The trial search has been updated to November 2005. Embase and CINAHL databases were included.
No new trials were identified in this updated search.
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 than birth weight) in future
studies. Caffeine, with its wider therapeutic margin (Blanchard 1992; Steer
1998) would be the better treatment to evaluate against placebo. Side effects
and neuro-developmental status at follow up should be included as outcomes.
Weaning from support may be prolonged or, even if extubation is achieved, frequent episodes of apnea may occur in association with respiratory failure (hypercarbia, hypoxemia and acidosis) of sufficient severity as to lead to reintubation and the use of IPPV. As a consequence, the use of IPPV is prolonged with associated costs for higher dependency care and a potential for morbidity from the intervention.
In non intubated preterm infants, methylxanthines appear to increase respiratory drive, reduce the number of apnoeic episodes and the need for IPPV (Henderson-Smart 05). Furthermore, there is some physiological evidence that methylxanthines increase the breathing response to carbon dioxide (Blanchard 1992).
Harmful effects could include acute toxicity (excessive central nervous system excitation or tachycardia) or alterations in neurological development. One observational study has suggested that administration is associated with higher rates of cerebral palsy but better scores of psychometric testing in very low birth weight infants (Davis 2000).
Each author extracted data separately, then compared results and resolved differences. Additional data were provided from authors of three trials (Barrington 1993; Muro 1992; Pearlman 1991).
The standard method of Neonatal Review Group was used to synthesise the data. Results are expressed as relative risk (RR) and risk difference (RD) and from 1/RD the number needed to treat.
Treatment consisted of aminophylline or theophylline in four trials (Barrington 1993; Durand 1987; Greenough 1985; Viscardi 1985), and caffeine in one trial (Muro 1992). In one trial (Pearlman 1991) there was a control group and two treatment arms, one caffeine and one theophylline (see table of included studies) and the results of these latter two were combined for this review.
Although all trials had the aim of improving the chances of successful extubation, protocols differed considerably. In three studies the infants were extubated at a set time and then the need for reintubation within five days (Viscardi 1985; Pearlman 1991; Muro 1992), seven days (Barrington 1993) or at any time (Durand 1987) evaluated. The remaining trial (Greenough 1985) examined how many infants were still intubated at 48 hrs.
One trial (Viscardi 1985) used routine postextubation nasal CPAP for 12 - 24 hours in all infants.
Overall, all trials used formal randomisation; all but one trial (Durand 1987) used blinding of the treatment with a placebo; almost all cases were accounted for in the analyses.
Two trials (Greenough 1985; Muro 1992) reported side effects that could be attributed to methylxanthines and only one trial (Durand 1987) examined neurodevelopmental outcome.
Only one trial (Durand 1987) reported follow up in a subgroup of infants born at less than 1 kg and there is differential loss between the treatment (one infant) and control group (six infants). Of 41 infants less than 1 kg analysed during the trial, two died before discharge, one died before follow up and four were lost (groups not specified).
Overall analysis of the six trials show that methylxanthine treatment results in a reduction in the incidence of failed extubation [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)]. There is significant heterogeneity in the RD meta-analysis (p = 0.007) related to the large variation in baseline rate in the control group (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 [summary RR 0.40 (0.16,0.95)]. 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 gms who had failed extubation once, no significant benefit could be shown.
Two trials reported side effects. Greenough 1985 found 2/18 of the treatment group and 0/20 of the control infants had tachycardia or agitation leading to cessation of treatment. The other small trial (Muro 1992) reported an increase in mean heart rate in infants treated with caffeine but treatment was not withheld in any infant.
Three trials reported rates of chronic lung disease defined as oxygen use at 28 days in two (Muro 1992; Pearlman 1991) and undefined in one (Durand 1987). In Muro 1992 there were no cases in either group, in Pearlman 1991 it occurred in 8/31 in the methylxanthine group and 5/14 in the placebo group and in Durand 1987 it occurred in 7/14 in the methylxanthine group versus 12/18 in the control infants of less than 1000 gms who were extubated in the first week. Author clarification is required before these results can be combined.
In the Greenough 1985 trial a significantly higher lung compliance was found in treated infants at six hours after commencing treatment.
One trial (Barrington 1993) examined mouth occlusion pressures as a measure of respiratory drive before and after trial entry and found no significant difference between infants in the treatment and control group.
Postextubation nasal CPAP was used routinely in one study (Viscardi 1985) but subgroup analysis suggests that the effects are similar whether or not it is used.
Infants of less than 1000 gms in the Durand 1987 study were followed and their neuro-developmental status at 30 months reported in an abstract by Piecuch in 1989. No significant difference was found.
Postextubation nasal CPAP, which reduces the failure rate when extubating preterm infants (Davis 2005) might have modified the response to methylxanthines. Subgroup analysis based on very small numbers of infants suggests that this does not account for any differences in results between trials.
Four of the six studies did not report side effects and only one study (Durand 1987) reported neuro-developmental status at follow up. There is also caution warranted in interpreting this one study as there were more losses to follow up in the control (6) than the treatment group (1). Assessment of these important outcomes is therefore unsatisfactory at this stage.
Prophylactic doxapram has also been used to assist extubation in preterm infants and is the subject of another review (Henderson-Smart 05a).
Study | Methods | Participants | Interventions | Outcomes | Notes | Allocation concealment |
Barrington 1993 | Randomisation by use of computer generated sequentially numbered vials, concealment - Yes; Blinding of intervention - Yes; Completeness of follow up - Yes; Blinding of outcome assessment - Yes | 20 infants < 2.5kg BW, >48 hrs old, intubated for resp. failure in 1st 24 hrs, in FiO2 <0.4 and ventilator rate and pressure reduced. Excluded if, unclamped intercostal drains, PDA or on sedatives or relaxants in last 12 hrs. | Aminophylline IV 4 mg/kg load, 2.5 mg/kg 6 hrly for 3 doses then 1.5 mg/kg 6 hrly vs placebo (not specified). No CPAP used. | Failure of extubation with in 7 days; airway occlusion pressure (100 msec, peak 1st breath and maximum) | Sample size and power calculation done on occlusion pressure (40% increase). Additional information on birth weight distribution and occlusion pressures obtained from authors. | A |
Durand 1987 | Randomised, method - not specified; Blinding of intervention - No; Completeness of follow up - Yes; Blinding of outcome assessment - No | a.
preterm infants with birth weights < 1 kg and ready for 1st extubation,
stratified by age < 1 week (32) or >1 week (9). b. preterm infants with birth weights > 1 kg and failed first extubation (10). | Aminophylline IV 7 mg/kg load and 1.5 mg/kg 8 hrly vs contol (no placebo) | Failure of extubation = use of reintubation at any time (pH<7.20, CO2>55, FiO2>0.5, or frequent stimulation or ventilatory resuscitation for apnea) | All extubated 24 hrs after randomisation. No CPAP used before or after extubation. | B |
Greenough 1985 | Randomised, concealed by pharmacy; Blinding of intervention - Yes; Completeness of follow up - Yes (only 2 with toxicity excluded); Blinding of outcome assessment - Yes | 40
infants < 34 weeks GA, < 10 days of age, IPPV for RDS, not paralysed,
PIP 20 and rate 20, author available to make compliance measurements. 2 infants
in the theophylline group excluded after randomisation because of tachycardia
(1) and agitation (1) | Theophylline 5 mg kg load, 5 mg/kg per day in 4 doses vs placebo, each given for 48 hrs. | Extubation, number of infants at 10, 24 and 48 hrs (latter used here); pulmonary compliance in those still intubated (this used for sample size calculation) | A | |
Muro 1992 | Randomised, concealment - Yes (sealed envelopes); Blinding of intervention - Yes; Completeness of follow up - Yes; Blinding of outcome assessment - Yes | 18 preterm infants, birth weights < 1750 gms, with RDS and on IPPV at 5 days of age. Exclusions - unknown. Caffeine group 12 infants, mean BW 1403 +/- 281 gms, GA 30 +/- 1.7 wks. Control - 6 infants, BW 1389 +/- 304 gms, GA 30 +/- 2.4 wks. | Caffeine citrate 20 mg/kg IV then 5 mg/kg orally per day. Placebo - characteristics not stated. | Failure (number intubated at 5 days) - some infants may have received NCPAP - information not available; adverse affects leading to cessation of treatment, BPD (at 28 days). | Additional information extracted from Dr Muro's MD Thesis by Dr Perez-Rodriquez. | A |
Pearlman 1991 | Randomised, concealment - Yes (carried out in hospital pharmacy); Blinding of intervention - Yes; Completeness of follow up - Yes; Blinding of outcome assessment - Yes | 45
preterm infants with BW < 2kg, clinical and radiological RDS, on minimal
IPPV (rate < 16, PIP <16 cms H2O, FiO2 < 0.31). Exclusions - infection, congenital abnormality. Three groups. Caffeine 19 infants mean +/- SD BW 1224 +/- 286 gms, GA 29 +/- 2.4 wks, study age 2.8 +/- 2 days. Theophylline 12 infants mean BW 1233 +/- 366 gms, GA 29 +/- 2.6 wks, study age 3.1 +/- 1.3 days. Placebo 14 infants mean BW 1317 +/- 383 gms, GA 30 +/- 2.3 wks, study age 3.6 +/- 1.7 days. | Caffeine 10 mg/kg IV then 2.5 mg/kg daily (+ 2 sham doses); Theopylline 7 mg/kg IV then 2.5 mg/kg 8 hrly; Placebo sham doses 8 hrly. | Failure (intubated for IPPV or given NCPAP for mod. apnea, pH <7.25 or PaCO2 55 mmHg or more or PaO2 <55 in FiO2 > 50 mmHg) NCPAP tried for 4 hours initially then intubated if still meeting failure criteria; BPD (not specified); NEC | Full unpublished manuscript provided by Dr Pearlman | A |
Viscardi 1985 | Random, concealment - Yes (prepackaged for individual patients); Blinding of intervention - Yes; Completeness of follow up - Yes; Blinding of outcome assessment - Yes | 25
preterm infants on IPPV, birth weight <1250 gms, FiO2 < 0.31, PIP <
21, rate < 11. Ineligible: major CNS cong. abnormalities, previous multiple
extubation failures. | Theophylline 6 mg/kg load and 2 mg/kg 12 hrly (all but 1 IV) vs Placebo (N saline) | Unable to extubate or need reintubation for IPPV within 5 days (reason: hypercarbia, acidisis, hypoxemia) | Nasal CPAP used for 1st 12 - 24 hrs then polygraph done. | A |
Study | Trial name or title | Participants | Interventions | Outcomes | Starting date | Contact information | Notes |
Schmidt 1999 | Caffeine for apnea of prematurity (CAP) trial | Multicentre international (19 centres recruiting in Feb 2001), preterm infants 500-1250 gms birth weight, 1-10 days of age, considered to be candidates for methylxanthine therapy (with apnea or likely to develop apnea after extubation). | Caffeine (Loading dose 20 mg/kg of caffeine citrate; maintenance dose 5 mg/kg once every 24 hours ) vs placebo | Primary outcome: survival without neurodevelopmental disability at a corrected age of 18 months. Other: bronchopulmonary dysplasia (oxygen dependency at 28 days, and at 36 weeks postconceptual age), necrotizing enterocolitis, intra-and periventricular hemorrhage, periventricular leucomalacia, ventriculomegaly, retinopathy of prematurity, or growth failure. A prospective economic evaluation is also planned. | Enrollment completed in 2004. | Barbara Schmidt: email - schmidt@mcmaster.ca |
* Barrington KJ, Finer NN. A randomized controlled trial of aminophylline in ventilatory weaning of premature infants. Critical Care Medicine 1993;21:846-50.
Barrington KJ, Finer NN. A randomized controlled trial of aminophylline in ventilatory weaning of premature infants. Pediatric Research 1992:342A.
Durand 1987 {published data only}
* Durand DJ, Goodman A, Ray P, Ballard RA, Clyman RI. Theophylline treatment in the extubation of infants weighing less than 1,250 grams: a controlled trial. Pediatrics 1987;80:684-8.
Piecuch RE, Leonard CH, Ballard RA, Clyman RI. Neurodevelopmental outcome of very low birthweight VLBW=<1000g) infants treated with theophylline (T) to facilitate extubation. Pediatric Research 1989;25:261A.
Greenough 1985 {published data only}
Greenough A, Elias-Jones A, Pool J, Morley CJ, Davis JA. The therapeutic actions of theophylline in preterm ventilated infants. Early Human Development 1985;12:15-22.
Muro 1992 {published data only}
Muro M, Perez-Rodriguez J, Garcia MJ, Arroyo I, Quero J. Efficacy of caffeine for weaning premature infants from mechanical ventilation. Effects on pulmonary function. Journal of Perinatal Medicine 1992;20:315.
* Muro M. Tratamiento farmacológico en la retirada de la ventilación mecánica del recién nacido pretérmino. Repercusión sobre la función pulmonar [Pharmacological treatment during the weaning of mechanical ventilation in preterm infants. Effects on pulmonary mechanics]. Tesis doctoral, Facultad de Medicina, Universidad Autonoma de Madrid, Madrid 1992.
Pearlman 1991 {published data only}
* Pearlman SA, Kepler JA, Stefano JL. Comparative efficacy of theophylline and caffeine in facilitating extubation of preterm infants with respiratory distress syndrome. Unpublished manuscript written in 1991, provided by author.
Pearlman SA, Stefano JL. Caffeine (C) vs theophylline (T) to facilitate extubation in preterm infants with RDS. In: Proceedings of the European Society for Paediatric Research. 1991:362.
Viscardi 1985 {published data only}
Viscardi RM, Faix RG, Nicks JJ, Grasela TH. Efficacy of theophylline for prevention of post-extubation respiratory failure in very low birth weight infants. Journal of Pediatrics 1985;107:469-72.
Schmidt B et al. Efficacy and safety of methylxanthines in very low birth weight infants. Randomized placebo controlled trial. Participants - preterm infants with birth weights 500 - 1250 grams who are candidates for methylxanthine treatment. Intervention - caffeine vs saline placebo. Primary outcome - combined rate of mortality and neurodevelopmental disability at 18 months of age. Contact - Barbara Schmidt - schmidt@mcmaster.ca.
* indicates the primary reference for the study
Blanchard PW, Aranda JV. Pharmacotherapy of respiratory control disorders. In: Beckerman RC, Brouillette RT, Hunt CE, editor(s). Respiratory Control Disorders in Infants and Children. Baltimore: Williams & Wilkins, 1992:161-77.
Davis P, Doyle L, Rickards A, Kelly E, Ford G, Davis N, Callanan C. Methylxanthines and sensorineural outcome at 14 years in children < 1501 g birthweight. Journal of Paediatric and Child Health 2000;36:47-50.
Davis PG, Henderson-Smart DJ. Prophylactic post-extubation nasal CPAP in preterm infants. In: The Cochrane Database of Systematic Reviews, Issue 4, 2005.
Henderson-Smart DJ, Steer P. Methylxanthine treatment for apnea in preterm infants. In: The Cochrane Database of Systematic Reviews, Issue 4, 2005.
Henderson-Smart DJ, Davis PG. Prophylactic doxapram for the prevention of morbidity and mortality in preterm infants undergoing endotracheal extubation. In: The Cochrane Database of Systematic Reviews, Issue 4, 2005.
Henderson-Smart DJ. Recurrent apnoea. In: Yu VYH, editor(s). Bailliere's Clinical Paediatrics. Vol. 3. No. 1 Pulmonary Problems in the Perinatal Period and their Sequelae. London: Bailliere Tindall, 1995:203-222.
Steer PA, Henderson-Smart DJ. Caffeine versus theophylline for apnea in preterm infants. In: The Cochrane Database of Systematic Reviews, Issue 2, 2003.
Henderson-Smart DJ, Davis PG. Prophylactic methylxanthines for extubation in preterm infants. In: Cochrane Database of Systematic Reviews, Issue 1, 1998.
Henderson-Smart DJ, Davis PG. Prophylactic methylxanthines for extubation in preterm infants. In: Cochrane Database of Systematic Reviews, Issue 1, 2003.
Comparison or outcome | Studies | Participants | Statistical method | Effect size |
---|---|---|---|---|
01 Methylxanthine vs control - all infants | ||||
01 Failed extubation | 6 | 197 | RR (fixed), 95% CI | 0.47 [0.32, 0.70] |
02 Side effects | 2 | 56 | RR (fixed), 95% CI | 5.53 [0.28, 107.96] |
02 Methylxanthine vs control - infants <1 kg | ||||
01 Failed extubation | 3 | 50 | RR (fixed), 95% CI | 0.58 [0.29, 1.16] |
02 Neurodevelopmental abnormality at 30 months | 1 | 32 | RR (fixed), 95% CI | 0.43 [0.13, 1.37] |
03 Methylxanthine vs control - infants >1 kg who failed first extubation | ||||
01 Failed extubation | 1 | 10 | RR (fixed), 95% CI | 0.24 [0.01, 4.72] |
The review is published as a Cochrane review in The
Cochrane Library, Issue 2, 2006 (see http://www.thecochranelibrary.com for
information). Cochrane reviews are regularly updated as new evidence
emerges and in response to comments and criticisms, and The Cochrane Library
should be consulted for the most recent version of the Review. |