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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 Previous systematic reviews are outdated and have summarized the evidence on the topic using only pairwise comparisons.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 -
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 -
Comparative Biochemistry and... Apr 2023Exposure of Drosophila skeletal muscle to bacterial lipopolysaccharides (LPS) rapidly and transiently hyperpolarizes membrane potential. However, the mechanism...
Exposure of Drosophila skeletal muscle to bacterial lipopolysaccharides (LPS) rapidly and transiently hyperpolarizes membrane potential. However, the mechanism responsible for hyperpolarization remains unclear. The resting membrane potential of the cells is maintained through multiple mechanisms. This study investigated the possibility of LPS activating calcium-activated potassium channels (K) and/or K2p channels. 2-Aminoethyl diphenylborinate (2-APB), blocks uptake of Ca into the endoplasmic reticulum (ER); thus, limiting release from ryanodine-sensitive internal stores to reduce the function of K channels. Exposure to 2-APB produces waves of hyperpolarization even during desensitization of the response to LPS and in the presence of doxapram. This finding in this study suggests that doxapram blocked the acid-sensitive K2p tandem-pore channel subtype known in mammals. Doxapram blocked LPS-induced hyperpolarization and depolarized the muscles as well as induced motor neurons to produce evoked excitatory junction potentials (EJPs). This was induced by depolarizing motor neurons, similar to the increase in extracellular K concentration. The hyperpolarizing effect of LPS was not blocked by decreased extracellular Caor the presence of Cd. LPS appears to transiently activate doxapram sensitive K2p channels independently of K channels in hyperpolarizing the muscle. Septicemia induced by gram-negative bacteria results in an increase in inflammatory cytokines, primarily induced by bacterial LPS. Currently, blockers of LPS receptors in mammals are unknown; further research on doxapram and other K2p channels is warranted. (220 words).
Topics: Animals; Doxapram; Membrane Potentials; Potassium Channels, Tandem Pore Domain; Lipopolysaccharides; Ryanodine; Mammals
PubMed: 36740004
DOI: 10.1016/j.cbpc.2023.109571 -
International Journal of Molecular... Dec 2022Bacterial septicemia is commonly induced by Gram-negative bacteria. The immune response is triggered in part by the secretion of bacterial endotoxin lipopolysaccharide...
Bacterial septicemia is commonly induced by Gram-negative bacteria. The immune response is triggered in part by the secretion of bacterial endotoxin lipopolysaccharide (LPS). LPS induces the subsequent release of inflammatory cytokines which can result in pathological conditions. There is no known blocker to the receptors of LPS. The larval muscle is an amendable model to rapidly screen various compounds that affect membrane potential and synaptic transmission such as LPS. LPS induces a rapid hyperpolarization in the body wall muscles and depolarization of motor neurons. These actions are blocked by the compound doxapram (10 mM), which is known to inhibit a subtype of the two-P-domain K+ channel (K2P channels). However, the K2P channel blocker PK-THPP had no effect on the larval muscle at 1 and 10 mM. These channels are activated by chloroform, which also induces a rapid hyperpolarization of these muscles, but the channels are not blocked by doxapram. Likewise, chloroform does not block the depolarization induced by doxapram. LPS blocks the postsynaptic glutamate receptors on muscle. Pre-exposure to doxapram reduces the LPS block of these ionotropic glutamate receptors. Given that the larval body wall muscles are depolarized by doxapram and hyperpolarized by chloroform, they offer a model to begin pharmacological profiling of the K2P subtype channels with the potential of identifying blockers for the receptors to mitigate the actions of the Gram-negative endotoxin LPS.
Topics: Animals; Doxapram; Lipopolysaccharides; Chloroform; Synaptic Transmission; Drosophila
PubMed: 36555429
DOI: 10.3390/ijms232415787 -
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 -
Comparative Biochemistry and... Jan 2023The resting membrane potential of most cells is maintained by potassium K2p channels. The pharmacological profile and distribution of various K2p channel subtypes in...
The resting membrane potential of most cells is maintained by potassium K2p channels. The pharmacological profile and distribution of various K2p channel subtypes in organisms are still being investigated. The Drosophila genome contains 11 subtypes; however, their function and expression profiles have not yet been determined. Doxapram is clinically used to enhance respiration in humans and blocks the acid-sensitive K2p TASK subtype in mammals. The resting membrane potential of larval Drosophila muscle and synaptic transmission at the neuromuscular junction are pH sensitive. The present study investigated the effects of doxapram on membrane potential and synaptic transmission using intracellular recordings of larval Drosophila muscles. Doxapram (1 mM and 10 mM) depolarizes the muscle and appears to depolarize motor neurons, causing an increase in the frequency of spontaneous quantal events and evoked excitatory junction potentials. Verapamil (1 and 10 mM) paralleled the action of doxapram. These changes were matched by an extracellular increase in KCl (50 mM) and blocked by Cd. It is assumed that the motor nerve depolarizes to open voltage-gated Ca channels in presynaptic nerve terminals because of exposure to doxapram. These findings are significant for building models to better understand the function of pharmacological agents that affect K2p channels and how K2p channels contribute to the physiology of tissues. Drosophila offers a genetically amenable model that can alter the tissue-specific expression of K2p channel subtypes to simulate known human diseases related to this family of channels.
Topics: Animals; Humans; Membrane Potentials; Drosophila; Doxapram; Neuromuscular Junction; Synaptic Transmission; Potassium Channels; Mammals
PubMed: 36306997
DOI: 10.1016/j.cbpc.2022.109497 -
Pediatric Research Mar 2023An oxygen saturation (SpO) histogram classification system has been shown to enable quantification of SpO instability into five types, based on histogram distribution...
BACKGROUND
An oxygen saturation (SpO) histogram classification system has been shown to enable quantification of SpO instability into five types, based on histogram distribution and time spent at SpO ≤ 80%. We aimed to investigate this classification system as a tool to describe response to doxapram treatment in infants with severe apnea of prematurity.
METHODS
This retrospective study included 61 very-low-birth-weight infants who received doxapram. SpO histograms were generated over the 24-h before and after doxapram start. Therapy response was defined as a decrease of ≥1 histogram types after therapy start.
RESULTS
The median (IQR) histogram type decreased from 4 (3-4) before to 3 (2-3) after therapy start (p < 0.001). The median (IQR) FiO remained constant before (27% [24-35%]) and after (26% [22-35%]) therapy. Thirty-six infants (59%) responded to therapy within 24 h. In 34/36 (94%) of the responders, invasive mechanical ventilation (IMV) was not required during the first 72 h of therapy, compared to 15/25 (60%) of non-responders (p = 0.002). Positive and negative predictive values of the 24-h response for no IMV requirement within 72 h were 0.46 and 0.94, respectively.
CONCLUSIONS
Classification of SpO histograms provides an objective bedside measure to assess response to doxapram therapy and can serve as a tool to detect changes in oxygenation status around respiratory interventions.
IMPACT
The SpO histogram classification system provides a tool for quantifying response to doxapram therapy. The classification system allowed estimation of the probability of invasive mechanical ventilation requirement, already within a few hours of treatment. The SpO histogram classification system allows an objective bedside assessment of the oxygenation status of the preterm infant, making it possible to assess the changes in oxygenation status in response to respiratory interventions.
Topics: Infant; Infant, Newborn; Humans; Doxapram; Infant, Premature; Respiratory System Agents; Retrospective Studies; Oxygen Saturation; Infant, Premature, Diseases; Oxygen
PubMed: 35739260
DOI: 10.1038/s41390-022-02158-w -
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 -
Cardiovascular Research Jun 2022
Topics: Atrial Fibrillation; Doxapram; Humans; Potassium Channels
PubMed: 35425974
DOI: 10.1093/cvr/cvac044 -
Journal of Veterinary Emergency and... Jul 2022To describe circumstances and outcomes following cardiopulmonary arrest (CPA) in hospitalized birds.
OBJECTIVE
To describe circumstances and outcomes following cardiopulmonary arrest (CPA) in hospitalized birds.
DESIGN
Retrospective case study.
SETTING
Academic medical center.
METHODS
The hospital medical records system was searched for avian cases that underwent CPR. Medical records were reviewed; data retrieved included association of CPA with anesthesia or handling, use of external compressions and intubation, drug administration, rates of return of spontaneous circulation (ROSC), and outcome. Cases with incomplete medical records were excluded.
RESULTS
Forty-one cases of avian CPR were identified. Anesthesia-related arrest was reported in 26 of 41 cases. The remainder of CPA events occurred during an examination (6/41) or were observed during hospitalization for treatment of disease or injury (11/41). Compressions were performed in 14 birds and manual ventilation performed in 21 of 41 cases via intubation (19/21), tight-fitting face mask (1/21), or air sac cannulation (1/21). Vascular access was achieved in 24 of 41 cases. Emergency drug administration was documented in 22 of 41 cases and included epinephrine (20/22), atropine (19/22), glycopyrrolate (3/22), doxapram (2/22), dextrose (3/22), mannitol (1/22), and furosemide (1/22). Fluid therapy was administered in 24 of 41 cases. There were 3 documented cases of ROSC (7%), all in patients under general anesthesia, and 1 (2%) CPA survivor.
CONCLUSIONS
There was no standardized approach to avian CPR in this study, and ROSC was rare. When ROSC was achieved, birds were under general anesthesia with direct monitoring by a clinician, were ventilated, and were administered anesthetic reversals and anticholinergic or catecholamine emergency medications. These poor outcomes suggest that further research and an updated standardized approach to avian CPR, with special consideration of the physiological differences from mammals, are needed.
Topics: Animals; Birds; Cardiopulmonary Resuscitation; Heart Arrest; Hospitalization; Mammals; Retrospective Studies
PubMed: 35318792
DOI: 10.1111/vec.13191