Clinical trial NCT01690988: The Prevention of Delirium and Complications Associated With Surgical Treatments Multi Center Clinical Trial
Official title: The Prevention of Delirium and Complications Associated With Surgical Treatments Multi Center Clinical Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Delirium
Keywords: Delirium
ketamine
surgery
neurological complications
Lead sponsor: Washington University School of Medicine
Sponsor class: OTHER
Collaborators: name: Asan Medical Center
name: Weill Medical College of Cornell University
name: Harvard Medical School (HMS and HSDM)
name: Medical College of Wisconsin
name: Memorial Sloan Kettering Cancer Center
name: Post Graduate Institute of Medical Education and Research, Chandigarh
name: University of Bern
name: University of Michigan
name: University of Manitoba
name: University Health Network, Toronto
name: Virginia Mason Hospital/Medical Center
First posted: 2012-09-24
Enrollment: 746
Sex: ALL
Minimum age (years): 60
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: 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).

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.

Eligibility criteria: 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)

Primary outcomes:
measure: Number of Patients With Incidence of Delirium Across All Patients at Baseline and Over Post-operative Days 1-3
timeFrame: Delirium incidence on postoperative days 1-3, calculated by any positive CAM on any day for all patients
Secondary outcomes:
measure: Daily Maximum Pain Recorded
timeFrame: Postoperative days 1-3, two assessment daily (morning and afternoon), with at least six hours between assessments
measure: Median Opioid Consumption
timeFrame: Postoperative days 0-3
measure: Number of Patients With Postoperative Nausea and Vomiting
timeFrame: Postoperative days 1-3
measure: ICU and/or Hospital Length of Stay
timeFrame: Postoperative period
measure: Adverse Outcomes (Number of Patients With Hallucinations)
timeFrame: Postoperative days 1-3
measure: Adverse Outcomes (Number of Patients With Nightmares)
timeFrame: Postoperative days 1-3
Other outcomes:
Locations:
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
Study officials:
affiliation: University of Michigan
name: George A Mashour, MD PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Washington University School of Medicine
name: Daniel A Emmert, MD PhD
role: STUDY_DIRECTOR
affiliation: Cornell
name: Kane Pryor, MBBS
role: STUDY_DIRECTOR
affiliation: University of Manitoba
name: Eric Jacobsohn, MB ChB
role: STUDY_DIRECTOR
affiliation: Medical College of Wisconsin
name: Judith Hudetz, PhD
role: STUDY_DIRECTOR
affiliation: University of Manitoba
name: Hilary P Grocott, MD
role: STUDY_CHAIR
affiliation: Washington University School of Medicine
name: Michael S Avidan, MBBCh
role: PRINCIPAL_INVESTIGATOR
affiliation: Harvard Medical School (HMS and HSDM)
name: Sharon Inouye
role: STUDY_DIRECTOR
affiliation: Memorial Sloan Kettering Medical Center
name: Robert Veselis
role: STUDY_DIRECTOR
affiliation: Post Graduate Institute of Medical Education and Research, Chandigarh
name: Jayant Aveek
role: STUDY_DIRECTOR
affiliation: University of Bern
name: Heiko Kaiser
role: STUDY_DIRECTOR
affiliation: University of Toronto
name: Stephen Choi
role: STUDY_CHAIR
affiliation: Virginia Mason Medical Center
name: Ryan Pong
role: STUDY_CHAIR
affiliation: Asan Medical Center
name: Gyujeong Noh
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.