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Children (Basel, Switzerland) Nov 2022QTc interval measurement is a widely used screening tool to assess the risk of cardiac diseases, arrhythmias, and is a useful biomarker for pharmacovigilance. However,... (Review)
Review
QTc interval measurement is a widely used screening tool to assess the risk of cardiac diseases, arrhythmias, and is a useful biomarker for pharmacovigilance. However, the interpretation of QTc is difficult in neonates due to hemodynamic maturational changes and uncertainties on reference values. To describe trends in QTc values throughout infancy (1 year of life), and to explore the impact of (non)-maturational changes and medicines exposure, a structured systematic review (PROSPERO CRD42022302296) was performed. In term neonates, a decrease was observed over the first week of life, whereafter values increased until two months of age, followed by a progressive decrease until six months. A similar pattern with longer QTc values was observed in preterms. QTc is influenced by cord clamping, hemodynamic changes, therapeutic hypothermia, illnesses and sleep, not by sex. Cisapride, domperidone and doxapram result in QTc prolongation in neonates. Further research in this age category is needed to improve primary screening practices and QTcthresholds, earlier detection of risk factors and precision pharmacovigilance.
PubMed: 36421220
DOI: 10.3390/children9111771 -
Journal of Clinical Medicine Dec 2023Necrotizing enterocolitis (NEC) is a critical gastrointestinal emergency with substantial morbidity and mortality risks, especially for very low-birth-weight (VLBW)... (Review)
Review
Necrotizing enterocolitis (NEC) is a critical gastrointestinal emergency with substantial morbidity and mortality risks, especially for very low-birth-weight (VLBW) infants, and unclear multifactorial pathophysiology. Whether common treatments for VLBW infants increase the NEC risk remains controversial. Indomethacin (utilized for patent ductus arteriosus) offers benefits but is concerning because of its vasoconstrictive impact on NEC susceptibility. Similarly, corticosteroids used to treat bronchopulmonary dysplasia may increase vulnerability to NEC by compromising immunity and altering the mesenteric blood flow. Histamine-2 receptor blockers (used to treat gastric bleeding) may inadvertently promote NEC by affecting bacterial colonization and translocation. Doxapram (used to treat apnea) poses a risk of gastrointestinal disturbance via gastric acid hypersecretion and circulatory changes. Glycerin enemas aid meconium evacuation but disrupt microbial equilibrium and trigger stress-related effects associated with the NEC risk. Prolonged antibiotic use may unintentionally increase the NEC risk. Blood transfusions for anemia can promote NEC via interactions between the immune response and ischemia-reperfusion injury. Probiotics for NEC prevention are associated with concerns regarding sepsis and bacteremia. Amid conflicting evidence, this review unveils NEC risk factors related to treatments for VLBW infants, offers a comprehensive overview of the current research, and guides personalized management strategies, thereby elucidating this clinical dilemma.
PubMed: 38202069
DOI: 10.3390/jcm13010062 -
Minerva Anestesiologica Oct 2023Shivering is a common side effect after general anesthesia. Risk factors are hypothermia, young age and postoperative pain. Severe complications of shivering are rare... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
Shivering is a common side effect after general anesthesia. Risk factors are hypothermia, young age and postoperative pain. Severe complications of shivering are rare but can occur due to increased oxygen consumption. Previous systematic reviews are outdated and have summarized the evidence on the topic using only pairwise comparisons. The objective of this manuscript was a quantitative synthesis of evidence on pharmacological interventions to treat postanesthetic shivering.
EVIDENCE ACQUSITION
Systematic review and frequentist network meta-analysis using the R package netmeta. Endpoints were the risk ratio (RR) of persistent shivering at one, five and 10 minutes after treatment with saline/placebo as the comparator. Data were retrieved from Medline, Embase, Central and Web of Science up to January 2022. Eligibility criteria were: randomized, controlled, and blinded trials comparing pharmacological interventions to treat shivering after general anesthesia. Studies on shivering during or after any type of regional anesthesia were excluded as well as sedated patients after cardiac surgery.
EVIDENCE SYNTHESIS
Thirty-two trials were eligible for data synthesis, including 28 pharmacological interventions. The largest network included 1431 patients. The network geometry was two-centered with most comparisons linked to saline/placebo or pethidine. The best interventions were after one minute: doxapram 2 mg/kg, tramadol 2 mg/kg and nefopam 10 mg, after 5 minutes: tramadol 2 mg/kg, nefopam 10 mg and clonidine 150 µg and after 10 minutes: nefopam 10 mg, methylphenidate 20 mg and tramadol 1 mg/kg, all reaching statistical significance. Pethidine 25 mg and clonidine 75 µg also performed well and with statistical significance in all networks.
CONCLUSIONS
Nefopam, tramadol, pethidine and clonidine are the most effective treatments to stop postanesthetic shivering. The efficacy of doxapram is uncertain since different doses showed contradictory effects and the evidence for methylphenidate is based on a single comparison in only one network. Furthermore, both lack data on side effects. Further studies are needed to clarify the efficacy of dexmedetomidine to treat postanesthetic shivering.
Topics: Humans; Adult; Shivering; Nefopam; Clonidine; Tramadol; Network Meta-Analysis; Doxapram; Meperidine; Methylphenidate
PubMed: 37458681
DOI: 10.23736/S0375-9393.23.17410-4 -
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 -
Journal of Veterinary Pharmacology and... Nov 2023Doxapram is marketed as a respiratory stimulant and is used by some veterinarians to help with neonatal apnoea, especially in puppies delivered by caesarean. There is a...
Doxapram is marketed as a respiratory stimulant and is used by some veterinarians to help with neonatal apnoea, especially in puppies delivered by caesarean. There is a lack of consensus as to whether the drug is effective and data on its safety are limited. Doxapram was compared to placebo (saline) in newborn puppies in a randomized, double-blinded clinical trial using two outcome measures: 7-day mortality rate and repeated APGAR score measurements. Higher APGAR scores have been positively correlated with survival and other health outcomes in newborns. Puppies were delivered by caesarean and a baseline APGAR score was measured. This was immediately followed by a randomly allocated intralingual injection of either doxapram or isotonic saline (of the same volume). Injection volumes were determined by the weight of the puppy and each injection was administered within a minute of birth. The mean dose of doxapram administered was 10.65 mg/kg. APGAR scores were measured again at 2, 5, 10 and 20 min. One hundred and seventy-one puppies from 45 elective caesareans were recruited into this study. Five out of 85 puppies died after receiving saline and 7 out of 86 died after receiving doxapram. Adjusting for the baseline APGAR score, the age of the mother and whether the puppy was a brachycephalic breed, there was insufficient evidence to conclude a difference in the odds of 7-day survival for puppies that received doxapram compared to those that received saline (p = .634). Adjusting for the baseline APGAR score, the weight of the mother, the litter size, the mother's parity number, the weight of the puppy and whether the puppy was a brachycephalic breed, there was insufficient evidence to conclude a difference in the probability of a puppy having an APGAR score of ten (the maximum APGAR score) between those that received doxapram compared to those that received saline (p = .631). Being a brachycephalic breed was not associated with an increased odds of 7-day mortality (p = .156) but the effect of the baseline APGAR score on the probability of having an APGAR score of ten was higher for brachycephalic than non-brachycephalic breeds (p = .01). There was insufficient evidence that intralingual doxapram provided an advantage (or disadvantage) compared to intralingual saline when used routinely in puppies delivered by elective caesarean and that were not apnoeic.
Topics: Pregnancy; Female; Animals; Dogs; Animals, Newborn; Doxapram; Apgar Score; Litter Size; Cesarean Section
PubMed: 37211671
DOI: 10.1111/jvp.13388 -
MBio Mar 2020Frequent and excessive use of antibiotics primes patients to infection (CDI), which leads to fatal pseudomembranous colitis, with limited treatment options. In earlier...
Frequent and excessive use of antibiotics primes patients to infection (CDI), which leads to fatal pseudomembranous colitis, with limited treatment options. In earlier reports, we used a drug repurposing strategy and identified amoxapine (an antidepressant), doxapram (a breathing stimulant), and trifluoperazine (an antipsychotic), which provided significant protection to mice against lethal infections with several pathogens, including However, the mechanisms of action of these drugs were not known. Here, we provide evidence that all three drugs offered protection against experimental CDI by reducing bacterial burden and toxin levels, although the drugs were neither bacteriostatic nor bactericidal in nature and had minimal impact on the composition of the microbiota. Drug-mediated protection was dependent on the presence of the microbiota, implicating its role in evoking host defenses that promoted protective immunity. By utilizing transcriptome sequencing (RNA-seq), we identified that each drug increased expression of several innate immune response-related genes, including those involved in the recruitment of neutrophils, the production of interleukin 33 (IL-33), and the IL-22 signaling pathway. The RNA-seq data on selected genes were confirmed by quantitative real-time PCR (qRT-PCR) and protein assays. Focusing on amoxapine, which had the best anti-CDI outcome, we demonstrated that neutralization of IL-33 or depletion of neutrophils resulted in loss of drug efficacy. Overall, our lead drugs promote disease alleviation and survival in the murine model through activation of IL-33 and by clearing the pathogen through host defense mechanisms that critically include an early influx of neutrophils. is a spore-forming anaerobic bacterium and the leading cause of antibiotic-associated colitis. With few therapeutic options and high rates of disease recurrence, the need to develop new treatment options is urgent. Prior studies utilizing a repurposing approach identified three nonantibiotic Food and Drug Administration-approved drugs, amoxapine, doxapram, and trifluoperazine, with efficacy against a broad range of human pathogens; however, the protective mechanisms remained unknown. Here, we identified mechanisms leading to drug efficacy in a murine model of lethal infection (CDI), advancing our understanding of the role of these drugs in infectious disease pathogenesis that center on host immune responses to Overall, these studies highlight the crucial involvement of innate immune responses, as well as the importance of immunomodulation as a potential therapeutic option to combat CDI.
Topics: Amoxapine; Animals; Clostridioides difficile; Clostridium Infections; Doxapram; Drug Repositioning; Female; Immunity, Innate; Immunomodulation; Male; Mice; Mice, Inbred C57BL; Microbiota; RNA-Seq; Specific Pathogen-Free Organisms; Trifluoperazine
PubMed: 32156806
DOI: 10.1128/mBio.00053-20 -
Journal of the American Veterinary... Jul 2016OBJECTIVE To investigate the prevalence and type of laryngeal abnormalities in dogs examined because of cough that did not have signs of upper airway disease and to...
OBJECTIVE To investigate the prevalence and type of laryngeal abnormalities in dogs examined because of cough that did not have signs of upper airway disease and to compare the prevalence of those abnormalities among dogs with various respiratory tract diseases. DESIGN Prospective study. ANIMALS 138 dogs with cough that did not have signs of upper airway disease. PROCEDURES The study was conducted between July 2001 and October 2014 and included dogs examined for cough that had laryngoscopic and bronchoscopic examinations performed by 1 examiner. Laryngeal hyperemia and swelling were recorded, and laryngeal function was assessed before and after doxapram stimulation when indicated. Results were compared among dogs on the basis of cough duration (acute [< 2 weeks], subacute [2 weeks to 2 months], and chronic [> 2 months]) and disease diagnosed (inflammatory airway disease, airway collapse, lower respiratory tract infection, and eosinophilic bronchopneumopathy). RESULTS Laryngeal hyperemia was detected in 73 of 134 (54%) dogs with cough of subacute or chronic duration, and its prevalence did not vary significantly among dogs with various diseases. Thirteen dogs had laryngeal paresis, and 13 dogs had laryngeal paralysis; dysphonia (n = 2) and stridor (1) were uncommon findings in those dogs. The prevalence of laryngeal dysfunction (paresis or paralysis) did not differ significantly among diseases. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that 26 of 138 (19%) dogs examined because of cough alone had laryngeal dysfunction, which suggested that a complete laryngoscopic examination should be included in the diagnostic evaluation of dogs with cough.
Topics: Airway Obstruction; Animals; Constriction, Pathologic; Cough; Dog Diseases; Dogs; Laryngeal Diseases; Larynx
PubMed: 27379595
DOI: 10.2460/javma.249.2.195 -
Archives of Disease in Childhood. Fetal... Jun 2024To assess the long-term neurodevelopmental impact of doxapram for treating apnoea of prematurity.
OBJECTIVE
To assess the long-term neurodevelopmental impact of doxapram for treating apnoea of prematurity.
DESIGN
Secondary analysis of the French national cohort study EPIPAGE-2. Recruitment took place in 2011. A standardised neurodevelopmental assessment was performed at age 5-6 years. A 2:1 propensity score matching was used to control for the non-randomised assignment of doxapram treatment.
SETTING
Population-based cohort study.
PATIENTS
All children born before 32 weeks' gestation alive at age 5-6 years.
INTERVENTIONS
Blind and standardised assessment by trained neuropsychologists and paediatricians at age 5-6 years.
MAIN OUTCOME MEASURES
Neurodevelopmental outcomes at age 5-6 years assessed by trained paediatricians and neuropsychologists: cerebral palsy, developmental coordination disorders, IQ and behavioural difficulties. A composite criterion for overall neurodevelopmental disabilities was built.
RESULTS
The population consisted of 2950 children; 275 (8.6%) received doxapram. Median (IQR) gestational age was 29.4 (27.6-30.9) weeks. At age 5-6 years, complete neurodevelopmental assessment was available for 60.3% (1780 of 2950) of children and partial assessment for 10.6% (314 of 2950). In the initial sample, children receiving doxapram had evidence of greater clinical severity than those not treated. Doxapram treatment was associated with overall neurodevelopmental disabilities of any severity (OR 1.43, 95% CI 1.07 to 1.92, p=0.02). Eight hundred and twenty-one children were included in the 2:1 matched sample. In this sample, perinatal characteristics of both groups were similar and doxapram treatment was not associated with overall neurodevelopmental disabilities (OR 1.09, 95% CI 0.76 to 1.57, p=0.63).
CONCLUSIONS
In children born before 32 weeks' gestation, doxapram treatment for apnoea of prematurity was not associated with neurodevelopmental disabilities.
Topics: Humans; Child, Preschool; Female; Male; Infant, Newborn; Infant, Premature, Diseases; Infant, Premature; Doxapram; Child; Apnea; Neurodevelopmental Disorders; Gestational Age; Cerebral Palsy; Developmental Disabilities; France; Cohort Studies
PubMed: 38228381
DOI: 10.1136/archdischild-2023-326170 -
Antimicrobial Agents and Chemotherapy Jan 2018Earlier, we reported that three Food and Drug Administration-approved drugs, trifluoperazine (TFP; an antipsychotic), amoxapine (AXPN; an antidepressant), and doxapram...
Earlier, we reported that three Food and Drug Administration-approved drugs, trifluoperazine (TFP; an antipsychotic), amoxapine (AXPN; an antidepressant), and doxapram (DXP; a breathing stimulant), identified from an murine macrophage cytotoxicity screen, provided mice with 40 to 60% protection against pneumonic plague when administered at the time of infection for 1 to 3 days. In the present study, the therapeutic potential of these drugs against pneumonic plague in mice was further evaluated when they were administered at up to 48 h postinfection. While the efficacy of TFP was somewhat diminished as treatment was delayed to 24 h, the protection of mice with AXPN and DXP increased as treatment was progressively delayed to 24 h. At 48 h postinfection, these drugs provided the animals with significant protection (up to 100%) against challenge with the agent of pneumonic or bubonic plague when they were administered in combination with levofloxacin. Likewise, when they were used in combination with vancomycin, all three drugs provided mice with 80 to 100% protection from fatal oral infection when they were administered at 24 h postinfection. Furthermore, AXPN provided 40 to 60% protection against respiratory infection with when it was administered at the time of infection or at 24 h postinfection. Using the same cytotoxicity assay, we identified an additional 76/780 nonantibiotic drugs effective against For , 121 nonantibiotic drugs were identified to inhibit bacterium-induced cytotoxicity in murine macrophages. Of these 121 drugs, 13 inhibited the macrophage cytotoxicity induced by two additional multiple-antibiotic-resistant strains. Six of these drugs decreased the intracellular survival of all three strains in macrophages. These results provided further evidence of the broad applicability and utilization of drug repurposing screening to identify new therapeutics to combat multidrug-resistant pathogens of public health concern.
Topics: Acinetobacter baumannii; Amoxapine; Animals; Anti-Bacterial Agents; Cell Line; Disease Models, Animal; Doxapram; Drug Repositioning; Drug Resistance, Multiple, Bacterial; Female; Klebsiella pneumoniae; Levofloxacin; Macrophages; Mice; Mice, Inbred C57BL; Plague; RAW 264.7 Cells; Trifluoperazine
PubMed: 29109161
DOI: 10.1128/AAC.01943-17 -
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