Safety and Efficacy Evaluation of S (+) - Ketamine in Adults

Safety and Efficacy Evaluation of S（+）-Ketamine for Postoperative Acute Pain in Adults in Perioperative Settings: A Multicenter, Randomized, Open-label, Active Controlled Pragmatic Clinical Trial

A multicenter, randomized, open-label, active controlled pragmatic clinical trial that evaluates the safety and efficacy of S (+) -ketamine for postoperative acute pain in adults in perioperative settings.

Study Overview

• Status: Not yet recruiting
• Conditions: Postoperative Pain; Anesthesia; Adults
• Intervention / Treatment: Drug: Conventional therapy; Drug: Conventional therapy + S (+)-Ketamine

Detailed Description

Patients often suffer acute pain after operation ，which may affect the recovery. Opioid such as morphine is the most commonly analgesic drugs, but opioid has many obviously adverse reactions ,for example respiratory depression,circulation inhibition,tolerance, addiction, nausea, vomiting, pruritus, etc. S (+) - ketamine has been described to decrease acute pain and opioid consumption,but it needs to confirm for chinese patients undergoing surgery.

Objective:Evaluate the efficacy and safety of S (+) - ketamine on acute perioperative pain for chinese adult patients,and look for the best dosage, mode of administration, timing, and compatibility ,as well explore the effect of S (+) - ketamine on postoperative delirium,anxiety ,depression and cognitive dysfunction.

• Study Type: Interventional
• Enrollment (Anticipated): 12000
• Phase: Phase 4

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• 1. Age ≥18 years old;
• 2. Scheduled for elective digestive tract surgery, gynecological surgery, urological surgery, thoracic surgery, orthopedic limb surgery, orthopedic spine surgery or body surface surgery (thyroid surgery or breast surgery), head and neck surgery;
• 3. ASA score Ⅰ～Ⅲ;
• 4. The informed consent form was signed by the patients.

Exclusion Criteria:

• 1. The expected length of hospital stay of the patient is less than 48h;
• 2. Patients expected to be admitted to the ICU after surgery;
• 3. Patients expected to return to the ward with tracheal catheter after surgery;
• 4. Be allergic to S (+) - ketamine;
• 5. Patients with severe disorder of consciousness or mental system diseases (schizophrenia, mania, bipolar disorder, psychosis, etc.) or cognitive dysfunction;
• 6. Patients with a history of severe cardiovascular disease (congestive heart failure, severe angina attack, or unstable angina or myocardial infarction within 6 months);
• 7. Patients during pregnancy or lactation;
• 8. Patients with MMSE score <18 points;

• 9. Patients with any of the following contraindications of S (+) - ketamine:

  1. Patients with risk of serious rise of blood pressure or intracranial pressure;
  2. Patients with high intraocular pressure (glaucoma) or penetrating ocular trauma;
  3. Patients with poorly controlled or untreated hypertension (Resting systolic blood pressure greater than 180 mmHg, or resting diastolic blood pressure greater than 100mmHg);
  4. Patients with untreated or undertreated hyperthyroidism.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: S (+)-Ketamine group; Drug: Conventional therapy + S (+)-Ketamine In principle, there are no specific restrictions on the dosage, mode of administration, timing, and compatibility of S-ketamine hydrochloride injection,but the recommended dosage is given, which is lower than the dosage specified in the instructions. Recommended use and dosage of S (+)-Ketamine: Bolus intravenous injection before skin incision, the dose is 0.1~0.5 mg/kg;; Bolus intravenous injection (dose 0.1~0.5 mg/kg) before skin incision +continuous intravenous infusion (dose of 0.1~0.25 mg/kg/h) during operation;; Continuous intravenous infusion after surgery with a dose of 0.02~0.1 mg/kg/h for 24~48 h.	Drug: Conventional therapy + S (+)-Ketamine; Patients who undergo general anesthesia using S(+)-ketamine hydrochloride for anesthesia induction,maintenance or postoperative analgesia.; Other Names: Conventional therapy + S-ketamine; Conventional therapy + Esketamine
ACTIVE_COMPARATOR: Control group; Drug: Conventional therapy Receiving conventional therapy without S (+)-Ketamine hydrochloride injection. There is no restrictions in drugs, doses and incompatibility, the researchers can choose appropriate medication regimens based on clinical practice, but other NMDA receptor antagonists are not be allowed to use, such as dextromethorphan and amantadine.	Drug: Conventional therapy; Receiving conventional therapy without S (+)-Ketamine hydrochloride injection. There is no restrictions in drugs, doses and incompatibility, the researchers can choose appropriate medication regimens based on clinical practice, but other NMDA receptor antagonists are not be allowed to use, such as dextromethorphan and amantadine.; Other Names: Routine treatment

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Opioid consumption	Total opioid consumption(conversion to equivalent morphine)	Hour 0-48 after surgery
The area under the broken line of NRS score	The score of Numerical Rating Scale(NRS) is 0-10, the higher the score, the more severe the pain.	Hour 0-48 after surgery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Recovery time	The time from the end of the operation to recovery(can be awakened)	Day 0
The incidence of adverse events after surgery	The incidence of adverse events from the end of the operation to 48h after surgery. Including nausea, vomiting, increased secretions, dizziness, oversedation, infection,anesthetic awareness, nightmares, restlessness, pruritus, disorientation, delirium, respiratory depression, diplopia, diarrhea, intestinal obstruction, urinary retention, gastroesophageal reflux, constipation, chills, hallucinations, etc.	Hour 0-48 after surgery
Pharmacoeconomic indicators	Calculating incremental cost-effectiveness ratio （ICER）based on cost-effectiveness analysis.	Hour 48 after surgery
NRS pain scores	The score of Numerical Rating Scale(NRS) is 0-10, the higher the score, the more severe the pain.	Hour 0-48 after surgery
Time of first rescue analgesia	The time from the end of the operation to the first rescue analgesics after the operation. Rescue analgesia refers to the analgesia according to the patient's requirements in addition to routine postoperative analgesia.	Hour 0-48 after surgery
The incidence of rescue analgesia	The incidence of rescue analgesia within 48h after surgery	Hour 0-48 after surgery
The incidence of unexpected intraoperative events	Unexpected events during operation include intraoperative cough, laryngeal spasm, body movement, tachycardia,decreased oxygen saturation, respiratory depression, bradycardia, hypertension and hypotension.	Intraoperative
The Patient Efficacy Questionnaire (IPOQ ) scores	Patient Efficacy Questionnaire (IPOQ ) scale include 13 questions , each question's score is 0-10 or 0-100%, it involves postoperative pain, mood and quality of life. The higher the score, the more severe the pain symptoms.	Hour 48 after surgery
Incidence of postoperative delirium	The Chinese version of the 3D-CAM scale is used for the diagnosis of delirium, and the assessment will be carried out at 24h, 48h and 72h after the operation. If the patient is discharged 72h after the patient is discharged, it may not be assessed.	Hour 0-48 after surgery
Simple Mental State Examination (MMSE) Scale score	The total score of Simple Mental State Examination Scale (MMSE) is 30,the higher the score, the better the cognitive function.	Hour 48 after surgery
Hospital Anxiety and Depression (HAD) Scale score	Hospital Anxiety and Depression Scale (HAD) includes anxiety measure(7questions,0-21pionts) and depression measure(7 questions,0-21pionts),the higher the score, the more severe thesymptoms.	Hour 48 after surgery

Collaborators and Investigators

• Sponsor: Chinese PLA General Hospital
• Collaborators: First Affiliated Hospital, Sun Yat-Sen University; Shengjing Hospital; First Affiliated Hospital Xi'an Jiaotong University; The Affiliated Hospital of Qingdao University; Beijing Hospital; Renmin Hospital of Wuhan University; Southern Medical University, China; Jiangsu Provincial People's Hospital

Publications and helpful links

General Publications

• Wang H, Duan CY, Huang WQ, Zhao P, Zhou LZ, Liu YH, Liu CM, Chu HC, Wang Q, Diao YG, Hua Z, Meng QT, Li H, Zhang XY, Mi WD, Chen PY. Perioperative intravenous S(+)-ketamine for acute postoperative pain in adults: study protocol for a multicentre, randomised, open-label, positive-controlled, pragmatic clinical trial (SAFE-SK-A trial). BMJ Open. 2021 Dec 16;11(12):e054681. doi: 10.1136/bmjopen-2021-054681.

Study record dates

Study Major Dates

• Study Start (ANTICIPATED): May 1, 2021
• Primary Completion (ANTICIPATED): June 1, 2022
• Study Completion (ANTICIPATED): June 30, 2022

Study Registration Dates

• First Submitted: April 6, 2021
• First Submitted That Met QC Criteria: April 6, 2021
• First Posted (ACTUAL): April 8, 2021

Study Record Updates

• Last Update Posted (ACTUAL): April 8, 2021
• Last Update Submitted That Met QC Criteria: April 6, 2021
• Last Verified: April 1, 2021

More Information

Terms related to this study

• Keywords: Delirium; Hyperalgesia; Acute Pain; S-ketamine,Esketamine,S (+) - ketamine; Depression, Anxiety
• Additional Relevant MeSH Terms: Pathologic Processes; Postoperative Complications; Pain; Neurologic Manifestations; Pain, Postoperative; 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; Psychotropic Drugs; Antidepressive Agents; Ketamine; Esketamine
• Other Study ID Numbers: SAFE-SK-A

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