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. 2000;2000(3):CD001966.
doi: 10.1002/14651858.CD001966.

Prophylactic doxapram for the prevention of morbidity and mortality in preterm infants undergoing endotracheal extubation

D J Henderson-Smart  1 , P G Davis
Affiliations

Prophylactic doxapram for the prevention of morbidity and mortality in preterm infants undergoing endotracheal extubation

D J Henderson-Smart et al. Cochrane Database Syst Rev. 2000.

Abstract

Background: When preterm infants have been given intermittent positive pressure ventilation (IPPV) for respiratory failure, weaning from support and tracheal extubation may be difficult. A significant contributing factor is thought to be the relatively poor respiratory effort and tendency to develop hypoventilation and apnea, particularly in very preterm infants. Doxapram stimulates breathing and appears to act via stimulation of both the peripheral chemoreceptors and the central nervous system. This effect might increase the chance of successful tracheal extubation.

Objectives: In preterm infants being weaned from IPPV and in whom endotracheal extubation is planned, does treatment with doxapram reduce the use of intubation and IPPV, or reduce other morbidity, without clinically important side effects? In this regard, how does doxapram compare with standard treatment or with an alternative treatment such as methylxanthine or CPAP? Subgroup analyses were prespecified according to birth weight and/or gestational age, use of co-interventions (methylxanthines or nasal CPAP), and route of administration (intravenous or oral).

Search strategy: The standard search strategy of the Neonatal Review Group as outlined in the Cochrane Library was used. This included searches of the Oxford Database of Perinatal Trials, Cochrane Controlled Trials Register, MEDLINE and EMBASE.

Selection criteria: Eligible studies included published trials utilising random or quasi-random patient allocation in which preterm or low birth weight infants being weaned from IPPV were given doxapram compared with standard care or other treatments, to facilitate weaning from IPPV and endotracheal extubation. Trials were independently assessed by the authors before inclusion.

Data collection and analysis: The standard methods of the Cochrane Collaboration and its Neonatal Review Group were used. Each author extracted data separately; the results were compared and any differences resolved. The data were synthesized using the standard method of Neonatal Review Group with use of relative risk and risk difference.

Main results: Two trials involving a total of 85 infants compared doxapram and placebo. In both the individual trials and the meta-analyses there were no significant differences between the doxapram and placebo groups in any of the outcomes (failed extubation, death before discharge, respiratory failure, duration of IPPV, side effects, oxygen at 28 days or oxygen at discharge). There was a trend towards an increase in side effects (hypertension or irritability leading to cessation of treatment) in the doxapram group [summary RR 3.21 (0.53, 19.43). In one of these two trials (Huon 1998) an 'alarming rise in blood pressure' occurred in five infants in the doxapram group and none of the controls, although in only one was treatment withdrawn. One additional trial involving only eight infants compared doxapram with aminophylline, but there were insufficient data for meaningful analysis.

Reviewer's conclusions: The evidence does not support the routine use of doxapram to assist endotracheal extubation in preterm infants who are eligible for methylxanthine and/or CPAP. The results should be interpreted with caution because the small number of infants studied does not allow reliable assessment of the benefits and harms of doxapram. Further trials are required to evaluate the benefits and harms of doxapram compared with no treatment or with other treatments, such as methylxanthines or CPAP, to evaluate whether it is more effective in infants not responding to these other treatments, and to assess whether the drug is effective when given orally.

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Conflict of interest statement

None

Figures

1.1
1.1. Analysis
Comparison 1 Doxapram vs control, Outcome 1 Failed extubation.
1.2
1.2. Analysis
Comparison 1 Doxapram vs control, Outcome 2 Death before discharge.
1.3
1.3. Analysis
Comparison 1 Doxapram vs control, Outcome 3 Days of IPPV.
1.4
1.4. Analysis
Comparison 1 Doxapram vs control, Outcome 4 Side effects causing cessation of therapy.
1.5
1.5. Analysis
Comparison 1 Doxapram vs control, Outcome 5 Oxygen at 28 days.
1.6
1.6. Analysis
Comparison 1 Doxapram vs control, Outcome 6 Oxygen at discharge in survivors.
See this image and copyright information in PMC

References

References to studies included in this review

Barrington 1998 {published data only}
    1. Barrington KJ, Muttitt SC. Randomized, controlled, blinded trial of doxapram for extubation of the very low birthweight infant. Acta Pediatrica 1998;87:191‐4. [MEDLINE: ] - PubMed
Eyal 1985 {published data only}
    1. Eyal FG, Sagi EF, Alpan G, Glaick B Arad I. Aminophylline versus doxapram in weaning premature infants from mechanical ventilation: preliminary report. Critical Care Medicine 1985;13:124‐5. - PubMed
Huon 1998 {published data only}
    1. Huon C, Moriette G, Mussat P, Parat S, Relier JP. Use of preestablished criteria for deciding on extubation in the very low birthweight newborn. Preliminary analysis of a randomized controlled study. Biology of the Neonate 1993;63:75‐9. - PubMed
    1. Huon C, Moriette G, Mussat P, Parat S, Rey E, Relier JP. Treatment of very low birth weight infants with a low dose of doxapram associated with caffeine: effects on weaning from mechanical ventilation. Proceedings of the 14th European Congress of Perinatal Medicine. 1994:81.
    1. Huon C, Rey E, Mussat P, Parat S, Moriette G. Low‐dose doxapram for treatment of apnoea following early weaning in low birthweight infants: a randomized, double‐blind study. Acta Pediatrica 1998;87:1180‐4. - PubMed

References to studies awaiting assessment

Carrizales 1990 {published data only}
    1. Carrizales E, Karna P, Dolanski E. Doxapram vs theophylline in weaning infants from low ventilation. Pediatric Research 1990;27:201A.

Additional references

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Henderson‐Smart 2003
    1. Henderson‐Smart DJ, Davis PG. Prophylactic methylxanthines for extubation in preterm infants. Cochrane Database of Systematic Reviews 2003, Issue 1. [DOI: 10.1002/14651858.CD000139] - DOI - PubMed
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References to other published versions of this review

Henderson‐Smart 2000
    1. Hennderson‐Smart D, Davis PG. Prophylactic doxapram for the prevention of morbidity and mortality in preterm infants undergoing endotracheal extubation. Cochrane Database of Systematic Reviews 2000, Issue 3. [DOI: 10.1002/14651858.CD001966] - DOI - PMC - PubMed
Henderson‐Smart 2006
    1. Henderson‐Smart D, Davis PA. Prophylactic doxapram for the prevention of morbidity and mortality in preterm infants undergoing endotracheal extubation. Cochrane Database of Systematic Reviews 2006, Issue 2. [DOI: 10.1002/14651858.CD001966] - DOI - PMC - PubMed

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