Prophylactic methylxanthines for extubation in preterm infants

Henderson-Smart DJ, Davis PG

Background - Methods - Results - Characteristics of Included Studies - References - Data Tables & Graphs

Cover sheet

Title

Reviewers

Henderson-Smart DJ, Davis PG

Dates

Date edited: 20/02/2006
Date of last substantive update: 24/10/2002
Date of last minor update: 22/12/2005
Date next stage expected 30/11/2007
Protocol first published:
Review first published: Issue 1, 1998

Contact reviewer

Prof David J Henderson-Smart
Director
NSW Centre for Perinatal Health Services Research
Queen Elizabeth II Research Institute
Building DO2
University of Sydney
Sydney
NSW AUSTRALIA
2006
Telephone 1: +61 2 93517318
Telephone 2: +61 2 93517728
Facsimile: +61 2 93517742
E-mail: dhs@perinatal.usyd.edu.au

Contribution of reviewers

Both reviewers participated in the development of the protocol, independent assessment of the trials for eligibility and quality, as well as data extraction. D Henderson-Smart wrote the text and entered the data into RevMan. P Davis checked data entry and assisted with editing the text.

Internal sources of support

NSW Centre for Perinatal Health Services Research, Sydney, AUSTRALIA
University of Melbourne, Melbourne, AUSTRALIA
Royal Prince Alfred Hospital, Sydney, AUSTRALIA
University of Sydney, AUSTRALIA
Royal Women's Hospital, Melbourne, AUSTRALIA

External sources of support

None

What's new

This updates the review 'Prophylactic methylxanthines for extubation in preterm infants", published in The Cochrane Library, Issue 1, 2003 (Henderson-Smart 2003).

The trial search has been updated to November 2005. Embase and CINAHL databases were included.

No new trials were identified in this updated search.

Dates

Date review re-formatted: 27/09/1999
Date new studies sought but none found: 22/12/2005
Date new studies found but not yet included/excluded: 22/12/2005
Date new studies found and included/excluded: 20/10/2002
Date reviewers' conclusions section amended: 20/10/2002
Date comment/criticism added: / /
Date response to comment/criticisms added: / /

Text of review

Synopsis

Using methylxanthines to help wean babies from mechanical ventilation might help some babies. Methylxanthines are drugs (such as caffeine) that can help improve breathing in preterm babies (babies born early). They can be given to preterm babies when weaning from machine-assisted breathing (extubation from mechanical ventilation) is planned. The review of trials found that they might be helpful for some babies. There is evidence to suggest they might be beneficial for babies born at less than 1000 g, and being taken off the ventilator during the first week after birth. However, they may not help in other situations.

Abstract

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

Search strategy

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 (CENTRAL, The Cochrane Library, Issue 4, 2005), MEDLINE (1966 to November 2005), CINAHL (1982 - November 2005) and EMBASE (1988 - November 2005).

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 & 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 (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 gms 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 gms who had failed extubation once, no significant benefit was found.

Reviewers' conclusions

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 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.

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 apnoea, particularly in very preterm infants. At any given gestational age the tendency to develop apnoea decreases with increasing postnatal age (Henderson-Smart 1995).

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).

Objectives

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?
As immaturity or co-interventions may affect the response the following subgroup analyses were prespecified:
1. birth weight and/or gestational age subgroups
2. postnatal age subgroups
3. use of postextubation nasal CPAP

Criteria for considering studies for this review

Types of studies

All published trials utilising random or quasi-random patient allocation were eligible.

Types of participants

Preterm or low birth weight infants being weaned from IPPV.

Types of interventions

Prophylactic methylxanthine (theophylline or caffeine) compared with control (placebo or no treatment).

Types of outcome measures

1. Failed extubation within one week of commencing treatment [unable to wean from IPPV and extubate, or reintubation for IPPV, or use of continuous positive airways pressure (CPAP)]
2. Side effects (tachycardia, agitation or feed intolerance, leading to cessation of treatment)
3. Chronic lung disease (oxygen dependency at 28 days or 36 weeks postmenstrual age)
4. Long term neurodevelopmental abnormality (cerebral palsy, delayed development)

Search strategy for identification of studies

The standard search strategy of the Cochrane Neonatal Review Group as outlined in The Cochrane Library was used. This included searches of the Oxford Database of Perinatal Trials, Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 4, 2005), MEDLINE (1966 to November 2005), CINAHL (1982 - November 2005) and EMBASE (1988 - November 2005) using MeSH terms infant-preterm and text terms methylxanthine, caffeine, theophylline, aminophylline together with publication type randomised-controlled-trial or clinical-trial. Reference lists of trials and previous reviews were examined. Abstracts of the Society for Pediatric Research and European Society for Pediatric Research, published in Pediatric Research, were also hand searched for the years 1996-2005.

Methods of the review

The standard methods of the Cochrane Collaboration and its Neonatal Review Group were used. The eligibility and methodological quality of each trial were independently reviewed by both authors.

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.

Description of studies

There was a wide range of gestational ages and birth weights in the infants enrolled in the studies. Details of each study are in the table of included studies.

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.

Methodological quality of included studies

Details of the methodological quality of each study are given in the table of included studies. The number of subjects in each study was small and power calculations were performed in only two of the trials. These were based on measurements of lung compliance (Greenough 1985) and mouth occlusion pressures (Barrington 1993) rather than on failure of extubation.

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).

Results

Six trials were included in the review. Three trials (Durand 1987; Muro 1992; Viscardi 1985) found significant reductions in failure of extubation within one week of commencing treatment.

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.

Discussion

The number of infants in these studies was small and so only a large difference in outcomes could be reliably detected. This is of particular concern in regard to side effects. Subgroup analysis in one trial (Durand 1987) suggests that the only benefit might be found in infants born at less than 1 kg and extubated in the first week. No placebo was used in this trial and this is a potential source of bias. The important question of which preterm infants are likely to benefit from methylxanthine requires further research.

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).

Reviewers' conclusions

Implications for practice

Methylxanthines increase the chances of successful extubation of preterm infants within one week of commencing treatment. 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 2003) would be the better treatment to evaluate against placebo. Side effects and neuro-developmental status at follow up should be included as outcomes.

Acknowledgements

Thanks to Keith Barrington, Stephen Pearlman and Jesus Perez-Rodriquez, who provided additional data from their studies.

Potential conflict of interest

None

Characteristics of included studies

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

Characteristics of ongoing studies

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

References to studies

References to included studies

Barrington 1993 {published and unpublished data}

* 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.

References to ongoing studies

Schmidt 1999 {published data only}

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

Other references

Additional references

Blanchard 1992

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 2000

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 2005

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 05

Henderson-Smart DJ, Steer P. Methylxanthine treatment for apnea in preterm infants. In: The Cochrane Database of Systematic Reviews, Issue 4, 2005.

Henderson-Smart 05a

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 1995

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 2003

Steer PA, Henderson-Smart DJ. Caffeine versus theophylline for apnea in preterm infants. In: The Cochrane Database of Systematic Reviews, Issue 2, 2003.

Other published versions of this review

Henderson-Smart 1998

Henderson-Smart DJ, Davis PG. Prophylactic methylxanthines for extubation in preterm infants. In: Cochrane Database of Systematic Reviews, Issue 1, 1998.

Henderson-Smart 2003

Henderson-Smart DJ, Davis PG. Prophylactic methylxanthines for extubation in preterm infants. In: Cochrane Database of Systematic Reviews, Issue 1, 2003.

Comparisons and data

01 Methylxanthine vs control - all infants
01.01 Failed extubation
01.02 Side effects

02 Methylxanthine vs control - infants <1 kg
02.01 Failed extubation
02.02 Neurodevelopmental abnormality at 30 months

03 Methylxanthine vs control - infants >1 kg who failed first extubation
03.01 Failed extubation

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]

Notes

Published notes

Contact details for co-reviewers

Dr Peter G Davis
Department of Obstetrics and Gynaecology
Royal Women's Hospital
132 Grattan Street
Carlton
Victoria AUSTRALIA
3053
Telephone 1: +61 3 93442151
Facsimile: +61 3 93471761
E-mail: pgd@unimelb.edu.au

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.