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

Henderson-Smart DJ, Davis PG

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

Cover sheet

Title

Reviewers

Henderson-Smart DJ, Davis PG

Dates

Date edited: 20/02/2006
Date of last substantive update: 23/05/2000
Date of last minor update: 17/01/2006
Date next stage expected 30/11/2007
Protocol first published: Issue 1, 2000
Review first published: Issue 3, 2000

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@perinatal.usyd.edu.au

Contribution of reviewers

Each reviewer independently evaluated the trials for quality and extracted the data. DHS double entered the data and wrote the text of the review.

Internal sources of support

NSW Centre for Perinatal Health Services Research, University of Sydney, AUSTRALIA
Royal Prince Alfred Hospital, Sydney, AUSTRALIA
Royal Women's Hospital, Melbourne, AUSTRALIA

External sources of support

None

What's new

This review updates the existing review 'Prophylactic doxapram for the prevention of morbidity and mortality in preterm infants undergoing endotracheal extubation', published in The Cochrane Library, Disk Issue 3, 2000. The search strategy has been updated to include the CINAHL database.

One abstract was found and has been added to the studies awaiting assessment.

The conclusions of this review are unchanged.

Dates

Date review re-formatted: / /
Date new studies sought but none found: / /
Date new studies found but not yet included/excluded: 10/01/2006
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 has not been shown to improve outcomes for babies being weaned off mechanical breathing support.

When preterm babies have been on mechanical breathing support in neonatal intensive care, it can be hard to wean them off the machine (tracheal extubation). Using drugs called methylxanthines, or breathing support via the nose (nasal CPAP - continuous positive airways pressure) can help. Doxapram stimulates breathing, and is another drug that is sometimes used around extubation. However, the review of trials found no evidence that doxapram can reduce problems for babies around extubation, and it may cause some adverse effects. Further research is needed.

Abstract

Background

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 Central Register of Controlled Trials (CENTRAL, The Cochrane Library), MEDLINE, EMBASE and CINAHL up to December 2005.

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 & 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.

Reviewers' 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.

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 (reviewed by Bancalari 1992; Henderson-Smart 1995).

Weaning from support may be prolonged or, if extubation is achieved, frequent episodes of apnea may occur in association with respiratory failure (hypercarbia, hypoxemia and acidosis) of sufficient severity as to lead to re-intubation and the use of IPPV. As a consequence, the use of IPPV is prolonged with associated costs for higher dependency care and a potential for morbidity from the intervention. Systematic reviews have suggested that methylxanthines (Henderson-Smart 2003) and nasal continuous positive airways pressure (CPAP) (Davis 2003) may assist weaning from IPPV and endotracheal extubation.

Doxapram stimulates breathing and appears to act via stimulation of both the peripheral chemoreceptors and the central nervous system (Blanchard 1992; Barrington 1986). This effect might increase the chance of successful tracheal extubation on its own or in combination with other treatments, such as methylxanthines or CPAP. Short term side effects (reviewed by Blanchard 1992) such as hypertension, excessive central nervous system stimulation, gastrointestinal disturbances with oral use (Tay-Uyboco 1991) and heart block (De Villiers 1998) have been reported.

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 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?

Prespecified subgroup analyses:
1. Birth weight (greater or less than about 1kg) and/or gestational age (greater or less than about 28 weeks) subgroups, as the baseline failure rate is likely to be higher in infants born at lower weights and gestational ages
2. Routine use, or not, of co-interventions (methylxanthines or nasal CPAP) as this would lower the baseline rate of failure
3. Administration route (intravenous or oral) as drug levels achieved and side effects may be different

Criteria for considering studies for this review

Types of studies

All published trials utilising random or quasi-random patient allocation.

Types of participants

Preterm or low birth weight infants being weaned from IPPV and in whom endotracheal extubation is planned.

Types of interventions

Doxapram compared with control (placebo or no treatment), and doxapram compared with an alternative treatment.

Types of outcome measures

Primary
Failed extubation (unable to wean from IPPV and extubate, or re-intubation for IPPV) within about one week

Secondary
1. Death before discharge
2. Duration of IPPV
3. Side effects leading to cessation of therapy (tachycardia, agitation, seizures, hypertension or feed intolerance)
3. Chronic lung disease (oxygen requirement at about 28 days and at about 36 weeks post menstrual age)
4. Reduced somatic growth (weight, length and head circumference) and delayed neurodevelopment (more than 2 SDs below the mean on a standard developmental assessment, or abnormal neurological signs) during infancy and childhood

Search strategy for identification of studies

The standard search strategy of the Neonatal Review Group as outlined in The Cochrane Library was used. This included searches of the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 4, 2005), MEDLINE (1966 - December 2005), CINAHL (1982 - December 2005) and EMBASE (1988 - December 2005). The text term 'doxapram' and MeSH term 'infant, premature' were used in these searches. Also searched were previous reviews including cross references, and abstracts published in the program issues of the Society for Pediatric Research and the European Society for Pediatric Research, 1995 - 2005. Expert informants were also consulted.

The title and abstract of each retrieved report was examined to assess eligibility. If there was uncertainty, the full paper was examined.

Methods of the review

The standard methods of the Cochrane Collaboration and its Neonatal Review Group were used. The methodological quality of each trial was reviewed independently by each review author. Where required, additional information was sought from trial authors to clarify methodology.

Each review 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.

Description of studies

Doxapram vs standard treatment

Two eligible trials were found. Barrington 1998 enrolled 56 preterm infants less than three weeks of age with birth weights less than 1251 gms and gestational age less than 30 (mean 25 - 26) weeks, while Huon 1998 enrolled 29 preterm infants less than six days of age with birth weights less than 1250 gms and gestational age less than 34 (mean 29 - 30) weeks. Treatment groups were well matched at entry in the Barrington 1998 trial. In Huon 1998 the doxapram group had a significantly lower birth weight and more male infants, and showed clinically important trends to higher gestational age and more small for gestational age infants.

Barrington 1998 used a loading dose of 3.5 mg/kg followed by 1 mg/kg/hr, whereas Huon 1998 had no loading dose of doxapram and the initial infusion rate was lower at 0.5 mg/kg/hr, with option of doubling if there was failure to respond . Both trials enrolled infants being weaned from IPPV although the amount of ventilatory support in Barrington 1998 was greater (FiO2 < 0.4, rate < 30, peak inspiratory pressure < 26 cms H2O) than in Huon 1998 (FiO2 < 0.26, rate < 16, peak inspiratory pressure < 10 cms H2O).

Barrington 1998 loaded infants with IV aminophylline during weaning of IPPV; then, one and a half days later on average, each infant was extubated to nasal CPAP for 72 hours. Huon 1998 loaded infants with caffeine eight hours prior to attempted extubation, after which CPAP was allowed if there was deterioration in respiratory function.

Doxapram vs an alternative treatment

One small pilot study of doxapram vs aminophylline in eight infants was found (Eyal 1985).

One study comparing doxapram vs theophylline was found in abstract form (Carrizales 1990) and is awaiting further assessment pending more information from an author.

Methodological quality of included studies

Both trials evaluating doxapram vs control are of high quality in terms of blinding of randomization, intervention and outcome assessment, as well as completeness of follow up. The one small trial comparing doxapram with aminophylline is of insufficient size for meaningful analysis.

Results

Doxapram vs standard care

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, side effects, oxygen at 28 days or oxygen at discharge). The data on 'failed extubation' (unable to extubate or reintubated within about one week) from Barrington 1998 were confounded by the use of open label doxapram in four control infants with severe apnea and so could not be used. There was no difference in the duration of IPPV between the doxapram and placebo groups in either trial or in the meta-analysis.

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 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.

Respiratory failure without the use of reintubation was not a prespecified outcome. Barrington 1998 reported that apnea was a cause of failure in fewer of the doxapram (4/12) compared with the placebo group (12/14). Huon 1998 also noted more apnea in the placebo group but this was only so for moderate apnea (> 10 sec. with bradycardia < 80 bpm for < 30 secs) and not for severe apnea (bradycardia > 30 secs).

There were no trial data as to the effect of doxapram without use of methylxanthine and/or CPAP, so the prespecified subgroup analysis of trials by use, or not, of co-interventions was not possible. Subgroup analyses by birth weight, gestational age or route of administration could not be carried out as the required data were not reported. No study reported later growth or development in the infants.

Doxapram vs aminophylline

In the only trial (Eyal 1985), six infants were randomized to doxapram and four failed extubation, while two received aminophylline and both failed to be extubated.

Discussion

Doxapram vs standard care

Both the trials eligible for this review used doxapram as an addition to standard measures [methylxanthines (Henderson-Smart 2003) and nasal CPAP (Davis 2003)] known to assist endotracheal extubation in preterm infants. In this setting doxapram did not appear to provide additional assistance. Observational studies suggest that doxapram could be useful in preterm infants who cannot be extubated despite standard treatments such as methylxanthines and CPAP (Barrington 1986). This has not been examined in a randomized controlled trial.

The Huon 1998 trial was stopped because the baseline rate of failed extubation in the control group was much lower than the rate prior to commencing the trials. They attribute this to the introduction of a standard protocol for endotracheal extubation.

The trend towards increased side effects including hypertension is consistent with observational studies (Blanchard 1992). The Huon 1998 trial emphasized this and reported higher blood levels despite lower dosage when doxapram was given in the first few days of life.

Doxapram vs aminophylline

There are insufficient data available for any conclusions to be made.

One additional study (Carrizales 1990), reported in abstract form, is awaiting assessment. It compared doxapram and theophylline and it reported that twelve infants were randomized to doxapram and two failed extubation (undefined), while thirteen infants were randomized to theophylline and five failed extubation. This study requires author clarification which has been sought.

Reviewers' conclusions

Implications for practice

The evidence does not support the routine use of doxapram to assist endotracheal extubation in preterm infants who are eligible to receive methylxanthine and/or CPAP. There are no data on the effects of doxapram vs control in the absence of use of methylxanthine 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.

Implications for research

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. Trials could also evaluate whether it is effective in infants not responding to these other treatments. Doxapram would be a more useful drug if it were effective when given orally although no randomised controlled trials have evaluated its use by this route.

Any future trials should include important outcomes including long term growth and development.

Acknowledgements

None

Potential conflict of interest

None

Characteristics of included studies

Study	Methods	Participants	Interventions	Outcomes	Notes	Allocation concealment
Barrington 1998	Blinding of randomization - yes; blinding of intevention - yes; complete followup - yes; blinding of outcome assessment - yes	56 infants (27 treatment and 29 control) weight <1251 gms and gestation <30 weeks at birth; less than 3 weeks old and in FiO2 <0.4 and ventilator rate < 30 and peak insp. pressure < 26 cms H2O. Exclusion criteria not given.	IV doxapram 3.5 mg/kg over 20 mins, then infusion of 1 mg/kg/hr Placebo was saline	Death before discharge; Failed extubation - not extubated or reintubation within 3 days Respiratory failure; apnoea > 3 in 12 hrs or PaCO2 > 60 mm Hg or FiO2 >80 to keep PaO2 >60; side effects; oxygen therapy at discharge	All extubated to nasal prong CPAP (6 cms H2O) for 72 hrs when vent rate 6 for 12 hrs and FiO2 < 0.45; all given aminopylline	A
Eyal 1985	Randomization not mentioned - double blind, numerically coded drugs - by pharmacy; blinding of treatment - yes; completeness of followup - yes; blinding of outcome assessment - yes.	8 preterm infants (6 treatment and 2 control) recovering from RDS, unable to wean vent. rate over 24 hrs. Mean gestational age 30 weeks, birthweight 1215 gms.	Doxapram 2.5 mg/kg/hr vs aminophylline 6 mg/kg load and 1.5 mg/kg/8hr IV. Each given for 48 hrs.	Failed to wean, failed to extubate	Infants who failed were given the alternative treatment after 48 hrs.	B
Huon 1998	Blinding of randomization - yes; blinding of intervention - yes; complete followup - yes; blinding of outcome assessment - yes	29 infants (14 treatment and 15 control) weight < 1250 gms and gestational age < 34 weeks at birth; and < 6 days old; and on IPPV but never needed more than FiO2 0.3; at entry FiO2 < 0.25, IMV <16, PIP <10, normal chest xray. Excluded - cong. abnormality, severe brain lesion (IVH > gd 2, white matter densities), PDA with L to R shunt, uncontolled infection or metabolic disorder	Doxapram IV 0.5 mg/kg/hr, dose could be doubled if no response Placebo was normal saline	Death before discharge; failed extubation (could not be extubated or reintubated within 5 days); side effects; oxygen therapy at 28 days; apnea; IVH or PVL; infection; NEC; ROP;	All infants given caffeine citrate (20 mg/kg load and 5 mg/kg/ day). Nasal CPAP could be used (number not given). Extubation was carried out 8 hrs after starting doxapram / placebo if possible	A

CPAP = continuous positive airways pressure; IPPV = intermittent positive pressure ventilation; IVH = intraventricular hemorrhage; PVL = periventricular leukomalacia; NEC = necrotizing enterocolitis; ROP = retinopathy of prematurity.

References to studies

References to included studies

Barrington 1998 {published data only}

Barrington KJ, Muttitt SC. Randomized, controlled, blinded trial of doxapram for extubation of the very low birthweight infant. Acta Pediatrica 1998;87:191-4.

Eyal 1985 {published data only}

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.

Huon 1998 {published data only}

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.

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. In: Proceedings of the 14th European Congress of Perinatal Medicine. 1994:81.

* 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.

References to studies awaiting assessment

Carrizales 1990 {published data only}

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

* indicates the primary reference for the study

Other references

Additional references

Bancalari 1992

Bancalari E, Sinclair JC. Mechanical ventilation. In: Sinclair JC, Bracken MB, editor(s). Effective care of the newborn infant. Oxford: Oxford University Press, 1992:200-20.

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, 1992:161-77.

Davis 2003

Davis PG, Henderson-Smart DJ. Nasal continuous positive airways pressure immediately after extubation for preventing morbidity in preterm infants. In: The Cochrane Database of Systematic Reviews, Issue 2, 2003.

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.

Henderson-Smart 1995

Henderson-Smart DJ. Recurrent apnoea. In: Ed Yu VYH, editor(s). Bailliere's Clinical Paediatrics. Vol. 3, No. 1. Pulmonary problems in the perinatal period and their sequelae. London: Bailliere Tindall, 1995:203-22.

Henderson-Smart 2003

Henderson-Smart DJ, Davis PG. Prophylactic methylxanthines for extubation in preterm infants. In: The Cochrane Database of Systematic Reviews, Issue 1, 2003.

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 2000

Hennderson-Smart D, Davis PG. Prophylactic doxapram for the prevention of morbidity and mortality in preterm infants undergoing endotracheal extubation. In: The Cochrane Database of Systematic Reviews, Issue 3, 2000.

Comparisons and data

01 Doxapram vs control
01.01 Failed extubation
01.02 Death before discharge
01.03 Days of IPPV
01.04 Side effects causing cessation of therapy
01.05 Oxygen at 28 days
01.06 Oxygen at discharge in survivors

Comparison or outcome	Studies	Participants	Statistical method	Effect size
01 Doxapram vs control
01 Failed extubation	1	29	RR (fixed), 95% CI	0.80 [0.22, 2.97]
02 Death before discharge	2	85	RR (fixed), 95% CI	1.43 [0.34, 6.01]
03 Days of IPPV	2	85	WMD (fixed), 95% CI	-0.36 [-2.85, 2.13]
04 Side effects causing cessation of therapy	2	85	RR (fixed), 95% CI	3.21 [0.53, 19.43]
05 Oxygen at 28 days	1	29	RR (fixed), 95% CI	3.20 [0.14, 72.62]
06 Oxygen at discharge in survivors	1	51	RR (fixed), 95% CI	0.88 [0.39, 1.99]

Notes

Published notes

Contact details for co-reviewers

Dr Peter G Davis
Department of Obstetrics and Gynaecology
Royal Women's Hospital
132 Grattan Street
Carlton
Victoria AUSTRALIA
3053
Telephone 1: +61 3 93442151
Facsimile: +61 3 93471761
E-mail: pgd@unimelb.edu.au

The review is published as a Cochrane review in The Cochrane Library, Issue 2, 2006 (see http://www.thecochranelibrary.com for information). Cochrane reviews are regularly updated as new evidence emerges and in response to comments and criticisms, and The Cochrane Library should be consulted for the most recent version of the Review.