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Pediatric Pulmonology Jun 2022This study aimed to evaluate the change in the waveform pattern of the electrical activity of the diaphragm (Edi) following the administration of doxapram in extremely...
OBJECTIVE
This study aimed to evaluate the change in the waveform pattern of the electrical activity of the diaphragm (Edi) following the administration of doxapram in extremely preterm infants ventilated with neurally adjusted ventilatory assist (NAVA).
STUDY DESIGN
We conducted this retrospective cohort study in our neonatal intensive care unit between November 2019 and September 2021. The study participants were extremely preterm infants under the gestational age of 28 weeks who were ventilated with NAVA and administered doxapram. We collected the data of the Edi waveform pattern and calculated the proportion. To analyze the change in the proportion of the Edi waveform pattern, we compared the proportion of the data for 1 h before and after doxapram administration.
RESULTS
Ten extremely preterm infants were included. Almost all the patients' respiratory condition improved after doxapram administration. The ventilatory parameters-Edi peak, Edi minimum, peak inspiratory pressure, time in backup ventilation, and number of switches to backup ventilation-did not change significantly. However, the proportion of phasic pattern significantly increased (before: 46% vs. after: 72%; p < 0.05), whereas the central apnea pattern significantly decreased after doxapram administration (before: 31% vs. after: 8.3%; p < 0.05). The proportion of irregular low-voltage patterns tended to decrease, albeit with no significant changes.
CONCLUSION
Our results indicated that the proportion of Edi waveform patterns changed following doxapram administration. Edi waveform pattern analysis could be a sensitive indicator of effect with other intervention for respiratory conditions.
Topics: Diaphragm; Doxapram; Humans; Infant; Infant, Extremely Premature; Infant, Newborn; Interactive Ventilatory Support; Retrospective Studies
PubMed: 35274498
DOI: 10.1002/ppul.25889 -
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 -
Journal of Equine Veterinary Science Apr 2022This randomized double-blinded study evaluated the recovery from isoflurane anesthesia in horses receiving doxapram and xylazine. 6 horses were anesthetized 4 times...
This randomized double-blinded study evaluated the recovery from isoflurane anesthesia in horses receiving doxapram and xylazine. 6 horses were anesthetized 4 times (minimum of 2-week washout period). Anesthesia was performed with xylazine (0.6 mg/kg), ketamine (2.2 mg/kg), midazolam (0.1 mg/kg), and maintained with isoflurane for 90 minutes. At recovery, horses received one of the following randomized treatments: RX: xylazine (0.2 mg/kg), RXD1: xylazine (0.2 mg/kg) and doxapram (0.1 mg/kg), RXD2: xylazine (0.2 mg/kg) and doxapram (0.2 mg/kg), or RS: saline. Recoveries were rope-assisted and evaluated with a descriptive qualitative scale. Heart rate, respiratory frequency (f), and blood gas analysis were evaluated at 5 minutes intervals while the horse allowed. Data were analyzed with ANOVA or Friedman test (P < .05). Times to sternal (minutes) were RX: 40.5 ± 12.3, RXD1: 25.8 ± 11.5, RXD2: 31.4 ± 7.0, and RS: 33.4 ± 5.3, and were not different. Times to standing (minutes) were RX: 41.0 ± 9.9, RXD1: 33.5 ± 6.2, RXD2: 40.0 ± 11.3, and RS: 36.3 ± 9.9, and were not different. Heart rate decrease over time within RXD1 and RXD2 (T0 = 47 ± 15 and 47 ± 15, T5 = 38 ± 8 and 38 ± 8, T10 = 39 ± 4 and 36 ± 6, respectively), but was not different among groups. There was no difference in f among groups or over time. There was no difference in recovery scores among groups. In conclusion, administration of doxapram to isoflurane-anesthetized horses did not change recovery time or quality.
Topics: Anesthesia Recovery Period; Anesthetics, Inhalation; Animals; Doxapram; Horses; Isoflurane; Xylazine
PubMed: 35074399
DOI: 10.1016/j.jevs.2022.103872 -
Anesthesiology Apr 2022Opioids may produce life-threatening respiratory depression and death from their actions at the opioid receptors within the brainstem respiratory neuronal network. Since...
Opioids may produce life-threatening respiratory depression and death from their actions at the opioid receptors within the brainstem respiratory neuronal network. Since there is an increasing number of conditions where the administration of the opioid receptor antagonist naloxone is inadequate or undesired, there is an increased interest in the development of novel reversal and prevention strategies aimed at providing efficacy close to that of the opioid receptor antagonist naloxone but with fewer of its drawbacks such as its short duration of action and lesser ability to reverse high-affinity opioids, such as carfentanil, or drug combinations. To give an overview of this highly relevant topic, the authors systematically discuss predominantly experimental pharmacotherapies, published in the last 5 yr, aimed at reversal of opioid-induced respiratory depression as alternatives to naloxone. The respiratory stimulants are discussed based on their characteristics and mechanism of action: nonopioid controlled substances (e.g., amphetamine, cannabinoids, ketamine), hormones (thyrotropin releasing hormone, oxytocin), nicotinic acetylcholine receptor agonists, ampakines, serotonin receptor agonists, antioxidants, miscellaneous peptides, potassium channel blockers acting at the carotid bodies (doxapram, ENA001), sequestration techniques (scrubber molecules, immunopharmacotherapy), and opioids (partial agonists/antagonists). The authors argue that none of these often still experimental therapies are sufficiently tested with respect to efficacy and safety, and many of the agents presented have a lesser efficacy at deeper levels of respiratory depression, i.e., inability to overcome apnea, or have ample side effects. The authors suggest development of reversal strategies that combine respiratory stimulants with naloxone. Furthermore, they encourage collaborations between research groups to expedite development of viable reversal strategies of potent synthetic opioid-induced respiratory depression.
Topics: Analgesics, Opioid; Humans; Naloxone; Narcotic Antagonists; Respiratory Insufficiency; Respiratory System Agents
PubMed: 34958670
DOI: 10.1097/ALN.0000000000004096 -
International Journal of Toxicology Dec 2021Respiratory monitoring, using impedance with implanted telemetry in socially housed animals, was not possible until the recent development of digital signal...
Combined Cardiopulmonary Assessments Using Impedance and Digital Implants in Conscious Freely Moving Cynomolgus Monkeys, Beagle Dogs, and Göttingen Minipigs: Pharmacological Characterization and Social Housing Effects.
Respiratory monitoring, using impedance with implanted telemetry in socially housed animals, was not possible until the recent development of digital signal transmission. The objective of this study was to evaluate digital telemetry monitoring of cardiopulmonary parameters (respiratory rate, tidal volume, minute volume, electrocardiography (DII), systemic arterial blood pressure, physical activity, and body temperature) in conscious, single-housed, non-rodent species commonly used in toxicology studies following administration of positive/negative controls (saline, dexmedetomidine, morphine, amphetamine, and doxapram), and also, the effects of various social housing arrangements in untreated female and/or male cynomolgus monkeys, Beagle dogs, and Göttingen minipigs (n = 4 per species). Aggressions were observed in socially housed male minipigs, however, which prevented pair-housed assessments in this species. All tested pharmacological agents significantly altered more than one organ system, highlighting important inter-organ dependencies when analyzing functional endpoints. Stress-related physiological changes were observed with single-housing or pair-housing with a new cage mate in cynomolgus monkeys and Beagle dogs, suggesting that stable social structures are preferable to limit variability, especially around dosing. Concomitant monitoring of cardiovascular and respiratory parameters from the same animals may help reduce the number of animals (3 Rs) needed to fulfill the S7A guidelines and allows for identification of organ system functional correlations. Globally, the data support the use of social housing in non-rodents for safety pharmacology multi-organ system (heart and lungs) monitoring investigations.
Topics: Amphetamine; Analgesics, Opioid; Animals; Cardiovascular System; Central Nervous System Stimulants; Dexmedetomidine; Dogs; Doxapram; Electric Impedance; Electrocardiography; Macaca fascicularis; Morphine; Swine; Swine, Miniature
PubMed: 34610777
DOI: 10.1177/10915818211040487 -
BMJ Open Sep 2021Apnoea affects 85% of premature infants under 34 weeks of age and would be an important risk factor for subsequent neuropsychological disorders. Currently, premature...
Protocol of controlled odorant stimulation for reducing apnoeic episodes in premature newborns: a randomised open-label Latin-square study with independent evaluation of the main endpoint (PREMODEUR).
INTRODUCTION
Apnoea affects 85% of premature infants under 34 weeks of age and would be an important risk factor for subsequent neuropsychological disorders. Currently, premature children with life-threatening apnoeas receive stimulants such as methylxanthines (mainly, caffeine) or doxapram (an analeptic unlicensed in children under 15). However, these products have undesirable effects (hyperarousal, irritability, sleep disorders, tachycardia) and are not always effective because apnoea does persist in some premature newborns. Previous studies have indicated that odorant stimulation, a non-invasive intervention, may stimulate the respiratory rhythm. The objective of the present protocol is to reduce the occurrence of apnoeic episodes in premature newborns by controlled odorant stimulation added to current pharmacological treatments.
METHODS AND ANALYSIS
The project is a randomised open-label Latin-square trial with independent evaluation of the main endpoint. It will include 60 preterm neonates from two university hospital neonatal intensive care units over 2 years (2021-2023). Each newborn will receive no (S0), sham (S1) or real olfactory stimulation (S2) in random order. During S2, three distinct odorants (mint, grapefruit and vanilla) will be delivered successively, in puffs, over 24 hours. Mint and grapefruit odours stimulate the main and the trigeminal olfactory pathways, whereas vanilla odour stimulates only the main olfactory pathway. A statistical analysis will compare the incidence of apnoeic episodes during S1 versus S2 using a mixed effects Poisson model.
ETHICS AND DISSEMINATION
Ethical approval was obtained from the Comité de Protection des Personnes Île-de-France XI (# 2017-AO13-50-53). The results will be disseminated through various scientific meetings, specialised peer-reviewed journals and, whenever possible, posted on appropriate public websites.
TRIAL REGISTRATION NUMBER
NCT02851979; Pre-results.
Topics: Apnea; Child; Humans; Infant; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Intensive Care Units, Neonatal; Odorants; Randomized Controlled Trials as Topic
PubMed: 34518252
DOI: 10.1136/bmjopen-2020-047141 -
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 -
Cardiovascular Research Jun 2022TASK-1 (K2P3.1) two-pore-domain potassium channels are atrial-specific and significantly up-regulated in atrial fibrillation (AF) patients, contributing to AF-related...
AIMS
TASK-1 (K2P3.1) two-pore-domain potassium channels are atrial-specific and significantly up-regulated in atrial fibrillation (AF) patients, contributing to AF-related electrical remodelling. Inhibition of TASK-1 in cardiomyocytes of AF patients was shown to counteract AF-related action potential duration shortening. Doxapram was identified as a potent inhibitor of the TASK-1 channel. In this study, we investigated the antiarrhythmic efficacy of doxapram in a porcine model of AF.
METHODS AND RESULTS
Doxapram successfully cardioverted pigs with artificially induced episodes of AF. We established a porcine model of persistent AF in domestic pigs via intermittent atrial burst stimulation using implanted pacemakers. All pigs underwent catheter-based electrophysiological investigations prior to and after 14 days of doxapram treatment. Pigs in the treatment group received intravenous administration of doxapram once per day. In doxapram-treated AF pigs, the AF burden was significantly reduced. After 14 days of treatment with doxapram, TASK-1 currents were still similar to values of sinus rhythm animals. Doxapram significantly suppressed AF episodes and normalized cellular electrophysiology by inhibition of the TASK-1 channel. Patch-clamp experiments on human atrial cardiomyocytes, isolated from patients with and without AF could reproduce the TASK-1 inhibitory effect of doxapram.
CONCLUSION
Repurposing doxapram might yield a promising new antiarrhythmic drug to treat AF in patients.
Topics: Animals; Anti-Arrhythmia Agents; Atrial Fibrillation; Doxapram; Heart Atria; Humans; Nerve Tissue Proteins; Potassium Channel Blockers; Potassium Channels, Tandem Pore Domain; Swine
PubMed: 34028533
DOI: 10.1093/cvr/cvab177 -
Frontiers in Pharmacology 2021Atrial fibrillation (AF) is the most common sustained arrhythmia with a prevalence of up to 4% and an upwards trend due to demographic changes. It is associated with an... (Review)
Review
Atrial fibrillation (AF) is the most common sustained arrhythmia with a prevalence of up to 4% and an upwards trend due to demographic changes. It is associated with an increase in mortality and stroke incidences. While stroke risk can be significantly reduced through anticoagulant therapy, adequate treatment of other AF related symptoms remains an unmet medical need in many cases. Two main treatment strategies are available: rate control that modulates ventricular heart rate and prevents tachymyopathy as well as rhythm control that aims to restore and sustain sinus rhythm. Rate control can be achieved through drugs or ablation of the atrioventricular node, rendering the patient pacemaker-dependent. For rhythm control electrical cardioversion and pharmacological cardioversion can be used. While electrical cardioversion requires fasting and sedation of the patient, antiarrhythmic drugs have other limitations. Most antiarrhythmic drugs carry a risk for pro-arrhythmic effects and are contraindicated in patients with structural heart diseases. Furthermore, catheter ablation of pulmonary veins can be performed with its risk of intraprocedural complications and varying success. In recent years TASK-1 has been introduced as a new target for AF therapy. Upregulation of TASK-1 in AF patients contributes to prolongation of the action potential duration. In a porcine model of AF, TASK-1 inhibition by gene therapy or pharmacological compounds induced cardioversion to sinus rhythm. The DOxapram Conversion TO Sinus rhythm (DOCTOS)-Trial will reveal whether doxapram, a potent TASK-1 inhibitor, can be used for acute cardioversion of persistent and paroxysmal AF in patients, potentially leading to a new treatment option for AF.
PubMed: 33897427
DOI: 10.3389/fphar.2021.638445 -
Frontiers in Veterinary Science 2021Sepsis is a frequent life-threatening condition in young calves, requiring rapid broad spectrum and bactericidal therapy to maximize survival chances. Few studies have...
Sepsis is a frequent life-threatening condition in young calves, requiring rapid broad spectrum and bactericidal therapy to maximize survival chances. Few studies have identified and characterized bacteria involved in sepsis in calves. This report demonstrates the involvement of a multidrug resistant , an emerging pathogen in human medicine, in a calf with suspected sepsis. was identified by MALDI-TOF MS from blood cultures of a critically ill calf. Susceptibility testing showed phenotypic resistance against ampicillin, gentamicin, potentiated sulphonamides, streptomycin, tetracyclines and intermediate susceptibility for enrofloxacin. Whole genome sequencing confirmed identification as and the multidrug resistant character of the isolate. Antimicrobial resistance genes acting against aminoglycosides, beta-lactam antibiotics, fosfomycin, quinolones, sulphonamides, trimethoprim and tetracyclines were found. The calf recovered after empirical parenteral therapy with enrofloxacin and sodium penicillin for seven days. Ancillary therapy consisted of fluid therapy, ketoprofen and doxapram hydrochloride. To the authors' knowledge, this is the first report characterizing a multidrug resistant isolate from blood culture in cattle. It is currently unknown whether animals and farms may act as reservoirs for multidrug resistant strains.
PubMed: 33842574
DOI: 10.3389/fvets.2021.631716