Esketamine vs. Ketorolac for Prevention of Postoperative Pain and Cognitive Dysfunction After Total Knee Arthroplasty

Esketamine vs. Ketorolac for Prevention of Postoperative Pain and Cognitive Dysfunction After Total Knee Arthroplasty in Patients: a Randomized Double-blind Controlled Trial

Purpose:

To compare esketamine and ketorolac separately and in combination to prevent postoperative pain and cognitive dysfunction after total knee arthroplasty

Study Overview

• Status: Recruiting
• Conditions: Postoperative Pain; Postoperative Cognitive Dysfunction; Total Knee Arthroplasty
• Intervention / Treatment: Drug: Normal saline; Drug: Esketamine at high dose; Drug: Ketorolac at high dose; Drug: Esketamine at low dose; Drug: Ketorolac at low dose

Detailed Description

With the increase in human life span, orthopedic injuries and subsequent repair surgery have become a major health problem which impairs the life quality of patients and burdens healthcare systems worldwide. Poor post-surgical pain control is a leading factor that hinders the physical rehabilitation and musculoskeletal functional recovery, and causes acute cognitive impairment and chronic pain syndrome. Therefore, prophylaxis of postoperative pain is indispensable to postoperative comfort and satisfaction. There is no denying the fact that pathologic pain is related to central glutaminergic system and N-methyl-d-aspartate (NMDA) receptor activation induced central sensitization. Also, it is previously reported that neuroinflammation is associated with pain development and cognitive dysfunction. Ketamine, a NMDA receptor antagonist, is effective in reversing NMDA receptor activation underlying pain states. But the side effects of ketamine limit its clinical application, such as gibberish and agitation. It is clarified that esketamine has lower side effects than ketamine and that antinociception of esketamine is stronger than ketamine. The following study is carried out to evaluate whether esketamine and ketorolac can prevent postoperative pain and cognitive impairment after total knee arthroplasty in patients.

• Study Type: Interventional
• Enrollment (Anticipated): 160
• Phase: Not Applicable

Contacts and Locations

Study Locations

• China
  • Tianjin, China, 300052
    • Recruiting
    • Tianjin Medical University General Hospital
    • Contact: Guolin Wang; Phone Number: +8618604755166

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 65 years to 85 years (Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Subject is scheduled to undergo total knee arthroplasty under a short general anesthesia of less than 2 hours
2. Subject's American Society of Anesthesiologists physical status is I-II.
3. The subject's parent/legally authorized guardian has given written informed consent to participate.

Exclusion Criteria:

1. Subject has a diagnosis of bronchial asthma, coronary heart disease, severe hypertension, renal failure or liver failure.
2. Subject has a diagnosis of Insulin dependent diabetes.
3. Subject is allergy and contraindication to esketamine or ketorolac.
4. Subject has a history of chronic pain, a history of alcohol or opioid abuse, pre- existing therapy with opioids.
5. Subject has any contraindication for the use of patient-controlled analgesia (PCA).
6. Subject is pregnant or breast-feeding.
7. Subject is obese (body mass index >30kg/m^2).
8. Subject is incapacity to comprehend pain assessment and cognitive assessment.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Normal saline in patients; After the induction of anesthesia, normal saline is intravenously injected in a volume of 2ml, and then a continuous infusion of 20 ml/h normal saline until starting skin suture.	Drug: Normal saline; After the induction of anesthesia, normal saline is intravenously injected in a volume of 2ml, and then a continuous infusion of 20ml/h normal saline until starting skin suture.; Other Names: 0. 9% Sodium Chloride Injection
Active Comparator: Esketamine in patients; After the induction of anesthesia, esketamine is intravenously injected at 0.4mg/kg, and then a continuous infusion of 0.4mg/kg/h esketamine until starting skin suture.	Drug: Esketamine at high dose; After the induction of anesthesia, esketamine is intravenously injected at 0.4mg/kg, and then a continuous infusion of 0.4mg/kg/h esketamine until starting skin suture.; Other Names: Esketamine Hydrochloride Injection
Active Comparator: Ketorolac in patients; After the induction of anesthesia, ketorolac is intravenously injected at 0.4mg/kg, and then a continuous infusion of 0.4mg/kg/h ketorolac until starting skin suture.	Drug: Ketorolac at high dose; After the induction of anesthesia, Ketorolac is intravenously injected at 0.4mg/kg, and then a continuous infusion of 0.4mg/kg/h Ketorolac until starting skin suture.; Other Names: Ketorolac Tromethamine
Active Comparator: Esketamine and Ketorolac in patients; After the induction of anesthesia, 0.2mg/kg esketamine and 0.2mg/kg ketorolac are intravenously injected, and then a continuous infusion of 0.2mg/kg/h esketamine and 0.2mg/kg/h ketorolac until starting skin suture.	Drug: Esketamine at low dose; After the induction of anesthesia, esketamine is intravenously injected at 0.2mg/kg, and then a continuous infusion of 0.2mg/kg/h esketamine until starting skin suture.; Other Names: Esketamine Hydrochloride Injection; Drug: Ketorolac at low dose; After the induction of anesthesia, Ketorolac is intravenously injected at 0.2mg/kg, and then a continuous infusion of 0.2mg/kg/h Ketorolac until starting skin suture.; Other Names: Ketorolac Tromethamine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cumulative opioid Consumption	Each patient was administered analgesics using a PCA (Patient-controlled analgesia) pump containing sufentanil in normal saline after leaving PACU (Postanesthesia care unit). Sufentanyl cumulative consumption is recorded 72 hours postoperatively	72 hours after surgery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time of First Postoperative Analgesic Requirement	First postoperative pain (NRS≥5) is initially controlled by titration of sufentanyl.	1 hour after surgery
Total Dose of First Postoperative Analgesic Requirement	First postoperative pain (NRS≥5) is initially controlled by titration of sufentanyl.	1 hour after surgery
Pain Score (NRS) after movement	The pain score after movement was evaluated by pain 11-point numerical rating scale (NRS): 0 = no pain, 10 = greatest imaginable pain.	72 hours after surgery
Mini-Mental State Examination (MMSE)	Cognitive performance was assessed with 0-30 points Mini-Mental State Examination (MMSE) scale. Greater scores means better outcome.	72 hours after surgery
The incidence of Side Effects	The number of patients with post-operative side effects including nausea, vomiting, dizziness, headache, shivering, and pruritus was recorded 72 hours after surgery.	72 hours after surgery
The levels of TNF-a in blood	Blood samples are collected to measure the levels of cytokine TNF-a using ELISA kits.	72 hours after surgery
The levels of chemokine CXCL1 in blood	Blood samples are collected to measure the levels of chemokine CXCL1 using ELISA kits.	72 hours after surgery
The levels of neuron specific enolase (NSE) in blood	Blood samples are collected to measure the levels of neuron specific enolase (NSE) using electrochemilumiscence kit.	72 hours after surgery
The levels of S-100 calcium-binding protein B in blood	Blood samples are collected to measure the levels of S-100 calcium-binding protein B using electrochemilumiscence kit.	72 hours after surgery
The levels of cortisol in blood	Blood samples are collected to measure the levels of cortisol using electrochemilumiscence kit.	72 hours after surgery
Pain Score (NRS) at rest	The pain score at rest was evaluated by pain 11-point numerical rating scale (NRS): 0 = no pain, 10 = greatest imaginable pain.	72 hours after surgery
The levels of chemokine CCL7 in blood	Blood samples are collected to measure the levels of chemokine CCL7 using ELISA kits.	72 hours after surgery
The levels of IL-18 in blood	Blood samples are collected to measure the levels of cytokine IL-18 using ELISA kits.	72 hours after surgery
The levels of IL-23 in blood	Blood samples are collected to measure the levels of cytokine IL-23 using ELISA kits.	72 hours after surgery
The levels of IL-17 in blood	Blood samples are collected to measure the levels of cytokine IL-17 using ELISA kits.	72 hours after surgery

Collaborators and Investigators

• Sponsor: Tianjin Medical University General Hospital
• Investigators: Principal Investigator: Guolin Wang, Tianjin Medical University General Hospital

Study record dates

Study Major Dates

• Study Start (Actual): November 30, 2021
• Primary Completion (Anticipated): July 15, 2022
• Study Completion (Anticipated): July 30, 2022

Study Registration Dates

• First Submitted: October 28, 2021
• First Submitted That Met QC Criteria: November 12, 2021
• First Posted (Actual): November 24, 2021

Study Record Updates

• Last Update Posted (Actual): April 15, 2022
• Last Update Submitted That Met QC Criteria: April 8, 2022
• Last Verified: April 1, 2022

More Information

Terms related to this study

• Keywords: esketamine; ketorolac
• Additional Relevant MeSH Terms: Mental Disorders; Pathologic Processes; Postoperative Complications; Pain; Neurologic Manifestations; Neurocognitive Disorders; Cognition Disorders; Pain, Postoperative; Cognitive Dysfunction; Postoperative Cognitive Complications; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase Inhibitors; Psychotropic Drugs; Antidepressive Agents; Ketorolac; Esketamine; Ketorolac Tromethamine
• Other Study ID Numbers: GWang020

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No