David J Henderson-Smart1, Peter A Steer2
Background - Methods - Results - Characteristics of Included Studies - References - Data Tables and Graphs
1NSW Centre for Perinatal Health Services Research, Queen Elizabeth II Research Institute, Sydney, Australia
2School of Medicine, Faculty of Health Sciences, University of Queensland, Children's Health Services District, Queensland Health, Brisbane, Australia
Citation example: Henderson-Smart DJ, Steer PA. Doxapram treatment for apnea in preterm infants. Cochrane Database of Systematic Reviews 2004, Issue 4. Art. No.: CD000074. DOI: 10.1002/14651858.CD000074.pub2.
NSW Centre for Perinatal Health Services Research
Queen Elizabeth II Research Institute
Building DO2
University of Sydney
Sydney
NSW
2006
Australia
E-mail: dhs@mail.usyd.edu.au
| Assessed as Up-to-date: | 01 June 2009 |
|---|---|
| Date of Search: | 16 April 2009 |
| Next Stage Expected: | 01 June 2011 |
| Protocol First Published: | Issue 1, 1997 |
| Review First Published: | Issue 1, 1997 |
| Last Citation Issue: | Issue 4, 2004 |
| Date / Event | Description |
|---|---|
| 27 April 2009 Updated | This review updates the review "Doxapram treatment for apnea in preterm infants", published in the Cochrane Database of Systematic Reviews, Issue 3, 2007 (Henderson-Smart 2007). Our updated search did not identify any additional trials for inclusion in this update. Conclusions unchanged. |
| Date / Event | Description |
|---|---|
| 03 June 2008 Amended | Converted to new review format. |
| 14 May 2007 Updated | This review updates the existing review 'Doxapram treatment for apnea in preterm infants' published in The Cochrane Library, Disk Issue 4, 2004 (Henderson-Smart 2004). |
| 29 July 2004 New citation: conclusions changed | Substantive amendment |
Recurrent apnea is common in preterm infants, particularly at very early gestational ages. Apnea can lead to hypoxemia and bradycardia, which may be severe enough to require resuscitation including use of positive pressure ventilation. Doxapram has been used to stimulate breathing and thereby prevent apnea and its consequences.
To evaluate the effect of doxapram treatment on apnea and the use of intermittent positive airways pressure (IPPV) in preterm infants with recurrent apnea.
We searched the Oxford Database of Perinatal Trials, the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 2, 2009), MEDLINE from 1966 to April 2009, EMBASE from 1980 to April 2009, CINAHL from 1982 to April 2009. We used the text words 'doxapram', 'apnea or apnoea' and the MeSH term 'infant, premature'. Previous reviews including cross references, abstracts from conferences and symposia proceedings were also examined. Abstracts of the Society for Pediatric Research were searched from 1996 to 2008 inclusive.
We included all trials utilising random or quasi-random patient allocation in which doxapram was used for the treatment of apnea in preterm infants.
Each review author evaluated the papers for quality and inclusion criteria and extracted data independently.
We found only one trial, which randomized 11 infants to intravenous doxapram and 10 infants to placebo. There were fewer treatment failures after 48 hours in the group of preterm infants treated with doxapram (4/11) compared with the group treated with placebo (8/10). The wide confidence intervals made this result non-significant [summary relative risk 0.45 (0.20 to 1.05)]. Only one infant, who was from the placebo group, was given IPPV.
Of the seven responders by 48 hours in the group of 11 who received doxapram, five failed to respond between 48 hours and seven days after commencement of therapy. This gives a late failure rate of 9/11, similar to the short-term failure rate in the placebo group of 8/10. It is not possible to evaluate the late responses of all those in the placebo group since they crossed over to a treatment arm.
Although intravenous doxapram might reduce apnea within the first 48 hours of treatment, there are insufficient data to evaluate the precision of this result or to assess potential adverse effects. No long-term outcomes have been measured. Further studies are needed to determine the role of this treatment in clinical practice.
Doxapram stimulates breathing. However, there is not enough evidence to know if it is helpful in premature infants with apnea. 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 are thought to stimulate breathing and are given to reduce apnea. The review of one small trial found that apnea might be reduced in the first few days after treatment, but there were not enough infants studied to know if this was a significant effect. There is no evidence from this trial on longer term effects or less common adverse effects. More research is needed on the effectiveness, potential harm and long-term benefits or adverse effects of these drugs.
Infant apnea is defined as a pause in breathing of greater than 20 seconds or one of less than 20 seconds associated with bradycardia, pallor and/or cyanosis (AAP 2003). Recurrent episodes of apnea are common in preterm infants and the incidence and severity increases at lower gestational ages. Although apnea can occur spontaneously and be attributed to prematurity alone, apnea can also be provoked or made more severe if there is some additional insult such as infection, hypoxemia or intracranial pathology.
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, although there are no data to support this. Frequent episodes may be accompanied by respiratory failure of sufficient severity to lead to intubation and the use of intermittent positive pressure ventilation (IPPV).
Methylxanthines have been used in clinical practice to stimulate breathing efforts and reduce apnea since the 1970's. Doxapram also appears to stimulate breathing and may be an alternative treatment.
Doxapram appears to act both on the peripheral chemoreceptors and central nervous system to augment breathing efforts (reviewed by Barrington 1986; Blanchard 1992).
Short-term side effects such as hypertension, excessive central nervous system stimulation, gastrointestinal disturbances (Tay-Uyboco 1991) and heart block (De Villiers 1998) have been reported (Blanchard 1992). One observational study has suggested an association between the total dose and duration of doxapram treatment and isolated mental developmental delay in infants weighing less than 1250 grams at birth (Sreenan 2001).
For general reviews of apnea in preterm infants and its treatment see Samuels 1992 and Henderson-Smart 1995. Other reviews compare doxapram and methylxanthines for apnea (Henderson-Smart 04c) and evaluate doxapram to assist extubation of preterm infants (Henderson-Smart 04b).
To evaluate the effect of doxapram treatment on apnea and the use of IPPV in preterm infants with recurrent apnea.
Preterm infants with recurrent apnea. 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' (AAP 2003).
Primary
Secondary
We searched the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 2, 2009), the Oxford Database of Perinatal trials, MEDLINE from 1966 to April 2009, EMBASE from 1980 to April 2009, CINAHL from 1982 to April 2009. We used the text words 'doxapram', 'apnea or apnoea' and the MeSH term 'infant, premature'. We examined the titles and abstracts of all potentially eligible trials and checked the full text if there was doubt as to eligibility.
We also examined previous reviews including cross references, abstracts from conferences and symposia proceedings (American Society for Pediatric Research, 1996 to 2008 and the European Society for Pediatric Research, 1996 to 2008). Prof. Y. Ogawa also made an expert informant's search in the Japanese language in 1996. We examined the titles and abstracts of all potentially eligible trials and checked the full text if there was doubt as to eligibility.
We searched clinical trials registries for ongoing or recently completed trials (clinicaltrials.gov; controlled-trials.com; and who.int/ictrp).
We used the standard methods of the Cochrane Neonatal Review Group.
We included all randomized and quasi-randomized controlled trials fulfilling the selection criteria described. We reviewed the results of the search and separately selected the studies for inclusion. We resolved any disagreement by discussion.
Each review author extracted the data separately. Data were then compared and differences resolved.
We assessed the methodological quality of the one included trial for the method of randomization, blinding of intervention, blinding of outcome, and completeness of follow-up. The methodological quality of the trial was reviewed independently by the second review author blinded to trial authors and institution(s). We have requested additional information from the authors of the study to clarify methodology.
Treatment effect was expressed as relative risk (RR), risk difference (RD) and number needed to treat (NNT) derived from 1/RD. The precision of the estimate of treatment effect was expressed as the 95% confidence interval.
If a meta-analysis was performed, we planned to examine heterogeneity between trials by inspecting the forest plots and quantifying the impact of heterogeneity using the I-squared statistic.
If meta-analysis was judged to be appropriate, the analysis would be done using Review Manager software (RevMan 5), supplied by The Cochrane Collaboration. For estimates of typical relative risk and risk difference, we planned to use the Mantel-Haenszel method. For measured quantities, we planned to use the inverse variance method. All meta-analyses were to be done using the fixed-effect model.
We found only one small study comparing short term (48 hours) response to intravenous doxapram with placebo (Peliowski 1990). This trial had three arms: Aminophylline, Doxapram and control. For the purpose of this review, we present data from the latter two arms. Details are given in the Characteristics of included studies table.
Details are given in the Characteristics of included studies table. Co-interventions, such as continuous positive airways pressure, were used in an unknown number of cases and controls. Three infants were withdrawn after trial entry; one because parents withdrew consent; one because of possible infection; and a third because of possible seizures. The groups to which these infants were assigned is not given and none of their data were analysed. Since seizures are known to complicate doxapram therapy, this needs clarification from the study author.
DOXAPRAM TREATMENT VS. PLACEBO (Comparison 1):
Failed treatment in first 48 hours (Outcome 1.1):
There were fewer treatment failures after 48 hours (continuing apnea and/or use of mechanical ventilation) in the group of preterm infants treated with doxapram (4/11) compared with the group treated with placebo (8/10). The wide confidence interval made this result non-significant (summary RR 0.45 (0.20 to 1.05)). Only one infant, who was from the placebo group, was given IPPV.
Of the seven responders by 48 hours in the group of 11 who received doxapram, five failed to respond between 48 hours and seven days after commencement of therapy. This gives a late failure rate of 9/11, similar to the short term failure rate in the placebo group of 8/10. It is not possible to evaluate the 48 hour to seven day responses of all those in the placebo group since they crossed over to a treatment arm. Two in the placebo group were considered longer term responders without treatment.
No adverse effects or outcomes beyond seven days from the commencement of treatment were reported.
The results of this small trial suggests that intravenous doxapram might reduce apnea of prematurity in the short term. Any possible effects of treatment were not sustained between 48 hours and seven days after commencement of doxapram treatment. The efficacy of doxapram for the short term control of apnea in preterm infants appears to be similar to that of methylxanthines (Henderson-Smart 04a).
Caution is warranted as the sample size is inadequate to evaluate doxapram for either benefit or harm. There were no side effects observed in the infants included in the study. One excluded infant had suspected seizures although the original group assignment was not given. Heart block has been reported by others (De Villiers 1998), but was not observed in the included study.
One observational study has suggested an association between the total dose and duration of doxapram treatment and isolated mental developmental delay in infants weighing less than 1250 grams at birth (Sreenan 2001). As discussed by the authors, they could not control for the severity of apnea, which has also been associated with poor neurodevelopmental outcome (Cheung 1999). Another suggested source of toxicity is benzyl alcohol used in the intravenous preparation of doxapram in the USA. It has been pointed out that the Sreenan 2001 observations were made in Canada where doxapram does not contain benzyl alcohol (Finer 2002).
An important limitation to the use of doxapram is that it is usually administered intravenously. Although observational studies suggest that it can be given orally, only about 50% is absorbed and gastrointestinal side effects have been reported (Bairam 1991; Tay-Uyboco 1991).
Although intravenous doxapram might reduce apnea within the first 48 hours of treatment, there are insufficient data to evaluate the precision of this result or to assess known potential adverse effects. No long term outcomes have been measured. Further studies are needed to determine the role of this treatment in clinical practice.
There is a need for studies of a larger number of infants stratified by gestation to clarify which infants are likely to benefit from this treatment. It would be valuable to include important clinical outcomes such as use of IPPV, side effects and subsequent growth and development in future studies.
The Cochrane Neonatal Review Group has been funded in part with Federal funds from the Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health, Department of Health and Human Services, USA, under Contract No. HHSN267200603418C.
| Methods | Concealed at randomization - yes (computer generated randomization code - placed in sealed envelopes); Blinding of intervention - yes; |
|---|---|
| Participants | 21 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 gm), postnatal age at study entry (4.8 vs 2.9 days) and baseline apnea rate (0.94 vs 0.70/hr). |
| Interventions | Doxapram intravenously; 3 mg/kg load and 1.5 mg/kg/hr vs saline placebo. |
| Outcomes | Apnea at 48 hours (failure of rate of events to fall below 0.33/hr or use of mechanical ventilation); use of IPPV. |
| Notes | Cross over design and simultaneous comparison with doxapram - not evaluated here. |
| Item | Judgement | Description |
|---|---|---|
| Adequate sequence generation? | Yes | Concealed at randomization |
| Allocation concealment? | Yes | Adequate |
| Blinding? | Yes | Blinding of intervention and outcome assessment |
| Incomplete outcome data addressed? | Unclear | Three infants (9.7%) withdrawn, groups not specified |
| Free of selective reporting? | Yes | |
| Free of other bias? | Yes |
American Academy of Pediatrics. Policy statement. Apnea, sudden infant death syndrome, and home monitoring. Pediatrics 2003;111:914-7.
Bairam A, Akramoff-Gershan L, Beharry K, Laudignon N, Papageorgiou A, Aranda JV. Gastrointestinal absorption of doxapram in neonates. American Journal of Perinatology 1991;8:110-3.
Barrington KJ, Finer NN, Peters KL, Barton J. Physiological effects of doxapram in idiopathic apnea of prematurity. Journal of Pediatrics 1986;108:125-9.
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, 1992:352-70.
Cheung PY, Barrington KJ, Finer NN, Robertson CM. Early childhood neurodevelopment in very low birth weight infants with predischarge apnea. Pediatric Pulmonology 1999;27:14-20.
De Villiers GS, Walele A, Van der Merwe PL, Kalis NN. Second-degree atrioventricular heart block after doxapram administration. Journal of Pediatrics 1998;133:149-50.
Finer NN, Barrington KJ. Doxapram and neurodevelopmental outcome (Letter). Journal of Pediatrics 2002;141:296.
Henderson-Smart DJ, Steer PA. Methylxanthine treatment for apnea in preterm infants. Cochrane Database of Systematic Reviews 2004, Issue 2. Art. No.: CD000140. DOI: 10.1002/14651858.CD000140.
Henderson-Smart DJ, Davis PG. Prophylactic doxapram for the prevention of morbidity and mortality in preterm infants undergoing endotracheal extubation. Cochrane Database of Systematic Reviews 2004, Issue 2. Art. No.: CD001966. DOI: 10.1002/14651858.CD001966.
Henderson-Smart DJ, Steer PA. Doxapram versus methylxanthine for apnea in preterm infants. Cochrane Database of Systematic Reviews 2004, Issue 2. Art. No.: CD000075. DOI: 10.1002/14651858.CD000075.
Henderson-Smart DJ. Recurrent apnoea. In: Yu, VYH, editor(s). Bailliere's Clinical Paediatrics. Pulmonary Problems in the Perinatal Period and their Sequelae. Vol. 3, No. 1. London: Bailliere Tindall, 1995:203-22.
Samuels MP, Southall DP. Recurrent apnea. In: Sinclair JC, Bracken MB, editor(s). Effective Care of the Newborn Infant. Oxford: Oxford University Press, 1992:385-97.
Henderson-Smart DJ, Steer PA. Doxapram for apnea in preterm infants. Cochrane Database of Systematic Reviews 1997, Issue 1. Art. No.: CD000074. DOI: 10.1002/14651858.CD000074.pub2.
Henderson-Smart DJ, Steer PA. Doxapram for apnea in preterm infants. Cochrane Database of Systematic Reviews 1999, Issue 4. Art. No.: CD000074. DOI: 10.1002/14651858.CD000074.pub2.
Henderson-Smart DJ, Steer PA. Doxapram for apnea in preterm infants. Cochrane Database of Systematic Reviews 2001, Issue 4. Art. No.: CD000074. DOI: 10.1002/14651858.CD000074.pub2.
| Outcome or Subgroup | Studies | Participants | Statistical Method | Effect Estimate |
|---|---|---|---|---|
| 1.1 Failed treatment in first 48 hours | 1 | 21 | Risk Ratio (M-H, Fixed, 95% CI) | 0.45 [0.20, 1.05] |
| 1.2 Use of IPPV in first 48 hours | 1 | 21 | Risk Ratio (M-H, Fixed, 95% CI) | 0.31 [0.01, 6.74] |
This review is published as a Cochrane review in The Cochrane Library, Issue 4, 2009 (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. |
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