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      Intraoperative ketamine does not affect postoperative delirium or pain after major surgery in older adults: an international, multicentre, double-blind, randomised clinical trial

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          Abstract

          Background

          Delirium and pain are common and serious postoperative complications. Subanaesthetic ketamine is often administered intraoperatively for postoperative analgesia and to spare postoperative opioids. Some evidence also suggests that ketamine prevents delirium. The primary purpose of this trial was to evaluate the effectiveness of ketamine in preventing postoperative delirium in older adults after major surgery. Secondary outcomes, viewed as strongly related to delirium, were postoperative pain and opioid consumption.

          Methods

          This was a multicentre, international, randomised trial that enrolled adults older than 60 undergoing major cardiac and noncardiac surgery under general anaesthesia. Participants were enrolled prior to surgery and gave written informed consent. We used a computer-generated randomisation sequence. Patients at study sites were randomised to one of three study groups in blocks of 15 to receive intraoperative administration of (i) placebo (intravenous normal saline), (ii) low dose ketamine (0.5 mg/kg) or (iii) high dose ketamine (1 mg/kg). Study drug was administered following induction of anaesthesia, prior to surgical incision. Participants, clinicians, and investigators were all masked to group assignment. Delirium and pain were assessed twice daily in the first three postoperative days using the Confusion Assessment Method and Visual Analog Scale, respectively. Postoperative opioid use was recorded, and hallucinations and nightmares were assessed. Analyses were performed by intention-to-treat and adverse events were evaluated. The Prevention of Delirium and Complications Associated with Surgical Treatments [PODCAST] trial is registered in clinicaltrials.gov; NCT01690988

          Findings

          Between February 6, 2014 and June 26, 2016, 1360 patients assessed and 672 were randomised, with 222 in the placebo group, 227 in the low dose ketamine group, and 223 in the high dose ketamine group. There was no difference in postoperative delirium incidence between those in the combined ketamine groups and those who received placebo (19.45% vs. 19.82%, respectively; absolute difference, 0.36%; 95% CI, −6.07% to 7.38%; p=0.92). There were no significant differences among the three groups in maximum pain scores (p=0.88) or median opioid consumption (p=0.47) over time. There were more postoperative hallucinations (p=0.01) and nightmares (p=0.03) with escalating doses of ketamine. Adverse events (cardiovascular, renal, infectious, gastrointestinal, bleeding), whether viewed individually (P value for each >0.40) or collectively (82/222 [36.9%] in placebo group, 90/227 [39.6%] in low dose ketamine group, 91/223 in high dose ketamine group [40.8%]; P=0.69), did not differ significantly across the three groups.

          Interpretation

          The administration of a single subanaesthetic dose of ketamine to older adults during major surgery did not show evidence of reducing postoperative delirium, pain, or opioid consumption, and might cause harm by inducing negative experiences. Given current evidence and guidelines related to ketamine and postoperative analgesia, the unexpected secondary findings regarding pain and opioid consumption warrant replication or refutation in subsequent research.

          Funding

          The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The principal investigators (MSA and GAM) had full access to all the data in the study and had final responsibility for the decision to submit for publication.

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          Most cited references25

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          Dexmedetomidine for prevention of delirium in elderly patients after non-cardiac surgery: a randomised, double-blind, placebo-controlled trial.

          Delirium is a postoperative complication that occurs frequently in patients older than 65 years, and presages adverse outcomes. We investigated whether prophylactic low-dose dexmedetomidine, a highly selective α2 adrenoceptor agonist, could safely decrease the incidence of delirium in elderly patients after non-cardiac surgery.
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            What you see may not be what you get: a brief, nontechnical introduction to overfitting in regression-type models.

            Statistical models, such as linear or logistic regression or survival analysis, are frequently used as a means to answer scientific questions in psychosomatic research. Many who use these techniques, however, apparently fail to appreciate fully the problem of overfitting, ie, capitalizing on the idiosyncrasies of the sample at hand. Overfitted models will fail to replicate in future samples, thus creating considerable uncertainty about the scientific merit of the finding. The present article is a nontechnical discussion of the concept of overfitting and is intended to be accessible to readers with varying levels of statistical expertise. The notion of overfitting is presented in terms of asking too much from the available data. Given a certain number of observations in a data set, there is an upper limit to the complexity of the model that can be derived with any acceptable degree of uncertainty. Complexity arises as a function of the number of degrees of freedom expended (the number of predictors including complex terms such as interactions and nonlinear terms) against the same data set during any stage of the data analysis. Theoretical and empirical evidence--with a special focus on the results of computer simulation studies--is presented to demonstrate the practical consequences of overfitting with respect to scientific inference. Three common practices--automated variable selection, pretesting of candidate predictors, and dichotomization of continuous variables--are shown to pose a considerable risk for spurious findings in models. The dilemma between overfitting and exploring candidate confounders is also discussed. Alternative means of guarding against overfitting are discussed, including variable aggregation and the fixing of coefficients a priori. Techniques that account and correct for complexity, including shrinkage and penalization, also are introduced.
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              Assessing pain in critically ill sedated patients by using a behavioral pain scale.

              To establish the validity and reliability of a new behavioral pain scale (BPS) for critically ill sedated adult patients. Prospective evaluation. Ten-bed trauma and surgical intensive care unit in a university teaching hospital. Thirty mechanically ventilated patients who were receiving analgesia and sedation. Assessments with the BPS were completed consecutively at standardized times (morning, afternoon, night) by pairs of evaluators (nurse and nurse's aide). They collected physiologic parameters and BPS results before and during care procedures: non-nociceptive (group 1, compression stockings application and central venous catheter dressing change), nociceptive (group 2, endotracheal suctioning and mobilization), and retested nociceptive (group 3). The BPS score was the sum of three items that had a range score of 1-4: facial expression, movements of upper limbs, and compliance with mechanical ventilation. Two hundred and sixty nine assessments were completed, including 104, 134, and 31 measurements in groups 1, 2 and 3, respectively. There was no difference in Ramsay scale scores between the three groups (Ramsay 4-6). Nociceptive stimulations (group 2) resulted in significantly higher BPS values than non-nociceptive ones (group 1, 4.9 vs. 3.5, p <.01), whereas the two groups had comparable BPS values before stimulation (3.1 vs. 3.0). A trend was found in group 2 between the dosage of sedation/analgesia and BPS: the higher the dosage, the lower BPS values and BPS changes to nociceptive stimulation. Group 3 had BPS values similar to group 2 at rest (3.2 vs. 3.2) and during the procedure (4.4 vs. 4.5), with good interrater correlations (r(2) =.71 and.50, respectively). These results indicate that the expression of pain can be scored validly and reliably by using the BPS in sedated, mechanically ventilated patients. Further studies are warranted regarding the utility of the BPS in making clinical decisions about the use of analgesic drugs in the intensive care unit.
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                Author and article information

                Contributors
                Role: Prof.
                Role: Prof.
                Role: Prof.
                Role: Prof.
                Role: Prof.
                Role: Prof.
                Role: Prof.
                Role: Prof.
                Role: Prof. On behalf of : on behalf of the PODCAST Research Group
                Journal
                2985213R
                5470
                Lancet
                Lancet
                Lancet (London, England)
                0140-6736
                1474-547X
                30 September 2017
                30 May 2017
                15 July 2017
                15 July 2018
                : 390
                : 10091
                : 267-275
                Affiliations
                Department of Anesthesiology, Washington University School of Medicine, Saint Louis, Missouri, US
                Department of Anesthesiology, Washington University School of Medicine, Saint Louis, Missouri, US
                Department of Anesthesiology, Washington University School of Medicine, Saint Louis, Missouri, US
                Department of Anesthesiology, Department of Internal Medicine, University of Manitoba, Winnipeg, Manitoba, CA
                Department of Anesthesiology, University of Michigan, Ann Arbor, Michigan, US
                Department of Anesthesiology, Weill Cornell Medicine, New York City, New York, US
                Department of Neuroanesthesiology, Memorial Sloan Kettering Cancer Center, New York City, New York, US
                Department of Anesthesia & Perioperative Medicine, University of Manitoba, Winnipeg, Manitoba, CA
                Department of Anesthesiology, Washington University School of Medicine, Saint Louis, Missouri, US
                Department of Anesthesiology, Weill Cornell Medicine, New York City, New York, US
                Department of Surgery, Memorial Sloan Kettering Cancer Center, New York City, New York, US
                Department of Anesthesiology, Memorial Sloan Kettering Cancer Center, New York City, New York, US
                Department of Anesthesiology, Asan Medical Center, Seoul, South Korea
                Department of Anesthesiology, Asan Medical Center, Seoul, South Korea
                Department of Medicine, Hartford Hospital, Hartford, Connecticut, US
                Department of Anaesthesiology and Intensive Care, Postgraduate Institute of Medical Education and Research, Chandigarh, India
                Department of Anesthesiology, Medical College of Wisconsin, Madison, Wisconsin, US
                Department of Anesthesiology, Medical College of Wisconsin, Madison, Wisconsin, US
                Department of Anesthesiology, Washington University School of Medicine, Saint Louis, Missouri, US
                Department of Anesthesiology, Washington University School of Medicine, Saint Louis, Missouri, US
                Department of Anesthesiology, Hartford Hospital, Hartford, Connecticut, US
                Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School; and Institute for Aging Research, Hebrew SeniorLife, Boston, Massachussetts, US
                Department of Anesthesiology, University of Michigan, Ann Arbor, Michigan, US
                Author notes
                Address correspondence to MS Avidan: Dr. Michael Avidan ( avidanm@ 123456wustl.edu ), 660 S. Euclid Ave., Campus Box 8125, St. Louis, MO 63110, 314-747-4155
                Article
                NIHMS882459
                10.1016/S0140-6736(17)31467-8
                5644286
                28576285
                e32e5636-ccfa-41cd-ba9a-498ec2489e59

                This manuscript version is made available under the CC BY-NC-ND 4.0 license.

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                Medicine
                Medicine

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