Background

When preterm infants have been given intermittent positive pressure ventilation (IPPV) for respiratory failure, weaning from support and tracheal extubation may be difficult. A significant contributing factor is thought to be the relatively poor respiratory drive and tendency to develop hypercarbia and apnea, particularly in very preterm infants. Methylxanthine treatment started before extubation might stimulate breathing and increase the chances of successful weaning from IPPV.

Objectives

To determine the effects of prophylactic methylxanthine treatment on the use of intubation and IPPV and other clinically important side effects in preterm infants being weaned from IPPV and in whom endotracheal extubation is planned.

Search methods

The standard search strategy of the Cochrane Neonatal Review Group was used. This included searches of The Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 4, 2007), the Oxford Database of Perinatal Trials, MEDLINE (1966 to January 2008), CINAHL (1982 to January 2008) and EMBASE (1988 to January 2008).

Selection criteria

All published trials utilising random or quasi‐random patient allocation in which treatment with methylxanthines (theophylline or caffeine) was compared with placebo or no treatment to improve the chances of successful extubation of preterm or low birth weight infants were included.

Data collection and analysis

The standard methods of the Cochrane Collaboration and its Neonatal Review Group were used. The second author assessed the quality of trials and extracted data independently. Results are expressed as relative risk (RR) and risk difference (RD) with 95% confidence intervals.

Main results

Overall analysis of the six published trials shows that methylxanthine treatment results in a reduction in failure of extubation within one week [summary RR 0.47 (95% CI 0.32, 0.70)]. Overall there is an absolute reduction of 27% in the incidence of failed extubation [summary RD ‐0.27 (95% CI ‐0.39, ‐0.15)]. Thus, overall in these six trials the number needed to treat (NNT) with methylxanthine to prevent one case of failed extubation is 4 (95% CI 3, 7). There is significant heterogeneity in the RD meta‐analysis (p = 0.007) related to the large variation in baseline rate in the control groups (range 20 ‐ 100%).

One study (Durand 1987) found that treatment was effective in reducing failed extubation in those born at less than 1000 g and who were less than one week old. In the small prespecified subgroups in this trial, infants of less than 1000 g birth weight and older than one week and those of birth weight 1000 ‐ 1250 g who had failed extubation once, no significant benefit was found.

Authors' conclusions

Implications for practice.
Methylxanthines increase the chances of successful extubation of preterm infants within one week of age. One trial suggests that this benefit is principally in infants of extremely low birth weight extubated in the first week of life. There is insufficient information to assess side effects or longer term effects on neonatal outcome or child growth and neurological development in the included trials.

Implications for research.
In any future trials there is a need to stratify infants by gestational age (a better indicator of immaturity than birth weight) . Caffeine, with its wider therapeutic margin (Blanchard 1992; Steer 2003) would be the better treatment to evaluate against placebo. Short and longer term side effects should be included as outcomes. Data on neonatal and longer term outcome might be available for infants given caffeine for extubation in the trial of general caffeine use that is, awaiting assessment (CAP Trial 2006).