Growing ex-preterm infants who undergo general anesthesia for surgery at about term-equivalent age may have episodes of apnea, cyanosis and bradycardia during the early postoperative period. A breathing stimulant such as caffeine given at the time of operation might prevent these episodes.

To determine the effect of the prophylactic use of caffeine to prevent episodes of apnea, cyanosis and bradycardia during the postoperative period in ex-preterm infants who undergo general anesthesia for surgery.

The standard strategy of the Neonatal Review Group was used. This included searches of the Oxford Database of Perinatal Trials, MEDLINE (1966 - July 2008), EMBASE 1980 - July 2008), CINAHL (1982 - July 2008) and the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 3, 2008. Search terms included text words 'postoperative', 'apnea or apnoea', 'caffeine' and MeSH heading 'infant, premature'. Searches were also made of previous reviews including cross references. Abstracts of the Society for Pediatric Research were hand searched for the years 1996 - 2008 inclusive.

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

The standard methods of the Cochrane Collaboration and its Neonatal Review Group were used to select trials, evaluate trial quality and to extract data. The methodological quality of each trial was reviewed by the second author blinded to trial authors and institution(s). Each author extracted data separately, and then compared and resolved any differences. Meta-analysis used relative risk and risk difference.

Three eligible trials were found. In each trial apnea/bradycardia occurred in fewer infants treated with caffeine. The typical estimate for relative risk is 0.09 (95% CI 0.02, 0.34). The typical estimate for absolute risk difference is -0.58 (95% CI -0.74, -0.43) indicating that fewer than two infants have to be treated with caffeine to expect to prevent one with postoperative apnea. In two trials (Welborn 1989; LeBard 1989), continuous recordings of oxygen saturation detected hypoxaemic episodes (< 90 %) in fewer treatment than control infants [typical RR 0.13 (95% CI 0.03, 0.63)]. No infant in any trial required intubation and mechanical ventilation. No adverse effects were reported.

Implications for practice. Caffeine can be used to prevent postoperative apnea/bradycardia and episodes of oxygen desaturation in growing preterm infants if this is deemed clinically necessary. In view of the small numbers of infants studied in these trials and uncertainty concerning the clinical significance of the episodes, caution is warranted in applying these results to routine clinical practice.

Implications for research. There is a need to determine which infants might benefit most by this treatment. Studies confined to those most at risk of apnea (prior history, younger postmenstrual age) and those that might require mechanical ventilation (chronic lung disease) would be of value.

Growing ex-preterm infants who undergo general anesthesia for surgery at about term equivalent age may have episodes of apnea, cyanosis and bradycardia during the early postoperative period.

The American Academy of Pediatrics defined 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 (AAP 2003). Recurrent episodes of apnea are common in preterm infants and the incidence and severity increases at lower gestational ages. By term equivalent age infants have usually 'outgrown' their tendency to spontaneous apnea. However, if some additional insult such as infection, or the administration of drugs that depress the central nervous system occurs (such as general anesthetic agents, Liu 1983), apnea and associated oxygen desaturations can recur. Attempts have been made to determine which infants are most at risk (Spear 1992; Welborn 1994; Cote 1995). Factors such as younger postmenstrual age and past history of apnea seem important, although such risk scoring does not detect all infants who develop postanesthesia problems (Cote 1995).

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 gastrointestinal tract or other organs, although there are no data to support this. 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 such as caffeine are thought to stimulate breathing efforts and have been used in clinical practice to reduce apnea in preterm infants since the late 1970's. The mechanism of their 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. Other reviews on the effects of methylxanthines such as caffeine on apnea, published in the Cochrane Library, include Henderson-Smart a; Henderson-Smart b; Henderson-Smart c and Henderson-Smart d. A systematic review has also been carried out on the effects of regional vs. general anesthesia on postoperative apnea (Craven 2003).

To determine the effect of the prophylactic use of caffeine on episodes of apnea, cyanosis and bradycardia during the postoperative period in ex-preterm infants who undergo general anesthesia for surgery.

Criteria for considering studies for this review

Search methods for identification of studies

Data collection and analysis

Description of studies

Risk of bias in included studies

Effects of interventions

Caffeine reduces the occurrence of apnea, bradycardia and oxygen desaturation after general anesthesia, although it has yet to be determined whether these episodes are clinically important. If such episodes are detected by monitors, responded to promptly by nurses and do not lead to a need for mechanical ventilation, then these episodes are of uncertain significance. Apnea and hypoxemia might be more important in infants at particularly high risk of respiratory failure, such as those with chronic lung disease. This has not been evaluated. No adverse effects of caffeine were reported, although the number of infants studied in these three trials is too small to exclude less common ones.

One study (Welborn 1990 ) has suggested that apnea is more common following general anesthesia than following spinal anesthesia without premedication in infants having inguinal hernia repair, one of the most common operative procedures in ex-preterm infants. A recent Cochrane Review (Craven 2003) did not find evidence to support that hypothesis.

Variations in the type of general anesthetic agents might affect postoperative ventilatory function. A trial (Sale 2006) compared two general anesthetic agents (desflurane and sevoflurane) in terms of postoperative ventilatory events or in the number of apneas in the postoperative period and found no difference

Implications for practice

Implications for research

LeBard 1989

Welborn 1988

Welborn 1989

LeBard 1989

Welborn 1988

Welborn 1989