Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Meta-Analysis
. 2010 Dec 8;2010(12):CD000139.
doi: 10.1002/14651858.CD000139.pub2.

Prophylactic methylxanthines for endotracheal extubation in preterm infants

David J Henderson-Smart  1 , Peter G Davis
Affiliations
Meta-Analysis

Prophylactic methylxanthines for endotracheal extubation in preterm infants

David J Henderson-Smart et al. Cochrane Database Syst Rev. .

Abstract

Background: Weaning and extubating preterm infants on intermittent positive pressure ventilation (IPPV) for respiratory failure 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. 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 strategy: 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 2, 2010), the Oxford Database of Perinatal Trials, MEDLINE (1966 to July 2010), CINAHL (1982 to July 2010) and EMBASE (1988 to July 2010).

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.

Main results: Seven studies were identified for inclusion. Methylxanthine treatment results in a reduction in failure of extubation within one week (summary RR 0.48, 95%CI 0.32 to 0.71; summary RD -0.27, 95%CI -0.39 to -0.15; NNT 4, 95%CI 3 to 7; six trials, 172 infants). There is significant heterogeneity in the RD meta-analysis perhaps related to the large variation in baseline rate in the control groups (range 20 to 100%).The CAP trial enrolled the largest number of infants, but did not report extubation rates. In the caffeine group, there were lower rates of bronchopulmonary dysplasia, PDA ligation, cerebral palsy and death or major disability at 18 to 21 months. Infants receiving caffeine had reduced postmenstrual ages at time of discontinuing oxygen therapy, positive pressure ventilation and endotracheal intubation.

Authors' conclusions: Methylxanthines increase the chances of successful extubation of preterm infants within one week of age. Important neurodevelopmental outcomes are improved by methylxanthine therapy. 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, would be the better treatment to evaluate against placebo.

PubMed Disclaimer

Conflict of interest statement

None

Figures

1.1
1.1. Analysis
Comparison 1 Methylxanthine vs control ‐ all preterm infants, Outcome 1 Failed extubation.
1.2
1.2. Analysis
Comparison 1 Methylxanthine vs control ‐ all preterm infants, Outcome 2 Side effects.
1.3
1.3. Analysis
Comparison 1 Methylxanthine vs control ‐ all preterm infants, Outcome 3 PDA ligation.
1.4
1.4. Analysis
Comparison 1 Methylxanthine vs control ‐ all preterm infants, Outcome 4 PMA at last oxygen therapy.
1.5
1.5. Analysis
Comparison 1 Methylxanthine vs control ‐ all preterm infants, Outcome 5 PMA at last Endotracheal Tube.
1.6
1.6. Analysis
Comparison 1 Methylxanthine vs control ‐ all preterm infants, Outcome 6 PMA at last Positive Pressure Ventilation.
1.7
1.7. Analysis
Comparison 1 Methylxanthine vs control ‐ all preterm infants, Outcome 7 Bronchopulmonary dysplasia at term age.
1.8
1.8. Analysis
Comparison 1 Methylxanthine vs control ‐ all preterm infants, Outcome 8 Cognitive delay.
1.9
1.9. Analysis
Comparison 1 Methylxanthine vs control ‐ all preterm infants, Outcome 9 Cerebral Palsy.
1.10
1.10. Analysis
Comparison 1 Methylxanthine vs control ‐ all preterm infants, Outcome 10 Death or major disability by 18‐21 months.
2.1
2.1. Analysis
Comparison 2 Methylxanthine vs control ‐ infants <1 kg, Outcome 1 Failed extubation.
2.2
2.2. Analysis
Comparison 2 Methylxanthine vs control ‐ infants <1 kg, Outcome 2 Neurodevelopmental abnormality at 30 months.
3.1
3.1. Analysis
Comparison 3 Methylxanthine vs control ‐ infants >1 kg who failed first extubation, Outcome 1 Failed extubation.
See this image and copyright information in PMC

Update of

References

References to studies included in this review

Barrington 1993 {published and unpublished data}
    1. Barrington KJ, Finer NN. A randomized controlled trial of aminophylline in ventilatory weaning of premature infants. Critical Care Medicine 1993;21:846‐50. - PubMed
    1. Barrington KJ, Finer NN. A randomized controlled trial of aminophylline in ventilatory weaning of premature infants. Pediatric Research 1992;31:342A. - PubMed
CAP 2006 {published data only}
    1. Davis PG, Schmidt B, Roberts RS, Doyle LW, Asztalos E, Haslam R, Sinha S, Tin W, Caffeine for Apnea of Prematurity Trial Group. Caffeine for Apnea of Prematurity trial: benefits may vary in subgroups. Journal of Pediatrics 2010;156:382‐7. - PubMed
    1. Schmidt B, Roberts RS, Davis P, Doyle LW, Barrington KJ, Ohlsson A, Solimano A, Tin W, Caffeine for Apnea of Prematurity Trial Group. Caffeine therapy for apnea of prematurity. New England Journal of Medicine 2006;354:2112‐21. - PubMed
    1. Schmidt B, Roberts RS, Davis P, Doyle LW, Barrington KJ, Ohlsson A. Solimano A, Tin W, Caffeine for Apnea of Prematurity Trial Group. Long‐term effects of caffeine therapy for apnea of prematurity. New England Journal of Medicine 2007;357:1893‐902. - PubMed
Durand 1987 {published data only}
    1. 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. - PubMed
    1. 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}
    1. 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. - PubMed
Muro 1992 {published data only}
    1. 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.
    1. 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.
Pearlman 1991 {published data only}
    1. 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.
    1. Pearlman SA, Stefano JL. Caffeine (C) vs theophylline (T) to facilitate extubation in preterm infants with RDS. Proceedings of the European Society for Paediatric Research. 1991:362.
Viscardi 1985 {published data only}
    1. 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. - PubMed

Additional references

Blanchard 1992
    1. 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
    1. 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. - PubMed
Davis 2001
    1. 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. [DOI: 10.1002/14651858.CD001078] - DOI - PubMed
Davis 2003
    1. PG Davis, DJ Henderson‐Smart. Intravenous dexamethasone for extubation of newborn infants. Cochrane Database of Systematic Reviews 2001, Issue 4. [DOI: 10.1002/14651858.CD000308] - PubMed
Davis 2003a
    1. 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. [DOI: 10.1002/14651858.CD000143] - DOI - PubMed
Henderson‐Smart 2005
    1. Henderson‐Smart DJ, Steer P. Methylxanthine treatment for apnea in preterm infants. Cochrane Database of Systematic Reviews 2005, Issue 4. [DOI: 10.1002/14651858.CD000140]
Henderson‐Smart 2000
    1. 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. [DOI: 10.1002/14651858.CD001966] - DOI - PMC - PubMed
Henderson‐Smart 2004
    1. Henderson‐Smart DJ. Recurrent apnoea. Evidence Based Pediatrics. Oxford: Blackwell, 2004.
Steer 1998
    1. Steer PA, Henderson‐Smart DJ. Caffeine versus theophylline for apnea in preterm infants. Cochrane Database of Systematic Reviews 1998, Issue 2. [DOI: 10.1002/14651858.CD000273] - PubMed
Steer 2003
    1. Steer PA, Flenady VJ, Sheerman A, LeeTC, Tudehope DI, Charles BJ. Periextubation caffeine in preterm neonates: randomised dose response trial. Journal of Paediatrics and Child Health 2003;39:511‐5. - PubMed

References to other published versions of this review

Henderson‐Smart 1998
    1. 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] - PubMed
Henderson‐Smart 2003
    1. 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] - PubMed
Henderson‐Smart 2006
    1. 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] - PubMed

MeSH terms

LinkOut - more resources