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Intraoperative ketamine for prevention of postoperative delirium or pain after major surgery in older adults: an international, multicentre, double-blind, randomised clinical trial.

ABSTRACT: BACKGROUND:Delirium is a common and serious postoperative complication. Subanaesthetic ketamine is often administered intraoperatively for postoperative analgesia, and some evidence suggests that ketamine prevents delirium. The primary purpose of this trial was to assess the effectiveness of ketamine for prevention of postoperative delirium in older adults. METHODS:The Prevention of Delirium and Complications Associated with Surgical Treatments [PODCAST] study is a multicentre, international randomised trial that enrolled adults older than 60 years undergoing major cardiac and non-cardiac surgery under general anaesthesia. Using a computer-generated randomisation sequence we randomly assigned patients to one of three groups in blocks of 15 to receive placebo (normal saline), low-dose ketamine (0·5 mg/kg), or high dose ketamine (1·0 mg/kg) after induction of anaesthesia, before surgical incision. Participants, clinicians, and investigators were blinded to group assignment. Delirium was assessed twice daily in the first 3 postoperative days using the Confusion Assessment Method. We did analyses by intention-to-treat and assessed adverse events. This trial is registered with clinicaltrials.gov, number NCT01690988. FINDINGS:Between Feb 6, 2014, and June 26, 2016, 1360 patients were assessed, and 672 were randomly assigned, with 222 in the placebo group, 227 in the 0·5 mg/kg ketamine group, and 223 in the 1·0 mg/kg ketamine group. There was no difference in delirium incidence between patients in the combined ketamine groups and the placebo group (19·45% vs 19·82%, respectively; absolute difference 0·36%, 95% CI -6·07 to 7·38, p=0·92). There were more postoperative hallucinations (p=0·01) and nightmares (p=0·03) with increasing ketamine doses compared with placebo. Adverse events (cardiovascular, renal, infectious, gastrointestinal, and bleeding), whether viewed individually (p value for each >0·40) or collectively (36·9% in placebo, 39·6% in 0·5 mg/kg ketamine, and 40·8% in 1·0 mg/kg ketamine groups, p=0·69), did not differ significantly across groups. INTERPRETATION:A single subanaesthetic dose of ketamine did not decrease delirium in older adults after major surgery, and might cause harm by inducing negative experiences. FUNDING:National Institutes of Health and Cancer Center Support.

SUBMITTER: Avidan MS

PROVIDER: S-EPMC5644286 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Intraoperative ketamine for prevention of postoperative delirium or pain after major surgery in older adults: an international, multicentre, double-blind, randomised clinical trial.

Avidan Michael S MS Maybrier Hannah R HR Abdallah Arbi Ben AB Jacobsohn Eric E Vlisides Phillip E PE Pryor Kane O KO Veselis Robert A RA Grocott Hilary P HP Emmert Daniel A DA Rogers Emma M EM Downey Robert J RJ Yulico Heidi H Noh Gyu-Jeong GJ Lee Yonghun H YH Waszynski Christine M CM Arya Virendra K VK Pagel Paul S PS Hudetz Judith A JA Muench Maxwell R MR Fritz Bradley A BA Waberski Witold W Inouye Sharon K SK Mashour George A GA

Lancet (London, England) 20170530 10091

<h4>Background</h4>Delirium is a common and serious postoperative complication. Subanaesthetic ketamine is often administered intraoperatively for postoperative analgesia, and some evidence suggests that ketamine prevents delirium. The primary purpose of this trial was to assess the effectiveness of ketamine for prevention of postoperative delirium in older adults.<h4>Methods</h4>The Prevention of Delirium and Complications Associated with Surgical Treatments [PODCAST] study is a multicentre, in ...[more]

PMID: 28576285

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Project description:Delirium is a neurobehavioural syndrome that frequently develops in the postoperative setting. The incidence of elderly patients who develop delirium during hospital stay ranges from 10 to 80% (Schonauer et al., J Pept Sci. 2017). Delirium was first described more than half a century ago in the cardiac surgery population (Blachy and Starr, Am J Psychiatry 121:371-5, 1964), where it was already discovered as a state that might be accompanied by serious complications such as prolonged ICU and hospital stay, reduced quality of life and increased mortality. Furthermore, the duration of delirium is associated with worse long-term cognitive function in the general ICU population (Sessler et al., Am J Respir Crit Care Med 166:1338-44, 2002). This long-term experience with delirium suggests a high socioeconomic burden and has been a focus of many studies (Nishio et al., Crit Care Med 5:953-7, 1997; Ehlenbach et al., JAMA 303:763-70, 2010; Jahangir et al., World J Cardiol 3:383-7, 2011; Abegunde et al., Lancet 370:1929-1938, 2007; Darmon et al., Intensive Care Med 43:829-840, 2017; Marino et al., J Nephrol 28:717-24, 2015; Ng LL et al., J Am Coll Cardiol 69:56-69, 2017; Sezen et al., J Pharmacol Exp Ther 287:238-45, 1998; Kim et al., Ann Lab Med 37:388-97, 2017). Due to the multifactorial origin of delirium, we have several but no incontestable options for prevention and symptomatic treatment. Overall, delirium represents a high burden not only for patient and family members, but also for the medical care team that aims to prevent postoperative delirium to avoid serious consequences associated with it. The purpose of this study is to determine whether postoperative delirium can be prevented by the combination of established preventive agents. In addition, measured levels of pre- and postoperative cortisol, neuron specific enolase (NSE) and S-100? will be used to investigate dynamics of these parameters in delirious and non-delirious patients after surgery.The Baden PRIDe Trial is an investigator-initiated, phase IV, two-centre, randomised, placebo-controlled, double-blind clinical trial for the prevention of delirium with haloperidol, ketamine, and the combination of both vs. placebo in 200 patients scheduled for surgery. We would like to investigate superiority of one of the three treatment arms (i.e., haloperidol, ketamine, combined treatment) to placebo.There is limited but promising evidence that haloperidol and ketamine can be used to prevent delirium. Clinical care for patients might improve as the results of this study may lead to better algorithms for the prevention of delirium.ClinicalTrials.gov, NCT02433041 . Registered on 7 April 2015. Swiss National Clinical Trial Portal, SNCTP000001628. Registered on 9 December 2015.

Project description:Postoperative delirium is a common complication associated with increased morbidity and mortality, longer hospital stays, and greater health care expenditures. Intraoperative electroencephalogram (EEG) slowing has been associated previously with postoperative delirium, but the relationship between intraoperative EEG suppression and postoperative delirium has not been investigated.In this observational cohort study, 727 adult patients who received general anesthesia with planned intensive care unit admission were included. Duration of intraoperative EEG suppression was recorded from a frontal EEG channel (FP1 to F7). Delirium was assessed twice daily on postoperative days 1 through 5 with the Confusion Assessment Method for the intensive care unit. Thirty days after surgery, quality of life, functional independence, and cognitive ability were measured using the Veterans RAND 12-item survey, the Barthel index, and the PROMIS Applied Cognition-Abilities-Short Form 4a survey.Postoperative delirium was observed in 162 (26%) of 619 patients assessed. When we compared patients with no EEG suppression with those divided into quartiles based on duration of EEG suppression, patients with more suppression were more likely to experience delirium (?(4) = 25, P < 0.0001). This effect remained significant after we adjusted for potential confounders (odds ratio for log(EEG suppression) 1.22 [99% confidence interval, 1.06-1.40, P = 0.0002] per 1-minute increase in suppression). EEG suppression may have been associated with reduced functional independence (Spearman partial correlation coefficient -0.15, P = 0.02) but not with changes in quality of life or cognitive ability. Predictors of EEG suppression included greater end-tidal volatile anesthetic concentration and lower intraoperative opioid dose.EEG suppression is an independent risk factor for postoperative delirium. Future studies should investigate whether anesthesia titration to minimize EEG suppression decreases the incidence of postoperative delirium. This is a substudy of the Systematic Assessment and Targeted Improvement of Services Following Yearlong Surgical Outcomes Surveys (SATISFY-SOS) surgical outcomes registry (NCT02032030).

Project description:ImportancePostoperative delirium occurs in 10% to 60% of elderly patients having major surgery and is associated with longer hospital stays, increased hospital costs, and 1-year mortality. Emerging literature suggests that dexmedetomidine sedation in critical care units is associated with reduced incidence of delirium. However, intraoperative use of dexmedetomidine for prevention of delirium has not been well studied.ObjectiveTo evaluate whether an intraoperative infusion of dexmedetomidine reduces postoperative delirium.Design, setting, and participantsThis study was a multicenter, double-blind, randomized, placebo-controlled trial that randomly assigned patients to dexmedetomidine or saline placebo infused during surgery and for 2 hours in the recovery room. Patients were assessed daily for postoperative delirium (primary outcome) and secondarily for postoperative cognitive decline. Participants were elderly (>68 years) patients undergoing major elective noncardiac surgery. The study dates were February 2008 to May 2014.InterventionsDexmedetomidine infusion (0.5 µg/kg/h) during surgery and up to 2 hours in the recovery room.Main outcomes and measuresThe primary hypothesis tested was that intraoperative dexmedetomidine administration would reduce postoperative delirium. Secondarily, the study examined the correlation between dexmedetomidine use and postoperative cognitive change.ResultsIn total, 404 patients were randomized; 390 completed in-hospital delirium assessments (median [interquartile range] age, 74.0 [71.0-78.0] years; 51.3% [200 of 390] female). There was no difference in postoperative delirium between the dexmedetomidine and placebo groups (12.2% [23 of 189] vs 11.4% [23 of 201], P = .94). After adjustment for age and educational level, there was no difference in the postoperative cognitive performance between treatment groups at 3 months and 6 months. Adverse events were comparably distributed in the treatment groups.Conclusions and relevanceIntraoperative dexmedetomidine does not prevent postoperative delirium. The reduction in delirium previously demonstrated in numerous surgical intensive care unit studies was not observed, which underscores the importance of timing when administering the drug to prevent delirium.Trial registrationclinicaltrials.gov Identifier NCT00561678.

Project description:BackgroundWe aimed to evaluate whether a single dose of ketamine or dexmedetomidine before induction of general anesthesia could reduce the incidence of postoperative delirium (primary outcome) or cognitive dysfunction (secondary outcome) in elderly patients undergoing emergency surgery.Patients and methodsThis randomized, double-blinded, placebo-controlled trial included 60 elderly patients who were scheduled for emergency surgery. The patients were randomly assigned into one of three groups (n = 20): group I received 0.9% normal saline, group II received 1 µg/kg dexmedetomidine, and group III received 1 mg/kg ketamine right before anesthesia induction. Patients were observed for three days after surgery and tested for postoperative delirium and cognitive dysfunction using the delirium observation screening scale and the mini-mental state examination score, respectively.ResultsThe dexmedetomidine group had the lowest incidence of delirium (p = 0.001) and cognitive dysfunction (p = 0.006) compared to the ketamine and placebo groups. The multivariate logistic regression model revealed that dexmedetomidine reduced the incidence of postoperative delirium by 32% compared to placebo (reference) (OR = 0.684, 95% CI: 0.240-0.971, p = 0.025), whereas ketamine increased the risk by threefold (OR = 3.012, 95% CI: 1.185-9.681, p = 0.013). Furthermore, dexmedetomidine reduced the incidence of postoperative cognitive dysfunction by 62% (OR = 0.375, 95% CI: 0.091-0.543, p = 0.012), whereas ketamine increased the risk by 4.5 times (OR = 4.501, 95% CI: 1.161-8.817, p = 0.006).ConclusionA single pre-anesthetic bolus of dexmedetomidine is a practical choice for preventing postoperative delirium in elderly patients undergoing emergency surgery.Trial registrationThis study was approved by the Ethics Committee of Aswan University Hospital (approval number: aswu/548/7/2021; registration date: 06/07/2021) and registered on ClinicalTrials.gov (NCT05341154) (22/04/2022).

Project description:BackgroundRemifentanil, an ultra-short-acting opioid, is widely used for pain control during surgery. However, regular dose (RD) remifentanil exacerbates postoperative pain in a dose-dependent manner. Recent studies suggest that high-dose (HD) remifentanil offers sustained analgesia in experimental studies. We thus hypothesized that intraoperative administration of high-dose remifentanil may attenuate postoperative pain.MethodsIn this prospective, randomized, double blind, controlled clinical study, sixty patients undergoing thyroidectomy (18-60 years-of-age) received an intraoperative infusion of 0.2 (RD group) or 1.2 μg kg(-1) min(-1) (HD group) remifentanil during thyroidectomy. A visual analogue scale (VAS) was used to measure pain intensity. Mechanical pain threshold on the forearm was assessed using von Frey filaments before surgery (baseline), 2 h postoperatively and 18-24 h postoperatively. The primary outcome was to compare the difference of VAS score at different time points after operation and morphine consumption 24 h postoperatively between RD and HD groups. The second outcome was to compare the difference of mechanical pain thresholds in the forearm postoperatively between RD and the HD groups.ResultsVAS scores were lower 30 min postoperatively in the HD group (1.29 ± 1.67, 95% CI 0.64-1.94) compared with the RD group (2.21 ± 1.67, 95% CI 1.57-2.84) (t = 3.427, p = 0.0043, RD group vs. HD group). Postoperative morphine consumption was much lower in the HD group compared with the RD group (1.27 ± 1.88 mg vs. 0.35 ± 1.25 mg, p = 0.033). In both groups, mechanical pain threshold was decreased 18-24 h postoperatively (2.93 ± 0.209 Ln(g) vs. 3.454 ± 2.072 Ln(g), p = 0.032 in RD group; 2.910 ± 0.196 Ln(g) vs. 3.621 ± 0.198 Ln(g), p = 0.006 in HD group, 18-24 h postoperatively vs baseline).ConclusionsIntraoperative administration of high-dose remifentanil decreased VAS scores and morphine consumption postoperatively. Thus, modulation of intraoperative opiates may be a simple and effective method of postoperative pain management.Trial registrationThis trial is registered in ClinicalTrials.gov, with the Name: Effect of Higher Doses of Remifentanil on Postoperative Pain in Patients Undergoing Thyroidectomy, and ID number: NCT01761149.

Dataset Information

Intraoperative ketamine for prevention of postoperative delirium or pain after major surgery in older adults: an international, multicentre, double-blind, randomised clinical trial.

Publications

Intraoperative ketamine for prevention of postoperative delirium or pain after major surgery in older adults: an international, multicentre, double-blind, randomised clinical trial.

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