Doxapram treatment for apnea in preterm infants

Henderson-Smart DJ, Steer PA

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

Dates

Date edited: 11/07/2007
Date of last substantive update: 29/07/2004
Date of last minor update: 14/05/2007
Date next stage expected 14/05/2009
Protocol first published: Issue 1, 1997
Review first published: Issue 1, 1997

Contact reviewer

Prof David J Henderson-Smart
Director
NSW Centre for Perinatal Health Services Research
Queen Elizabeth II Research Institute
Building DO2
University of Sydney
Sydney
NSW AUSTRALIA
2006
Telephone 1: +61 2 93517318
Telephone 2: +61 2 93517728
Facsimile: +61 2 93517742
E-mail: dhs@mail.usyd.edu.au

Contribution of reviewers

Both 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.

Internal sources of support

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 of support

None

What's new

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.

Dates

Date review re-formatted: 20/08/1999
Date new studies sought but none found: 23/05/2007
Date new studies found but not yet included/excluded: / /
Date new studies found and included/excluded: / /
Date reviewers' conclusions section amended: / /
Date comment/criticism added: / /
Date response to comment/criticisms added: / /

Text of review

Synopsis

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.

Abstract

Background

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. 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 strategy

Selection criteria

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

Data collection & analysis

Each author evaluated the papers for quality and inclusion criteria. Independent data extraction was carried out.

Main results

Only one trial, which randomized 11 infants to intravenous doxapram and 10 infants to placebo, was found. 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, 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.

Reviewers' 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.

Background

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. It appears to act both on the peripheral chemoreceptors and central nervous system to augment breathing efforts (reviewed by Blanchard 1992; Barrington 1986).

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 evaluates 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.

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)
1. Failed treatment (continuing apnea, or use of IPPV, or death during study)
2. Use of IPPV
3. Side effects including seizures, hypertension, gastrointestinal disturbances and heart block.
4. Development (mental and motor evaluated with standard test and clinical examination) and growth in childhood. This outcome has been added to the protocol in the current update as they have been in our recommendation for future research from the outset and are a standard outcome in our other reviews (Henderson-Smart 04a; Henderson-Smart 04b). Furthermore, recent observational studies suggest that developmental outcome may be a concern and needs evaluation.

Search strategy for identification of studies

Searches were made of the Oxford Database of Perinatal trials, the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 1, 2007), MEDLINE from 1966 - April 2007, EMBASE from 1980 - April 2007, CINAHL from 1982- April 2007. Text words 'doxapram', 'apnea or apnoea' and the MeSH term 'infant, premature' were used. Previous reviews including cross references, abstracts from conferences and symposia proceedings were also examined (American Society for Pediatric Research, 1996- 2006 and European Society for Pediatric Research, 1996 - 2003). Also an expert informant's search in the Japanese language was made by Prof. Y. Ogawa in 1996. The titles and abstracts of all potentially eligible trials were examined, with the full text being checked if there was doubt as to eligibility.

Methods of the review

The methodological quality of the one included trial was assessed 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 author blinded to trial authors and institution(s). Additional information has been requested from the authors of the study to clarify methodology.

Each author extracted the data separately. Then data were compared and differences resolved.

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.

Description of studies

Only one small study comparing short term (48 hrs) response to intravenous doxapram with placebo was found (Peliowski 1990). This trial had tree arms: Aminophylline, Doxapram and control. For the purpose of this review, data from the latter two arms are presented. Details are given in the included studies table.

Methodological quality of included studies

Details are given in the 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 author clarification.

Results

DOXAPRAM TREATMENT VS. PLACEBO (Comparison 01):
Failed treatment in first 48 hours (Outcome 01.01):

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, 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 7 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).

Reviewers' 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

None

Potential conflict of interest

None

Characteristics of included studies

Study	Methods	Participants	Interventions	Outcomes	Notes	Allocation concealment
Peliowski 1990	Concealed at randomisation - yes; blinding of intervention - yes; complete followup - ? (three withdrawals, groups not specified); blinding of outcome assessment - yes.	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 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 saline placebo.	Apnea at 48 hours (failure of rate of events to fall below 0.33/hr or use of mechanical ventilation); use of IPPV.	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).	A

Characteristics of excluded studies

Study	Reason for exclusion
Poets 1999	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.

References to studies

References to included studies

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.

References to excluded studies

Poets 1999 {published data only}

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.

* indicates the primary reference for the study

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, 1992:352-370.

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 P-L, et al. 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. In: Cochrane Database of Systematic Reviews, Issue 2, 2004. Chichester, UK: John Wiley & Sons, Ltd.

Henderson-Smart 04b

Henderson-Smart DJ, Davis PG. Prophylactic doxapram for the prevention of morbidity and mortality in preterm infants undergoing endotracheal extubation. In: Cochrane Database of Systematic Reviews, Issue 2, 2004. Chichester, UK: John Wiley & Sons, Ltd.

Henderson-Smart 04c

Henderson-Smart DJ, Steer PA. Doxapram versus methylxanthine for apnea in preterm infants. In: Cochrane Database of Systematic Reviews, Issue 2, 2004. Chichester, UK: John Wiley & Sons, Ltd.

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, 1992:385-397.

Sreenan 2001

Sreenan C, Etches PC, Demianczuk N, Robertson CMT. Isolated mental developmental delay in low birth weight infants: assosciation 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 P. Doxapram for apnea in preterm infants (Cochrane Review). In: Cochrane Database of Systematic Reviews, Issue 1, 1997. Oxford: Update Software.

Henderson-Smart 1999

Henderson-Smart DJ, Steer PA. Doxapram for apnea in preterm infants (Cochrane Review). In: Cochrane Database of Systematic Reviews, Issue 4, 1999. Oxford: Update Software.

Henderson-Smart 2001

Henderson-Smart DJ, Steer PA. Doxapram for apnea in preterm infants (Cochrane Review). In: Cochrane Database of Systematic Reviews, Issue 4, 2001.

Henderson-Smart 2004

Henderson-Smart DJ, Steer PAS. Doxapram treatment for apnea in preterm infants. In: Cochrane Database of Systematic Reviews, Issue 4, 2004.

Comparisons and data

Comparison or outcome	Studies	Participants	Statistical method	Effect size
01 Doxapram vs placebo
01 Failed treatment in first 48 hours	1	21	RR (fixed), 95% CI	0.45 [0.20, 1.05]
02 Use of IPPV in first 48 hours	1	21	RR (fixed), 95% CI	0.31 [0.01, 6.74]

01 Doxapram vs placebo

01.01 Failed treatment in first 48 hours

01.02 Use of IPPV in first 48 hours

Contact details for co-reviewers

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.