In an updated and extended search to October 2002, four potentially eligible studies were identified: two were excluded (Dani, Zanardo) and two are awaiting assessment (Fang, Laubscher).
Therefore, this update does not include any new studies.
Some evidence that caffeine is as effective as theophylline in the short term for reducing apnea in premature babies, is better tolerated and easier to give.
Apnea is a pause in breathing of greater than 20 seconds. It may occur repeatedly in preterm babies (born before 34 weeks). Apnea may be harmful to the developing brain or organs if it continues. Methylxanthines (such as theophylline and caffeine) are drugs that are believed to stimulate breathing efforts and have been used to reduce apnea. The review of trials found that caffeine has similar effects to theophylline but has a larger gap between levels that are therapeutic and those with toxic effects. Caffeine is more easily absorbed and has a longer half-life that allows once daily doses.
Recurrent apnea is common in preterm infants, particularly at very early gestational ages. These episodes of loss of effective breathing can lead to hypoxemia and bradycardia which may be severe enough to require resuscitation including use of positive pressure ventilation. Two forms of methylxanthine (caffeine and theophylline) have been used to stimulate breathing and so prevent apnea and its consequences.
To assess the effects of caffeine compared to theophylline in preterm infants with recurrent apnea.
The standard search strategy of the Cochrane Neonatal Review Group was used. This included searches of electronic databases: Oxford Database of Perinatal Trials; Cochrane Controlled Trials Register (The Cochrane Library, Issue 3, 2002); MEDLINE (1966 - October 2002); and EMBASE Drugs and Pharmacology (1990 - October 2002), previous reviews including cross references.
Randomized and quasi-randomized trials comparing caffeine to theophylline for treating apnea in preterm infants.
Each reviewer assessed eligibility, trial quality and extracted data separately, then compared and resolved differences. Study authors were contacted for additional information.
Three trials involving a total of 66 infants were included. The quality of these small trials was fair to good. No difference in failure rate (less than 50% reduction in apnea/bradycardia) was found between caffeine and theophylline after one to three days treatment (based on two studies) or five to seven days treatment (based on one study). Infants on caffeine showed a higher rate of apnea after one to three days treatment than those on theophylline (weighted mean difference 0.40 episodes per 100 minutes, 95% confidence interval 0.33 to 0.46, based on three studies). However no difference in apnea rate between caffeine and theophylline was found after five to seven days treatment (based on two studies).
Adverse effects, indicated by tachycardia or feed intolerance leading to change in dosing, were lower in the caffeine group (relative risk 0.17, 95% confidence interval 0.04 to 0.72). This was consistent across the three studies.
No trial reported the use of ventilation and no data were available to assess effects on growth and development.
Caffeine appears to have similar short term effects on apnea/bradycardia as does theophylline, although caffeine has certain therapeutic advantages over theophylline. The possibility that higher doses of caffeine might be more effective in extremely preterm infants needs further evaluation in randomized clinical trials.
Recurrent episodes of apnea are common in preterm infants and the incidence and severity increases at lower gestational ages (Henderson-Smart 1995). Although apnea can occur spontaneously and be attributed to prematurity alone, it can also be provoked or made more severe if there is some additional insult such as infection, hypoxemia or intracranial pathology. Infant apnea has been defined as a pause in breathing of greater than 20 seconds or one of less than 20 seconds and associated with bradycardia and/or cyanosis (NIH 1987).
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 gut 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 are thought to stimulate breathing efforts and have been used in clinical practice to reduce apnea since the 1970's. Theophylline and caffeine are two forms that have been used. The efficacy compared with control is evaluated in another review in the Cochrane Library (Henderson-Smart 2002). 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 generalized central nervous system excitation.
Caffeine has potential therapeutic advantages over theophylline due to its higher therapeutic ratio, more reliable enteral absorption and the longer half life allows once daily administration (Blanchard 1992).
Main question: in preterm infants with recurrent apnea, how does treatment with caffeine compare with treatment with theophylline in leading to a clinically important reduction in apnea and use of mechanical ventilation, without clinically important side effects?
All trials utilising random or quasi-random patient allocation, in which caffeine was compared with theophylline for the treatment of apnea, were eligible. There must have been an effort to exclude specific causes of apnea. Measures of the severity of apnea as well as the response to treatment must have been consistent with an evaluation of 'clinical apnea' (NIH 1987).
Preterm neonates being treatment for apnea of prematurity.
Caffeine compared with theophylline for the treatment of apnea of prematurity. Trials in which caffeine and theophylline were compared as prophylactic therapy in preterm infants at risk of developing apnea or those in which they were used to assist extubation following IPPV were not eligible.
1. Apnea (failed treatment = no clinically important reduction in apnea
, use of IPPV or death during study)
2. Mean rates of apnea
2. Use of IPPV
3. Side effects such as tachycardia or feed intolerance leading to alteration
in treatment
4. Longer term growth and development
The standard strategy of the Neonatal Review Group was used. This included searches of the Oxford Database of Perinatal Trials, the Cochrane Controlled Trials Register (The Cochrane Library, Issue 3, 2002), MEDLINE (1966 - October 2002), and EMBASE Drugs and Pharmacology (1990 - October 2002) using key words 'caffeine', 'theophylline' and 'apnea', MeSH terms 'infant, preterm', and 'randomized controlled trial' or 'controlled clinical trial'. Searches were also made of previous reviews including cross references, abstracts, conferences and symposia proceedings, expert informants and journal handsearching mainly in the English language.
Criteria and methods used to assess the methodological quality of the
trials:
The standard methods of the Cochrane Collaboration and its Neonatal Review
Group were used. The methodological quality of each trial was reviewed by
the second author blinded to trial authors and institution(s). Studies were
assessed using the following key criteria: blindness of randomisation, blindness
of intervention, completeness of follow up and blinding of outcome measurement.
Data were extracted independently by the reviewers. Differences were resolved
by discussion and consensus of the reviewers. Where necessary, investigators
were contacted for additional information or data.
Additional data were requested from authors of all trials and was provided for two of these (Bairam 1987; Scanlon 1992).
For individual trials, mean differences (and 95% confidence intervals) are reported for continuous variables. For categorical outcomes, the relative risk and risk difference (and 95% confidence intervals) are reported. For the meta-analysis, weighted mean differences (and 95% confidence intervals) are reported for continuous variables, and the relative risk and risk difference (and 95% confidence intervals) for categorical outcomes. A fixed effects model was used.
Nine trials were considered to be potentially eligible for this review.
Details of the three included studies (Brouard 1985; Bairam 1987; Scanlon 1992) are available in the included studies table.
Three trials were excluded from the analysis (Fuglsang 1989; Dani 2000; Zanardo 1995). In the Fuglsang 1989 trial, nine infants were excluded post randomization of the reported 18 infants enrolled. The rationale for some of these patients' exclusion was the need for IPPV, thus precluding the evaluation of an important outcome measure for treatment of apnea. Two trials were excluded (Dani 2000; Zanardo 1995) as no clinical outcome data were available.
A further three trials are awaiting assessment pending further information on clinical outcome data (Fang 1998; Kumar 1992; Laubscher 1998) .
The overall quality of the three included studies was fair/good. Concealment of treatment allocation by blinded randomization was undertaken in two trials (Bairam 1987 and Scanlon 1992). The method of randomization was not clear in the Brouard 1985 trial. Blinding of the intervention was undertaken in only one trial (Bairam 1987). In all three trials all randomized infants were included in the analysis. In one trial (Bairam 1987) blinded assessment of outcomes was conducted.
There is no difference in the failure rate (< 50% reduction in apnea/bradycardia) of treatment with caffeine or theophylline at 1-3 (two studies) or 5-7 days (one study). There was a higher mean rate of apnea in the standard caffeine group at 1-3 days [three studies, weighted mean difference (WMD) 0.40; 95% confidence interval (CI) 0.33,0.46 /100min] but not at 5-7 days (two studies).
Side effects, as indicated by tachycardia or feed intolerance leading to change in dosing, are lower in the caffeine group [typical relative risk (RR) 0.17; 95% CI 0.04,0.72, risk difference (RD) -0.29; 95% CI -0.47,-0.10, number needed to treat (NNT) 3.5; 95% CI 2.1, 9.6]. This was consistent across the three studies.
No trial reported the use of IPPV and no data are available to assess the effects on growth and development.
The results of this review should be interpreted with caution. The number of infants in each study is small. There is some variability in the characteristics of participants in terms of gestational age as well as clinical status. For example Scanlon 1992 examined infants who were of lower gestational age and who were oxygen dependent. This trial contributed the most weight to the difference in mean rates of apnea/bradycardia at 1-3 days. It also examined a third treatment arm of higher dose caffeine but this has not been included here.
All studies found standard caffeine treatment to have less short term side effects, consistent with known caffeine pharmacology.
Although standard caffeine treatment appeared to be less effective than theophylline as measured by mean apnea frequency (day 1 to day 3 of treatment) this difference was not maintained (day 5 to day 7). The studies demonstrate a decreased incidence of side effects with caffeine treatment. The NNT of 3.5 indicates that for every three to four patients treated with caffeine, one patient having a significant adverse event can be avoided. There are no data from these studies on long term effectiveness or safety.
One additional study (Kumar 1992), that has been reported in abstract form and is awaiting assessment, found that mean rates of apnea (15 seconds or more) and episodes of oxygen desaturation (<85%) were no different in the 13 infants treated with theophylline than in the 11 treated with caffeine. However, the mean rates of bradycardia (< 80 /min) were lower with theophylline at one, three and seven days after commencement of treatment with theophylline. This study requires author clarification which has been sought.
Another clinical question is whether caffeine or theophylline are effective alternative treatments in preterm infants who continue to have apnea despite methylxanthine treatment. This is not addressed in this review.
While there are no data from these studies on the long term effectiveness and safety, caffeine appears to have similar short term effects on apnea/bradycardia to theophylline. In view of the other therapeutic advantages of caffeine (a higher therapeutic ratio, more reliable enteral absorption and a longer half life) this is the preferred treatment for apnea in preterm infants.
There is a need for clinical trials with larger numbers of infants born at lower gestation to demonstrate the effectiveness and safety of caffeine compared to theophylline treatment with respect to clinically important outcomes including safety and longterm effects on neurodevelopmental outcome. The appropriate dose of methylxanthine therapy requires further investigation.
The possibility that higher doses of caffeine might be more effective in extremely preterm infants needs further evaluation in randomized clinical trials.
Both reviewers were investigators on a trial of caffeine in preterm infants:
"High dose caffeine for extubation of preterm Infants: a randomised controlled
trial."
| Study | Methods | Participants | Interventions | Outcomes | Notes | Allocation concealment |
| Bairam 1987 | Single centre. Blinding of randomization - yes* Blinding of intervention - yes Complete followup - yes * Blinding of outcome measure - yes *extra information provided by the author (personal correspondence)
|
20 preterm infants (mean gestational age 30 wks) included after 24 hour recording documented >= 3 apneas | Exp: standard caffeine = loading dose 10 mg/kg, maintenance dose
1.25 mg/kg/12hrs Control: theophylline = loading dose 6 mg/kg, mainenance dose 2 mg/kg/12hrs |
Frequency of apnea, systolic arterial pressure, tachycardia, weight gain, gastrointestinal intolerance, behavioural assessment (scaled-score of motor activity, reactivity and sucking) |
Apnea defined as cessation of breathing >15 seconds | A |
| Brouard 1985 | Single centre Blinding of randomization - can't tell Blinding of intervention - no Complete followup - yes Blinding of outcome measure - can't tell |
16 preterm infants (mean gestational age 30 weeks) enrolled infants where >= 3 severe apneas noted per 24 hours | Exp: standard caffeine = loading dose 10 mg/kg, maintenance dose
2.5 mg/kg to target serum level of 8 - 16 mg/l) Control: theophylline = loading dose 5.5 mg/kg, maintenance dose adjusted to maintain plasma levels at 5 - 10 mg/kg |
Apnea frequency on day 0, 1, and 5 Tachycardia Weight |
Severe apnea defined as cessation of breathing for 10 secs with heart rate < 80 for > 30 seconds or <60 for > 15 seconds | B |
| Scanlon 1992 | Single centre Blinding of randomization - yes Blinding of intervention - no Complete followup - yes Blinding of outcome measure - no
|
30 preterm infants <= 30 week gestation with apnea (>= 10 in 8 hours or 4 in 1 hour) | Exp: standard caffeine = loading dose 12.5 mg/kg and maintenance
3 mg/kg/12 hours. Control : theophylline = loading dose 7.5 mg/kg/8hrs (aiming for plasma levels of 13 - 20 mg/l) |
Apnea frequency over 48 hours number of infants with > 50 % reduction in apnea frequency |
Apnea defined as a decrease in heart rate of 40 beats per minute with cessation of breathing and requiring stimulation | A |
| Study | Reason for exclusion |
| Dani 2000 | No clinical outcome data available |
| Fuglsang 1989 | Nine out of the 18 infants randomised were excluded post randomisation, mainly because they needed IPPV. No information is available as to the group assignment of these excluded infants. |
| Zanardo 1995 | No clinical outcome data available |
Bairam A, Boutroy M, Badonnel Y, Vert P. Le choix entre theophylline et cafeine dans le traitement des apnees du premature. Arch Fr Pediatr 1990;47:461-5.
Bairam A, Boutroy MJ, Badonnel Y, Vert P. The choice between theophylline and caffeine in the treatment of apneas of prematurity (transl) Arch Fr Pediatr 1990;47:461-465.
* Bairam A, Boutroy MJ, Badonnel Y, Vert P. Theophylline versus caffeine: comparative effects in treatment of idiopathic apnea in the preterm infant. J Pediatr 1987;110:636- 639.
Brouard 1985 {published data only}
Brouard C, Moriette G, Murat I, Flouvat B, Pajot N, Walti H, deGamarra E, Relier JP. Comparative efficacy of theophylline and caffeine in the treatment of idiopathic apnea in premature infants. Am J Dis Child 1985;139:698-700.
Scanlon 1992 {published and unpublished data}
Scanlon JEM, Chin KC, Morgan MEI, Durbin GM, Hale KA, Brown SS. Caffeine or theophylline for neonatal apnoea? Arch Dis Child 1992;67:425-528.
Dani C, Bertini G, Reali M, Tronchin M, Wiechmann L, Martelli E, Rubaltelli F. Brain hemodynamic changes in preterm infants after maintenance dose caffeine and aminophylline treatment. Biol Neonate 2000;78:27-32.
Fuglsang 1989 {published data only}
Fuglsang G, Nielsen K, Kjaer Nielsen L, Sennels F, Jakobsen P, Thelle T. The effect of caffeine compared with theophylline in the treatment of idiopathic apnea in premature infants. Acta Paediatrica Scand 1989;78:786-788.
Zanardo 1995 {published data only}
Zanardo V, Dani C, Trevisanuto D, Meneghetti S, Guglielmi A, Zacchello G, Cantarutti F. Methylxanthines increase renal calcium excretion in preterm infants. Biol Neonate 1995;68:169-174.
Fang S, Sherwood R, Gamsu H, Marsden J, Peters T, Greenough A. Comparison of the effects of theophylline and caffeine on serum erythropoietin concentration in premature infants. Eur J Pediatr 1998;157:406-9.
Kumar 1992 {published data only}
Kumar SP, Mehta PN, Bradley BS, Ezhuthachan SG. Documented monitoring (DM) shows theophylline (T) to be more effective than caffeine (C) in prematurity apnea (PA). Pediatr Res 1992;31:208A.
Laubscher 1998 {published data only}
Laubscher B, Greenough A, Dimitriou G. Camparative effects of theophylline and caffeine on respiratory function of prematurely born infants. Early Hum Dev 1998;50:185-192.
* indicates the primary reference for the study
Blanchard PW, Aranda JV. Pharmacotherapy of respiratory control disorders. In: Beckerman RC, Brouillette RT, Hunt CE, editor(s). Respiratory Control Disorders in Infants and Children. Baltimore: Williams & Wilkins, 1992:352-370.
Henderson-Smart. Recurrent apnea. In: Yu VYH, editor(s). Bailliere's Clinical Paediatrics. Pulmonary Problems in the Perinatal Period. Vol. 3, No. 1. London: Bailliere Tindall, 1995:203-222.
Henderson-Smart DJ, Steer P. Methylxanthine treatment for apnea in preterm infants. In: The Cochrane Library, Issue 3, 2002. Oxford: Update Software.
National Institutes of Health. National Institutes of Health Consensus Development on Infantile Apnea and Home Monitoring. Pediatrics 1987:292-299.
Steer P, Henderson-Smart D. Caffeine versus theophylline for apnea in preterm infants (Cochrane Review). In: The Cochrane Library, Issue 2, 1998. Oxford: Update Software.
| Comparison or outcome | Studies | Participants | Statistical method | Effect size |
|---|---|---|---|---|
| 01 All infants | ||||
| 01 Continuing apnea at 1-3 days | 2 | 50 | RR (fixed), 95% CI | 1.49 [0.56, 3.98] |
| 02 Continuing apnea at 5-7 days | 1 | 20 | RR (fixed), 95% CI | 1.50 [0.32, 7.14] |
| 03 Mean rate of apnea at 1-3 days | 3 | 60 | WMD (fixed), 95% CI | 0.40 [0.33, 0.46] |
| 04 Mean rate of apnea at 5-7 days | 2 | 36 | WMD (fixed), 95% CI | 0.01 [-0.05, 0.07] |
| 05 Use of IPPV | 0 | 0 | RR (fixed), 95% CI | No numeric data |
| 06 Side effects | 3 | 66 | RR (fixed), 95% CI | 0.17 [0.04, 0.72] |