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Prophylactic methylxanthines for extubation in preterm infants

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Authors

David J Henderson-Smart1, Peter G Davis2

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


1NSW Centre for Perinatal Health Services Research, Queen Elizabeth II Research Institute, Sydney, Australia [top]
2Department of Paediatrics, Royal Women's Hospital, Parkville, Australia [top]

Citation example: Henderson-Smart DJ, Davis PG. Prophylactic methylxanthines for extubation in preterm infants. Cochrane Database of Systematic Reviews 2003, Issue 1. Art. No.: CD000139. DOI: 10.1002/14651858.CD000139.

Contact person

David J Henderson-Smart

NSW Centre for Perinatal Health Services Research
Queen Elizabeth II Research Institute
Building DO2
University of Sydney
Sydney
NSW
2006
Australia

E-mail: dhs@mail.usyd.edu.au

Dates

Assessed as Up-to-date: 18 April 2008
Date of Search: 31 January 2008
Next Stage Expected: 18 April 2010
Protocol First Published: Issue 1, 1996
Review First Published: Issue 1, 1998
Last Citation Issue: Issue 1, 2003

What's new

Date / Event Description
08 February 2008
Amended

Converted to new review format.

08 February 2008
Updated

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

The trial search was updated to include Embase and CINAHL databases in November 2005 and published as a minor update in Issue 1, 2006.

The current update includes a new study referenced in "Studies awaiting classification" to include in the review. This is the CAP Trial with two publications in 2006 and 2007.

History

Date / Event Description

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

To determine the effects of prophylactic methylxanthine treatment on the use of intubation and IPPV and other clinically important side effects in preterm infants being weaned from IPPV and in whom endotracheal extubation is planned.

Search methods

The standard search strategy of the Cochrane Neonatal Review Group was used. This included searches of The Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 4, 2007), the Oxford Database of Perinatal Trials, MEDLINE (1966 to January 2008), CINAHL (1982 to January 2008) and EMBASE (1988 to January 2008).

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 and 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.

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 (95% CI 0.32, 0.70)]. Overall there is an absolute reduction of 27% in the incidence of failed extubation [summary RD -0.27 (95% CI -0.39, -0.15)]. Thus, overall in these six trials the number needed to treat (NNT) with methylxanthine to prevent one case of failed extubation is 4 (95% CI 3, 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 g and who were less than one week old. In the small prespecified subgroups in this trial, infants of less than 1000 g birth weight and older than one week and those of birth weight 1000 - 1250 g who had failed extubation once, no significant benefit was found.

Authors' conclusions

Implications for practice.
Methylxanthines increase the chances of successful extubation of preterm infants within one week of age. One trial suggests that this benefit is principally in infants of extremely low birth weight extubated in the first week of life. There is insufficient information to assess side effects or longer term effects on neonatal outcome or child growth and neurological development in the included trials.

Implications for research.
In any future trials there is a need to stratify infants by gestational age (a better indicator of immaturity than birth weight). Caffeine, with its wider therapeutic margin (Blanchard 1992; Steer 2003) would be the better treatment to evaluate against placebo. Short and longer term side effects should be included as outcomes. Data on neonatal and longer term outcome might be available for infants given caffeine for extubation in the trial of general caffeine use that is, awaiting assessment (CAP Trial 2006).

Plain language summary

Prophylactic methylxanthines for extubation in preterm infants

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.

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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 2004).

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 apneic episodes and the need for IPPV (Henderson-Smart 2005). 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

To determine the effects of prophylactic methylxanthine treatment on the use of intubation and IPPV and other clinically important side effects in preterm infants being weaned from IPPV and in whom endotracheal extubation is planned.

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

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Methods

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

Primary
  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. Death before discharge
Secondary

Acute side effects (tachycardia, agitation or feed intolerance, leading to cessation of treatment)

Neonatal morbidity such as - patent ductus arteriosus requiring treatment, intracranial hemorrhage, necrotizing enterocolitis,

  1. Duration of IPPV
  2. Duration of oxygen therapy
  3. Chronic lung disease (oxygen dependency at 28 days or 36 weeks postmenstrual age)
  4. Long-term growth and neurodevelopmental abnormalities (cerebral palsy, delayed development)

Search methods 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 Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 4, 2007), the Oxford Database of Perinatal Trials, MEDLINE (1966 to January 2008), CINAHL (1982 to January 2008) and EMBASE (1988 to January 2008) 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 to 2005.

Data collection and analysis

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. The fixed effects model was used unless there was significant heterogeneity based on I2 statistic, that is unresolved by subgroup analysis. In this case, the random effects RR was also reported.

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Results

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.

A new trial (CAP Trial 2006) comparing outcomes at discharge and infant follow-up of caffeine versus placebo is 'awaiting assessment'. It can not be included in this review yet because although one indication for inclusion of participants (prophylactic methylxanthines for extubation in preterm infants) was appropriate, there were two other indications for inclusion in the trial and published in the combined results were prophylactic methylxanthine for apnea of prematurity and methylxanthine treatment of apnea of prematurity. The latter are potentially eligible for two other Cochrane Reviews (Henderson-Smart 2003, Henderson-Smart 1999)

Risk of bias in 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 to follow-up (groups not specified).

Effects of interventions

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 (95% CI 0.32, 0.70)]. Overall there is an absolute reduction of 27 % in the incidence of failed extubation [summary RD -0.27 (95% CI -0.39, -0.15)]. There is significant heterogeneity in the RD meta-analysis (p = 0.007, I2 = 68.6) possibly 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 g and who were less than one week old [RR 0.40 (95% CI 0.16, 0.95)]. In the small prespecified subgroups in this trial, infants of less than 1000 g birth weight and older than one week and those of birth weight 1000 - 1250 g 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. The number of infants with reported side effects was small and the differences not significant.

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 g 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 g in the Durand 1987 study were followed and their neurodevelopmental 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 1000 g 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 2003a) 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 neurodevelopmental 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.

Of particularly concern is the lack of trial data on neonatal morbidity and long-term growth and development. The CAP Trial (CAP Trial 2006) has published outcomes at discharge and growth and development at 18 to 21 months. These results include a large number of very low birthweight infants (Caffeine group 1006, placebo group 1000) with any one of the three indications for trial entry (prophylactic prevention of apnea in 23%, treatment of apnea in 41% or prophylaxis for extubation in 36%). At present the results can not be included in this review on prophylaxis for extubation, although they do provide an overall assessment of the effect of caffeine use, indicating that there is improved outcome at discharge and in neurodevelopment at follow-up. The CAP Trial authors have been requested to evaluate outcomes for each indication which will make the trial eligible for inclusion in this review and also the other two Cochrane Reviews dealing with the other two indications for inclusion in the CAP Trial (Henderson-Smart 2003, Henderson-Smart 1999).

Other Cochrane reviews evaluate other interventions to assist extubation. There are insufficient trial data to evaluate the use of Doxapram (Henderson-Smart 2000). Dexamethasone (Davis 2003) is effective in some infants. Low rate IPPV is more effective than CPAP via endotracheal tube prior to extubation (Davis 2003a) .

Authors' 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 neonatal outcome or child growth and neurological development in the included trials.

Implications for research

In any future trials there is a need to stratify infants by gestational age (a better indicator of immaturity than birth weight). Caffeine, with its wider therapeutic margin (Blanchard 1992; Steer 1998) would be the better treatment to evaluate against placebo. Short and longer term side effects should be included as outcomes. Data on neonatal and longer term outcome might be available for infants given caffeine for extubation in the trial of general caffeine use, awaiting assessment (CAP Trial 2006).

Acknowledgements

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

Contributions of authors

Both review authors 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.

Declarations of interest

  • None noted.

Differences between protocol and review

  • None noted.

Additional tables

  • None noted.

Potential conflict of interest

  • None noted.

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Characteristics of studies

Characteristics of Included Studies

Barrington 1993

Methods

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

Participants

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.

Interventions

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.

Outcomes

Failure of extubation with in 7 days; airway occlusion pressure (100 msec, peak 1st breath and maximum)

Notes

Sample size and power calculation done on occlusion pressure (40% increase). Additional information on birth weight distribution and occlusion pressures obtained from authors.

Risk of bias table
Item Judgement Description
Allocation concealment? Yes

A - Adequate

Durand 1987

Methods

Randomised, method - not specified;
Blinding of intervention - No;
Completeness of follow up - Yes;
Blinding of outcome assessment - No

Participants

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).

Interventions

Aminophylline IV 7 mg/kg load and 1.5 mg/kg 8 hrly vs control (no placebo)

Outcomes

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)

Notes

All extubated 24 hrs after randomisation. No CPAP used before or after extubation.

Risk of bias table
Item Judgement Description
Allocation concealment? Unclear

B - Unclear

Greenough 1985

Methods

Randomised, concealed by pharmacy; Blinding of intervention - Yes;
Completeness of follow up - Yes (only 2 with toxicity excluded);
Blinding of outcome assessment - Yes

Participants

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)

Interventions

Theophylline 5 mg kg load, 5 mg/kg per day in 4 doses vs placebo, each given for 48 hrs.

Outcomes

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)

Notes
Risk of bias table
Item Judgement Description
Allocation concealment? Yes

A - Adequate

Muro 1992

Methods

Randomised, concealment - Yes (sealed envelopes); Blinding of intervention - Yes;
Completeness of follow up - Yes;
Blinding of outcome assessment - Yes

Participants

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.

Interventions

Caffeine citrate 20 mg/kg IV then 5 mg/kg orally per day.
Placebo - characteristics not stated.

Outcomes

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).

Notes

Additional information extracted from Dr Muro's MD Thesis by Dr Perez-Rodriquez.

Risk of bias table
Item Judgement Description
Allocation concealment? Yes

A - Adequate

Pearlman 1991

Methods

Randomised, concealment - Yes (carried out in hospital pharmacy); Blinding of intervention - Yes;
Completeness of follow up - Yes;
Blinding of outcome assessment - Yes

Participants

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.

Interventions

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.

Outcomes

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

Notes

Full unpublished manuscript provided by Dr Pearlman

Risk of bias table
Item Judgement Description
Allocation concealment? Yes

A - Adequate

Viscardi 1985

Methods

Random, concealment - Yes (prepackaged for individual patients); Blinding of intervention - Yes;
Completeness of follow up - Yes;
Blinding of outcome assessment - Yes

Participants

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.

Interventions

Theophylline 6 mg/kg load and 2 mg/kg 12 hrly (all but 1 IV) vs Placebo (N saline)

Outcomes

Unable to extubate or need reintubation for IPPV within 5 days (reason: hypercarbia, acidisis, hypoxemia)

Notes

Nasal CPAP used for 1st 12 - 24 hrs then polygraph done.

Risk of bias table
Item Judgement Description
Allocation concealment? Yes

A - Adequate

Characteristics of studies awaiting classification

CAP Trial 2006

Methods
Participants
Interventions
Outcomes
Notes

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References to studies

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;31:342A.

Durand 1987

* 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

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

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. Pharmacological treatment during the weaning of mechanical ventilation in preterm infants. Effects on pulmonary mechanics [Tratamiento farmacológico en la retirada de la ventilación mecánica del recién nacido pretérmino. Repercusión sobre la función pulmonar]. Tesis doctoral, Facultad de Medicina, Universidad Autonoma de Madrid, Madrid 1992.

Pearlman 1991

* 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

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 excluded studies

  • None noted.

Studies awaiting classification

CAP Trial 2006

Schmidt B, Roberts RS, Davis P, Doyle LW, Barrington KJ, Ohlsson A., Solimano A, Tin W, for Caffeine for Apnea of Prematurity Trial Group. Caffeine therapy for apnea of prematurity. New England Journal of Medicine 2006;354:2179-81.

Schmidt B. Roberts RS. Davis P. Doyle LW. Barrington KJ. Ohlsson A. Solimano A. Tin W. Effects of Caffeine Therapy for Apnea of Prematurity. New England Journal of Medicine 2007;357:1893-1902.

Ongoing studies

  • None noted.

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 2001

PG Davis, DJ Henderson-Smart. Extubation from low-rate intermittent positive airways pressure versus extubation after a trial of endotracheal continuous positive airways pressure in intubated preterm infants. Cochrane Database of Systematic Reviews 2001, Issue 4. Art. No.: CD001078. DOI: 10.1002/14651858.CD001078.

Davis 2003

PG Davis, DJ Henderson-Smart. Intravenous dexamethasone for extubation of newborn infants. Cochrane Database of Systematic Reviews 2001, Issue 4. Art. No.: CD000308. DOI: 10.1002/14651858.CD000308.

Davis 2003a

Davis PG, Henderson-Smart DJ. Nasal continuous positive airway pressure immediately after extubation for preventing morbidity and mortality in preterm infants. Cochrane Database of Systematic Reviews 2003, Issue 2. Art. No.: CD000143. DOI: 10.1002/14651858.CD000143.

Henderson-Smart 2005

Henderson-Smart DJ, Steer P. Methylxanthine treatment for apnea in preterm infants. Cochrane Database of Systematic Reviews 2005, Issue 4. Art. No.: CD000140. DOI: 10.1002/14651858.CD000140.

Henderson-Smart 1999

Henderson-Smart DJ, Steer P. Prophylactic methylxanthine for the prevention of apnea in preterm infants. Cochrane Database of Systematic Reviews 1999, Issue 2. Art. No.: CD000432. DOI: 10.1002/14651858.CD000432.

Henderson-Smart 2000

Henderson-Smart DJ, Davis PG. Prophylactic doxapram for the prevention of morbidity and mortality in preterm infants undergoing endotracheal extubation. Cochrane Database of Systematic Reviews 2000, Issue 3. Art. No.: CD001966. DOI: 10.1002/14651858.CD001966.

Henderson-Smart 2004

Henderson-Smart DJ. Recurrent apnoea. In: Evidence Based Pediatrics. Oxford: Blackwell, 2004.

Steer 1998

Steer PA, Henderson-Smart DJ. Caffeine versus theophylline for apnea in preterm infants. Cochrane Database of Systematic Reviews 1998, Issue 2. Art. No.: CD000273. DOI: 10.1002/14651858.CD000273.

Other published versions of this review

Henderson-Smart 1998

Henderson-Smart DJ, Davis PG. Prophylactic methylxanthines for extubation in preterm infants. Cochrane Database of Systematic Reviews 1998, Issue 1. Art. No.: CD000139. DOI: 10.1002/14651858.CD000139.

Henderson-Smart 2003

Henderson-Smart DJ, Davis PG. Prophylactic methylxanthines for extubation in preterm infants. Cochrane Database of Systematic Reviews 2003, Issue 1. Art. No.: CD000139. DOI: 10.1002/14651858.CD000139.

Henderson-Smart 2006

Henderson-Smart DJ, Davis PG. Prophylactic methylxanthines for extubation in preterm infants. Cochrane Database of Systematic Reviews 2006, Issue 1. Art. No.: CD000139. DOI: 10.1002/14651858.CD000139.

Classification pending references

  • None noted.

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Data and analyses

1 Methylxanthine vs control - all infants

Outcome or Subgroup Studies Participants Statistical Method Effect Estimate
1.1 Failed extubation 6 197 Risk Ratio (M-H, Fixed, 95% CI) 0.48 [0.32, 0.71]
1.1.1 NCPAP use routine 1 25 Risk Ratio (M-H, Fixed, 95% CI) 0.39 [0.19, 0.81]
1.1.2 NCPAP use not routine 5 172 Risk Ratio (M-H, Fixed, 95% CI) 0.51 [0.32, 0.80]
1.2 Side effects 2 56 Risk Ratio (M-H, Fixed, 95% CI) 5.53 [0.28, 107.96]

2 Methylxanthine vs control - infants < 1 kg

Outcome or Subgroup Studies Participants Statistical Method Effect Estimate
2.1 Failed extubation 2 50 Risk Ratio (M-H, Fixed, 95% CI) 0.58 [0.29, 1.16]
2.1.1 Age less than one week 2 41 Risk Ratio (M-H, Fixed, 95% CI) 0.51 [0.25, 1.07]
2.1.2 Age more than one week 1 9 Risk Ratio (M-H, Fixed, 95% CI) 2.00 [0.18, 22.06]
2.2 Neurodevelopmental abnormality at 30 months 1 32 Risk Ratio (M-H, Fixed, 95% CI) 0.43 [0.13, 1.37]

3 Methylxanthine vs control - infants >1 kg who failed first extubation

Outcome or Subgroup Studies Participants Statistical Method Effect Estimate
3.1 Failed extubation 1 10 Risk Ratio (M-H, Fixed, 95% CI) 0.24 [0.01, 4.72]

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Figures

  • None noted.

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Sources of support

Internal sources

  • University of Melbourne, Melbourne, Australia
  • Centre for Perinatal Health Services Research, University of Sydney, Australia
  • Royal Women's Hospital, Melbourne, Australia

External sources

  • No sources of support provided.

This review is published as a Cochrane review in The Cochrane Library, Issue 3, 2008 (see http://www.thecochranelibrary.comExternal Web Site Policy for information). Cochrane reviews are regularly updated as new evidence emerges and in response to feedback. The Cochrane Library should be consulted for the most recent recent version of the review.