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

Phase 3

Completed

• Conditions: Delirium
• Interventions: Drug: Ketamine (0.5 mg/kg); Drug: Ketamine (1 mg/kg); Drug: Normal Saline (placebo)

• Registration Number: NCT01690988
• Lead Sponsor: Washington University School of Medicine

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.

Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations

Study Timeline

• Study First Submitted: 2012-08-07
• Study First Submitted QC: 2012-09-21
• Study First Posted: 2012-09-24
• Study Start: 2014-02-01
• Primary Completion: 2016-06-26
• Study Completion: 2017-07
• Results First Submitted: 2017-09-15
• Status Verified: 2017-11
• Results First Submitted QC: 2018-03-30
• Results First Posted: 2018-05-02
• Last Update Submitted: 2018-05-02
• Last Update Posted: 2018-06-06

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 746

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).

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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)

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Ketamine (0.5 mg/kg)	Ketamine (0.5 mg/kg)	Low dose (sub-anesthetic) 0.5 mg/kg ketamine following induction of anesthesia or administration of sedative medications.
Ketamine (1 mg/kg)	Ketamine (1 mg/kg)	Low dose (sub-anesthetic) 1 mg/kg ketamine following induction of anesthesia or administration of sedative medications.
Normal saline (placebo)	Normal Saline (placebo)	Intravenous normal saline

Primary Outcome Measures

Name	Time	Method
Number of Patients With Incidence of Delirium Across All Patients at Baseline and Over Post-operative Days 1-3	Delirium incidence on postoperative days 1-3, calculated by any positive CAM on any day for all patients	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.

Secondary Outcome Measures

Name	Time	Method
ICU and/or Hospital Length of Stay	Postoperative period	Assessed from patients' medical charts
Number of Patients With Postoperative Nausea and Vomiting	Postoperative days 1-3	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.
Median Opioid Consumption	Postoperative days 0-3	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)
Daily Maximum Pain Recorded	Postoperative days 1-3, two assessment daily (morning and afternoon), with at least six hours between assessments	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.
Adverse Outcomes (Number of Patients With Hallucinations)	Postoperative days 1-3	Assessed via Confusion Assessment Method or Confusion Assessment Method for Intensive Care Unit
Adverse Outcomes (Number of Patients With Nightmares)	Postoperative days 1-3	Assessed via Confusion Assessment Method or Confusion Assessment Method for Intensive care Unit

Trial Locations

Locations (1)

Washington University School of Medicine; 🇺🇸 Saint Louis, Missouri, United States