Prophylactic doxapram for the prevention of morbidity and mortality in preterm infants undergoing endotracheal extubation
Henderson-Smart DJ, Davis PG
Cover sheet
Title
Prophylactic doxapram for the prevention of morbidity and mortality in preterm infants undergoing endotracheal extubationReviewers
Henderson-Smart DJ, Davis PGDates
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.auContribution 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
NoneWhat'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
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 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 differentCriteria 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 childhoodSearch 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
NonePotential conflict of interest
NoneCharacteristics 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 1992Bancalari
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 2000Hennderson-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.
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