Doxapram treatment for apnea in preterm infants

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Authors

David J Henderson-Smart1, Peter A Steer2

Background - Methods - Results - Characteristics of Included Studies - References - Data Tables & Graphs


1NSW Centre for Perinatal Health Services Research, Queen Elizabeth II Research Institute, Sydney, Australia [top]
2School of Medicine, Faculty of Health Sciences, University of Queensland, Children's Health Services District, Queensland Health, Brisbane, Australia [top]

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.

Contact person

David J Henderson-Smart

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

Dates

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

What's new

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.

History

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).

No additional eligible trials have been identified in this update and the conclusions are unchanged.

29 July 2004
New citation: conclusions changed

Substantive amendment

Abstract

Background

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.

Objectives

To evaluate the effect of doxapram treatment on apnea and the use of intermittent positive airways pressure (IPPV) in preterm infants with recurrent apnea.

Search methods

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.

Selection criteria

We included all trials utilising random or quasi-random patient allocation in which doxapram was used for the treatment of apnea in preterm infants.

Data collection and analysis

Each review author evaluated the papers for quality and inclusion criteria and extracted data independently.

Results

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.

Authors' conclusions

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.

Plain language summary

Doxapram treatment for apnea in preterm infants

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.

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Background

Description of the condition

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).

Description of the intervention

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.

How the intervention might work

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).

Why it is important to do this review

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).

Objectives

To evaluate the effect of doxapram treatment on apnea and the use of IPPV in preterm infants with recurrent apnea.

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Methods

Criteria for considering studies for this review

Types of studies

All trials utilising random or quasi-random patient allocation.

Types of participants

Preterm infants with recurrent apnea. There must have been an effort to exclude specific causes of apnea.

Types of interventions

Doxapram used for the treatment of apnea.

Types of outcome measures

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
  1. Failed treatment (continuing apnea, or use of IPPV, or death during study)
  2. Apnea frequency
  3. Use of IPPV
  4. Mortality
Secondary
  1. Side effects including seizures, hypertension, gastrointestinal disturbances and heart block
  2. Development (mental and motor evaluated with standard test and clinical examination) and growth in childhood

Search methods for identification of studies

Electronic searches

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.

Searching other resources

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 External Web Site Policy, and WHO International Clinical Trials Registry Platform (ICTRP) External Web Site Policy).

Data collection and analysis

We used the standard methods of the Cochrane Neonatal Review Group.

Selection of studies

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.

Data extraction and management

Each review author extracted the data separately. Data were then compared and differences resolved.

Assessment of risk of bias in included studies

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.

Measures of treatment effect

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.

Assessment of heterogeneity

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.

Data synthesis

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.

Subgroup analysis and investigation of heterogeneity

If we detected statistical heterogeneity, we planned to explore the possible causes (for example, differences in study quality, participants, intervention regimens, or outcome assessments) using subgroup analyses.

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Results

Description of studies

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.

Risk of bias in included studies

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.

Effects of interventions

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.

Discussion

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).

Authors' conclusions

Implications for practice

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.

Implications for research

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.

Acknowledgements

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.

Contributions of authors

Both review authors developed the protocol, evaluated trials and extracted data.
Henderson-Smart wrote the review and entered data into RevMan.
Henderson-Smart has been responsible for searching for trials and updating the review with approval of Steer.

Declarations of interest

  • None noted.

Differences between protocol and review

  • None noted.

Additional tables

  • None noted.

Potential conflict of interest

  • None noted.

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Characteristics of studies

Characteristics of Included Studies

Peliowski 1990

Methods

Concealed at randomization - yes (computer generated randomization code - placed in sealed envelopes); Blinding of intervention - yes;
Complete follow-up - Unclear (three withdrawals, groups not specified)
Blinding of outcome assessment - 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.
Additional treatment with CPAP allowed - no information on who received this (author clarification requested).

Risk of bias table
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

Characteristics of excluded studies

Poets 1999

Reason for exclusion

This study is listed in databases as a randomized controlled trial. This is not stated in the methodology of the paper and author clarification has confirmed that it is not an RCT.

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References to studies

Included studies

Peliowski 1990

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.

Excluded studies

Poets 1999

Poets CF, Darraj S, Bohnhorst B. Effect of doxapram on episodes of apnoea, bradycardia and hypoxaemia in preterm infants. Biology of the Neonate 1999;76:207-13.

Studies awaiting classification

  • None noted.

Ongoing studies

  • None noted.

Other references

Additional references

AAP 2003

American Academy of Pediatrics. Policy statement. Apnea, sudden infant death syndrome, and home monitoring. Pediatrics 2003;111:914-7.

Bairam 1991

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 1986

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 1992

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 1999

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 1998

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 2002

Finer NN, Barrington KJ. Doxapram and neurodevelopmental outcome (Letter). Journal of Pediatrics 2002;141:296.

Henderson-Smart 04a

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 04b

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 04c

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 1995

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 1992

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.

Sreenan 2001

Sreenan C, Etches PC, Demianczuk N, Robertson CMT. Isolated mental developmental delay in low birth weight infants: association with prolonged doxapram therapy for apnea. Journal of Pediatrics 2001;139:832-7.

Tay-Uyboco 1991

Tay-Uyboco J, Kwiatkowski K, Cates DB, Seifert B, Hasan SU, Rigatto H. Clinical and physiological responses to prolonged nasogastric administration of doxapram for apnea of prematurity. Biology of the Neonate 1991;59:190-200.

Other published versions of this review

Henderson-Smart 1997

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 1999

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 2001

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.

Henderson-Smart 2004

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.

Henderson-Smart 2007

Henderson-Smart DJ, Steer PA. Doxapram treatment for apnea in preterm infants. Cochrane Database of Systematic Reviews 2007, Issue 3. Art. No.: CD000074. DOI: 10.1002/14651858.CD000074.pub2.

Classification pending references

  • None noted.

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Data and analyses

1 Doxapram vs placebo

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]

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Sources of support

Internal sources

  • Pediatrics, McMaster Childrens Hospital, Ontario, Canada
  • Centre for Perinatal Health Services Research, University of Sydney, Australia
  • Neonatal Medicine, Royal Prince Alfred Hospital, Sydney, Australia

External sources

  • No sources of support provided.

This review is published as a Cochrane review in The Cochrane Library, Issue 4, 2009 (see http://www.thecochranelibrary.com External Web Site Policy 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 recent version of the review.