Measures of overnight oxygen saturation to characterize sleep apnea severity and predict postoperative respiratory depression.

BACKGROUND: Sleep apnea syndrome, characterized by recurrent cessation (apnea) or reduction (hypopnea) of breathing during sleep, is a major risk factor for postoperative respiratory depression. Challenges in sleep apnea assessment have led to the proposal of alternative metrics derived from oxyhemoglobin saturation (SpO2), such as oxygen desaturation index (ODI) and percentage of cumulative sleep time spent with SpO2 below 90% (CT90), as predictors of postoperative respiratory depression. However, their performance has been limited with area under the curve of 0.60 for ODI and 0.59 for CT90. Our objective was to propose novel features from preoperative overnight SpO2 which are correlated with sleep apnea severity and predictive of postoperative respiratory depression. METHODS: Preoperative SpO2 signals from 235 surgical patients were retrospectively analyzed to derive seven features to characterize the sleep apnea severity. The features included entropy and standard deviation of SpO2 signal; below average burden characterizing the area under the average SpO2; average, standard deviation, and entropy of desaturation burdens; and overall nocturnal desaturation burden. The association between the extracted features and sleep apnea severity was assessed using Pearson correlation analysis. Logistic regression was employed to evaluate the predictive performance of the features in identifying postoperative respiratory depression. RESULTS: Our findings indicated a similar performance of the proposed features to the conventional apnea-hypopnea index (AHI) for assessing sleep apnea severity, with average area under the curve ranging from 0.77 to 0.81. Notably, entropy and standard deviation of overnight SpO2 signal and below average burden showed comparable predictive capability to AHI but with minimal computational requirements and individuals' burden, making them promising for screening purposes. Our sex-based analysis revealed that compared to entropy and standard deviation, below average burden exhibited higher sensitivity in detecting respiratory depression in women than men. CONCLUSION: This study underscores the potential of preoperative SpO2 features as alternative metrics to AHI in predicting postoperative respiratory.

Implementation of Continuous Capnography Protocol in a Postanesthesia Care Unit for Adult Patients at High-risk of Postoperative Respiratory Depression.

PURPOSE: This project aimed to implement a continuous capnography protocol in the postanesthesia care unit (PACU) for postoperative adult patients who are at high risk for respiratory failure. DESIGN: A preintervention and postintervention quality improvement design with retrospective chart reviews evaluated patient demographics (age, weight, body mass index [BMI], perioperative fluid intake and output, use of intraoperative positive-end expiratory pressure), length of surgery, average length of PACU stay, incidence of respiratory events, and adherence to a PACU capnography protocol. METHODS: Preimplementation data were collected from retrospective chart reviews over a 3-month period. A continuous capnography protocol was implemented for same-day surgery patients with a BMI of 35 kg/m2 or greater and who received general anesthesia. Postimplementation data were collected over 3 months in addition to adherence to the capnography protocol. This was presented using descriptive statistics. FINDINGS: Age, length of surgery, weight, BMI, perioperative fluid intake and output, and use of positive-end expiratory pressure did not impact PACU length of stay. The average PACU length of stay decreased from 76.76 to 71.82 minutes postimplementation but was not statistically significant (P = .470). The incidence of respiratory events was 6% (n = 3). After the implementation of the continuous capnography protocol, adherence to the continuous capnography monitoring was 86% (n = 43). CONCLUSIONS: Patients who are at high risk for postoperative respiratory failure may benefit from continuous capnography monitoring in the PACU. Capnography monitoring may decrease PACU length of stay and provide earlier detection of pending respiratory depression or failure than pulse oximetry alone.

Assessment of the antinociceptive, respiratory-depressant, and reinforcing effects of the low pKa fluorinated fentanyl analogs, FF3 and NFEPP.

RATIONALE: Recent studies report that fentanyl analogs with relatively low pKa values produce antinociception in rodents without other mu opioid-typical side effects due to the restriction of their activity to injured tissue with relatively low pH values. However, it is unclear if and to what degree these compounds may produce mu opioid-typical side effects (respiratory depression, reinforcing effects) at doses higher than those required to produce antinociception. OBJECTIVES: The present study compared the inflammatory antinociceptive, respiratory-depressant, and reinforcing effects of fentanyl and two analogs of intermediate (FF3) and low (NFEPP) pKa values in terms of potency and efficacy in male and female Sprague-Dawley rats. METHODS: Nociception was produced by administration of Complete Freund's Adjuvant into the hind paw of subjects, and antinociception was measured using an electronic Von Frey test. Respiratory depression was measured using whole-body plethysmography. Reinforcing effects were measured in self-administration using a progressive-ratio schedule of reinforcement. The dose ranges tested for each drug encompassed no effect to maximal effects. RESULTS: All compounds produced full effects in all measures but varied in potency. FF3 and fentanyl were equipotent in antinociception and self-administration, but FF3 was less potent than fentanyl in respiratory depression. NFEPP was less potent than fentanyl in every measure. The magnitude of potency difference between antinociception and other effects was greater for FF3 than for NFEPP or fentanyl, indicating that FF3 had the widest margin of safety when relating antinociception to respiratory-depressant and reinforcing effects. CONCLUSIONS: Low pKa fentanyl analogs possess potential as safer analgesics, but determining the optimal degree of difference for pKa relative to fentanyl will require further study due to some differences between the current results and findings from prior work with these analogs.

Exploring the mechanism of cytisine in treating respiratory depression following venomous snake bites based on network pharmacology and molecular docking.

OBJECTIVE: To investigate the antivenom mechanism of cytisine through network pharmacology and molecular docking (MD) techniques, with the intention of exploring its clinical applications. METHODS: The cytisine target and the snakebite respiratory inhibition target were obtained using the Swiss Target Prediction platform and the Gene Cards database. The two target sets were overlapped to form a protein interaction network. Additionally, pathway enrichment analysis was conducted on cross targets, and the related pathways for the treatment of snake venom-induced respiratory failure were obtained. Verification of the MD between cytisine and its related targets was performed using the Autodock 1.5.7 software. The respiratory depression model of rats bitten by venomous snakes was established, and the expression of key target genes in the rat model was verified by western blot (WB). RESULT: A total of 16 targets of cytisine and 9 potential targets of cytisine in treating snake venom-induced respiratory depression were obtained. Core targets including CHRNA7, CHRNG, CHRNB1, CHRND, CHRNA1 and DRD2 were obtained. These targets are mainly enriched in neuroactive ligand-receptor interaction pathway and cholinergic synaptic pathway. The MD results demonstrated favorable docking activity of cytisine with its related targets. WB experiments showed that snake venom reduced the levels of CHRNA7 and CHRNG. Treatment with serum and cytisine could slow down this decline. CONCLUSION: Cytisine may synergistically target CHRNA7, CHRNG, CHRNB1, CHRND, CHRNA1, DRD2 and other proteins, modulating cholinergic and neuroactive pathways to alleviate neuromuscular block and protect acetylcholine receptors.

A machine learning algorithm for detecting abnormal patterns in continuous capnography and pulse oximetry monitoring.

Continuous capnography monitors patient ventilation but can be susceptible to artifact, resulting in alarm fatigue. Development of smart algorithms may facilitate accurate detection of abnormal ventilation, allowing intervention before patient deterioration. The objective of this analysis was to use machine learning (ML) to classify combined waveforms of continuous capnography and pulse oximetry as normal or abnormal. We used data collected during the observational, prospective PRODIGY trial, in which patients receiving parenteral opioids underwent continuous capnography and pulse oximetry monitoring while on the general care floor [1]. Abnormal ventilation segments in the data stream were reviewed by nine experts and inter-rater agreement was assessed. Abnormal segments were defined as the time series 60s before and 30s after an abnormal pattern was detected. Normal segments (90s continuous monitoring) were randomly sampled and filtered to discard sequences with missing values. Five ML models were trained on extracted features and optimized towards an Fß score with ß = 2. The results show a high inter-rater agreement (> 87%), allowing 7,858 sequences (2,944 abnormal) to be used for model development. Data were divided into 80% training and 20% test sequences. The XGBoost model had the highest Fß score of 0.94 (with ß = 2), showcasing an impressive recall of 0.98 against a precision of 0.83. This study presents a promising advancement in respiratory monitoring, focusing on reducing false alarms and enhancing accuracy of alarm systems. Our algorithm reliably distinguishes normal from abnormal waveforms. More research is needed to define patterns to distinguish abnormal ventilation from artifacts.

The association between different anesthetic techniques and outcomes in patients undergoing transfemoral aortic valve replacement.

Background: There is an increasing number of patients undergoing transfemoral aortic valve replacement (TAVR) with sedation. There is limited data assessing the efficacy and safety of the different types of sedative drugs. The objective was to compare two sedation techniques with regard to the need for vasoactive support, respiratory support, rate of conversion to general anesthesia (GA), common perioperative morbidities, intensive care unit (ICU) stay, and in-hospital mortality. Methods: A retrospective chart review study conducted among patients who underwent TAVR at a specialized cardiac center between January 2016 and December 2019. Data collection included patient diagnosis, preoperative comorbidities, intraoperative outcomes, and postoperative outcomes. Results: A total of 289 patients received local anesthesia; 210 received propofol infusion and 79 received a mixed propofol-ketamine infusion (Ketofol). The average age was 75.5 ± 8.9 years and 58.1% of the patients were females. Comparing propofol and ketofol groups, 31.2% and 34.2% of the patients required drug support, 7.6% and 6.3% required conversion to GA, 46.7% and 59.5% required respiratory support, respectively. These intraoperative outcomes were not significantly different between groups, P = 0.540, P = 0.707, and P = 0.105, respectively. In-hospital 30-day mortality in propofol and ketofol groups were 1.9% and 3.8%, respectively, P = 0.396. In both groups, the median post-procedure coronary care unit stay was 26 hours while post-procedure hospital stay was 3 days. Conclusions: There were no significant differences in perioperative or postoperative outcomes in TAVR patients receiving either propofol or ketofol. Propofol infusion, either alone or with ketamine, is reliable and safe, with minimal side effects.

Development of fentanyl-specific monoclonal antibody (mAb) to antagonize the pharmacological effects of fentanyl.

Fentanyl, a critical component of opioid analgesics, poses a severe threat to public health, exacerbating the drug problem due to its potential fatality. Herein, we present two novel haptens designed with different attachment sites conjugated to keyhole limpet hemocyanin (KLH), aiming to develop an efficacious vaccine against fentanyl. KLH-Fent-1 demonstrated superior performance over KLH-Fent-2 in antibody titer, blood-brain distribution, and antinociceptive tests. Consequently, we immunized mice with KLH-Fent-1 to generate fentanyl-specific monoclonal antibodies (mAbs) using the hybridoma technique to compensate for the defects of active immunization in the treatment of opioid overdose and addiction. The mAb produced by hybridoma 9D5 exhibited the ability to recognize fentanyl and its analogs with a binding affinity of 10-10 M. Subsequently, we developed a human IgG1 chimeric mAb to improve the degree of humanization. Pre-treatment with murine and chimeric mAb significantly reduced the analgesic effect of fentanyl and altered its blood-brain biodistribution in vivo. Furthermore, in a mouse model of fentanyl-induced respiratory depression, the chimeric mAb effectively reversed respiratory depression promptly and maintained a certain level during the week. The development of high-affinity chimeric mAb gives support to combat the challenges of fentanyl misuse and its detrimental consequences. In conclusion, mAb passive immunization represents a viable strategy for addressing fentanyl addiction and overdose.

PBPK-PD model for predicting morphine pharmacokinetics, CNS effects and naloxone antagonism in humans.

Morphine and morphine-6-glucuronide (M6G) produce central nervous system (CNS) effects by activating mu-opioid receptors, while naloxone is used mainly for the reversal of opioid overdose, specifically for the fatal complication of respiratory depression, but also for alleviating opioid-induced side effects. In this study we developed a physiologically-based pharmacokinetic-pharmacodynamic (PBPK-PD) model to simultaneously predict pharmacokinetics and CNS effects (miosis, respiratory depression and analgesia) of morphine as well as antagonistic effects of naloxone against morphine. The pharmacokinetic and pharmacodynamic parameters were obtained from in vitro data, in silico, or animals. Pharmacokinetic and pharmacodynamic simulations were conducted using 39 and 36 clinical reports, respectively. The pharmacokinetics of morphine and M6G following oral or intravenous administration were simulated, and the PBPK-PD model was validated using clinical observations. The Emax model correlated CNS effects with free concentrations of morphine and M6G in brain parenchyma. The predicted CNS effects were compared with observations. Most clinical observations fell within the 5th-95th percentiles of simulations based on 1000 virtual individuals. Most of the simulated area under the concentration-time curve or peak concentrations also fell within 0.5-2-fold of observations. The contribution of morphine to CNS effects following intravenous or oral administration was larger than that of M6G. Pharmacokinetics and antagonistic effects of naloxone on CNS effects were also successfully predicted using the developed PBPK-PD model. In conclusion, the pharmacokinetics and pharmacodynamics of morphine and M6G, antagonistic effects of naloxone against morphine-induced CNS effects may be successfully predicted using the developed PBPK-PD model based on the parameters derived from in vitro, in silico, or animal studies.

Adverse Drug Events Observed with the Newly Approved Remimazolam in Comparison to Propofol for General Anesthesia in Patients Undergoing Surgery: A Meta-analysis.

INTRODUCTION: Developments in anesthetic pharmacology have been aiming at minimizing physiological disturbance in addition to maintaining and improving titrateability, recovery profile, and patient experience. Remimazolam, a GABAAlpha receptor agonist, is a new intravenous anesthetic agent which has recently been approved for use. This analysis aimed to systematically compare the adverse drug events reported with the newly approved remimazolam in comparison to propofol for general anesthesia (GA) in patients undergoing surgery. METHODS: Electronic databases were searched from 15 May to 20 December 2023 for relevant publications which compared the outcomes reported with the newly approved remimazolam versus propofol in patients undergoing surgery. Relevant reported adverse drug events were the endpoints of this study. The statistical analysis was carried out using the latest version of the RevMan software. Data analysis was represented by risk ratio (RR) with 95% confidence intervals (CI). RESULTS: Sixteen studies with a total number of 1897 participants were included in this analysis; 1104 participants received remimazolam and 793 participants received propofol. The risks for hypotension (RR 0.50, 95% CI 0.43-0.58; P = 0.00001), hypoxemia (RR 0.43, 95% CI 0.19-0.99; P = 0.05), bradycardia (RR 0.53, 95% CI 0.36-0.78; P = 0.001), pain at injection site (RR 0.07, 95% CI 0.01-0.56; P = 0.01), and total adverse events (RR 0.33, 95% CI 0.24-0.47; P = 0.00001) were significantly lower with remimazolam. However, no significant differences were observed in terms of postoperative nausea and vomiting (RR 0.98, 95% CI 0.66-1.46; P = 0.93), dizziness (RR 0.42, 95% CI 0.11-1.57; P = 0.20), psychiatric symptoms (RR 1.09, 95% CI 0.45-2.67; P = 0.85), and respiratory depression (RR 0.81, 95% CI 0.24-2.76; P = 0.74). CONCLUSION: Our current analysis showed that the newly approved remimazolam was apparently associated with significantly fewer adverse drug events in comparison to propofol for GA in patients undergoing surgery. Therefore, this new drug should be further studied and more research with larger population sizes should be carried out to confirm this hypothesis.

Reversal of Opioid-Induced Respiratory Depression in Healthy Volunteers: Comparison of Intranasal Nalmefene and Intranasal Naloxone.

An open-label, randomized, crossover study in healthy volunteers compared the reversal of remifentanil-induced respiratory depression by intranasal (IN) naloxone hydrochloride (4 mg) to IN nalmefene (2.7 mg) (NCT04828005). Subjects were administered a hypercapnic gas mixture which produces an elevation in minute ventilation (MV), a result of the ventilatory response to hypercapnia. Subjects breathed a hypercapnic gas mixture through a tight-fitting mask for an initial period of 46 min prior to a series of mask "holidays" introduced to reduce subject discomfort and encourage study completion. Ten minutes after initiating the hypercapnic gas mixture, a remifentanil bolus was administered, and an infusion continued for the study duration. Subjects were administered either naloxone or nalmefene 15 min after initiating the remifentanil infusion and MV monitored for 21 min followed by a mask holiday. Both nalmefene and naloxone produced a time-dependent reversal of remifentanil-induced reductions in MV measured 2.5-20 min post administration. At the primary endpoint (5 min post administration), nalmefene increases in MV (5.75 L/min) were nearly twice that produced by naloxone (3.01 L/min) (P < .0009); the point estimate favors nalmefene, demonstrating non-inferiority and superiority. In this model of opioid-induced respiratory depression, nalmefene has a more rapid onset of action than naloxone, which required 20 min to achieve a comparable reversal of respiratory depression. Both nalmefene and naloxone were well tolerated by healthy volunteers. This rapid onset of action may prove particularly valuable in an era when over 90% of fatalities are linked to synthetic opioid overdose.

Fact vs. fiction: naloxone in the treatment of opioid-induced respiratory depression in the current era of synthetic opioids.

Opioid-induced respiratory depression (OIRD) deaths are ~80,000 a year in the US and are a major public health issue. Approximately 90% of fatal opioid-related deaths are due to synthetic opioids such as fentanyl, most of which is illicitly manufactured and distributed either on its own or as an adulterant to other drugs of abuse such as cocaine or methamphetamine. Other potent opioids such as nitazenes are also increasingly present in the illicit drug supply, and xylazine, a veterinary tranquilizer, is a prevalent additive to opioids and other drugs of abuse. Naloxone is the main treatment used to reverse OIRD and is available as nasal sprays, prefilled naloxone injection devices, and generic naloxone for injection. An overdose needs to be treated as soon as possible to avoid death, and synthetic opioids such as fentanyl are up to 50 times more potent than heroin, so the availability of new, higher-dose, 5-mg prefilled injection or 8-mg intranasal spray naloxone preparations are important additions for emergency treatment of OIRDs, especially by lay people in the community. Higher naloxone doses are expected to reverse a synthetic overdose more rapidly and the current formulations are ideal for use by untrained lay people in the community. There are potential concerns about severe withdrawal symptoms, or pulmonary edema from treatment with high-dose naloxone. However, from the perspective of first responders, the balance of risks would point to administration of naloxone at the dose required to combat the overdose where the risk of death is very high. The presence of xylazines as an adulterant complicates the treatment of OIRDs, as naloxone is probably ineffective, although it will reverse the respiratory depression due to the opioid. For these patients, hospitalization is particularly vital. Education about the benefits of naloxone remains important not only in informing people about how to treat emergency OIRDs but also how to obtain naloxone. A call to emergency services is also essential after administering naloxone because, although the patient may revive, they may overdose again later because of the short half-life of naloxone and the long-lasting potency of fentanyl and its analogs.

A Single Ascending-Dose Study of the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the Novel Respiratory Stimulant ENA-001.

Background ENA-001 (formerly known as GAL-021) is a novel, first-in-class respiratory stimulant. Pharmacokinetic and pharmacodynamic properties, plus safety and tolerability, were assessed in a randomized, single-center study of healthy volunteers. Methodology This four-period study was designed to test continuous two-hour intravenous infusion regimens of ENA-001 at doses of 0.96, 1.44, and 1.92 mg/kg/hour versus placebo. Each participant received four infusions with a seven-day minimum washout between them: one infusion each of the three doses of ENA-001 and one placebo. Pharmacokinetic and pharmacodynamic parameters were assessed and adverse events were recorded. Results A total of 17 participants completed the study. ENA-001 was generally safe and well tolerated over the dose range studied (0.96 to 1.92 mg/kg/hour). ENA-001 was able to drive hyperventilation in a dose-dependent manner in healthy participants. Increases in ventilation due to ENA-001 were not associated with like-magnitude blood pressure response. ENA-001-stimulated decreases in ETCO2 were associated with small, statistically significant, increases in SpO2 levels. Hyperventilation occurred in two participants at the highest dose level, leading to study discontinuation. The terminal half-life of ENA-001 was 6.33 hours. Conclusions The respiratory stimulant ENA-001 demonstrated well-behaved pharmacokinetics following the two-hour infusion. Mean peak plasma concentrations and the mean total systemic exposure values were approximately dose-proportional in the dose range studied.

Analysis of Sedation Accident Records Available in the Japan Council for Quality Health Care Public Database.

OBJECTIVE: Medical accidents occur frequently. However, only a few studies have been conducted on sedation-related medical accidents. This study aimed to classify sedation accidents and analyze their causes using the (Patient-management Software Hardware Environment Livewear (P-mSHELL) model. METHODS: The Japan Council for Quality Health Care database on medical accidents was used. Sedation accidents that occurred during procedures between January 2010 and June 2022 were included. After examining the accident details for several variables, the accident factors were classified by factors in the P-mSHELL model, and statistical analyses, including multivariate analysis of each factor and outcome (presence or absence of residual disability), were conducted. RESULTS: Regarding the influence of the P-mSHELL factors on outcome, P factor (odds ratio = 6.347, 95% confidence interval = 2.000, 20.144) was a factor for having disability. There was a significant association between outcome and accident timing (that is, preoperative, intraoperative, or postoperative; p =0.01). No significant association was found between the outcomes and types of drugs used (p =1, 0.722, 0.594); however, there was a significant association between the incidence of respiratory depression and multiple drug use (p <0.001). CONCLUSIONS: To prevent sedation accidents, it is important to monitor patients throughout the perioperative period. However, it is especially important to know the patient's condition in advance, and strict postoperative management is essential, especially for high-risk patients, to prevent serious accidents.

Enantiomeric contributions to methamphetamine's bidirectional effects on basal and fentanyl-depressed respiration in mice.

RATIONALE: Fentanyl remains the primary cause of fatal overdoses, and its co-use with methamphetamine (METH) is a growing concern. We previously demonstrated that racemic METH can either enhance or mitigate opioid-induced respiratory depression (OIRD) dependent upon whether a low or high dose is administered. The optical isomers of METH, dextromethamphetamine (d-METH) and levomethamphetamine (l-METH), differ substantially in their selectivity and potency to activate various monoamine (MA) receptors, and these pharmacological differences may underlie the bidirectional effects of the racemate. Since it is unknown which of METH's MA receptor mechanisms mediate these respiratory effects, examination of METH's pharmacologically distinct enantiomers may provide insight into treatment targets for OIRD. METHODS: The two optical isomers of METH, d-METH and l-METH, were tested in adult male mice to determine their effects on basal and fentanyl-depressed respiratory frequency, tidal volume, and minute ventilation (MVb; i.e., respiratory frequency x tidal volume) using whole-body plethysmography. RESULTS: When tested at dose ranges of 1.0-10 mg/kg, d-METH elevated MVb and l-METH decreased basal MVb. A dose of 30 mg/kg l-METH increased basal MVb. Under fentanyl-depressed conditions, the bidirectional effects of racemic METH were observed with d-METH treatment while l-METH significantly exacerbated OIRD at 1.0 and 3.0 mg/kg. CONCLUSIONS: d-METH and l-METH differentially contribute to the bidirectional respiratory modulation observed by the racemate, with d-METH exhibiting predominantly stimulatory effects and l-METH exhibiting primarily depressant effects depending on dose.

[Analysis on early predictors of respiratory depression in patients with glufosinate poisoning].

Objective: To investigate the early predictors of respiratory depression in patients with glufosinate poisoning, and provide reference for clinicians to make decisions. Methods: In March 2022, the clinical data of patients with glufosinate poisoning admitted to the intensive care unit of the Affiliated Xiangshan Hospital of Wenzhou Medical University from March 2018 to January 2022 were retrospectively analyzed. The patients were divided into respiratory depression group and non-respiratory depression group according to the occurrence of respiratory depression during hospitalization. The clinical data such as age, gender, past history, intake, initial treatment and laboratory examination were compared between the two groups. Multivariate logistic regression was used to analyze the predictors of respiratory depression in patients with glufosinate poisoning, and its predictive value was analyzed by receiver operating characteristic (ROC) curve. Results: A total of 34 patients with glufosinate poisoning were enrolled, including 13 patients in non-respiratory depression group and 21 patients in respiratory depression group. There were significant differences in intake, blood amylase and bicarbonate radical in arterial blood gas between the two groups (P<0.05). Respiratory depression occurred at 6.5-48.0 h after ingestion, with a median of 15.0 (9.5, 24.0) h. Multivariate logistic regression analysis showed that the intake of glufosinate (OR=1.440, 95%CI: 1.033-2.009, P=0.032) and bicarbonate radical in arterial blood gas (OR=0.199, 95%CI: 0.040-0.994, P=0.049) were predictors of respiratory depression in patients with glufosinate poisoning, and the area under the curve (AUC) of ROC curves were 0.936 and 0.842. The optimal cut-off values were 15.0 g (sensitivity=95.2%, specificity=76.9%) and 17.6 mmol/L (sensitivity=71.4%, specificity=84.6%), respectively. Conclusion: The intake of glufosinate and bicarbonate radical in arterial blood gas have good prediction effects on the occurrence of respiratory depression in patients with glufosinate poisoning.

Modeling Effects of Variable preBötzinger Complex Network Topology and Cellular Properties on Opioid-Induced Respiratory Depression and Recovery.

The preBötzinger complex (preBötC), located in the medulla, is the essential rhythm-generating neural network for breathing. The actions of opioids on this network impair its ability to generate robust, rhythmic output, contributing to life-threatening opioid-induced respiratory depression (OIRD). The occurrence of OIRD varies across individuals and internal and external states, increasing the risk of opioid use, yet the mechanisms of this variability are largely unknown. In this study, we utilize a computational model of the preBötC to perform several in silico experiments exploring how differences in network topology and the intrinsic properties of preBötC neurons influence the sensitivity of the network rhythm to opioids. We find that rhythms produced by preBötC networks in silico exhibit variable responses to simulated opioids, similar to the preBötC network in vitro. This variability is primarily due to random differences in network topology and can be manipulated by imposed changes in network connectivity and intrinsic neuronal properties. Our results identify features of the preBötC network that may regulate its susceptibility to opioids.

Role of continuous pulse oximetry and capnography monitoring in the prevention of postoperative respiratory failure, postoperative opioid-induced respiratory depression and adverse outcomes on hospital wards: A systematic review and meta-analysis.

OBJECTIVE: The current standards of postoperative respiratory monitoring on medical-surgical floors involve spot-pulse oximetry checks every 4-8 h, which can miss the opportunity to detect prolonged hypoxia and acute hypercapnia. Continuous respiratory monitoring can recognize acute respiratory depression episodes; however, the existing evidence is limited. We sought to review the current evidence on the effectiveness of continuous pulse oximetry (CPOX) with and without capnography versus routine monitoring and their effectiveness for detecting postoperative respiratory failure, opioid-induced respiratory depression, and preventing downstream adverse events. METHODS: We performed a systematic literature search on Ovid Medline, Embase, and Cochrane Library databases for articles published between 1990 and April 2023. The study protocol was registered in Prospero (ID: 439467), and PRISMA guidelines were followed. The NIH quality assessment tool was used to assess the quality of the studies. Pooled analysis was conducted using the software R version 4.1.1 and the package meta. The stability of the results was assessed using sensitivity analysis. DESIGN: Systematic Review and Meta-Analysis. SETTING: Postoperative recovery area. PATIENTS: 56,538 patients, ASA class II to IV, non-invasive respiratory monitoring, and post-operative respiratory depression. INTERVENTIONS: Continuous pulse oximetry with or without capnography versus routine monitoring. MEASUREMENTS: Respiratory rate, oxygen saturation, adverse events, and rescue events. RESULTS: 23 studies (17 examined CPOX without capnography and 5 examined CPOX with capnography) were included in this systematic review. CPOX was better at recognizing desaturation (SpO2 < 90%) OR: 11.94 (95% CI: 6.85, 20.82; p < 0.01) compared to standard monitoring. No significant differences were reported for ICU transfer, reintubation, and non-invasive ventilation between the two groups. CONCLUSIONS: Oxygen desaturation was the only outcome better detected with CPOX in postoperative patients in hospital wards. These comparisons were limited by the small number of studies that could be pooled for each outcome and the heterogeneity between the studies.

Effects of the orexin receptor 2 agonist danavorexton on emergence from general anaesthesia and opioid-induced sedation, respiratory depression, and analgesia in rats and monkeys.

BACKGROUND: Delayed emergence from general anaesthesia, opioid-induced sedation, and opioid-induced respiratory depression is associated with perioperative complications. We characterised the preclinical effects of the orexin receptor 2 (OX2R)-selective agonist danavorexton (TAK-925) on emergence from anaesthesia and reversal of fentanyl-induced sedation, respiratory depression, and analgesia. METHODS: Emergence from isoflurane- or propofol-induced anaesthesia and fentanyl-induced sedation were investigated by righting reflex, rotarod, and electroencephalography in rats or monkeys. Fentanyl-induced respiratory depression was assessed by arterial blood gas analysis and whole-body plethysmography in rats and monkeys. Analgesia was evaluated using formalin- and skin incision-induced pain models in rats. RESULTS: Danavorexton shortened emergence from isoflurane- or propofol-induced anaesthesia and from fentanyl-induced sedation at 1 (P=0.005), 3 (P=0.006), and 3 mg kg-1 s.c. (P=0.022), respectively, by righting reflex in rats. Danavorexton (10 mg kg-1 s.c.) accelerated recovery from isoflurane-, propofol- and fentanyl-induced motor impairment in separate rotarod tests in rats (P=0.008, P=0.007, P=0.017, respectively), and reversed anaesthesia and fentanyl-induced delta-power increases. Danavorexton shortened emergence (return of righting reflex) from isoflurane- or propofol-induced anaesthesia at 1 (P=0.002) and 3 mg kg-1 (P=0.004), respectively, in cynomolgus monkeys. Danavorexton (10 mg kg-1 s.c.) reversed fentanyl-induced increase in Pco2 (P=0.006), and decrease in Po2 (P=0.015) and pH (P<0.001) in rats, and at 3 mg kg-1 s.c. reversed fentanyl-induced increase in Pco2 (P=0.007), and decrease in Po2 (P=0.013) and SO2 (P=0.036) in monkeys. Danavorexton increased minute volume and tidal volume in fentanyl-treated animals. Danavorexton at ≤10 mg kg-1 s.c. did not compromise fentanyl analgesia in rat formalin- and skin incision-induced pain models. CONCLUSIONS: Danavorexton promoted recovery from anaesthesia and fentanyl-induced sedation, and antagonised fentanyl-induced respiratory depression without compromising fentanyl analgesia.