No new trials have been included and the conclusions are unchanged.
Two trials are awaiting assessment:
Moeller 1999 requires more data from the author.
Wang 2000 requires translation from Chinese and author clarification.
Infant apnea is a pause in breathing of greater than 20 seconds. This can be harmful to the developing brain and cause dysfunction of the gastrointestinal tract or other organs. Drugs such as doxapram and methylxanthine are thought to stimulate breathing and are given to reduce apnea. The review of three small trials found that there was no large difference between the drugs in the short term. There is not enough evidence to exclude a small difference in benefit, long term effects or a difference in less common adverse effects. More research is needed into the long term and adverse effects of these drugs.
If prolonged, apnea can lead to hypoxemia and reflex bradycardia that 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. 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 1970s. Theophylline and caffeine are two forms that have been used and meta-analysis of the four RCTs evaluating the effect against placebo or no treatment indicates a large reduction in apnea and in the use of IPPV ( Henderson-S 2000c).
Doxapram also appears to stimulate breathing and may be an alternative treatment. It appears to act both on the peripheral chemoreceptors and central nervous system to augment breathing efforts (Blanchard 1992). In one small placebo controlled trial, doxapram has been shown to reduce apnea in the short term (reviewed by Henderson-S 2000a).
Short term side effects of doxapram, such as hypertension, excessive central nervous system stimulation, gastrointestinal disturbances (Tay-Uyboco 1991) and heart block (De Villiers 1998) have been reported. No studies of long term effects on growth and development have been reported.
This review updates the existing review of 'Doxapram versus methylxanthine for apnea of prematurity' which was originally published in The Cochrane Library, Disk Issue 2, 1997 (Henderson-Smart 1997). One additional potentially eligible trial (Moller 1999) has been identified in this update, but author clarification is required before the results can be incorporated.
Meta-analysis was carried out with use of relative risk and risk difference.
One potentially eligible study (Moller 1999) requires author clarification before the data can be used. Fifty-two infants with recurrent apnea/bradycardia, birth weights less than 1500 grams and gestational ages less than 35 weeks at birth were randomized to intravenous doxapram or theophylline. Thirty-five per cent of infants were excluded after randomization (usually due to loss of intravenous access) and median rates of apnea are presented for the seven day study period. The author is helping with analysis of missing subjects, but the data is not yet available. A small Chinese study (Wang 2000) has been found but not included as translation and author clarification is still required.
The number of infants in each study was small. Although patients were similar at entry, the method of randomization was not stated in the trial of Romeo et al. (Romeo 1991). There was a risk of bias in this trial since the treatments were not blinded to the caretakers or analyzers and clinical charts were used to assess response. The trial by Eyal et al. (Eyal 1985) also used clinical charts to assess response, but the treatment was blinded.
DOXAPRAM VS. METHYLXANTHINE (Comparison 01):
In these three included trials involving 63 preterm infants with apnea of prematurity, failed treatment in the first 48 hours (Outcome 01 - 01) occurred in seven of 32 infants receiving doxapram and six of 31 infants receiving methylxanthine. This result is consistent across trials is not significantly different (summary relative risk 1.16, 95% CI 0.43, 3.13). One trial (Peliowski 1990) of 28 infants reported failed treatment at seven days (Outcome 01 - 02) and found no difference (summary RR 1.30 (0.72, 2.36).
Use of mechanical ventilation and long term follow up was not reported in any trial.
Theoretically, the use of intravenous methylxanthine (aminophylline or caffeine) has the advantage of being easily converted to the enteral route (theophylline), whereas doxapram is poorly absorbed and causes gastrointestinal disturbance when given orally (Tay-Uyboco 1991) and is therefore usually administered intravenously. Furthermore, short term side effects of doxapram, such as hypertension, excessive central nervous system stimulation, and heart block (De Villiers 1998) have been reported.
| Study | Methods | Participants | Interventions | Outcomes | Notes | Allocation concealment |
| Eyal 1985 | Blinding of randomization: yes; apnea/bradycardia assessed by blinded nursing observations of infants and monitors, exclusions not mentioned. Blinding of intervention: yes Complete followup: can't tell Blinding of outcome measurement: yes | 16 preterm infants (9 doxapram, 7 theophylline), mean gestational age 30 weeks, with apnea associated with cyanosis and bradycardia <100 bpm. | Doxapram 2.5 mg/kg/hr IV vs aminophylline 6 mg/kg load and 1.5 mg/kg/8 hrly. Each treatment was given for 48 hrs. | Apnea/bradycardia < 50% reduction. | A | |
| Peliowski 1990 | Concealed randomisation; placebo controlled; Three withdrawals, groups not specified. Blinding of randomization: yes Blinding of intervention: yes Complete followup: can't tell Blinding of outcome measurement: yes | 28 (13 doxapram, 15 theophylline) preterm infants (<35 weeks gestation) with apnea; ( apnea > 20 sec with > 25% fall in heart rate and 10% fall in oxygen saturation or 5 torr or more fall in transcutaneous oxygen tension; 0.33 or more events per hr, = 8 or more per day) ; other causes of apnea excluded; similar mean gestational age (30.7 vs 31.3 weeks), birth weight (1441 vs 1303 gms), postnatal age at study entry (4.8 vs 2.9 days) and baseline apnea rate (0.94 vs 0.70/hr) | Doxapram intravenously; 3 mg/kg load and 1.5 mg/kg/hr vs intravenous theophylline 8 mg/kg load followed by 0.5 mg/kg/hr. | Apnea (failure of rate of events to fall below 0.33/hr or use of mechanical ventilation); use of mechanical ventilation | Additional treatment with CPAP allowed - no information on who received this. Cross over design and simultaneous comparison with doxapram - not evaluated here. | A |
| Romeo 1991 | Random allocation method not specified, not blinded, clinical assessment by unblinded staff, exclusions not mentioned. Blinding of randomization: can't tell Blinding of intervention: no Complete followup: can't tell Blinding of outcome measurement: no | 19 (10 doxapram, 9 aminophylline) preterm infants with 3 or more episodes of apnea >10 sec with cyanosis and bradycardia (< 40 bpm below baseline) in 8 hours. Mean gestational ages 29.6 weeks for aminophylline group and 29.9 weeks for doxapram group. | Doxapram 1.5 mg/kg/hr vs aminophylline 5 mg/kg load and 2.5 mg/kg ?frequency. | Apnea < 50% reduction by 48 hours after treatment. | B |
Eyal F, Alpan G, Sagi E, Glick B, Peleg O, Dgani Y, Arad I. Aminophylline vs doxapram in idiopthic apnea of prematurity; a double-blind controlled study. Pediatrics 1985;75:709-13.
Peliowski 1990 {published data only}
Peliowski A, Finer NN. A blinded, randomized, placebo-controlled trial to compare theophylline and doxapram for the treatment of apnea of prematurity. Journal of Pediatrics 1990;116:648-53.
Romeo 1991 {published data only}
Romeo MG, Proto N, Tina LG, Parisi MG, Distefano G. Comparison of the effectiveness of aminophylline and doxapram in the prevention of idiopathic apnea in preterm infants (transl.). La Pediatria Medica e Chirurgica 1991;13:77-82.
Moller JC, Austing A, Pust B, Kohl M, Reiss I, Iven H, Gortner L. Vergleichende untersuchung zur wirkung von theophyllin und doxapram bei apnoean [A comparative study about the therapeutic effect of theophylline and doxapram in apnoeic disorders]. Klinische Pädiatrie 1999;211:86-91.
Wang 2000 {published data only}
Wang HB, Yan YP, Wang TY. Observation of curative effects of Doxapram and Aminophylline on primary premature apnea. Hebei Medicine 2000;6:981-2.
* 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.
De Villiers GS, Walele A, Van der Merwe P-L, et al. Second-degree atrioventricular heart block after doxapram administration. Journal of Pediatrics 1998;133:149-50.
Henderson-Smart DJ, Steer PA. Doxapram treatment for apnea in preterm infants. In: Cochrane Database of Systematic Reviews, Issue 1, 2000. Oxford: Update Software.
Henderson-Smart DJ, Steer PA. Prophylactic doxapram for the prevention of morbidity and mortality in preterm infants undergoing endotracheal extubation. In: Cochrane Database of Systematic Reviews, Issue 3, 2000. Oxford: Update Software.
Henderson-Smart DJ, Steer PA. Methylxanthine treatment for apnea in preterm infants. In: Cochrane Database of Systematic Reviews, Issue 3, 2000. Oxford: Update Software.
Henderson-Smart DJ, Davis PG. Prophylactic methylxanthine for extubation in preterm infants. In: Cochrane Database of Systematic Reviews, Issue 3, 2000. Oxford: Update Software.
Henderson-Smart DJ. Recurrent apnoea. In: Yu VYH, editor(s). Pulmonary Problems in the Perinatal Period and their Sequelae. Vol. 3, No. 1. London: Bailliere Tindall, 1995:203-222.
National Institutes of Health Consensus Development Panel on Infantile Apnea and Home Monitoring. Consensus statement. Pediatrics 1987;79:292-9.
Tay-Uyboco J, Kwiatkowski K, Cates DB, et al. Clinical and physiological responses to prolonged nasogastric administration of doxapram for apnea of prematurity. Biology of the Neonate 1991;59:190-200.
Henderson-Smart DJ, Steer PA. Doxapram versus methylxanthine for apnea in preterm infants. In: Cochrane Database of Systematic Reviews, Issue 2, 1997. Oxford: Update Software.
Henderson-Smart DJ, Steer PA.. Doxapram versus methylxanthine for apnea in preterm infants. In: Cochrane Database of Systematic Reviews, Issue 4, 2000.
| Comparison or outcome | Studies |
Participants |
Statistical method |
Effect size |
|---|---|---|---|---|
| 01 Doxapram vs aminophylline | ||||
| 01 Failed treatment in the first 48 hrs | 3 |
63 |
RR (fixed), 95% CI |
1.16 [0.43, 3.13] |
| 02 Failed treatment before 7 days | 1 |
28 |
RR (fixed), 95% CI |
1.30 [0.72, 2.36] |
01.01 Failed treatment in the first 48 hrs
01.02 Failed treatment before 7 days
Dr Peter A Steer, MBBS, FRACP
President
McMaster Children's Hospital
McMaster University Medical Centre
1200 Main Street West
Hamilton
Ontario CANADA
L8N 3Z5
Telephone 1: +1 905 521 2100 extension: 75605
E-mail: steerp@mcmaster.ca
| This review is published as a Cochrane review in The Cochrane Library, Issue 3, 2007 (see http://www.thecochranelibrary.com for information). Cochrane reviews are regularly updated as new evidence emerges and in response to feedback. The Cochrane Library should be consulted for the most recent version of the review. |
