Are methylxanthines effective in preventing or reducing apnoeic spells in infants with bronchiolitis?
Date First Published:
March 10, 2005
Last Updated:
March 10, 2005
Report by:
Pavanasam Ramesh, Martin Samuels, Staff Grade and Consultant Paediatrician respectively (University Hospital of North Staffordshire)
Search checked by:
Bob Phillips, University Hospital of North Staffordshire
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
Search Details:
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
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)
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):
| Study Title | Patient Group | Study type (level of evidence) | Outcomes | Key results | Study Weaknesses |
|---|---|---|---|---|---|
| Caffeine in the treatment of apnea associated with respiratory syncytial virus infection in neonates and infants. Tobias JD. 2000 | 7 infants with RSV associated apnoea. Gestational age 28-32 weeks. Age at presentation 14-64 days |
Retrospective review. (4). | Prevention of mechanical ventilation | No infant had episodes of apnoea or bradycardia from 2 to18 hours after the initial loading dose | Initial 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. |
| Virus induced apnea and theophylline (letter). Johnston DM, Kuzemko JA. 1992 | 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 weeks |
Case report (4) | Prevention of mechanical ventilation | Respiration became regular with disappearance of apnoea immediately after administration of aminophylline | 5 mg/kg of iv aminophylline followed by 5-7 days of oral theophylline |
| Respiratory syncytial virus with apnoea treated with theophylline (letter). DeBuse P, Cartwright D. 1979 | 1 infant with RSV positive bronchiolitis. Gestational age 29 weeks. Post conceptual age 38 weeks. |
Case report (4) | Prevention of mechanical ventilation | No apnoec episodes occurred 9 hours after administration of theophylline | Oral theophylline. Loading dose of 10 mg/kg in aliquots ,then 4 mg/kg 6 hrly x24 hours followed by 1 mg/kg |
| Methylxanthine treatment for apnea in preterm infants (Cochrane review). Henderson-Smart DJ, Steer P. 2001 | 192 preterm infants in 5 trials | Systematic review (1a) | Reduction in apnoea and use of IPPV | RRR 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 |
| Prophylactic caffeine to prevent postoperative apnea following general anesthesia in preterm infants (Cochrane review). Henderson-Smart DJ, Steer P. 2001 | 78 ex.preterm infants undergoing general anaesthesia for surgery. Gestational age 30-32 weeks. Post conceptual age 40-44 weeks | Systematic Review (1a) | Reduction in the incidence of apnoea and bradycardia in the post operative period | RRR 91% (95%CI 66 to 98).ARR 58%.No infant in either control or treatment group required intubation | Intravenous caffeine in a single dose during general anaesthesia. Dosage 5-10 mg/kg |
| Aminophylline for the prevention of apnea during prostaglandin E1 infusion. Lim DS, Kulik JT et al. 2003 | 42 term infants requiring PGE1 infusion for duct dependant congenital heart disease | RCT (1b) | Reduction in intubation for apnoea | 6/21 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 |
Author Commentary:
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.
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.
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.
However, there is only limited evidence from case reports for the use of caffeine in infants presenting with bronchiolitis associated apnoeas.
References:
- Tobias JD.. Caffeine in the treatment of apnea associated with respiratory syncytial virus infection in neonates and infants.
- Johnston DM, Kuzemko JA.. Virus induced apnea and theophylline (letter).
- DeBuse P, Cartwright D.. Respiratory syncytial virus with apnoea treated with theophylline (letter).
- Henderson-Smart DJ, Steer P.. Methylxanthine treatment for apnea in preterm infants (Cochrane review).
- Henderson-Smart DJ, Steer P.. Prophylactic caffeine to prevent postoperative apnea following general anesthesia in preterm infants (Cochrane review).
- Lim DS, Kulik JT et al.. Aminophylline for the prevention of apnea during prostaglandin E1 infusion.
- RCPCH. Medicines for children.