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Journal of Tropical Pediatrics Advance Access originally published online on December 10, 2006
Journal of Tropical Pediatrics 2007 53(2):76-77; doi:10.1093/tropej/fml058
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© The Author [2006]. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Clinical Review

Evidence behind the WHO Guidelines: Hospital Care for Children: Is Caffeine Useful in the Prevention of Apnoea of Prematurity?

Primary Reviewer: Andrew D. McCalluma

aEdinburgh University, Scotland

Secondary Reviewer: Trevor Dukeb

bUniversity of Melbourne, Australia

Correspondence: Andrew D. McCallum, Edinburgh University, Scottland. E-mail < andrewmccallum{at}doctors.org.uk>.

The World Health Organization has produced guidelines for the management of common illnesses in hospitals with limited resources. This series reviews the scientific evidence behind WHO's recommendations. The WHO guidelines, and more reviews are available at http://www.ichrc.org. This review addresses the question: The WHO Pocketbook of Hospital Care for Children recommends caffeine citrate and aminophylline to prevent apnoea in premature babies, caffeine is preferred if it is available. The loading dose of caffeine citrate is 20 mg/kg orally or i.v., a maintenance dose should be prescribed. If an apnoea monitor is available, this should be used.


   Introduction
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Although, all premature neonates, as well as many full-term neonates, have periodic respiration pauses, these are usually brief and cause no physiological changes. Apnoea is cessation of respiration exceeding an arbitrary duration of 20 s, or <20 s but with bradycardia or oxygen de-saturation [1].

Prolonged apnoea may lead to hypoxaemia and reflex bradycardia, and may increase the risk of intraventricular haemorrhage, hydrocephalus and abnormal neurological development during the first year of life [2]. Frequent episodes of apnoea require ventilatory support using continuous positive airway pressure, or intubation and mechanical ventilation [3].

The use of methylxanthines, of which caffeine is a member, has been evaluated in a Cochrane Review. Caffeine has been shown to reduce the number of apnoeic episodes and the requirement for mechanical ventilation, when given to premature neonates who are having apnoea [3]. This current review attempts to establish whether prophylactic use of caffeine in a population of otherwise well premature neonates can prevent apnoea of prematurity, and its associated bradycardia and hypoxia.


   Methods
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The MeSH terms ‘caffeine’, ‘apnoea’, ‘infant;premature’ and ‘premature birth’ were utilized.

Initially, the Cochrane Library was searched with the simple search strategy ‘caffeine AND apnoea AND prematurity’. Nine Cochrane reviews were retrieved, of which one looked specifically at prophylactic methylxanthine for prevention of apnoea in preterm infants [4]. A further review assessed prophylactic caffeine in the prevention of postoperative apnoea in preterm infants following general anaesthesia [5]. The Cochrane Central Register for Controlled Trials (CENTRAL) was searched concurrently.

The PubMed ‘Clinical Queries’ framework was utilized to search for more recent studies on use of caffeine in apnoea of prematurity. The articles regarding prophylactic or preventative use of caffeine were favoured. The search strategy employed was as follows: (caffeine AND apnoea AND prematurity) AND (randomized controlled trial [Publication Type] OR (randomized[Title/Abstract] AND controlled [Title/Abstract] AND trial[Title/Abstract])). Clinical filters for both ‘therapy’ and ‘narrow, specific’ were used, and no new relevant articles were identified. Reference lists were hand searched and abstracts were read. Where relevance was in doubt, the complete article was sourced.

Articles were restricted to the English language. When searching on PubMed, articles older than the most recent update to the Cochrane Review were excluded to prevent duplication of findings. Methodological quality of selected articles was assessed using the Oxford Centre for Evidence-Based Medicine Levels of Evidence.


   Results
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Discussion
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The evidence for the use of prophylactic methylxanthine (caffeine) for the prevention of apnoea in preterm infants was the topic of a Cochrane Review last updated in November 2004 [4]. This systematic review was evidence level 1a, and identified two high-quality randomized controlled trials examining a total of 104 infants [6, 7]. In both studies, the caffeine and placebo groups were comparable, and meta-analysis of the two outcomes common to the studies—i.e. use of intermittent positive pressure ventilation and tachycardia—found no significant differences between treatment and placebo groups.

In one of the trials, however, 30 patients of 54 (56%) were followed up [7]. This was incomplete and reported by apnoea incidence rather than trial treatment group.

A second Cochrane Review identified three randomized controlled trials assessing prophylactic use of i.v. caffeine during general anaesthesia in ex-preterm infants [5]. By term-equivalent age, the tendency towards spontaneous apnoea tends to have gone, however, depression of the central nervous system such as during general anaesthetic may cause further apnoeas and oxygen de-saturations. In each trial, fewer apnoeic/bradycardic episodes occurred in the treated than in the control infants. Typical evidence for relative risk is 0.09 (0.02, 0.34), and absolute risk difference is –0.58 (–0.74, –0.43) indicating that fewer than two infants required treatment with caffeine to prevent one with postoperative apnoea. No infant required intubation or mechanical ventilation, and there were no adverse effects. Completeness of follow up was not clearly stated.


   Discussion
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The number of infants identified by the first Cochrane Review (104) is small and thus statistical analysis was only able to detect large differences. Of the two trials assessed, one measured mild bradycardia and hypoxaemia as outcomes rather than apnoea itself [6]. The second trial, recorded events of apnoea and bradycardia and found no significant differences between infants receiving prophylactic caffeine and placebo [7].

Some evidence was found that prophylactic caffeine may be given to ex-preterm infants to prevent postoperative apnoea/bradycardia following general anaesthesia [5]. Only 78 participants were included, so it is not possible to exclude less common adverse effects. Though fewer apnoeic/bradycardic episodes occurred in treated than control infants, it is unclear whether these episodes are clinically significant and could lead to mechanical ventilation.


   Summary
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This review does not support the use of prophylactic caffeine for preterm infants at high risk of apnoea, bradycardia or hypoxaemic episodes, and concludes that larger studies are required. Caffeine has been shown to be an effective treatment for apnoea in premature neonates, and to prevent the indirect consequences for neonates having frequent apnoea (such as the need for assisted ventilation). The studies that have focused exclusively on caffeine in the prevention of apnoea in low risk populations carry high risks of type II errors. Further studies should assess higher-risk infants, and perhaps use a greater dose of caffeine [4]. Caffeine may be used prophylactically to prevent apnoea in preterm infants following general anaesthesia if deemed clinically necessary, but further studies are appropriate to evaluate this treatment in infants at high risk of apnoea, or those that might require mechanical ventilation [5].


   Notes
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Section Editors: Trevor Duke and Julian Kelly

For more information on this project to evaluate the evidence behind the WHO Hospital Care for Children, see J Trop Pediatr 2006; 52: 12. If you would like suggest a topic or contribute a review, please contact Dr Julian Kelly: E-mail <julian.kelly{at}rch.org.au>.


   References
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  1. Santin RL and Porat R. Apnea of prematurity. eMedicine © 2005 (cited 19 January 2006). http://www.emedicine.com/ped/topic1157.htm.
  2. Butcher-Puech MC, Henderson-Smart DJ, Holley D, et al. (1985) Relation between apnoea duration and type and neurological status of preterm infants. Arch Dis Child 60:953–8.[Abstract]
  3. Henderson-Smart DJ and Steer P. Methylxanthine treatment for apnea in preterm infants. The Cochrane Database of Systematic Reviews 2001 Issue 3 Art. No.: CD000140. DOI: 10.1002/14651858.CD000140.
  4. Henderson-Smart DJ and Steer PA. Prophylactic methylxanthine for prevention of apnea in preterm infants. The Cochrane Database of Systematic Reviews 1999 Issue 2 Art. No.: CD000432. DOI: 10.1002/14651858.CD000432.
  5. Henderson-Smart DJ and Steer P. Prophylactic caffeine to prevent postoperative apnea following general anaesthesia in preterm infants. The Cochrane Database of Systematic Reviews 2001 Issue 4 Art. No.: CD000048. DOI: 10.1002/14651858.CD000048.
  6. Bucher HU and Duc G. (1988) Does caffeine prevent hypoxaemic episodes in premature infants? A randomized controlled trial. Eur J Pediatr 147:288–91.[CrossRef][ISI][Medline]
  7. Levitt GA and Harvey DR. The use of prophylactic caffeine in the prevention of neonatal apnoeic attacks. Unpublished manuscript.

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This Article
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