Bronchodilators for the prevention and treatment of chronic lung disease in preterm infants

Chronic lung disease (CLD) occurs frequently in preterm infants (< 37 weeks gestational age) and has a multifactorial etiology. Bronchodilators have the potential effect of dilating small airways with muscle hypertrophy. Increase in compliance and tidal volume and decrease in pulmonary resistance have been documented with use of bronchodilators in short term studies of pulmonary mechanics in infants with CLD. Therefore it is possible that bronchodilators might have a role in the prevention and treatment of CLD.

To evaluate the effect of bronchodilators, given prophylactically or as treatment for chronic lung disease, on mortality and other complications of preterm births.

The search strategy used to identify studies was according to the guidelines of the Cochrane Neonatal Review Group. Searches were made of MEDLINE 1966 to December 2000, EMBASE 1980 to January 2001, CINAHL 1982 to December 2000, the Cochrane Library Issue 1, 2001, personal files and reference lists of identified trials. The following terms were used: bronchopulmonary dysplasia, chronic lung disease, bronchodilator agents, adrenergic agents, anticholinergic agents, albuterol, aminophylline, atropine, caffeine, clenbuterol, cromakalim, ephedrine, epinephrine, fenoterol, hexoprenaline, ipratropium, isoetharine, isoproterenol, orciprenaline, procaterol, terbutaline, theophylline, tretoquinol.

newborn, infant; human, clinical trial or controlled clinical trial, meta analysis, multicenter study or randomised controlled trial. No language restrictions were applied.

Randomised controlled clinical trials involving preterm infants. Initiation of bronchodilator therapy had to occur within two weeks of birth for prevention of CLD. For treatment of CLD treatment should have been initiated before discharge from the neonatal unit. The intervention had to include the randomised administration of a bronchodilator either by nebulisation, metered dose inhaler with or without a spacer device, intravenously or orally, versus placebo or no intervention. Eligible studies had to include at least one of the following outcomes: mortality, CLD at 28 days or at 36 weeks corrected GA, number of days on oxygen, number of days on ventilator, patent ductus arteriosus (PDA), pulmonary interstitial emphysema (PIE), pneumothorax, any grade of intraventricular haemorrhage, necrotizing enterocolitis (NEC), sepsis and adverse effects of bronchodilators.

We used the standard method for the Cochrane Collaboration as described in the Cochrane Collaboration handbook. Two investigators (GN, AO) extracted and assessed all data for each study. Any disagreement was resolved by discussion. Relative risk (RR) and risk difference (RD) with 95% confidence intervals (CI) are reported for dichotomous outcomes and mean difference (WMD) for continuous data.

One eligible study was found dealing with prevention of CLD; this study used salbutamol and enrolled 173 infants. No eligible studies were found dealing with treatment of CLD. Prophylaxis with salbutamol did not show a statistically significant difference in mortality [RR 1.08 (95% CI 0.50, 2.31); RD 0.01 (95% CI -0.09, 0.11)], CLD (mild, moderate or severe) [RR 1.03 (95% CI 0.78, 1.37); RD 0.02 (95% CI -0.13, 0.17)], need for iv dexamethasone [RR 0.77 (95% CI 0.49, 1.19); RD -0.08 (95% CI -0.22, 0.05)], respiratory infections [RR 0.61 (95% CI 0.27, 1.39); RD -0.06 (95% CI -0.16, 0.04)] or positive blood culture [RR 1.06 (95% CI 0.54, 2.06); RD 0.01 (95% CI -0.10, 0.12)]. There was no statistically significant difference in duration of ventilatory support [MD -1.63 days (95% CI -5.63, 2.37)], duration of oxygen supply [MD -2.82 days (95% CI -11.91, 6.27)] or age of weaning from respiratory support (defined as assisted ventilation or oxygen supplementation) [MD -2.87 days (95% CI -11.28, 5.54)]. No side effects due to salbutamol were commented on in this study.

There are insufficient data to reliably assess the use of salbutamol for the prevention of CLD. Further clinical trials are necessary to assess the role of salbutamol or other bronchodilator agents in prophylaxis or treatment of CLD.