Prophylactic methylxanthines for extubation in preterm infants

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.

In preterm infants being weaned from IPPV and in whom endotracheal extubation is planned, does treatment with methylxanthine reduce the use of intubation and IPPV, without clinically important side effects?

The standard search strategy of the Cochrane Neonatal Review Group was used. This included searches of the Oxford Database of Perinatal Trials, The Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 3 2002), MEDLINE (1966 to October 2002).

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.

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.

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 (0.32, 0.70)]. Overall there is an absolute reduction of 27 % in the incidence of failed extubation [summary RD -.27 (-.39, -.15)]. Thus, overall in these six trials the number needed to treat (NNT) with methylxanthine to prevent one case of failed extubation is 3.7 (2.7, 6.7). 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 grams and who were less than one week old. In the small prespecified subgroups in this trial, infants of less than 1 kg birth weight and older than one week and those of birth weight 1000-1250 grams who had failed extubation once, no significant benefit was found.

Implications for practice. Methylxanthines increase the chances of successful extubation of preterm infants within one week. One trial suggests that this benefit is principally in infants of extremely low birth weight extubated in the first week. There is insufficient information to assess side effects or longer term effects on child development. Implications for research. Further trials are required comparing methylxanthines with placebo for extubation of very preterm infants. There is a need to stratify infants by gestational age (a better indicator of immaturity) rather than birth weight in future studies. Caffeine, with its wider therapeutic margin (Blanchard 1992, Steer 2002) would be the better treatment to evaluate against placebo. Side effects and neuro-developmental status at follow up should be included as outcomes.