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Three Part Question

[In preterm newborns] does a [higher dose of caffeine] lead to a [more successful extubation]?

Clinical Scenario

A 2 day old baby born at 28 weeks gestation is currently on ventilator. He is doing well on minimal respiratory support and you decide to extubate him. You decide to start caffeine prior to extubation.

Search Strategy

Search was done using secondary (Cochrane library 2005) and primary sources (Medline, Embase and CINAHL)
Search criteria : (preterm OR premature) AND caffeine AND extubation

Search Outcome

Secondary search: no relevant articles.
Primary search: 12 articles found of which only 2 were directly relevant to the question.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
PA Steer, VJ Flenady, A Shearman et al 22.01.2003 Australia	127 babies <32 weeks gestation ventilated for more than 48 hours	Randomised, double blinded. ( I b) 3, 15 and 30 mg/kg/day of caffeine citrate for pre extubation management	Primary outcome – successful extubation;	Secondary outcome – reduction in number of apnoeas	1. small population 2. study was terminated before full recruitment since the initial results showed no significant difference for the primary outcome - which also show some bias. 3. very wide range of gestational ages of the population with inclusion of the more mature infants > 30 weeks could have affected the study. 4.. selection of doses – 3 mg/kg and 30 mg/kg caffeine citrate are not commonly used in neonatal units.
P Steer, V Flenady, A Shearman et al 12.05.2004 Australia	234 newborns < 30 weeks gestation ventilated for more than 48 hours	Randomised, double blinded ( I b) 5 mg/kg/ day and 20 mg/kg/ day caffeine citrate for pre extubation management	Primary outcome – successful extubation;Secondary outcome – reduction in the number of apnoeas	Significant reduction in extubation failure in the 20 mg/kg/day group (p value <0.01);Significant reduction in the number of apnoeas in the higher dose group 4 v 7 (p value < 0.01); insufficient data to calculate NNT	1.details of apnoeic episodes not clear from the tables.

Comment(s)

Methylxanthines have been the mainstay of treatment of apnoea of prematurity since the 1980s . They also have a definite role in facilitating extubation in the preterm very low birth weight infants. Caffeine, with its longer elimination half life and lesser toxicity is often preferred to theophylline, though they have comparable efficacy . Despite their widespread use, there are not many studies on the dose response relationship of caffeine. The two randomised studies on the dose response relationship of caffeine are summarised in table 1. Though the population studied is different, both studies show a significant reduction in the number of apnoeas in the higher dose group. From the available evidence we can conclude that a higher dose of caffeine does significantly reduce the incidence of apnoeas. Recurrent apnoeas is a common indication for reintubation in neonatal units. The evidence is less conclusive in terms of its effect on extubation failure. However there is a trend, in both studies, towards a better response with a lower gestational age. A lower gestational age confers a higher risk of extubation failure and this is probably reflected in the better response to caffeine seen in the more preterm babies. Any change in current practice favouring a higher dose of caffeine should also take into account its potential adverse effects. Caffeine citrate is generally well tolerated and has a wide therapeutic index . The most common side effect noticed in these two studies has been tachycardia without hemodynamic compromise. There were no significant differences in the adverse effects between the groups in both the studies. Though side effects with caffeine have been reported to be minimal with serum concentrations up to 80 mg/l , studies on the long term effects of methylxanthines are lacking. The ongoing caffeine for apnoea of prematurity study will hopefully throw more light on this aspect.

Clinical Bottom Line

1. A higher dose of caffeine citrate (20 mg/kg/dose) is more effective than a lower dose, in reducing apnoea of prematurity (Grade of recommendation A). 2. A higher dose of caffeine citrate may be more effective in reducing extubation failure in preterm newborns, especially those less than 30 weeks gestation (Grade of recommendation D)

References

1. PA Steer, VJ Flenady, A Shearman et al Periextubation caffeine in preterm neonates: A randomized dose response trial J. Paediatr. Child Health 2003; 39: 511 - 515
2. P Steer, V Flenady, A Shearman et al High dose caffeine citrate for extubation of preterm infants: a randomised controlled trial Arch. Dis. Child. Fetal Neonatal Ed 2004;89:499-503