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Seminars in Fetal & Neonatal Medicine Oct 2023This chapter focuses on the pharmacological management of newborn infants in the peri-extubation period to reduce the risk of re-intubation and prolonged mechanical... (Review)
Review
This chapter focuses on the pharmacological management of newborn infants in the peri-extubation period to reduce the risk of re-intubation and prolonged mechanical ventilation. Drugs used to promote respiratory drive, reduce the risk of apnoea, reduce lung inflammation and avoid bronchospasm are critically assessed. When available, Cochrane reviews and randomised trials are used as the primary sources of evidence. Methylxanthines, particularly caffeine, are well studied and there is accumulating evidence to guide clinicians on the timing and dosage that may be used. Efficacy and safety for doxapram, steroids, adrenaline and salbutamol are summarised. Management of term infants, extubation following surgery, accidental and complicated extubation and the use of cuffed endotracheal tubes are presented. Overall, caffeine is the only drug with a substantial evidence base, proven to increase the likelihood of successful extubation in preterm infants; no drugs are needed to facilitate extubation in most term infants. Future studies might further define the role of caffeine in late preterm infants and evaluate medications for post-extubation stridor, bronchospasm or apnoea not responsive to methylxanthines.
Topics: Infant, Newborn; Humans; Infant, Premature; Caffeine; Apnea; Ventilator Weaning; Bronchial Spasm; Intermittent Positive-Pressure Ventilation; Airway Extubation
PubMed: 38030435
DOI: 10.1016/j.siny.2023.101490 -
Cureus Jan 2022Premature babies often suffer apnea of prematurity as a physiological consequence of an immature respiratory system. Hypercapnia may develop, and neonates with apnea of... (Review)
Review
Premature babies often suffer apnea of prematurity as a physiological consequence of an immature respiratory system. Hypercapnia may develop, and neonates with apnea of prematurity are at an increased risk of morbidity and mortality. The long-term effects of apnea of prematurity or their treatments are less clear. While a number of treatment options exist for apnea of prematurity, there is no clear-cut "first-line" approach or gold standard of care. Effective treatments, such as caffeine citrate, carbon dioxide inhalation, nasal continuous positive airway pressure, nasal intermittent positive pressure ventilation, and others, may be associated with safety concerns. More conservative treatments are available, such as kangaroo care, postural changes, and sensory stimulation, but they may not be effective. While apnea of prematurity resolves spontaneously as the respiratory system matures, it can complicate neonatal care and may have both short-term and long-term consequences. The role, if any, that apnea of prematurity may play in mortality of preterm neonates is not clear.
PubMed: 35251853
DOI: 10.7759/cureus.21783 -
Pediatric Research Apr 2021Doxapram is used for the treatment of apnea of prematurity in dosing regimens only based on bodyweight, as pharmacokinetic data are limited. This study describes the...
BACKGROUND
Doxapram is used for the treatment of apnea of prematurity in dosing regimens only based on bodyweight, as pharmacokinetic data are limited. This study describes the pharmacokinetics of doxapram and keto-doxapram in preterm infants.
METHODS
Data (302 samples) from 75 neonates were included with a median (range) gestational age (GA) 25.9 (23.9-29.4) weeks, bodyweight 0.95 (0.48-1.61) kg, and postnatal age (PNA) 17 (1-52) days at the start of continuous treatment. A population pharmacokinetic model was developed using non-linear mixed-effects modelling (NONMEM®).
RESULTS
A two-compartment model best described the pharmacokinetics of doxapram and keto-doxapram. PNA and GA affected the formation clearance of keto-doxapram (CL) and clearance of doxapram via other routes (CL). For a median individual of 0.95 kg, GA 25.6 weeks, and PNA 29 days, CL was 0.115 L/h (relative standard error (RSE) 12%) and CL was 0.645 L/h (RSE 9%). Oral bioavailability was estimated at 74% (RSE 10%).
CONCLUSIONS
Dosing of doxapram only based on bodyweight results in the highest exposure in preterm infants with the lowest PNA and GA. Therefore, dosing may need to be adjusted for GA and PNA to minimize the risk of accumulation and adverse events. For switching to oral therapy, a 33% dose increase is required to maintain exposure.
IMPACT
Current dosing regimens of doxapram in preterm infants only based on bodyweight result in the highest exposure in infants with the lowest PNA and GA. Dosing of doxapram may need to be adjusted for GA and PNA to minimize the risk of accumulation and adverse events. Describing the pharmacokinetics of doxapram and its active metabolite keto-doxapram following intravenous and gastroenteral administration enables to include drug exposure to the evaluation of treatment of AOP. The oral bioavailability of doxapram in preterm neonates is 74%, requiring a 33% higher dose via oral than intravenous administration to maintain exposure.
Topics: Administration, Oral; Body Weight; Doxapram; Female; Gestational Age; Humans; Infant; Infant, Low Birth Weight; Infant, Newborn; Infant, Newborn, Diseases; Infant, Premature; Infant, Premature, Diseases; Male; Nonlinear Dynamics; Reproducibility of Results; Risk; Sleep Apnea, Central
PubMed: 32698193
DOI: 10.1038/s41390-020-1037-9 -
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 -
Anesthesiology May 2018The ventilatory control system is highly vulnerable to exogenous administered opioid analgesics. Particularly respiratory depression is a potentially lethal complication... (Review)
Review
The ventilatory control system is highly vulnerable to exogenous administered opioid analgesics. Particularly respiratory depression is a potentially lethal complication that may occur when opioids are overdosed or consumed in combination with other depressants such as sleep medication or alcohol. Fatalities occur in acute and chronic pain patients on opioid therapy and individuals that abuse prescription or illicit opioids for their hedonistic pleasure. One important strategy to mitigate opioid-induced respiratory depression is cotreatment with nonopioid respiratory stimulants. Effective stimulants prevent respiratory depression without affecting the analgesic opioid response. Several pharmaceutical classes of nonopioid respiratory stimulants are currently under investigation. The majority acts at sites within the brainstem respiratory network including drugs that act at α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (ampakines), 5-hydroxytryptamine receptor agonists, phospodiesterase-4 inhibitors, D1-dopamine receptor agonists, the endogenous peptide glycyl-glutamine, and thyrotropin-releasing hormone. Others act peripherally at potassium channels expressed on oxygen-sensing cells of the carotid bodies, such as doxapram and GAL021 (Galleon Pharmaceuticals Corp., USA). In this review we critically appraise the efficacy of these agents. We conclude that none of the experimental drugs are adequate for therapeutic use in opioid-induced respiratory depression and all need further study of efficacy and toxicity. All discussed drugs, however, do highlight potential mechanisms of action and possible templates for further study and development.
Topics: Analgesia; Analgesics, Opioid; Animals; Carotid Body; Dipeptides; Humans; Phosphodiesterase 4 Inhibitors; Receptors, Dopamine D1; Respiratory Insufficiency; Respiratory System Agents
PubMed: 29553984
DOI: 10.1097/ALN.0000000000002184 -
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 -
Pharmaceutics Mar 2022Atrial fibrillation (AF) is an arrhythmia associated with an increased stroke risk and mortality rate. Current treatment options leave unmet needs in AF therapy....
Atrial fibrillation (AF) is an arrhythmia associated with an increased stroke risk and mortality rate. Current treatment options leave unmet needs in AF therapy. Recently, doxapram has been introduced as a possible new option for AF treatment in a porcine animal model. To better understand its pharmacokinetics, three German Landrace pigs were treated with intravenous doxapram (1 mg/kg). Plasma and brain tissue samples were collected. For the analysis of these samples, an ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) assay for the simultaneous measurement of doxapram and its active metabolite 2-ketodoxapram was developed and validated. The assay had a lower limit of quantification (LLOQ) of 10 pg/mL for plasma and 1 pg/sample for brain tissue. In pigs, doxapram pharmacokinetics were biphasic with a terminal elimination half-life (t) of 1.38 ± 0.22 h and a maximal plasma concentration (c) of 1780 ± 275 ng/mL. Its active metabolite 2-ketodoxapram had a t of 2.42 ± 0.04 h and c of 32.3 ± 5.5 h after administration of doxapram. Protein binding was 95.5 ± 0.9% for doxapram and 98.4 ± 0.3% for 2-ketodoxapram with a brain-to-plasma ratio of 0.58 ± 0.24 for doxapram and 0.12 ± 0.02 for 2-ketodoxapram. In conclusion, the developed assay was successfully applied to the creation of pharmacokinetic data for doxapram, possibly improving the safety of its usage.
PubMed: 35456597
DOI: 10.3390/pharmaceutics14040762 -
Epilepsy & Behavior : E&B Jun 2017Sudden unexpected death in epilepsy (SUDEP) is a devastating event, and both DBA/1 and DBA/2 mice have been shown to be relevant animal models for studying SUDEP. DBA... (Review)
Review
Sudden unexpected death in epilepsy (SUDEP) is a devastating event, and both DBA/1 and DBA/2 mice have been shown to be relevant animal models for studying SUDEP. DBA mice exhibit seizure-induced respiratory arrest (S-IRA), leading to cardiac arrest and subsequent sudden death after generalized audiogenic seizures (AGSs). This sequence of terminal events is also observed in the majority of witnessed human SUDEP cases. Several pathophysiological mechanisms, including respiratory/cardiac dysfunction, have been proposed to contribute to human SUDEP. Several (but not all) selective serotonin (5-HT) reuptake inhibitors (SSRIs), including fluoxetine, can reversibly block S-IRA, and abnormal expression of 5-HT receptors is found in the brainstem of DBA mice. DBA mice, which do not initially show S-IRA, exhibit S-IRA after treatment with a nonselective 5-HT antagonist. These studies suggest that abnormalities of 5-HT neurotransmission are involved in the pathogenesis of S-IRA in DBA mice. Serotonergic (5-HT) transmission plays an important role in normal respiration, and DBA mice exhibiting S-IRA can be resuscitated using a rodent ventilator. It is important and interesting to know if fluoxetine blocks S-IRA in DBA mice by enhancing respiratory ventilation. To test this, the effects of breathing stimulants, doxapram, and 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (PK-THPP) were compared with the effects of fluoxetine on S-IRA in DBA/1 mice. Although fluoxetine reduces the incidence of S-IRA in DBA/1 mice, as reported previously, the same dose of fluoxetine fails to enhance baseline respiratory ventilation in the absence of AGSs. Doxapram and PK-THPP augment the baseline ventilation in DBA/1 mice. However, these breathing stimulants are ineffective in preventing S-IRA in DBA/1 mice. These data suggest that fluoxetine blocks S-IRA in DBA/1 mice by cellular/molecular mechanisms other than enhancement of basal ventilation. Future research directions are also discussed. This article is part of a Special Issue entitled "Genetic and Reflex Epilepsies, Audiogenic Seizures and Strains: From Experimental Models to the Clinic".
Topics: Animals; Brain Stem; Death, Sudden; Disease Models, Animal; Epilepsy, Reflex; Fluoxetine; Humans; Male; Mice; Mice, Inbred DBA; Receptors, Serotonin; Respiration; Respiration Disorders; Seizures; Serotonergic Neurons; Serotonin; Selective Serotonin Reuptake Inhibitors; Synaptic Transmission
PubMed: 26272185
DOI: 10.1016/j.yebeh.2015.06.008 -
Veterinary Surgery : VS Oct 2021To compare the effects of two doses of doxapram intravenous injection and carbon dioxide inhalation on the cardiovascular and laryngeal functions of anesthetized hounds.
OBJECTIVE
To compare the effects of two doses of doxapram intravenous injection and carbon dioxide inhalation on the cardiovascular and laryngeal functions of anesthetized hounds.
STUDY DESIGN
Experimental study.
ANIMALS
Six healthy adult dogs.
METHODS
In a Latin-square design, the mean arterial blood pressure (MABP) and heart rate (HR) were recorded continuously. The inspiratory normalized glottic gap areas (iNGGA) were measured before and after each stimulation with 0.55 mg/kg of doxapram (L-DOX), 2.2 mg/kg of doxapram (H-DOX), or 90 s of inhalation of 10% carbon dioxide in oxygen (I-CO ). The stimulations were tested in duplicate or triplicate. Video clips of the laryngeal movement were scored by board-certified surgeons masked to the treatment.
RESULTS
The MABP increased with L-DOX and H-DOX up to 81% (both p < .001 compared to I-CO ), and persisted during the other stimulations (both p < .001). An intermittent tachycardic effect of up to 79% increase in HR was observed with doxapram. The HR following H-DOX was higher than L-DOX and I-CO (both p < .016). Neither hypertension nor tachycardia was observed with I-CO . The iNGGA increased with all treatments (p < .001). The iNGGA was greater with H-DOX than L-DOX and I-CO (both p < .007). All treatments received higher scores (all p < .001) with acceptable inter- and intra-observers Krippendorff's alphas.
CONCLUSION
All treatments were effective respiratory stimulants in anesthetized dogs; however, doxapram caused hypertension and tachycardia.
CLINICAL SIGNIFICANCE
Carbon dioxide inhalation might improve arytenoid motion without cardiovascular effects in dogs during clinical airway examinations.
Topics: Animals; Arytenoid Cartilage; Carbon Dioxide; Dogs; Doxapram; Glottis; Larynx
PubMed: 34355421
DOI: 10.1111/vsu.13709 -
Trials Oct 2023Apnoea of prematurity (AOP) is one of the most common diagnoses among preterm infants. AOP often leads to hypoxemia and bradycardia which are associated with an...
BACKGROUND
Apnoea of prematurity (AOP) is one of the most common diagnoses among preterm infants. AOP often leads to hypoxemia and bradycardia which are associated with an increased risk of death or disability. In addition to caffeine therapy and non-invasive respiratory support, doxapram might be used to reduce hypoxemic episodes and the need for invasive mechanical ventilation in preterm infants, thereby possibly improving their long-term outcome. However, high-quality trials on doxapram are lacking. The DOXA-trial therefore aims to investigate the safety and efficacy of doxapram compared to placebo in reducing the composite outcome of death or severe disability at 18 to 24 months corrected age.
METHODS
The DOXA-trial is a double blinded, multicentre, randomized, placebo-controlled trial conducted in the Netherlands, Belgium and Canada. A total of 396 preterm infants with a gestational age below 29 weeks, suffering from AOP unresponsive to non-invasive respiratory support and caffeine will be randomized to receive doxapram therapy or placebo. The primary outcome is death or severe disability, defined as cognitive delay, cerebral palsy, severe hearing loss, or bilateral blindness, at 18-24 months corrected age. Secondary outcomes are short-term neonatal morbidity, including duration of mechanical ventilation, bronchopulmonary dysplasia and necrotising enterocolitis, hospital mortality, adverse effects, pharmacokinetics and cost-effectiveness. Analysis will be on an intention-to-treat principle.
DISCUSSION
Doxapram has the potential to improve neonatal outcomes by improving respiration, but the safety concerns need to be weighed against the potential risks of invasive mechanical ventilation. It is unknown if the use of doxapram improves the long-term outcome. This forms the clinical equipoise of the current trial. This international, multicentre trial will provide the needed high-quality evidence on the efficacy and safety of doxapram in the treatment of AOP in preterm infants.
TRIAL REGISTRATION
ClinicalTrials.gov NCT04430790 and EUDRACT 2019-003666-41. Prospectively registered on respectively June and January 2020.
Topics: Humans; Infant; Infant, Newborn; Bronchopulmonary Dysplasia; Caffeine; Doxapram; Gestational Age; Infant, Premature; Multicenter Studies as Topic; Randomized Controlled Trials as Topic; Double-Blind Method
PubMed: 37817255
DOI: 10.1186/s13063-023-07683-5