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Toby J Lasserson - One of the best experts on this subject based on the ideXlab platform.
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Doxapram for ventilatory failure due to exacerbations of chronic obstructive pulmonary disease
Cochrane Database of Systematic Reviews, 2002Co-Authors: M Greenstone, Toby J LassersonAbstract: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 methods 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. An updated electronic search conducted in October 2003 did not yield any further studies. 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 Two reviewers 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. Authors' 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.
Robert B Flint - One of the best experts on this subject based on the ideXlab platform.
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p31 no interaction between Doxapram and caffeine for the treatment of preterm neonates with apnea
Archives of Disease in Childhood, 2019Co-Authors: A Engbers, Robert B Flint, Swantje Voller, C A J Knibbe, Ikm Reiss, B C P Koch, Shp SimonsAbstract:Background In preterm neonates with apneas, co-administration with Doxapram is often initiated in case of inadequate response to caffeine alone. While Doxapram is exclusively registered for adults, there is limited information on its use in preterm infants. To examine whether the observed effects of Doxapram are actually due to Doxapram itself, and not a pharmacokinetic interaction between both respiratory stimulants, we studied the pharmacokinetics (PK) of caffeine in a population of preterm neonates receiving both caffeine and Doxapram. Methods Caffeine concentrations from patients in the DINO study (NCT02421068) who received both caffeine and Doxapram were analyzed using NONMEM V7.3. A PK model of caffeine in preterm neonates was used as a basis to estimate the PK parameters of caffeine when co-administered with Doxapram with F fixed to 1 and ka fixed to 1.48 h-1.1 The results of the current study were compared to those of the reference population published by Charles et al.1 Results In 15 preterm infants 58 samples were collected in which caffeine plasma levels were determined. Median gestational age (GA) was 26.3 (range 24–28) weeks, postnatal age (PNA) was 25 (0–63) days and current weight was 1100 (600–2140) grams. Caffeine CL and Vd for an individual with a PNA of 12 days were estimated 0.2 L/h/70kg (RSE 28%) and 68.2 L/70kg (RSE 73%), respectively. Maturation of CL was best described by a power function with an exponent of 0.404 (RSE 89%). These results seem in good agreement with the reference population of preterm neonates receiving caffeine without Doxapram with values of 0.167 L/kg/70 kg, 58.6 L/70kg and 0.358.1 Conclusion In this pharmacokinetic study in preterm neonates receiving both caffeine and Doxapram, we found similar values for CL, Vd and maturation of CL with PNA compared to literature values obtained in preterm neonates receiving caffeine alone. References BG C. et al. Caffeine citrate treatment for extremely premature infants with apnea: population pharmacokinetics, absolute bioavailability, and implications for therapeutic drug monitoring. Ther. Drug Monit 2008;30:709–716. Disclosure(s) Nothing to disclose
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o17 the bioavailability and maturing clearance of Doxapram in preterm infants
Archives of Disease in Childhood, 2019Co-Authors: Shp Simons, Robert B Flint, Ikm Reiss, P Andriessen, K D Liem, Plj Degraeuwe, R Ter Heine, Agj Engbers, B C P KochAbstract:Background Doxapram is used for intravenous and oral treatment of apnea of prematurity in preterm infants. Dosing is currently based on bodyweight, however pharmacokinetic and bioavailability data are limited. To develop individualized dosing strategies, we characterized pharmacokinetics of Doxapram in this vulnerable patient population. Methods Data (302 samples) from 75 neonates were included with median (range) gestational age (GA) 25.9 (23.9–29.4) weeks, bodyweight 0.95 (0.48–1.61) kg, postnatal age (PNA) 17 (1–52) days at start of continuous treatment, and treatment duration of 16.8 (1.4–26.9) days. A population pharmacokinetic model was developed for Doxapram and keto-Doxapram. Results A two-compartment model best described the pharmacokinetics of Doxapram and its metabolite. PNA and GA affected the formation clearance of keto-Doxapram (CLD-KD) and clearance of Doxapram via other routes (CLD). For an individual of 0.95 kg, GA of 25.9 weeks and PNA of 17 days, CLD-KD was 0.096 L/h (residual standard error (RSE) 22%) and CLD0.493 L/h (RSE 13%). Compared to PNA 30 days, estimated CLD-KD was 13% at PNA day 1 and 69% at day 15, and estimated CLD was 12% and 68%, respectively. Compared to GA 28 weeks, estimated CLD-KD was 65% at GA 24 weeks and 80% at 26 weeks, and estimated CLD was 67% and 81%, respectively. Oral bioavailability was estimated 74% (RSE 13%). Conclusions With bodyweight-based dosing alone, preterm infants with the lowest PNA and GA had relatively low Doxapram CL and the highest exposure. Therefore, the dose may be reduced by 50% up to PNA day 9, and by 25% for day 10–15. In addition, for GA dose may be reduced by 40% and 20% in newborns with GA of 24–25 weeks and 26–27 weeks, respectively, compared to 28–29 weeks. For switch to oral therapy a 33% dose increase is required to maintain plasma concentrations. Disclosure(s) Nothing to disclose
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big data analyses for continuous evaluation of pharmacotherapy a proof of principle with Doxapram in preterm infants
Current Pharmaceutical Design, 2018Co-Authors: Robert B Flint, Willem Van Weteringen, Swantje Voller, Jarinda A Poppe, Birgit C P Koch, Ronald De Groot, Dick Tibboel, Catherijne A J Knibbe, Irwin Reiss, Sinno H P SimonsAbstract:Background: Drug effect evaluation is often based on subjective interpretation of a selection of patient data. Continuous analyses of high frequency patient monitor data are a valuable source to measuring drug effects. However, these have not yet been fully explored in clinical care. We aim to evaluate the usefulness and applicability of high frequency physiological data for analyses of pharmacotherapy. Methods: As a proof of principle, the effects of Doxapram, a respiratory stimulant, on the oxygenation in preterm infants were studied. Second-to-second physiological data were collected from 12 hours before until 36 hours after start of Doxapram loading dose plus continuous maintenance dose in seven preterm infants. Besides physiological data, plasma concentrations of Doxapram and keto-Doxapram were measured. Results: Arterial oxygen saturation (SpO2) increased after the start of Doxapram treatment alongside an increase in heart rate. The respiratory rate remained unaffected. The number of saturation dips and the time below a saturation of 80%, as well as the area under the 80%-saturation-time curve (AUC), were significantly lowered after the start of Doxapram. The AUC under 90% saturation also significantly improved after start of Doxapram. Plasma concentrations of Doxapram and keto-Doxapram were measured. Conclusion: Using high-frequency monitoring data, we showed the detailed effects over time of pharmacotherapy. We could objectively determine the respiratory condition and the effects of Doxapram treatment in preterm infants. This type of analysis might help to develop individualized drug treatments with tailored dose adjustments based on a closed-loop algorithm.
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retrospective study shows that Doxapram therapy avoided the need for endotracheal intubation in most premature neonates
Acta Paediatrica, 2017Co-Authors: Robert B Flint, Nienke M Halbmeijer, Naomi J Meesters, Joost Van Rosmalen, Irwin K M Reiss, Monique Van Dijk, Sinno H P SimonsAbstract:Aim Using Doxapram to treat neonates with apnoea of prematurity might avoid the need for endotracheal intubation and invasive ventilation. We studied whether Doxapram prevented the need for intubation and identified the predictors of the success. Methods This was a retrospective study of preterm infants born from January 2006 to August 2014 who received oral or intravenous Doxapram. Success was defined as no need for endotracheal intubation, due to apnoea, during Doxapram therapy. Univariable and multivariable logistic regression analyses identified predictors of success during the first 48 hours of Doxapram therapy. Results Data on 203 patients with a median gestational age of 26.1 (interquartile range 25.1–27.4) weeks were analysed. During the first 48 hours of Doxapram therapy, 157 (77%) patients did not need endotracheal intubation and 127 (63%) patients were successfully treated over the entire treatment course. The median postnatal age at the start of Doxapram therapy was 20 days (interquartile range 12–30). Postnatal age and a lower fraction of inspired oxygen at the start of Doxapram therapy were significant predictors of success (odds ratio 0.964, 95% confidence interval 0.938–0.991, p = 0.001). Conclusion Oral and intravenous Doxapram effectively treated most cases of apnoea in preterm infants, avoiding the need for intubation.
M Greenstone - One of the best experts on this subject based on the ideXlab platform.
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Doxapram for ventilatory failure due to exacerbations of chronic obstructive pulmonary disease.
The Cochrane database of systematic reviews, 2020Co-Authors: M GreenstoneAbstract: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. 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. 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. Randomised trials comparing Doxapram with other treatments or placebo in people with ventilatory failure due to exacerbations of chronic obstructive pulmonary disease. One reviewer assessed trial quality and extracted data. 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). Doxapram may improve blood gas exchange in the short term, but newer techniques such as non-invasive ventilation may be more effective.
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Doxapram for ventilatory failure due to exacerbations of chronic obstructive pulmonary disease
Cochrane Database of Systematic Reviews, 2002Co-Authors: M Greenstone, Toby J LassersonAbstract: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 methods 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. An updated electronic search conducted in October 2003 did not yield any further studies. 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 Two reviewers 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. Authors' 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.
Chris Peers - One of the best experts on this subject based on the ideXlab platform.
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Doxapram stimulates dopamine release from the intact rat carotid body in vitro
Neuroscience Letters, 1995Co-Authors: R Andersonbeck, L Wilson, S Brazier, I E Hughes, Chris PeersAbstract:Abstract Hypoxic chemotransduction by the carotid body is believed to involve inhibition of K+ channels in type I cells, leading to depolarization and the opening of Ca2+ channels which triggers catecholamine release. We have investigated whether the clinically used ventilatory stimulant Doxapram (which, like hypoxia, blocks K+ channels in isolated type I cells) also stimulates catecholamine release from the intact carotid body in vitro, by pre-incubating tissues with [3H]tyrosine. 3H overflow was evoked by raised extracellular [K+] (60 mM) and by cyanide (2 mM). Doxapram (15–150 μM) also evoked 3H overflow in a concentration dependent manner, and Doxapram-evoked release was inhibited by the Cat+ channel blocker nifedipine (5 μM). Analysis of released tritiated compounds suggested that Doxapram preferentially stimulated the release of dopamine. Our results indicate that the mechanism of action of Doxapram shares similarities with that of hypoxia in the carotid body.
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effects of Doxapram on ionic currents recorded in isolated type i cells of the neonatal rat carotid body
Brain Research, 1991Co-Authors: Chris PeersAbstract:Abstract Whole-cell patch-clamp recordings were used to investigate the effects of the respiratory stimulant Doxapram on K+ and Ca2+ currents in isolated type I cells of the neonatal rat carotid body. Doxapram (1–100 μM) caused rapid, reversible and dose-dependent inhibitions of K+ currents recorded in type I cells (IC50 approximately 13 μM). Inhibition was voltage-dependent, in that the effects of Doxapram were maximal at test potentials where a shoulder in the current-voltage relationship was maximal. These K+ currents were composed of both Ca2+-activated and Ca2+-independent components. Using high [Mg2+], low [Ca2+] solutions to inhibit Ca2+-activated K+ currents, Doxapram was also seen to directly inhibit Ca2+-independent K+ currents. This effect was voltage-independent and was less potent (IC50 approximately 20 μM) than under control conditions. suggesting that Doxapram was a more potent inhibitor of the Ca2+-activated K+ currents recorded under control conditions. Doxapram (10 μM) was without effect on L-type Ca2+ channel currents recorded under conditions where K+ channel activity was minimized and was also without significant effect on K+ currents recorded in the neuronal cell line NG-108 15, suggesting a selective effect on carotid body type I cells. The effects of Doxapram on type I cells show similarities to those of the physiological stimuli of the carotid body, suggesting that Doxapram may share a similar mechanism of action in stimulating the intact organ.
M J Fettman - One of the best experts on this subject based on the ideXlab platform.
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the effects of Doxapram hydrochloride dopram v on laryngeal function in healthy dogs
Journal of Veterinary Internal Medicine, 2002Co-Authors: Carrie Jean Miller, Brendan C Mckiernan, Jennifer Pace, M J FettmanAbstract:Laryngeal dysfunction is assessed most accurately by direct visualization of the larynx under a light plane of anesthesia. If the plane of anesthesia used is too deep, laryngeal structures may appear paralyzed and remain in a paramedian position. Doxapram hydrochloride is a known respiratory stimulant. We hypothesized that Doxapram would significantly increase intrinsic laryngeal motion in healthy anesthetized dogs. The goal of this study was to evaluate the effect of Doxapram on the area of rima glottidis (RG) in healthy dogs. Thirty healthy dogs were studied. Dogs were premedicated with butorphanol tartrate (0.22 mg/kg IV), acepromazine maleate (0.05 mg/kg SC), and glycopyrrolate (0.005 mg/kg SC), followed by induction with propofol (4 mg/kg IV). Intrinsic laryngeal motion observed in each dog was recorded on videotape after induction. Doxapram then was administered (2.2 mg/kg IV) and respirations again were recorded. Representative breaths for each dog were photographed during 4 phases of respiration (inspiration at rest, inspiration with Doxapram, expiration at rest, and expiration with Doxapram). The area of the RG then was calculated by using a computer-assisted analysis program. Results of each category were compared by using a 1-way analysis of variance; P ≤.05 was considered significant. Doxapram visibly increased respiratory effort, and was associated with increased intrinsic laryngeal motion. Compared to the resting state, the area of the RG was significantly increased after Doxapram administration during both inspiration and expiration. We propose the routine use of Doxapram during laryngoscopy to increase intrinsic laryngeal motion and aid in the diagnosis of laryngeal dysfunction.
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The Effects of Doxapram Hydrochloride (Dopram‐V) on Laryngeal Function in Healthy Dogs
Journal of Veterinary Internal Medicine, 2002Co-Authors: Carrie Jean Miller, Brendan C Mckiernan, Jennifer Pace, M J FettmanAbstract:Laryngeal dysfunction is assessed most accurately by direct visualization of the larynx under a light plane of anesthesia. If the plane of anesthesia used is too deep, laryngeal structures may appear paralyzed and remain in a paramedian position. Doxapram hydrochloride is a known respiratory stimulant. We hypothesized that Doxapram would significantly increase intrinsic laryngeal motion in healthy anesthetized dogs. The goal of this study was to evaluate the effect of Doxapram on the area of rima glottidis (RG) in healthy dogs. Thirty healthy dogs were studied. Dogs were premedicated with butorphanol tartrate (0.22 mg/kg IV), acepromazine maleate (0.05 mg/kg SC), and glycopyrrolate (0.005 mg/kg SC), followed by induction with propofol (4 mg/kg IV). Intrinsic laryngeal motion observed in each dog was recorded on videotape after induction. Doxapram then was administered (2.2 mg/kg IV) and respirations again were recorded. Representative breaths for each dog were photographed during 4 phases of respiration (inspiration at rest, inspiration with Doxapram, expiration at rest, and expiration with Doxapram). The area of the RG then was calculated by using a computer-assisted analysis program. Results of each category were compared by using a 1-way analysis of variance; P ≤.05 was considered significant. Doxapram visibly increased respiratory effort, and was associated with increased intrinsic laryngeal motion. Compared to the resting state, the area of the RG was significantly increased after Doxapram administration during both inspiration and expiration. We propose the routine use of Doxapram during laryngoscopy to increase intrinsic laryngeal motion and aid in the diagnosis of laryngeal dysfunction.