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The Cochrane Database of Systematic... Oct 2023Apnea of prematurity is a common problem in preterm infants that may have significant consequences on their development. Methylxanthines (aminophylline, theophylline,... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Apnea of prematurity is a common problem in preterm infants that may have significant consequences on their development. Methylxanthines (aminophylline, theophylline, and caffeine) are effective in the treatment of apnea of prematurity. Doxapram is used as a respiratory stimulant in cases refractory to the methylxanthine treatment.
OBJECTIVES
To evaluate the benefits and harms of doxapram administration on the incidence of apnea and other short-term and longer-term clinical outcomes in preterm infants.
SEARCH METHODS
We used standard, extensive Cochrane search methods. The latest search date was March 2023.
SELECTION CRITERIA
We included randomized controlled trials (RCTs) assessing the role of doxapram in prevention and treatment of apnea of prematurity and prevention of reintubation in preterm infants (less than 37 weeks' gestation). We included studies comparing doxapram with either placebo or methylxanthines as a control group, or when doxapram was used as an adjunct to methylxanthines and compared to methylxanthines alone as a control group. We included studies of doxapram at any dose and route.
DATA COLLECTION AND ANALYSIS
We used standard Cochrane methods. Our primary outcomes were clinical apnea, need for positive pressure ventilation after initiation of treatment, failed apnea reduction after two to seven days, and failed extubation (defined as unable to wean from invasive intermittent positive pressure ventilation [IPPV] and extubate or reintubation for IPPV within one week). We used GRADE to assess the certainty of evidence for each outcome.
MAIN RESULTS
We included eight RCTs enrolling 248 infants. Seven studies (214 participants) provided data for meta-analysis. Five studied doxapram for treatment of apnea in preterm infants. Three studied doxapram to prevent reintubation in preterm infants. None studied doxapram in preventing apnea in preterm infants. All studies administered doxapram intravenously as continuous infusions. Two studies used doxapram as an adjunct to aminophylline compared to aminophylline alone and one study as an adjunct to caffeine compared to caffeine alone. When used to treat apnea, compared to no treatment, doxapram may result in a slight reduction in failed apnea reduction (risk ratio [RR] 0.45, 95% confidence interval [CI] 0.20 to 1.05; 1 study, 21 participants; low-certainty evidence). The evidence is very uncertain about the effect of doxapram on need for positive pressure ventilation after initiation of treatment (RR 0.31, 95% CI 0.01 to 6.74; 1 study, 21 participants; very low-certainty evidence). Doxapram may result in little to no difference in side effects causing cessation of therapy (0 events in both groups; risk difference [RD] 0.00, 95% CI -0.17 to 0.17; 1 study, 21 participants; low-certainty evidence). Compared to alternative treatment, the evidence is very uncertain about the effect of doxapram on failed apnea reduction (RR 1.35, 95% CI 0.53 to 3.45; 4 studies, 84 participants; very low-certainty evidence). The evidence is very uncertain about the effect of doxapram on need for positive pressure ventilation after initiation of treatment (RR 2.40, 95% CI 0.11 to 51.32; 2 studies, 37 participants; very-low certainty evidence; note 1 study recorded 0 events in both groups. Thus, the RR and CIs were calculated from 1 study rather than 2). Doxapram may result in little to no difference in side effects causing cessation of therapy (0 events in all groups; RD 0.00, 95% CI -0.15 to 0.15; 37 participants; 2 studies; low-certainty evidence). As adjunct therapy to methylxanthine, the evidence is very uncertain about the effect of doxapram on failed apnea reduction after two to seven days (RR 0.08, 95% CI 0.01 to 1.17; 1 study, 10 participants; very low-certainty evidence). No studies reported on clinical apnea, chronic lung disease at 36 weeks' postmenstrual age (PMA), death at any time during initial hospitalization, long-term neurodevelopmental outcomes in the three comparisons, and need for positive pressure ventilation and side effects when used as adjunct therapy to methylxanthine. In studies to prevent reintubation, when compared to alternative treatment, the evidence is very uncertain about the effect of doxapram on failed extubation (RR 0.43, 95% CI 0.10 to 1.83; 1 study, 25 participants; very low-certainty evidence). As adjunct therapy to methylxanthine, doxapram may result in a slight reduction in 'clinical apnea' after initiation of treatment (RR 0.36, 95% CI 0.13 to 0.98; 1 study, 56 participants; low-certainty evidence). Doxapram may result in little to no difference in failed extubation (RR 0.92, 95% CI 0.52 to 1.62; 1 study, 56 participants; low-certainty evidence). The evidence is very uncertain about the effect of doxapram on side effects causing cessation of therapy (RR 6.42, 95% CI 0.80 to 51.26; 2 studies, 85 participants; very low-certainty evidence). No studies reported need for positive pressure ventilation, chronic lung disease at 36 weeks' PMA, long-term neurodevelopmental outcomes in the three comparisons; failed extubation when compared to no treatment; and clinical apnea, death at any time during initial hospitalization, and side effects when compared to no treatment or alternative treatment. We identified two ongoing studies, one conducted in Germany and one in multiple centers in the Netherlands and Belgium.
AUTHORS' CONCLUSIONS
In treating apnea of prematurity, doxapram may slightly reduce failure in apnea reduction when compared to no treatment and there may be little to no difference in side effects against both no treatment and alternative treatment. The evidence is very uncertain about the need for positive pressure ventilation when compared to no treatment or alternative treatment and about failed apnea reduction when used as alternative or adjunct therapy to methylxanthine. For use to prevent reintubation, doxapram may reduce apnea episodes when administered in adjunct to methylxanthine, but with little to no difference in failed extubation. The evidence is very uncertain about doxapram's effect on death when used as adjunct therapy to methylxanthine and about failed extubation when used as alternative or adjunct therapy to methylxanthine. There is a knowledge gap about the use of doxapram as a therapy to prevent apnea. More studies are needed to clarify the role of doxapram in the treatment of apnea of prematurity, addressing concerns about long-term outcomes. The ongoing studies may provide useful data.
Topics: Infant, Newborn; Humans; Doxapram; Apnea; Caffeine; Aminophylline; Infant, Premature; Lung Diseases
PubMed: 37877431
DOI: 10.1002/14651858.CD014145.pub2 -
Neonatology 2017Apnea of prematurity (AOP) is a common complication of preterm birth, for which caffeine is the first treatment of choice. In case of persistent AOP, doxapram has been... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Apnea of prematurity (AOP) is a common complication of preterm birth, for which caffeine is the first treatment of choice. In case of persistent AOP, doxapram has been advocated as an additional therapy.
OBJECTIVE
To identify and appraise all existing evidence regarding efficacy and safety of doxapram use for AOP in infants born before 34 weeks of gestational age.
METHODS
All studies reporting on doxapram use for AOP were identified by searching electronic databases, references from relevant studies, and abstracts from the Societies for Pediatric Research. Two reviewers independently assessed study eligibility and quality, and extracted data on study design, patient characteristics, efficacy and safety outcomes.
RESULTS
The randomized controlled trials showed less apnea during doxapram treatment when compared to placebo, but no difference in treatment effect when compared to theophylline. No serious adverse effects were reported. We identified 28 observational studies consisting mainly of cohort studies and case series (n = 1,994). There was considerable heterogeneity in study design and quality. Most studies reported a positive effect of doxapram on apnea rate. A few studies reported on long-term outcomes with conflicting results. A range of possible doxapram-related short-term adverse effects were reported, sometimes associated with the use of higher doses.
CONCLUSION
Based on the limited number of studies and level of evidence, no firm conclusions on the efficacy and safety of doxapram in preterm infants can be drawn. For this reason, routine use cannot be recommended. A large multicenter randomized controlled trial is urgently needed to provide more conclusive evidence.
Topics: Apnea; Caffeine; Doxapram; Gestational Age; Humans; Infant; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Randomized Controlled Trials as Topic; Respiratory System Agents; Theophylline
PubMed: 27760427
DOI: 10.1159/000448941 -
Lancet (London, England) May 1973
Topics: Doxapram; Humans; Morphine; Respiration
PubMed: 4122029
DOI: 10.1016/s0140-6736(73)90421-2 -
The Cochrane Database of Systematic... 2000Recurrent apnea is common in preterm infants, particularly at very early gestational ages. These episodes of loss of effective breathing can lead to hypoxemia and... (Review)
Review
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 so prevent apnea and its consequences.
OBJECTIVES
In preterm infants with recurrent apnea, does treatment with doxapram lead to a clinically important reduction in apnea and use of Intermittent positive airways pressure (IPPV), without clinically important side effects?
SEARCH STRATEGY
Searches were made of the Oxford Database of Perinatal trials, the Cochrane Collaboration Clinical Trials Register, MEDLINE (using text words 'doxapram', 'apnea or apnoea' and Mesh term 'infant, premature') previous reviews including cross references, abstracts, conferences and symposia proceedings, expert informants, mainly in the English language. Also an expert informant's search in the Japanese language was made by Prof. Y. Ogawa in 1996.
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 AND 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 [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 late responses of all those in the placebo group since they crossed over to a treatment arm.
REVIEWER'S 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 longterm outcomes have been measured. Further studies are needed to determine the role of this treatment in clinical practice.
Topics: Apnea; Doxapram; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Respiratory System Agents
PubMed: 10796114
DOI: 10.1002/14651858.CD000074 -
The Cochrane Database of Systematic... 2001Recurrent apnea is common in preterm infants, particularly at very early gestational ages. These episodes of loss of effective breathing can lead to hypoxemia and... (Review)
Review
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 so prevent apnea and its consequences.
OBJECTIVES
In preterm infants with recurrent apnea, does treatment with doxapram lead to a clinically important reduction in apnea and use of intermittent positive airways pressure (IPPV), without clinically important side effects?
SEARCH STRATEGY
Searches were made of the Oxford Database of Perinatal trials, the Cochrane Collaboration Clinical Trials Register, MEDLINE 1966 - July 2001, Embase 1980 - July 2001, CINAHL 1982 - July 2001 (using text words 'doxapram', 'apnea or apnoea' and MeSH term 'infant, premature'), previous reviews including cross references, abstracts, conferences and symposia proceedings, expert informants, mainly in the English language. Abstracts of the Society for Pediatric Research were searched from 1996 - 2001 inclusive. Also an expert informant's search in the Japanese language was made by Prof. Y. Ogawa in 1996.
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 AND 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 [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 late responses of all those in the placebo group since they crossed over to a treatment arm.
REVIEWER'S 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 longterm outcomes have been measured. Further studies are needed to determine the role of this treatment in clinical practice.
Topics: Apnea; Doxapram; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Respiratory System Agents
PubMed: 11687067
DOI: 10.1002/14651858.CD000074 -
The Cochrane Database of Systematic... Oct 2004Recurrent apnea is common in preterm infants, particularly at very early gestational ages. These episodes of loss of effective breathing can lead to hypoxemia and... (Review)
Review
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 so prevent apnea and its consequences.
OBJECTIVES
In preterm infants with recurrent apnea, does treatment with Doxapram lead to a clinically important reduction in apnea and use of intermittent positive airways pressure (IPPV), without clinically important side effects?
SEARCH STRATEGY
Searches were made of the Oxford Database of Perinatal trials, the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 3, 2004), MEDLINE from 1966 - June 2004, EMBASE from 1980 - June 2001, CINAHL from 1982- June 2004. 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. Abstracts of the Society for Pediatric Research were searched from 1996 - 2004 inclusive.
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 AND 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 [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 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.
Topics: Aminophylline; Apnea; Doxapram; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Respiratory System Agents
PubMed: 15494987
DOI: 10.1002/14651858.CD000074.pub2 -
Cardiovascular Research Jun 2022
Topics: Atrial Fibrillation; Doxapram; Humans; Potassium Channels
PubMed: 35425974
DOI: 10.1093/cvr/cvac044 -
The Cochrane Database of Systematic... 2003COPD is a progressive illness and in the later stages, exacerbations may lead to ventilatory failure. The combination of hypoxia and hypercapnia can lead to coma and... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
COPD is a progressive illness and in the later stages, exacerbations may lead to ventilatory failure. The combination of hypoxia and hypercapnia can lead to coma and death. Correction of these blood gas abnormalities is a medical emergency. Doxapram is a respiratory stimulant used to stimulate respiration in this setting.
OBJECTIVES
The objective of this review was to assess the effects of doxapram on gas exchange and clinical outcomes in people with ventilatory failure due to acute exacerbations of chronic obstructive pulmonary disease.
SEARCH STRATEGY
We searched the Cochrane Airways Group trials register and reference lists of articles. We also contacted experts in the field, study authors and drug companies. Following electronic searches conducted in November 2001 one further unpublished study has been included in the review.
SELECTION CRITERIA
Randomised trials comparing doxapram with other treatments or placebo in people with ventilatory failure due to exacerbations of chronic obstructive pulmonary disease.
DATA COLLECTION AND ANALYSIS
One reviewer assessed trial quality and extracted data.
MAIN RESULTS
Four trials involving 176 people were included. The trials were of variable quality. Doxapram was marginally superior to placebo in preventing blood gas deterioration. In the two studies comparing doxapram and non-invasive ventilation the results were conflicting: an early small study suggested non-invasive ventilation was superior. However, a subsequent larger study in severe participants suggested doxapram was equally effective in terms of blood gases changes, with no differences observed in mortality and frequent treatment failure.
REVIEWER'S CONCLUSIONS
Doxapram can improve blood gas exchange over the first few hours of treatment. Newer techniques such as non-invasive ventilation may prove to be more effective, although there is no randomised trial evidence to this effect.
Topics: Acute Disease; Doxapram; Humans; Lung Diseases, Obstructive; Randomized Controlled Trials as Topic; Respiratory Insufficiency; Respiratory System Agents
PubMed: 12535393
DOI: 10.1002/14651858.CD000223 -
The Cochrane Database of Systematic... 2000COPD is a progressive illness and in the later stages, exacerbations may lead to ventilatory failure. The combination of hypoxia and hypercapnia can lead to coma and... (Review)
Review
BACKGROUND
COPD is a progressive illness and in the later stages, exacerbations may lead to ventilatory failure. The combination of hypoxia and hypercapnia can lead to coma and death. Correction of these blood gas abnormalities is a medical emergency. Doxapram is a respiratory stimulant used to stimulate breathing in this setting.
OBJECTIVES
The objective of this review was to assess the effects of doxapram on gas exchange and clinical outcomes in people with ventilatory failure due to acute exacerbations of chronic obstructive pulmonary disease.
SEARCH STRATEGY
We searched the Cochrane Airways Group trials register and reference lists of articles. We also contacted experts in the field, study authors and drug companies.
SELECTION CRITERIA
Randomised trials comparing doxapram with other treatments or placebo in people with ventilatory failure due to exacerbations of chronic obstructive pulmonary disease.
DATA COLLECTION AND ANALYSIS
One reviewer assessed trial quality and extracted data.
MAIN RESULTS
Three trials involving 127 people were included. The trials were of variable quality. Doxapram was marginally superior to placebo in preventing blood gas deterioration (odds ratio 0.38, 95% confidence interval 0.14 to 1.02). In one small study, of 17 patients, doxapram and non-invasive ventilation appeared equally effective in terms of blood gases changes, although there were slightly more deaths with doxapram (odds ratio 11.34, 95% confidence interval 1.00 to 128.03).
REVIEWER'S CONCLUSIONS
Doxapram may improve blood gas exchange in the short term, but newer techniques such as non-invasive ventilation may be more effective.
Topics: Acute Disease; Doxapram; Humans; Lung Diseases, Obstructive; Respiratory Insufficiency; Respiratory System Agents
PubMed: 10796514
DOI: 10.1002/14651858.CD000223 -
Neonatology 2019Doxapram is a treatment option for severe apnea of prematurity (AOP). However, the effect of doxapram on the diaphragm, the main respiratory muscle, is not known. (Observational Study)
Observational Study
BACKGROUND
Doxapram is a treatment option for severe apnea of prematurity (AOP). However, the effect of doxapram on the diaphragm, the main respiratory muscle, is not known.
OBJECTIVES
To investigate the effect of doxapram on diaphragmatic activity measured with transcutaneous electromyography of the diaphragm (dEMG).
METHODS
A pilot study was conducted in a tertiary neonatal intensive care unit. Diaphragmatic activity was measured from 30 min before up to 3 h after the start of doxapram treatment. dEMG parameters were compared to baseline (5 min before doxapram treatment) and at 15, 60, 120 and 180 min after the start of doxapram infusion.
RESULTS
Eleven preterm infants were included with a mean gestational age of 25.5 ± 1.2 weeks and birth weight of 831 ± 129 g. The amplitudedEMG, peakdEMG and tonicdEMG values did not change in the 3 h after the start of doxapram infusion compared to baseline. Clinically, the number of apnea episodes in the 24 h after doxapram treatment decreased significantly.
CONCLUSION
Doxapram infusion does not alter diaphragmatic activity measured with transcutaneous dEMG in preterm infants with AOP, indicating that its working mechanism is primarily on respiratory drive and not on respiratory muscle activity.
Topics: Apnea; Birth Weight; Diaphragm; Doxapram; Electromyography; Female; Gestational Age; Humans; Infant, Extremely Low Birth Weight; Infant, Extremely Premature; Infant, Newborn; Infant, Premature, Diseases; Intensive Care Units, Neonatal; Male; Netherlands; Pilot Projects; Prospective Studies; Respiratory System Agents
PubMed: 30352445
DOI: 10.1159/000493359