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Are methylxanthines effective in preventing or reducing apnoeic spells in infants with bronchiolitis?

Three Part Question

In [infants with bronchiolitis] does [caffeine] [reduce or prevent apnoeas]?

Clinical Scenario

A 2-week-old infant, born at 36 weeks gestation was admitted to the paediatric ward in November with a 24h history of runny nose, cough and episodes of shallow breathing and apnoeas. This was thought to be due to bronchiolitis, and the consultant paediatrician suggested starting the baby on caffeine (theophylline derivative with less side effects). As the resident middle grade doctor, I knew that caffeine has been used widely in neonatal units for apnoea of prematurity, but I wondered if there was any evidence for its use in this clinical situation.

Search Strategy

Cochrane and Medline plus August 2004
Medline plus (No limits): Search terms: Infants and bronchiolitis/respiratory syncytial virus infections/virus/infection and apnoea/apnea and caffeine/xanthine/methylxanthine/ phosphodiesterase inhibitors/ theophylline

Search Outcome

Cochrane database of systematic reviews: No directly relevant study found, but there was one systematic review on the efficacy of methyl xanthines in reducing apnoea of prematurity (Henderson-Smart) and another systematic review on the prophylactic use of caffeine to prevent post operative apnoea following general anaesthesia in ex.preterm infants (ibib).
There was one retrospective review (Tobias) and two case reports (Johnston, DeBuse) (in the form of letters to the editor) directly addressing the problem. There was also one randomised controlled trial on the usefulness of aminophylline in reducing apnoeas and intubation in term infants during prostaglandin E1 infusion (Lim)

Relevant Paper(s)

Author, date and country Patient group Study type (level of evidence) Outcomes Key results Study Weaknesses
7 infants with RSV associated apnoea. Gestational age 28-32 weeks. Age at presentation 14-64 daysRetrospective review. (4).Prevention of mechanical ventilationNo infant had episodes of apnoea or bradycardia from 2 to18 hours after the initial loading doseInitial dose of caffeine base was 10 mg/kg and if further doses are needed, given as 5mg/kg as second dose and 2.5 mg/kg as third dose.
Johnston et al
2 infants 1.RSV positive. Gestational age 33 weeks. Post conceptual age 40 weeks 2.Echo virus type 2. Gestational age 36 weeks. Post conceptual age 37 weeksCase report (4)Prevention of mechanical ventilationRespiration became regular with disappearance of apnoea immediately after administration of aminophylline5 mg/kg of iv aminophylline followed by 5-7 days of oral theophylline
DeBuse et al
1 infant with RSV positive bronchiolitis. Gestational age 29 weeks. Post conceptual age 38 weeks.Case report (4)Prevention of mechanical ventilationNo apnoec episodes occurred 9 hours after administration of theophyllineOral theophylline. Loading dose of 10 mg/kg in aliquots ,then 4 mg/kg 6 hrly x24 hours followed by 1 mg/kg
Henderson-Smart DJ, Steer P
192 preterm infants in 5 trialsSystematic review (1a)Reduction in apnoea and use of IPPVRRR for apnoea 0.45 (95% CI 0.31-0.60). RRR for IPPV 0.34 (95% CI 0.12-0.97)3 studies used caffeine and 2 studies theophylline
Henderson-Smart and Steer
78 ex.preterm infants undergoing general anaesthesia for surgery. Gestational age 30-32 weeks. Post conceptual age 40-44 weeksSystematic Review (1a)Reduction in the incidence of apnoea and bradycardia in the post operative periodRRR 91% (95%CI 66 to 98).ARR 58%.No infant in either control or treatment group required intubationIntravenous caffeine in a single dose during general anaesthesia. Dosage 5-10 mg/kg
Lim DS,Kulik TJ et al
42 term infants requiring PGE1 infusion for duct dependant congenital heart diseaseRCT (1b)Reduction in intubation for apnoea6/21 required intubation in the placebo compared to 0/21 in the aminophylline group (p=0.02)6 mg/kg iv aminophylline followed by 2mg/kg iv 8 hourly for 72 hours


Recurrent apnoea is a common problem in otherwise well preterm infants. By term equivalent age, infants have usually 'outgrown' their tendency to spontaneous apnoea. However, with an additional stress, such as infection (eg bronchiolitis) or administration of drugs that depress the central nervous system (eg general anaesthesia, prostaglandin), then apnoea and oxygen desaturations can recur. Caffeine is recognised to reduce apnoea and the need for mechanical ventilation in preterm infants with apnoea of prematurity (Henderson-Smart ). In addition caffeine prevents apnoea, bradycardia and episodes of desaturation in growing preterm infants following general anaesthesia (Henderson-Smart ), while aminophylline, which is another widely used theophylline derivative, was found to be effective for the prevention of apnoea and intubation during prostaglandin E1 infusion in term infants (Lim). However, we could only find 3 reports (Tobias, Johnston, DeBuse) involving a total of 10 infants, all of whom were born pre term and presented with bronchiolitis associated apnoeas approximately around term equivalent age. These reports have concluded that theophylline derivatives are effective in reducing the incidence of apnoeas and avoided the need for mechanical ventilation in this clinical situation Caffeine has a favourable therapeutic index than aminophylline. No major adverse effects were reported from the studies included in the systematic reviews (Henderson-Smart). Jitteriness, tachycardia and raised blood glucose are the common side effects, but routine drug level monitoring is not necessary at standard dosage (RCPCH). Whilst these three reports claim that the use of caffeine helped avoid intubation in infants with viral infection induced apnoea, there are no data from randomised controlled trials confirming these benefits. As intubation for apnoea in bronchiolitis is uncommon, a large multi-centred trial would be needed.

Clinical Bottom Line

In addition to its proven efficacy in apnoea of prematurity, caffeine has also been shown to reduce the incidence of apnoea in ex.preterm infants following general anaesthesia. A recent RCT has shown that aminophylline has been effective in term infants in reducing apnoeas following prostaglandin infusion However, there is only limited evidence from case reports for the use of caffeine in infants presenting with bronchiolitis associated apnoeas.


  1. Tobias JD. Caffeine in the treatment of apnea associated with respiratory syncytial virus infection in neonates and infants. South Med J 2000;93:294-6.
  2. Johnston DM, Kuzemko JA. Virus induced apnea and theophylline (letter). Lancet 1992;340: 1352.
  3. DeBuse P, Cartwright D. Respiratory syncytial virus with apnoea treated with theophylline (letter). Med J Aus 1979;2:307-308.
  4. Henderson-Smart DJ, Steer P. Methylxanthine treatment for apnea in preterm infants (Cochrane review). In: The Cochrane Library, Issue 2, 2004.
  5. Henderson-Smart DJ, Steer P. Prophylactic caffeine to prevent postoperative apnea following general anesthesia in preterm infants (Cochrane review). In: The Cochrane Library, Issue 2, 2004.
  6. Lim DS, Kulik JT et al. Aminophylline for the prevention of apnea during prostaglandin E1 infusion. Pediatrics 2003 July 112 (1 pt 1) : e27-29.
  7. RCPCH Medicines for children. 2nd edition 2003: 80.