP and theophylline, are now rarely used in modern neonatal care, where nasal prong CPAP and caffeine or aminophylline are more common.
What is apnoea of prematurity, and how is it treated?
Apnoea of prematurity is when a preterm baby stops breathing for over 20 seconds or has shorter pauses with a slow heart rate or blue skin. It is most common in babies born before 28 weeks of pregnancy and becomes rare after 34 weeks. Apnoea of prematurity can happen due to immaturity but may worsen with infections or low oxygen levels. If untreated, it can cause low oxygen and slow heart rates, which might lead to the need for breathing support. Apnoea can be due to immaturity of the brain that results in it not signalling the lung muscles to breathe (central), or immaturity of the airway resulting in blockage (obstructive), or both (mixed, the most common type). CPAP is a type of breathing support that helps babies keep their lungs open. Methylxanthines, such as theophylline, are medicines that help stimulate breathing. Both treatments are often used to treat apnoea of prematurity, but they work differently and may cause different side effects.
Why is this important for the treatment of apnoea of prematurity?
It is important to directly compare these treatments to better understand their benefits and harms. In low- and middle-income countries, access to continuous positive airway pressure or certain methylxanthines, like caffeine, may be limited. Comparing these treatments could help healthcare providers in resource-limited settings make informed decisions on the best option available.
What did we want to find out?
We wanted to find out which treatment has more benefits and fewer harms for managing apnoea of prematurity. This comparison is especially important for guiding care in resource-limited settings, where access to these treatments may vary.
What did we do?
This is the second update of a review first published in 1998 comparing CPAP and theophylline. In this update, we expand the scope by including newer types of CPAP and other methylxanthines beyond theophylline, to reflect current clinical practice and find out whether the original findings remain applicable to contemporary neonatal care. We searched for and selected studies that compared CPAP to methylxanthines (such as theophylline, caffeine, or aminophylline) for treating apnoea in premature babies born before 34 weeks. We only included studies where the treatments were used individually, not combined (e.g. CPAP and methylxanthines together). We carefully reviewed the studies to ensure that they met our criteria and assessed their quality before summarising the results. Finally, we rated our confidence in the findings based on the quality and reliability of the evidence.
What did we find?
We found only one study, conducted 40 years ago in the United Kingdom, which included 32 infants born before 34 weeks of gestation. Based on this limited data, we do not yet know whether CPAP helps reduce or might increase the chances of the treatment not working during the hospital stay, the risk of dying within the first year, or the chance of developing a fast heartbeat soon after starting treatment. We also found no information comparing the treatments on how they might affect the babies' brain development, learning, or long-term growth, or their risk of serious conditions such as lung disease (bronchopulmonary dysplasia).
What are the limitations of the evidence?
We only found one small study from 1981, involving 32 premature babies born before 34 weeks of pregnancy in a high-income country. The treatments compared in the study are not commonly used in the same way today. CPAP was delivered using a face mask at lower pressures than what is currently used, and theophylline was used instead of caffeine, which has been shown to have advantages over theophylline and is now used in many places. The study did not give clear information on some important outcomes, such as how the treatments affected the babies' brain development, feeding, or risk of serious complications like lung damage or injuries to the nostrils. The small number of babies in the study makes the results uncertain. In addition, the babies assigned to the CPAP group were sicker at the start of the study and therefore might respond less well to the treatment.
What does this mean?
Even though previous reviews found theophylline to be better than face mask CPAP, in this review, where we have applied a more rigorous assessment of study quality, we do not know whether there is any difference between the use of CPAP and methylxanthine for the treatment of apnoea of prematurity.
How up-to-date is this evidence?
The review is current to 28 August 2024.
Lire le résumé complet
Recurrent apnea is common in preterm infants, particularly at very early gestational ages. These episodes of loss of effective breathing can lead to hypoxemia and bradycardia which may be severe enough to require resuscitation including use of positive pressure ventilation. Theophylline and continuous positive airways pressure (CPAP) are two treatments that have been used to prevent apnea and its consequences.
Objectifs
To evaluate the benefits and harms of CPAP compared to methylxanthines for apnoea of prematurity in preterm infants.
Stratégie de recherche documentaire
We searched CENTRAL, MEDLINE, Embase, CINAHL, three clinical trials databases, and conference proceedings. We checked references in included studies and related systematic reviews up to August 2024.
Critères de sélection
All trials using random or quasi-random allocation to CPAP or theophylline in preterm infants with clinical recurrent apnea/bradycardia were eligible.
Recueil et analyse des données
Data were extracted using standard methods of the Cochrane Collaboration and its Neonatal Review Group, with separate evaluation of trial quality and data extraction by each author and synthesis of data using relative risk.
Résultats principaux
Only one eligible trial was found. The use of mask CPAP is associated with a higher treatment failure rate as measured by less than a 50% reduction in apnea or use of an alternative treatment [RR 2.89 (95% CI 1.12, 7.47); RD 0.42 (95% CI 0.11, 0.74)]. For every 2.4 infants (95% CI 1.4, 9.5) treated with mask CPAP rather than theophylline, there results one treatment failure. In the mask CPAP group there is more use of IPPV [RR 3.09 (1.42, 6.70); RD 0.58 (95% CI 0.30, 0.86). For every 1.7 infants (95% CI 1.2, 3.3) treated with mask CPAP rather than theophylline, one infant is intubated for IPPV.
In the mask CPAP group, there are trends towards more deaths in the first year, and in death or major disability in survivors at follow up, which do not reach significance. There are no differences in rates of necrotizing enterocolitis or major disability in survivors at follow up.
Conclusions des auteurs
From the single, small included study, performed more than 40 years ago, we are very uncertain whether there is any clinically meaningful difference in the effect of CPAP and theophylline on apnoea of prematurity. Both interventions, CPAP and theophylline, have largely been replaced by nasal prong CPAP and caffeine or aminophylline in modern neonatal care, limiting the applicability of these findings to current practice. However, since caffeine is not readily available in some low- and middle-income countries, and CPAP access remains limited in certain settings, further research may still be relevant. If further trials are conducted, these should use modern CPAP delivery methods and caffeine rather than theophylline.
This is the second update of a review first published in 1998.
Financement
This Cochrane review had no dedicated funding.
Enregistrement
This is an update of the existing review 'Continuous positive airway pressure versus theophylline for apnoea in preterm infants' originally published in The Cochrane Library, Disk 2, 1998 (Henderson-Smart d) and updated on Disk 4, 2001 (Henderson-Smart e). Previous versions are available via DOI: 10.1002/14651858.CD001072.
The title was amended from 'Continuous positive airway pressure versus theophylline for apnoea in preterm infants' to 'Continuous positive airway pressure versus methylxanthine for apnoea in preterm infants' in May 2024.
