Prophylactic methylxanthine 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.

Main question: 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 Neonatal Review Group, as outlined in the Cochrane Library, was used.

All published trials utilising random or quasi-random patient allocation, in which treatment with methylxanthine (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 blinded to the authors and extracted data independently. Relative risk and risk difference was used in the meta-analysis.

Overall analysis of the 4 published trials suggests that methylxanthine treatment results in a reduction in the use of mechanical ventilation. Three of the 4 studies are consistent with this overall result while one small trial (Barrington 1993) found no benefit. One study (Durand 1987) found that treatment was effective 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 could be shown.

Implications for practice. Methylxanthines might increase the chances of successful extubation of some preterm infants but the results of this meta-analysis do not allow firm recommendations to be made for clinical practice. One trial suggests that this benefit is principally in infants of extremely low birth weight extubated in the first week. There are no trial data to support the routine use of methylxanthines for the extubation of infants with a birth weight over 1000 gms or those that are older than one week. 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) would be the better treatment to evaluate against placebo. Side effects and neuro-developmental status at follow up should be included in as outcomes.