Prophylactic methylxanthine for prevention of apnea in preterm infants

Henderson-Smart DJ, Steer PA

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

Cover sheet

Title

Reviewers

Henderson-Smart DJ, Steer PA

Dates

Date edited: 20/02/2006
Date of last substantive update: 04/02/1999
Date of last minor update: 17/01/2006
Date next stage expected 30/11/2007
Protocol first published: Issue 2, 1999
Review first published: Issue 2, 1999

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

Internal sources of support

NSW Centre for Perinatal Health Services Research, University of Sydney, AUSTRALIA
Mater Children's Hospital, Brisbane, AUSTRALIA
Royal Prince Alfred Hospital, Sydney, AUSTRALIA

External sources of support

None

What's new

This review updates the existing review of 'Prophylactic methylxanthine for prevention of apnea in preterm infants' which was published in The Cochrane Library, Disk Issue 2, 2002.

The search strategy has been updated to include the databases, EMBASE and CINAHL. One new trial was identified as a result of the most recent search and was excluded.

Therefore, there is no change in the conclusion that there is no evidence from randomized trials to support the use of prophylactic caffeine in preterm infants at risk of apnea, bradycardia or hypoxemic episodes.

Dates

Date review re-formatted: 17/09/1999
Date new studies sought but none found: / /
Date new studies found but not yet included/excluded: / /
Date new studies found and included/excluded: 17/01/2006
Date reviewers' conclusions section amended: / /
Date comment/criticism added: / /
Date response to comment/criticisms added: / /

Text of review

Synopsis

No evidence to show the benefit of using caffeine to prevent apnea in premature babies considered at risk.

Apnea is a pause in breathing of greater than 20 seconds. It may occur repeatedly in preterm babies (born before 34 weeks). Methylyxanthines (such as theophylline and caffeine) are drugs that are believed to stimulate breathing efforts and have been used to reduce apnea. It has been suggested that preterm babies with apnea should receive prophylactic caffeine (as a preventative measure). The review of trials found no evidence to support the use of prophylactic caffeine for preterm babies at risk of apnea. More research is needed.

Abstract

Background

Recurrent apnea is common in preterm infants, particularly at very early gestational ages. These episodes of loss of effective breathing can lead to hypoxemia and bradycardia which may be severe enough to require resuscitation including use of positive pressure ventilation. In infants with apnea, methylxanthines have been successful as treatment to prevent further episodes. It is possible that prophylactic therapy, given to all very preterm infants from soon after birth, might prevent apnea and its associated hypoxemia and bradycardia.

Objectives

Search strategy

The standard search strategy of the Neonatal Review Group was used. This included searches of the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 4, 2005), Oxford Database of Perinatal Trials, MEDLINE (1966 - December 2005), CINAHL (1982 - December 2005) and EMBASE (1988 - December 2005) using MeSH term infant-newborn, and text terms methylxanthines, caffeine, apnea, and premature as well as a search of previous reviews including cross references, and conference proceedings including abstracts from the Society for Pediatric Research meeting 2001 - 2005.

Selection criteria

All trials utilising random or quasi-random patient allocation, in which prophylactic methylxanthine (caffeine or theophylline) was compared with placebo or no treatment were eligible. Outcomes sought included the rate of apnea, bradycardia, hypoxemic episodes, use of IPPV, side effects such as tachycardia or feed intolerance, as well as longer term abnormal growth and development.

Data collection & analysis

The standard methods of the Cochrane Collaboration and its Neonatal Review Group were used. The methodological quality of each trial was reviewed independently by each author. Each review author extracted data separately, then results were compared and differences resolved. The standard method of the Cochrane Neonatal Review Group was used to analyze the data, utilizing relative risk (RR) and risk difference (RD) .

Main results

Two studies examining a total of 104 infants were found. Both studied the effects of prophylactic caffeine. There were no meaningful differences between the caffeine and placebo groups in the number of infants with apnea, bradycardia, hypoxemic episodes, use of IPPV or side effects in either of the studies. Only two outcomes (use of IPPV and tachycardia) were common to the two studies and meta-analysis showed no substantive differences between the groups.

Reviewers' conclusions

The results of this review do not support the use of prophylactic caffeine for preterm infants at risk of apnea, bradycardia or hypoxemic episodes.

Any future studies need to examine the effects of prophylactic methylxanthines in preterm infants at higher risk of apnea, bradycardia or hypoxemic episodes. This should include examination of important clinical outcomes such as need for IPPV, length of hospital stay and long term development.

Background

Recurrent episodes of apnea are common in preterm infants and the incidence as well as the severity increase at lower gestational ages (Henderson-Smart 1995). Although apnea can occur spontaneously and be attributed to prematurity alone, it can also be provoked or made more severe if there is some additional insult such as infection, hypoxemia or intracranial pathology. The American Academy of Pediatrics defines infant apnea as a pause in breathing of greater than 20 seconds, or one of less than 20 seconds and associated with bradycardia and/or cyanosis (Nelson 1978).

If prolonged, apnea can lead to hypoxemia and reflex bradycardia which may require active resuscitative efforts to reverse. There are clinical concerns that these episodes might be harmful to the developing brain or cause dysfunction of the gut or other organs (reviewed by Henderson-Smart 1995). Frequent episodes may be accompanied by respiratory failure of sufficient severity as to lead to intubation and the use of intermittent positive pressure ventilation (IPPV).

Methylxanthines are thought to stimulate breathing efforts and have been used in clinical practice to reduce apnea since the 1970's. Theophylline and caffeine are two forms of methylxanthine that have been used and they are effective for the treatment of infants with recurrent apnea (Henderson-Smart 2005). Their mechanism of action is not certain. Possibilities include increased chemoreceptor responsiveness (based on increased breathing responses to CO2), enhanced respiratory muscle performance and generalised central nervous system excitation.

In the treatment of apnea, caffeine has similar effects to theophylline (Steer 2005) but has potential therapeutic advantages due to the larger gap between therapeutic blood levels and those associated with toxic effects, more reliable enteral absorption and the longer half life which allows once daily administration (Blanchard 1992).

Objectives

In preterm infants, does prophylactic treatment with methylxanthine lead to less apnea, bradycardia, episodes of hypoxemia and use of mechanical ventilation, without clinically important side effects? Is there a difference in response depending on quality of the study, type (caffeine or theophylline) or dose of methylxanthine, gestational or postnatal age at study entry, or duration of treatment?

Criteria for considering studies for this review

Types of studies

All trials utilising random or quasi-random patient allocation, in which treatment was compared with placebo or no treatment, were eligible.

Types of participants

Preterm infants, particularly those born at less than 34 weeks gestation, who are at risk of developing recurrent apnea, bradycardia and hypoxic episodes.

Types of interventions

Prophylactic methylxanthine (caffeine or theophylline) vs placebo or no treatment.

Types of outcome measures

1. Apnea
2. Bradycardia
3. Hypoxemic episodes
4. Use of IPPV
5. Side effects such as tachycardia or feed intolerance
6. Longer term growth and development

Search strategy for identification of studies

Methods of the review

The standard methods of the Cochrane Collaboration and its Neonatal Review Group were used. The methodological quality of each trial was reviewed by the second author blinded to trial authors and institution(s). Additional information was supplied by Bucher 1988 to clarify methodology. The manuscript reporting the unpublished results of a trial were supplied by Levitt 1988.

Each review author extracted data separately, then results were compared and differences resolved. An outcome was analysed if there was more than 80% ascertainment.

The standard method of the Cochrane Neonatal Review Group was used to analyze the data, utilizing relative risk (RR) and risk difference (RD).

Description of studies

Details of the two included studies are in the Table Characteristics of Included Studies. One study, Larsen 1995, was excluded due to not having a control group.

Bucher 1988 studied preterm infants of less than 33 weeks gestation (mean about 30 weeks). Levitt 1988 entered infants of less than 31 weeks gestation (mean about 29 weeks).

Both studies used a loading dose of 20 mg/kg of caffeine citrate but Levitt 1988 used 5 mg/kg/day as maintenance, half that used in Bucher 1988. While in Levitt treatment was continued until the infants reached 32 weeks post menstrual age, only 96 hours of treatment was given in Bucher 1988.

Bucher 1988 did not report apnea; instead, he recorded episodes of bradycardia and hypoxemia, which often occur during apnea. These were obtained from a computerised record of heart rate (bradycardia = more than 20% fall in heart rate over 20 sec.) and transcutaneous oxygen tension (hypoxemia = more than 20% fall in oxygen over 20 seconds). Levitt 1988 used a combination of clinical and polygraphic studies to record apnea [apnea of more than 20 seconds with bradycardia (less than 100 bpm)].

Methodological quality of included studies

Both studies are generally of high quality except that follow up was incomplete in Levitt 1988.

Results

Two trials examining a total of 104 infants were found and both studied the effects of prophylactic caffeine. There were no differences between the caffeine and placebo groups in either of the studies in the number of infants with apnea, bradycardia, hypoxemic episodes, use of IPPV or side effects . Only two outcomes (use of IPPV and tachycardia) were common to the two studies and meta-analysis showed no significant differences between the treatment and placebo groups.

One trial reported followup of 30 (56%) of 54 infants (Levitt 1988). This was not only incomplete but was reported by apnea incidence rather than by trial treatment group.

Discussion

The total number of infants (104) studied in these two trials is small. As a result, only large differences (e.g. 50% relative risk reduction) could be detected, even for outcomes which are common, such as bradycardia (> 24 /day) and hypoxemic episodes (> 12 /day) where, in the study of Bucher 1988, there is more than 60% incidence in the control group.

Although no effect of caffeine used as prophylaxis was found here, methylxanthines, including caffeine, are effective in reducing apnea and the use of IPPV when used to treat infants with apnea (Henderson-Smart 2005). Another review has suggested that methylxanthines prior to extubation might be of benefit in reducing the rate of respiratory failure, which is due in part to hypoventilation and apnea (Henderson-Smart 05a).

It is possible that failure to observe an effect of prophylactic caffeine in the Bucher 1988 trial was due to measurement of hypoxemia and mild bradycardia as primary outcomes - events associated with apnea, rather than apnea itself. It could be argued that such events might be increased in the treatment group if caffeine increased arousal, movements and metabolic rate. This would minimise any differences due to a reduction in apnea, if that occurred. In the Levitt 1988 trial, however, the clinical events of apnea and bradycardia were recorded and no differences were found between infants who received prophylactic caffeine and those on placebo.

The trials in this review did not allow subgroup analyses to determine whether the results varied by the type (caffeine or theophylline) or dose of methylxanthine, gestational or postnatal age at study entry, or duration of treatment.

Reviewers' conclusions

Implications for practice

The results of this review do not support the use of prophylactic caffeine for preterm infants at risk of apnea, bradycardia or hypoxemic episodes.

Implications for research

Any future studies should address the effects of prophylactic methylxanthines in preterm infants at higher risk of apnea, bradycardia or hypoxemic episodes, and possibly address the question of whether a higher dose of caffeine might be more effective. This should include examination of important clinical outcomes such as need for IPPV, length of hospital stay and long term development.

Acknowledgements

Thanks to Dr Levitt for a copy of her unpublished paper and to Prof. Bucher for additional information about his study.

Potential conflict of interest

None

Characteristics of included studies

Study	Methods	Participants	Interventions	Outcomes	Notes	Allocation concealment
Bucher 1988	Concealment of randomization - yes; blinding of intervention - yes; follow up complete; blinding of outcome assessment - yes.	50 preterm infants < 33 weeks gestation (stratified into those born at 26-29, 30-32 weeks), 48 hrs old, spontaneous breathing for 24 hrs, in a single centre.	Caffeine citrate 20 mg/kg load at 48 hrs and 10 mg/kg at 72 and 96 hrs of age. Total duration of study period 96hrs. Saline placebo	Polygraph recording of bradycardia (>20% fall in heart rate over 20 sec); hypoxemic episodes (> 20% decrease over 20 sec); use of IPPV; tachycardia		A
Levitt 1988	Concealment of randomization - yes (off site in pharmacy); blinding of intervention - yes ; follow up 96% for apnea; blinding of outcome assessment - yes.	54 preterm infants born at < 31 weeks, ventilatory support discontinued by one week. Exclusions - major congenital abnormality, intraventricular hemorrhage, congestive heart failure, metabolic disorder, septicemia.	Caffeine citrate 20 mg/kg load and 5 mg/kg/day until 32 weeks post menstrual age. Saline placebo	Apnea >20 sec with bradycardia (<100 bpm) or cyanosis, use of IPPV, withdrawal for definitive caffeine treatment (open label), tachycardia, hyponatremia.	30 of 54 (56%) followed up to 16-36 months for neurodevelopmental assessment. Not reported by treatment group.	A

Characteristics of excluded studies

Study	Reason for exclusion
Larsen 1995	This trial compared aminophyilline to caffeine citrate without a control group

References to studies

References to included studies

Bucher 1988 {published and unpublished data}

Bucher HU, Duc G. Does caffeine prevent hypoxaemic episodes in premature infants? A randomized controlled trial. European Journal of Pediatrics 1988;147:288-91.

Levitt 1988 {published and unpublished data}

Levitt GA, Harvey DR. The use of prophylactic caffeine in the prevention of neonatal apnoeic attacks. Unpublished manuscript.

Levitt GA, Mushin A, Bellman S, Harvey DR. Outcome of preterm infants who suffered neonatal apnoeic attacks. Early Human Development 1988;16:235-43.

References to excluded studies

Larsen 1995 {published data only}

Larsen PB, Brendstrup L, Skov L, Flachs H. Aminophylline versus caffeine citrate for apnea and bradycardia prophylaxis in premature neonates. Acta Paediatrica 1995;84:360-4.

* 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, 1992:352-70.

Henderson-Smart 05a

Henderson-Smart DJ, Davis PG. Prophylactic methylxanthine for extubation in preterm infants. In: The Cochrane Database of Systematic Reviews, Issue 4, 2005.

Henderson-Smart 1995

Henderson-Smart DJ. Recurrent apnea. 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.

Henderson-Smart 2005

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

Nelson 1978

Nelson NM. Members of the task force on prolonged apnea of the Americal Academy of Pediatrics. Pediatrics 1978;61:651-2.

Samuels 1992

Samuels MP, Southall DP. Recurrent Apnea. In: Sinclair JC, Bracken MB, editor(s). Effective Care of the Newborn Infant. Oxford: Oxford University Press, 1992:385-97.

Steer 2005

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

Other published versions of this review

Henderson-Smart 1999

Henderson-Smart DJ, Steer PA. Prophylactic methylxanthine for prevention of apnea in preterm infants. In: The Cochrane Database of Systematic Reviews, Issue 2, 1999.

Henderson-Smart 2002

Henderson-Smart DJ, Steer PA. Prophylactic methylxanthine for prevention of apnea in preterm infants. In: The Cochrane Database of Systematic Reviews, Issue 2, 2002.

Comparisons and data

01 All infants
01.01 Apnea (more than 4/day)
01.02 Apnea (more than 10/day)
01.03 Bradycardia (more than 12/day)
01.04 Bradycardia (more than 24/day)
01.05 Hypoxemic episodes (more than 12/day)
01.06 Withdrawal for definitive caffeine treatment
01.07 Use of IPPV
01.08 Tachycardia
01.09 Hyponatremia

Comparison or outcome	Studies	Participants	Statistical method	Effect size
01 All infants
01 Apnea (more than 4/day)	1	54	RR (fixed), 95% CI	0.87 [0.52, 1.45]
02 Apnea (more than 10/day)	1	54	RR (fixed), 95% CI	0.86 [0.49, 1.50]
03 Bradycardia (more than 12/day)	1	50	RR (fixed), 95% CI	Not estimable
04 Bradycardia (more than 24/day)	1	50	RR (fixed), 95% CI	1.18 [0.84, 1.64]
05 Hypoxemic episodes (more than 12/day)	1	50	RR (fixed), 95% CI	1.16 [0.89, 1.51]
06 Withdrawal for definitive caffeine treatment	1	54	RR (fixed), 95% CI	0.89 [0.40, 1.96]
07 Use of IPPV	2	104	RR (fixed), 95% CI	0.60 [0.15, 2.36]
08 Tachycardia	2	104	RR (fixed), 95% CI	4.00 [0.48, 33.50]
09 Hyponatremia	1	54	RR (fixed), 95% CI	1.71 [0.80, 3.68]

Notes

Published notes

Contact details for co-reviewers

Dr Peter A Steer, MBBS, FRACP
President
McMaster Children's Hospital
McMaster University Medical Centre
1200 Main Street West
Hamilton
Ontario CANADA
L8N 3Z5
Telephone 1: +1 905 521 2100 extension: 75605
E-mail: steerp@mcmaster.ca

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.