Intravenous Bolus of Dexmedetomidine for Treatment of Severe Shivering After Caesarean Delivery Under Combined Spinal-Epidural Anaesthesia: A Randomized Dose-Response Study

Alvarez-Jimenez R., Weerink M.A., Hannivoort L.N., Su H., Struys M.M., Loer S.A., Colin P.J.

Background Numerous pharmacokinetic models have been published aiming at more accurate and safer dosing of dexmedetomidine. The vast majority of the developed models underpredict the measured plasma concentrations with respect to the target concentration, especially at plasma concentrations higher than those used in the original studies. The aim of this article was to develop a dexmedetomidine pharmacokinetic model in healthy adults emphasizing linear versus nonlinear kinetics. Methods The data of two previously published clinical trials with stepwise increasing dexmedetomidine target-controlled infusion were pooled to build a pharmacokinetic model using the NONMEM software package (ICON Development Solutions, USA). Data from 48 healthy subjects, included in a stratified manner, were utilized to build the model. Results A three-compartment mamillary model with nonlinear elimination from the central compartment was superior to a model assuming linear pharmacokinetics. Covariates included in the final model were age, sex, and total body weight. Cardiac output did not explain between-subject or within-subject variability in dexmedetomidine clearance. The results of a simulation study based on the final model showed that at concentrations up to 2 ng · ml–1, the predicted dexmedetomidine plasma concentrations were similar between the currently available Hannivoort model assuming linear pharmacokinetics and the nonlinear model developed in this study. At higher simulated plasma concentrations, exposure increased nonlinearly with target concentration due to the decreasing dexmedetomidine clearance with increasing plasma concentrations. Simulations also show that currently approved dosing regimens in the intensive care unit may potentially lead to higher-than-expected dexmedetomidine plasma concentrations. Conclusions This study developed a nonlinear three-compartment pharmacokinetic model that accurately described dexmedetomidine plasma concentrations. Dexmedetomidine may be safely administered up to target-controlled infusion targets under 2 ng · ml–1 using the Hannivoort model, which assumed linear pharmacokinetics. Consideration should be taken during long-term administration and during an initial loading dose when following the dosing strategies of the current guidelines. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

Sween L.K., Xu S., Li C., O'Donoghue M.A., Ciampa E.J., Kowalczyk J.J., Li Y., Hess P.E.

Intravenous dexmedetomidine 30 µg reduces shivering after cesarean delivery but can result in sedation and dry mouth. We hypothesized that prophylactic administration of 10 µg of IV dexmedetomidine would reduce the patient-reported severity of shivering after cesarean delivery, without an increased incidence of side effects.After institutional review board approval and informed written consent, women undergoing scheduled cesarean delivery with spinal or combined spinal-epidural anesthesia were randomized to receive either intravenous normal saline or dexmedetomidine 10 µg immediately after delivery. The primary outcome was a patient-rated subjective shivering score using a 10-cm visual analog scale at 30 and 60 min after arrival in the Post-Anesthesia Care Unit. Secondary outcomes included subjective scores for pain, nausea, itching, dry mouth, and sedation, as well as 24-h medication administration and investigator-rated observations of shivering, vomiting, pruritus, and sedation. Repeated measures ANOVA with Tukey-Kramer multiple-comparison test was applied for primary outcomes.One hundred patients were enrolled, and 85 completed the study and were included in analysis. The mean ± SD shivering score in the dexmedetomidine group was significantly lower by repeated measures analysis than among controls across the first 60 min (P=0.0002), and individually at both 30 and 60 min (placebo 1.8 ± 2.6 vs. dexmedetomidine 0.6 ± 1.4 at 30 min; 1.2 ± 2.1 vs. 0.3 ± 0.6 at 60 min; both P

Tang Y., Yang M., Fu F., Huang X., Feng Y., Chen X.

Study objective Studies have showed that intrathecal dexmedetomidine as supplements to local anesthetics can improve the quality of the spinal anesthesia and reduce the local anesthetic requirement of spinal anesthesia for cesarean section. However, the magnitude of this effect has not been fully quantified. Therefore, we conducted the present study to investigate the ED50 of intrathecal hyperbaric ropivacaine with or without dexmedetomidine for cesarean section in healthy parturients. ED50 values obtained were compared to estimate the effect of intrathecal dexmedetomidine versus placebo on ropivacaine requirement. Design Single-blinded, prospective, randomized study. Setting Department of Anesthesia, Women's Hospital, Zhejiang University School of Medicine. Patients Sixty healthy parturients under elective cesarean section with combined spinal-epidural anesthesia were randomized into Group C (intrathecal ropivacaine alone) and Group D (intrathecal ropivacaine + 5 μg dexmedetomidine). Interventions The dose of intrathecal ropivacaine for the first parturient in both groups was 11 mg. An increment or decrement of 0.5 mg intrathecal ropivacaine was made for the subsequent parturient based on the effective or ineffective response of the previous parturient. Effective dose was defined as a bilateral T6 or above sensory block level was achieved within 15 min after induce of spinal anesthesia and no additional epidural anesthetics was required during surgery. The Dixon and Massay sequential method and Probit regression were applied to calculate the ED50 of intrathecal ropivacaine in both groups. Measurements Characteristics of spinal anesthesia and side effects were recorded. Main results The ED50 of hyperbaric ropivacaine calculated by Dixon and Massay formula was 11.4 mg (95% CI, 11.1–11.7 mg) in Group C, and 9.4 mg (95% CI, 9.0–9.7 mg) in Group D (P  Conclusion Under the conditions of the present study, intrathecal dexmedetomidine (5 μg) reduced the ED50 of intrathecal hyperbaric ropivacaine by approximately 18% for cesarean section in healthy parturients under combined spinal-epidural anesthesia.

Gan T.J., Belani K.G., Bergese S., Chung F., Diemunsch P., Habib A.S., Jin Z., Kovac A.L., Meyer T.A., Urman R.D., Apfel C.C., Ayad S., Beagley L., Candiotti K., Englesakis M., et. al.

This consensus statement presents a comprehensive and evidence-based set of guidelines for the care of postoperative nausea and vomiting (PONV) in both adult and pediatric populations. The guidelines are established by an international panel of experts under the auspices of the American Society of Enhanced Recovery and Society for Ambulatory Anesthesia based on a comprehensive search and review of literature up to September 2019. The guidelines provide recommendation on identifying high-risk patients, managing baseline PONV risks, choices for prophylaxis, and rescue treatment of PONV as well as recommendations for the institutional implementation of a PONV protocol. In addition, the current guidelines focus on the evidence for newer drugs (eg, second-generation 5-hydroxytryptamine 3 [5-HT3] receptor antagonists, neurokinin 1 (NK1) receptor antagonists, and dopamine antagonists), discussion regarding the use of general multimodal PONV prophylaxis, and PONV management as part of enhanced recovery pathways. This set of guidelines have been endorsed by 23 professional societies and organizations from different disciplines (Appendix 1).Guidelines currently available include the 3 iterations of the consensus guideline we previously published, which was last updated 6 years ago; a guideline published by American Society of Health System Pharmacists in 1999; a brief discussion on PONV management as part of a comprehensive postoperative care guidelines; focused guidelines published by the Society of Obstetricians and Gynecologists of Canada, the Association of Paediatric Anaesthetists of Great Britain & Ireland and the Association of Perianesthesia Nursing; and several guidelines published in other languages.The current guideline was developed to provide perioperative practitioners with a comprehensive and up-to-date, evidence-based guidance on the risk stratification, prevention, and treatment of PONV in both adults and children. The guideline also provides guidance on the management of PONV within enhanced recovery pathways.The previous consensus guideline was published 6 years ago with a literature search updated to October 2011. Several guidelines, which have been published since, are either limited to a specific populations or do not address all aspects of PONV management. The current guideline was developed based on a systematic review of the literature published up through September 2019. This includes recent studies of newer pharmacological agents such as the second-generation 5-hydroxytryptamine 3 (5-HT3) receptor antagonists, a dopamine antagonist, neurokinin 1 (NK1) receptor antagonists as well as several novel combination therapies. In addition, it also contains an evidence-based discussion on the management of PONV in enhanced recovery pathways. We have also discussed the implementation of a general multimodal PONV prophylaxis in all at-risk surgical patients based on the consensus of the expert panel.

Jun J., Chung M.H., Jun I., Kim Y., Kim H., Kim J.H., Choi Y.R., Choi E.M.

Peri-operative hypothermia and shivering are frequent events in patients during caesarean delivery under spinal anaesthesia.We assessed the efficacy of combined pre-anaesthetic forced-air warming in combination with warmed intravenous fluid infusion for preventing hypothermia and shivering during caesarean delivery under spinal anaesthesia.A randomised controlled study.A tertiary care teaching hospital from July 2017 to April 2018.A total of 50 pregnant women, American Society of Anaesthesiologists physical status 2, aged 20 to 45 years, scheduled for caesarean delivery under spinal anaesthesia.Patients were enrolled and randomised into two groups: an active warming group (n = 25), which received combined pre-anaesthetic whole body forced-air warming for 15 min and prewarmed intravenous fluids, and a control group, which received no active warming or warmed fluids (C group; n = 25). Spinal anaesthesia was induced with 10 mg bupivacaine containing fentanyl (10 μg).Tympanic membrane temperature and shivering severity were measured at baseline and every 10 min during surgery, and then every 10 min for 1 h postoperatively. Neonatal outcomes (tympanic membrane temperature at birth, umbilical venous blood pH, Apgar score) were also recorded.The incidences of peri-operative hypothermia (0 vs. 48%, P < 0.001) and shivering (22 vs. 52%, P = 0.031) were significantly lower in the active warming than in the C group. The maximum temperature change was also significantly lower in the active warming than in the C group. Maternal thermal comfort scores were higher in the active warming than in the C group. Neonatal parameters were not significantly different between the groups.The combination of pre-anaesthetic forced-air warming and warmed intravenous fluid infusions appears to be effective for preventing hypothermia and shivering during caesarean delivery under spinal anaesthesia.This trial was registered with Clinical Trials.gov (identifier: NCT03256786).

Wang C., Chen F., Wu J., Fu S., Xu X., Chen J., Jiang Y., Lian Q., Liu H.

Aims Dexmedetomidine is highly specific α2-adrenoceptor agonist. A single bolus of dexmedetomidine can achieve clinical therapeutic effect. Therefore, it is essential to know the safety margin between the clinical effectiveness dosages of dexmedetomidine and its side effect. Methods A total of 42 patients who underwent elective thyroidectomy were enrolled in this study. Dexmedetomidine was given as a single bolus injection 30 min towards the end of surgery. The up-and-down sequential schedule was used in this study. The starting dose of dexmedetomidine was set at 0.1 μg/kg in the first patient and the next patient would then receive a dose of dexmedetomidine decremented by 0.05 μg/kg if the prior patient's baseline heart rate (HR) had a decrease of ≥20% and/or mean arterial blood pressure (MAP) increase or decrease of ≥20%, otherwise, the following patient would receive an incremental 0.05 μg/kg dose of dexmedetomidine. The analytic techniques of linear, linear-logarithmic, exponential regressions and centred isotonic regression were used to determine the ED50 of dexmedetomidine and the residual standard errors were calculated for the comparison of goodness of fit among the different models. Results The median (interquartile range [range]) lowest HR was 57 beats/min (53-63.3[46-76]) with an average HR decrease of 8.0 beats/min (5-13 [4 to 23]). The median (interquartile range [range]) highest MAP was 98 mmHg (91.8-105 [83-126]) with a MAP increase of 10.0 mmHg (6.8-18.0 [2-24]). The ED50 (95% confidence interval) from 4 different statistical approaches (linear, linear-logarithmic, exponential regressions and centred isotonic regression) were 0.262 μg/kg (0.243, 0.306), 0.252 μg/kg (0.238, 0.307), 0.283 μg/kg (0.238, 0.307), and 0.278 μg/kg, respectively. Among the 4 models, the exponential regression had the least residual standard error (0.03618). Conclusion The ED50 derived from 4 statistical models for an intravenous bolus of dexmedetomidine without significant haemodynamic effects was distributed in a narrow range of 0.252-0.283 μg/kg, and the exponential regression was the model to best match the study data.

Lamontagne C., Lesage S., Villeneuve E., Lidzborski E., Derstenfeld A., Crochetière C.

About 55% of patients undergoing a Cesarean delivery under spinal or epidural anesthesia will experience shivering, which may interfere with the monitoring of vital signs. Recent studies have shown that dexmedetomidine could potentially help to alleviate shivering associated with anesthesia. We investigated whether dexmedetomidine, an alpha 2-adrenergic agonist, reduces the duration of shivering associated with neuraxial anesthesia during Cesarean delivery. Eighty parturients undergoing Cesarean delivery under neuraxial anesthesia and experiencing shivering were enlisted in this prospective, randomized, double-blind trial. After childbirth, the intervention group (n = 40) received a single intravenous bolus of dexmedetomidine (30 µg) while the control group (n = 40) received saline. Randomization and allocation were based on a computer-generated list. The primary outcome measure was the time required for an observable decrease in shivering after the intervention. One hundred fifty-five patients were recruited, 80 of whom presented with shivering and were randomized. Our study showed that dexmedetomidine reduced the mean (standard deviation) duration of shivering after a single intravenous bolus to 2.6 (2.1) min after dexmedetomidine from 17.9 (12.6) min after saline (difference in means, -15.3 min; 95% confidence interval [CI], -11.2 to -19.4). The effect of dexmedetomidine persisted 15 min after the bolus was administered, as shivering had completely stopped in 90% of the patients in the intervention group vs 22.5% in the control group (relative risk, 4.0; 95% CI, 2.2 to 7.2). No adverse effects, including bradycardia, were observed. A single intravenous bolus of dexmedetomidine decreased the duration of shivering for up to 15 min during Cesarean delivery under neuraxial anesthesia. www.clinicaltrials.gov (NCT02384343); registered 10 March, 2015.

Bautista L., George R.B.

Yu G., Jin S., Chen J., Yao W., Song X.

Abstract Objective: Meperidine used to control shivering during perioperative period has associated side effects. The present study compared the safety of selective α2-adrenoreceptor agonist dexmedetomidine and meperidine for anti-shivering in primiparas after caesarean delivery under combined spinal-epidural anesthesia (CSEA). Methods: 100 primiparas scheduled for caesarean delivery were randomly allocated to dexmedetomidine group (Group D, n=50) and meperidine positive control group (Group M, n=50). Primiparas experienced shivering that continued to cord clamping were treated with dexmedetomidine (0.5 μg/kg) or meperidine (0.5 mg/kg) after cord clamping. The primary outcome measures were incidence of nausea, vomiting, and respiratory depression. Secondary outcome measures were shivering score, vital signs including blood pressure, heart rate and O2 saturation, tympanic temperature, and sedation score. Results: Dexmedetomidine provided similar anti-shivering effects as meperidine in patients after caesarean delivery under CSEA, evidenced as all shivering primiparas responded to either dexmedetomidine or meperidine treatment within 15 min. However, incidence of nausea and vomiting were significantly lower after dexmedetomidine treatment, accompanied with more stable blood pressure. Dexmedetomidine also provided well regulation of tympanic temperature and good sedation. Conclusion: Selective α2-adrenoreceptor agonist dexmedetomidine has a better safety profile compared with meperidine for anti-shivering in primiparas undergoing caesarean delivery. Dexmedetomidine could be a better choice for anti-shivering in patients requiring caesarean section. The mechanism of anti-shivering for dexmedetomidine may relate to well regulation of temperature and good sedation.

Liu J., Wang Y., Ma W.

Sng B.L., Dabas R., Sia A.T.

Ameta N., Jacob M., Hasnain S., Ramesh G.

Jelting Y., Klein C., Harlander T., Eberhart L., Roewer N., Kranke P.

Intraoperative nausea and vomiting (IONV) or postoperative nausea and vomiting (PONV) affecting women undergoing regional anesthesia for cesarean section is an important clinical problem since these techniques are used widely. There are burdens of literature about IONV/PONV and several in parturient and cesarean. However, it needs more attention. The underlying mechanisms of IONV and PONV in the obstetrical setting mainly include hypotension due to sympathicolysis during neuraxial anesthesia, bradycardia owing to an increased vagal tone, the visceral stimulation via the surgical procedure and intravenously administered opioids.Given the high and even increasing rate of cesarean sections and the sparse information on the etiology, incidence and severity of nausea and vomiting and the impact of prophylactic measures on the incidence of PONV/IONV, this article aims to review the available information and provide pragmatic suggestions on how to prevent nausea and vomiting in this patient cohort. Current literature and guidelines were identified by electronic database searching (MEDLINE via PubMed and Cochrane database of systematic reviews) up to present, searching through reference lists of included literature and personal contact with experts.Taking into account the current guidelines and literature as well as everyday clinical experience, the first step for decreasing the incidence of IONV and PONV is a comprehensive management of circulatory parameters. This management includes liberal perioperative fluid administration and the application of vasopressors as the circumstances require. By using low-dose local anesthetics, an additional application of intrathecal or spinal opioids or hyperbaric solutions for a sufficient controllability of neuraxial distribution, maternal hypotension might be reduced. Performing a combined spinal-epidural anesthesia or epidural anesthesia may be considered as an alternative to spinal anesthesia. Antiemetic drugs may be administered restrainedly due to off-label use in pregnant women for IONV or PONV prophylaxis and may be reserved for treatment.

Colin P.J., Hannivoort L.N., Eleveld D.J., Reyntjens K.M., Absalom A.R., Vereecke H.E., Struys M.M.

Dexmedetomidine, a selective α 2 -adrenoreceptor agonist, has unique characteristics, with little respiratory depression and rousability during sedations. We characterized the haemodynamic properties of dexmedetomidine by developing a pharmacokinetic-pharmacodynamic (PKPD) model with a focus on changes in mean arterial blood pressure (MAP) and heart rate.Dexmedetomidine was delivered i.v. to 18 healthy volunteers in a step-up fashion by target-controlled infusion using the Dyck model. Exploratory PKPD modelling and covariate analysis were conducted in NONMEM.Our model adequately describes dexmedetomidine-induced hypotension, hypertension, and bradycardia, with a greater effective concentration for the hypertensive effect. Changes in MAP were best described by a double-sigmoidal E max model with hysteresis. Covariate analysis revealed no significant covariates apart from age on the baseline MAP in the population pharmacokinetic model used to develop this PKPD model. Simulations revealed good general agreement with published descriptive studies of haemodynamics after dexmedetomedine infusion.The present integrated PKPD model should allow tighter control over the desired level of sedation, while limiting potential haemodynamic side-effects.NCT01879865.

Kundra T., Kuthiala G., Shrivastava A., Kaur P.

Soloniuk L.J., Jones J., Baker C., Bishawi M., Pasca I., Sinha A.

The rarity of Huntington’s disease (HD) parturients implies that anesthesiologists have little exposure to the management of these patients. We explore techniques for the management of a 21-year-old parturient with symptomatic HD who underwent successful neuraxial anesthesia for labor and subsequent cesarean delivery. We provide guidance on perioperative medications for comorbidities associated with HD. Dexmedetomidine, which we administered neuraxially, appears to have significant potential for the perioperative diminution of choreiform movements. Current anesthetic management of HD cannot be informed by traditional research methodology and therefore much information must be gleaned from the limited available case reports.

Douglas M.S., Soloniuk L.J., Jones J., Derderian R., Baker C., Stier G.