The Prevention of Delirium and Complications Associated With Surgical Treatments Multi Center Clinical Trial (PODCAST)

Delirium is a medical term or condition that includes a temporary inability to focus attention and to think clearly. Delirium occurs commonly (10% to 70%) in patients older than 60 undergoing large surgeries. The purpose of this study is to test rigorously whether a drug called ketamine can decrease the chance that patients will experience delirium after their surgery. The investigators are also testing whether ketamine decreases postoperative pain, postoperative opioid consumption, postoperative nausea and vomiting, ICU and hospital length of stay, and adverse outcomes (e.g. hallucinations and nightmares).

Study Overview

• Status: Completed
• Conditions: Delirium
• Intervention / Treatment: Drug: Ketamine (0.5 mg/kg); Drug: Normal Saline (placebo); Drug: Ketamine (1 mg/kg)

Detailed Description

Postoperative delirium is one of the most common complications of major surgery, affecting between 10% and 70% of all elderly surgical patients. Delirium manifests as poor attention and inability to think logically, and is associated with longer intensive care unit and hospital stay, long lasting cognitive deterioration, and increased mortality rate. Studies have shown that a low sub-anesthetic dose of ketamine, an anesthetic drug, has the potential to decrease several postoperative complications, including delirium, pain, opioid consumption, and nausea and vomiting. Low dose ketamine would be particularly appealing as a drug to prevent delirium and other postoperative complications, as it is inexpensive and extremely safe. However, these proposed benefits of ketamine in the perioperative setting have not yet been tested in a large clinical trial. The investigators are therefore proposing a pragmatic, exploratory clinical trial to support or refute the contention that low dose ketamine decreases the incidence of postoperative delirium, with the possibility of conducting a larger randomized clinical trial pending the results of this study. At the time of enrollment, patients will undergo the same delirium and pain evaluation that will be used postoperatively. Additionally patients will be screened for functional dependence using the Barthel Index of Activities of Daily Living, for depression using the Geriatric Depression Scale - Short Form, and for obstructive sleep apnea using the STOP-Bang criteria. They will also be asked about any falls they have experienced in the six months prior to surgery. Comorbid conditions, including the components of the Charlson Comorbidity Index, will be obtained by reviewing the patients' medical records. Any available preoperative lab results, including electrolytes and blood counts, will also be recorded.

Patients will be randomized to receive low dose ketamine or placebo following induction of anesthesia and prior to surgical incision. Blinded observers will assess delirium on the afternoon/evening of postoperative day 0 (if feasible) and twice daily (morning and afternoon/evening with at least six hours between assessments) on postoperative days 1-3 using the Confusion Assessment Method or the Confusion Assessment Method for Intensive Care Unit. Acute pain will be assessed via the observer-based Behavioral Pain Scale or Behavioral Pain Scale (Non-Intubated) with subsequent administration of the patient-reported Visual Analog Scale from postoperative days 0-3. Postoperative opioid consumption will be assessed from the patients' medical charts for postoperative days 0-3. Postoperative nausea and vomiting will be assessed via a patient-reported section of the Behavioral Pain Scale or Behavioral Pain Scale (Non-Intubated) for postoperative days 0-3. ICU and/or hospital length of stay will be assessed from the patients' medical charts. Adverse outcomes (e.g. hallucinations and nightmares) will be assessed via the Confusion Assessment Method or the Confusion Assessment Method for Intensive Care Unit for postoperative days 0-3.

• Study Type: Interventional
• Enrollment (Actual): 746
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 60 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients 60 and older
• Competent to provide informed consent
• Undergoing major surgery (e.g., open cardiac surgery, open or thoracoscopic thoracic surgery, abdominal surgery, open urological surgery, open gynecological surgery, major orthopedic surgery, major vascular surgery including endovascular procedures, major ear, nose and throat surgery).

Exclusion Criteria:

• Patients with an allergy to ketamine
• Those in whom a significant elevation of blood pressure would constitute a serious hazard (e.g., pheochromocytoma, aortic dissection)
• Unable to provide informed consent
• Patients with drug misuse history (e.g., ketamine, cocaine, heroin, amphetamine, methamphetamine, MDMA, phencyclidine, lysergic acid, mescaline, psilocybin)
• Patients taking anti-psychotic medications (e.g., chlorpromazine, clozapine, olanzapine, risperidone, haloperidol, quetiapine, risperidone, paliperidone, amisulpride, sertindole)
• Patients with a weight outside the range 50 kg - 200 kg (110 lbs - 440 lbs)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ketamine (0.5 mg/kg); Low dose (sub-anesthetic) 0.5 mg/kg ketamine following induction of anesthesia or administration of sedative medications.	Drug: Ketamine (0.5 mg/kg); Low dose (sub-anesthetic) 0.5 mg/kg ketamine following induction of anesthesia or administration of sedative medications.; Other Names: Ketalar
Placebo Comparator: Normal saline (placebo); Intravenous normal saline	Drug: Normal Saline (placebo); Normal saline IV following induction of anesthesia or administration of sedative medications; Other Names: Normal saline
Experimental: Ketamine (1 mg/kg); Low dose (sub-anesthetic) 1 mg/kg ketamine following induction of anesthesia or administration of sedative medications.	Drug: Ketamine (1 mg/kg); Low dose (sub-anesthetic) 1 mg/kg ketamine following induction of anesthesia or administration of sedative medications.; Other Names: Ketalar

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Patients With Incidence of Delirium Across All Patients at Baseline and Over Post-operative Days 1-3	According to Confusion Assessment Method or Confusion Assessment Method for Intensive Care Unit criteria the number of patients that had any positive CAM on any day for all patients. The main effect evaluated will be to determine whether ketamine decreases delirium, table 3 of the protocol provides a useful guide for the potential findings of the current study with their implications. To further clarify, delirium will be assessed on the day of surgery, when possible and on the subsequent three days POD 1-3, as long as as patients remain in the hospital and are assessable (i.e., not sedated to a RASS <-3). The assessments on POD 1-3 will be done twice daily, once in the morning and once in the afternoon. The primary outcome of the study includes only the delirium incidence on POD 1-3. The primary comparison will be between the combined ketamine groups and the placebo group.	Delirium incidence on postoperative days 1-3, calculated by any positive CAM on any day for all patients

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Daily Maximum Pain Recorded	Assessed by observer-based Behavioral Pain Scale or Behavioral Pain Scale (Non-Intubated) with subsequent administration of patient-reported Visual Analog Scale The behavioral pain scale has three domains and ranges from 3 to 15. The visual analog scale is a continuous scale from 0 to 100 mm. Daily Maximum Pain accounted for pain level in the AM or PM for both the VAS and the BPS/BPS-NI a higher value means a worse outcome.	Postoperative days 1-3, two assessment daily (morning and afternoon), with at least six hours between assessments
Median Opioid Consumption	Assessed from patients' medical charts. All morphine equivalent drugs consumed by patients perioperatively Opioid Drugs included: * Postoperatively while still in hospital, the list of pain medication used included Morphine, Hydromorphone, Meperidine, Nalbuphine, Oxycodone,Oxymorphone, Tramadol, bupivacaine, (Codeine, Fentanyl, Naloxone) Total Opiates (Morphine Equivalent) in milligrams The median(IQR) opioid consumption was compared across the three study groups Placebo vs. Lo-K (0.5 mg/kg) vs. Hi-K (1 mg/kg)	Postoperative days 0-3
Number of Patients With Postoperative Nausea and Vomiting	Assessed from patient-reported postoperative nausea and vomiting section of Behavioral Pain Scale or Behavioral Pain Scale (Non-Intubated) Patients where asked whether they "currently have nausea/vomiting" AM & PM the response choices: None, Mild, Moderate, Severe Incidence of nausea\vomiting accounted for any positive reporting(Mild, moderate, or sever) Daily incidence accounted for any positive incidence AM/PM in each POD Any POD nausea/vomiting reports the incidence across day 1-3 The incidence of nausea and or vomiting was compared across the three study groups Placebo vs. Lo-K (0.5 mg/kg) vs. Hi-K (1 mg/kg) for POD 1-3 and overall.	Postoperative days 1-3
ICU and/or Hospital Length of Stay	Assessed from patients' medical charts	Postoperative period
Adverse Outcomes (Number of Patients With Hallucinations)	Assessed via Confusion Assessment Method or Confusion Assessment Method for Intensive Care Unit	Postoperative days 1-3
Adverse Outcomes (Number of Patients With Nightmares)	Assessed via Confusion Assessment Method or Confusion Assessment Method for Intensive care Unit	Postoperative days 1-3

Collaborators and Investigators

• Sponsor: Washington University School of Medicine
• Collaborators: Harvard Medical School (HMS and HSDM); University of Manitoba; University Health Network, Toronto; Memorial Sloan Kettering Cancer Center; University of Michigan; Medical College of Wisconsin; Weill Medical College of Cornell University; Asan Medical Center; University of Bern; Postgraduate Institute of Medical Education and Research; Virginia Mason Hospital/Medical Center
• Investigators: Principal Investigator: George A Mashour, MD PhD, University of Michigan; Study Director: Daniel A Emmert, MD PhD, Washington University School of Medicine; Study Director: Kane Pryor, MBBS, Cornell; Study Director: Eric Jacobsohn, MB ChB, University of Manitoba; Study Director: Judith Hudetz, PhD, Medical College of Wisconsin; Study Chair: Hilary P Grocott, MD, University of Manitoba; Study Director: Sharon Inouye, Harvard Medical School (HMS and HSDM); Study Director: Robert Veselis, Memorial Sloan Kettering Medical Center; Study Director: Jayant Aveek, Postgraduate Institute of Medical Education and Research; Study Director: Heiko Kaiser, University of Bern; Study Chair: Stephen Choi, University of Toronto; Study Chair: Ryan Pong, Virginia Mason Medical Center; Study Director: Gyujeong Noh, Asan Medical Center

Publications and helpful links

General Publications

• Avidan MS, Fritz BA, Maybrier HR, Muench MR, Escallier KE, Chen Y, Ben Abdallah A, Veselis RA, Hudetz JA, Pagel PS, Noh G, Pryor K, Kaiser H, Arya VK, Pong R, Jacobsohn E, Grocott HP, Choi S, Downey RJ, Inouye SK, Mashour GA. The Prevention of Delirium and Complications Associated with Surgical Treatments (PODCAST) study: protocol for an international multicentre randomised controlled trial. BMJ Open. 2014 Sep 17;4(9):e005651. doi: 10.1136/bmjopen-2014-005651.
• Avidan MS, Maybrier HR, Abdallah AB, Jacobsohn E, Vlisides PE, Pryor KO, Veselis RA, Grocott HP, Emmert DA, Rogers EM, Downey RJ, Yulico H, Noh GJ, Lee YH, Waszynski CM, Arya VK, Pagel PS, Hudetz JA, Muench MR, Fritz BA, Waberski W, Inouye SK, Mashour GA; PODCAST Research Group. Intraoperative ketamine for prevention of postoperative delirium or pain after major surgery in older adults: an international, multicentre, double-blind, randomised clinical trial. Lancet. 2017 Jul 15;390(10091):267-275. doi: 10.1016/S0140-6736(17)31467-8. Epub 2017 May 30. Erratum In: Lancet. 2017 Jul 15;390(10091):230.
• Vlisides PE, Thompson A, Kunkler BS, Maybrier HR, Avidan MS, Mashour GA; PODCAST Research Group. Perioperative Epidural Use and Risk of Delirium in Surgical Patients: A Secondary Analysis of the PODCAST Trial. Anesth Analg. 2019 May;128(5):944-952. doi: 10.1213/ANE.0000000000004038.
• Mashour GA, Ben Abdallah A, Pryor KO, El-Gabalawy R, Vlisides PE, Jacobsohn E, Lenze E, Maybrier HR, Veselis RA, Avidan MS; PODCAST Research Group. Intraoperative ketamine for prevention of depressive symptoms after major surgery in older adults: an international, multicentre, double-blind, randomised clinical trial. Br J Anaesth. 2018 Nov;121(5):1075-1083. doi: 10.1016/j.bja.2018.03.030. Epub 2018 Sep 19.

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2014
• Primary Completion (Actual): June 26, 2016
• Study Completion (Actual): July 1, 2017

Study Registration Dates

• First Submitted: August 7, 2012
• First Submitted That Met QC Criteria: September 21, 2012
• First Posted (Estimate): September 24, 2012

Study Record Updates

• Last Update Posted (Actual): June 6, 2018
• Last Update Submitted That Met QC Criteria: May 2, 2018
• Last Verified: November 1, 2017

More Information

Terms related to this study

• Keywords: surgery; ketamine; Delirium; neurological complications
• Additional Relevant MeSH Terms: Mental Disorders; Nervous System Diseases; Neurologic Manifestations; Confusion; Neurobehavioral Manifestations; Neurocognitive Disorders; Delirium; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anesthetics, Dissociative; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Ketamine
• Other Study ID Numbers: 201206071