Influence of genetic variants on remifentanil sensitivity in Chinese women.

WHAT IS KNOWN AND OBJECTIVE: Significant individual differences have been observed in pain sensitivity and analgesic effect of opioids. Previous studies have shown that genetic factors contributed to analgesics requirement obviously. Therefore, we investigated the role of genetic polymorphisms in the sensitivity to the analgesic effect of remifentanil in this study. METHODS: One hundred thirty-seven patients undergoing gynaecological surgery were observed. Before procedures, we measured the basal pain threshold of each patient, including the pressure pain threshold and pressure pain tolerance threshold. Subsequently, patients received a continuous remifentanil infusion for 15 min at a constant rate of 0.2 µg/(kg min). The pain thresholds were measured again after the remifentanil infusion. Moreover, respiratory depression was estimated using oxygen saturation during infusion. DNA was extracted from peripheral venous blood and genotyped using SNaPshot technology. RESULTS AND DISCUSSION: Polymorphisms were found in genes associated with the individual variation in analgesia. Participants carrying OPRM1 rs9397685 AA, ADRB1 rs1801253 CC, and GCH1 rs8007267 CC polymorphisms showed higher sensitivity to analgesic effect induced by remifentanil, and the participants carrying the OPRD1 rs2234918 TT showed lower sensitivity to remifentanil-related respiratory depression. Moreover, individual susceptibility to remifentanil increases with age. WHAT IS NEW AND CONCLUSION: Gene variation in OPRM1 rs9397685 AA, ADRB1 rs1801253 CC, GCH1 rs8007267 CC, and OPRD1 rs2234918 TT were related to the conspicuous interindividual differences in the analgesia and respiratory depression of remifentanil, mainly by affecting the target protein receptors and relative metabolic enzymes.

Effect of age and ICU types on mortality in invasive mechanically ventilated patients with sepsis receiving dexmedetomidine: a retrospective cohort study with propensity score matching.

Background: Dexmedetomidine is recommended for sedation in patients on mechanical ventilation. Whether age or ICU types could alter mortality in invasive mechanically ventilated patients with sepsis receiving dexmedetomidine is unknown. Methods: We included patients with sepsis receiving invasive mechanical ventilation from the Medical Information Mart for Intensive Care IV database. The exposure was intravenous dexmedetomidine administration during ICU stay. The primary outcome was 28-day mortality. The secondary outcomes were the length of ICU stay and liberation from invasive mechanical ventilation. Propensity score matching (PSM) and Cox proportional hazards regression were used to adjust for confounders and investigate any association. Restricted cubic spline models were used to evaluate potential nonlinear associations. Results: The pre-matched and propensity score-matched cohorts included 5,871 and 2016 patients, respectively. In the PSM cohorts, dexmedetomidine exposure was related to lower 28-day mortality (186 [17.7%] vs. 319 [30.3%]; p < 0.001). Patients receiving dexmedetomidine, regardless of whether they were younger (≤65 years; hazard ratio [HR], 0.31; 95% confidence interval [CI], 0.23-0.42; p < 0.001) or elderly (>65 years; HR, 0.65; 95% CI, 0.52-0.83; p < 0.001), was associated with lower 28-day mortality (61 [10.3%] vs. 168 [28.2%] for younger; 125 [27.2%] vs. 152 [33.0%] for elderly). Patients receiving dexmedetomidine was also associated with lower 28-day mortality (53 [12.6%] vs. 113 [26.5%] for surgical intensive care unit [SICU]; 133 [21.0%] vs. 206 [32.9%] for non-SICU) regardless of whether the first admission to the SICU (HR, 0.36; 95% CI, 0.25-0.50; p < 0.001) or non-SICU (HR, 0.50; 95% CI, 0.40-0.62; p < 0.001). Moreover, both dose and duration of dexmedetomidine administration were related to lower 28-day mortality than no dexmedetomidine in younger patients (p < 0.001), but it not statistically significant in elderly patients. Conclusion: Dexmedetomidine was associated with lower 28-day mortality in critically ill patients with sepsis receiving invasive mechanical ventilation, regardless of whether patients were younger or elderly, the first admission to the SICU or non-SICU.

Polymorphisms contribute to differences in the effect of rocuronium in Chinese patients.

Rocuronium is widely utilized in clinical general anaesthesia, and individual differences in pharmacology and clearance have been observed. Two hundred thirty-six Chinese patients undergoing selective thyroid/breast mass resection were studied. Total intravenous anaesthesia was induced with a single dose of propofol (2 mg·kg-1 ), sufentanil (0.5 µg·kg-1 ), and rocuronium (0.6 mg·kg-1 ) and maintained with propofol (3-5 mg·kg-1 ·h-1 ) and remifentanil (0.2-0.4 µg·kg-1 ·min-1 ). Intubation conditions and a train-of-four index of patients were utilized to assess the effects and duration of rocuronium. The data from 228 patients were analysed and reported. Genotypes NR1I2 rs2472677 C > T, NR1I2 rs6785049 G > A, SLCO1B1 rs4363657 T > C, SLCO1A2 rs4762699 T > C, and UGT1A1 rs4148323 G > A contributed to individual variation in rocuronium. Of the clinical variables tested, age, BMI, total dose of propofol, NR1I2 rs2472677, and SLCO1A2 rs4762699 correlated significantly (P < 0.05 for all) with the clinical duration or total clinical action time of rocuronium in a multiple linear regression model. No significant interactions were observed in intubation conditions. Genetic variations in NR1I2 rs2472677, NR1I2 rs6785049, SLCO1B1 rs4363657, SLCO1A2 rs4762699, and UGT1A1 rs4148323 were related to extensive interindividual variability in the clinical duration and total clinical action time of rocuronium.

Electroencephalogram Signatures of Agitation Induced by Sevoflurane and Its Association With Genetic Polymorphisms.

Background: Volatile anesthetic-induced agitation, also called paradoxical excitation, is not uncommon during anesthesia induction. Clinically, patients with agitation may lead to self-injury or disrupt the operative position, increasing the incidence of perioperative adverse events. The study was designed to investigate clinical features of sevoflurane-induced agitation and examined whether any gene polymorphisms can potentially be used to predict agitation. Methods: One hundred seventy-six patients underwent anesthesia induction with sevoflurane were included in this study. Frontal electroencephalogram (EEG), electromyography (EMG), and hemodynamics were recorded continuously during anesthesia induction. DNA samples were genotyped using the Illumina Infinium Asian Screening Array and the SNaPshot technology. Genetic association was analyzed by genome-wide association study. Logistic regression analysis was used to determine the role of variables in the prediction of agitation. Results: Twenty-five (14.2%) patients experienced agitation. The depth of anesthesia index (Ai index) (p < 0.001), EMG (p < 0.001), heart rate (HR) (p < 0.001), and mean arterial pressure (MAP) (p < 0.001) rapidly increased during the agitation. EEG exhibited a shift toward high frequencies with spikes during agitation. The fast waves (alpha and beta) were more pronounced and the slow rhythms (delta) were less prominent during the occurrence of agitation. Moreover, three SNPs in the methionine synthase reductase (MTRR) gene were correlated to the susceptibility to agitation (p < 5.0 × 10-6). Carrying rs1801394 A > G (odds ratio 3.50, 95% CI 1.43-9.45) and/or rs2307116 G > A (3.31, 1.36-8.95) predicted a higher risk of agitation. Discussion: This study suggests that the agitation/paradoxical excitation induced by sevoflurane is characterized as increases in Ai index, EMG, HR and MAP, and the high frequency with spikes in EEG. Moreover, our results provide preliminary evidence for MTRR genetic polymorphisms, involving folate metabolism function, may be related to the susceptibility to agitation. Clinical Trial Number and Registry URL: ChiCTR1900026218; http://www.chictr.org.cn/showproj.aspx?proj=40655.

Sevoflurane Increases Hippocampal Theta Oscillations and Impairs Memory Via TASK-3 Channels.

Sevoflurane can induce memory impairment during clinical anesthesia; however, the underlying mechanisms are largely unknown. TASK-3 channels are one of the potential targets of sevoflurane. Accumulating evidence supports a negative role of intracranial theta rhythms (4-12 Hz) in memory formation. Here, we investigated whether TASK-3 channels contribute to sevoflurane-induced memory impairment by regulating hippocampal theta rhythms. In this study, the memory performance of mice was tested by contextual fear conditioning and inhibitory avoidance experiments. The hippocampal local field potentials (LFPs) were recorded from chronically implanted electrodes located in CA3 region. The results showed that sevoflurane concentration-dependently impaired the memory function of mice, as evidenced by the decreased time mice spent on freezing and reduced latencies for mice to enter the shock compartment. Our electrophysiological results revealed that sevoflurane also enhanced the spectral power of hippocampal LFPs (1-30 Hz), particularly in memory-related theta rhythms (4-12 Hz). These effects were mitigated by viral-mediated knockdown of TASK-3 channels in the hippocampal CA3 region. The knockdown of hippocampal TASK-3 channels significantly reduced the enhancing effect of sevoflurane on hippocampal theta rhythms and alleviated sevoflurane-induced memory impairment. Our data indicate that sevoflurane can increase hippocampal theta oscillations and impair memory function via TASK-3 channels.