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

Safety and Efficacy Evaluation of S (+) -Ketamine for Postoperative Acute Pain in Children 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 children in perioperative settings.

Study Overview

• Status: Enrolling by invitation
• Conditions: Delirium; Postoperative Pain; Analgesia; Children; Acute Pain; Depression, Anxiety; Hyperalgesia; S-ketamine; Esketamine
• Intervention / Treatment: Drug: Conventional therapy + S (+)-Ketamine; Drug: Conventional therapy

Detailed Description

Children often suffer acute pain,awakening delirium, anxiety and depression after operation which may affect the recovery of children. S (+) - ketamine has been described to decrease acute pain and opioid consumption,but it needs to confirm for chinese children undergoing surgery.

Objective:

To evaluate the analgesic effect of perioperative administration of S (+) - ketamine on postoperative acute pain in children undergoing surgery, and explore the effects of S (+) - ketamine on postoperative awakening delirium, postoperative anxiety and depression mood ,as well find the best usage, including dose, timing, compatibility, and type of operation.

• Study Type: Interventional
• Enrollment (Estimated): 3000
• Phase: Phase 4

Contacts and Locations

Study Locations

• China
  • Beijing
    • Beijing, Beijing, China
      • Chinese PLA General Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 17 years (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Age ≤17 years;
2. Scheduled for elective digestive tract surgery, orthopedic surgery, urological surgery , ear surgery or other surgeries under general anesthesia;
3. ASA physical status I～Ⅲ;
4. The informed consent form was signed by the patients or the guardians.

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 congenital heart disease or severely developmental retardation;

7. 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 Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: S (+)-Ketamine group; Patients who undergo general anesthesia using S(+)-ketamine hydrochloride for anesthesia induction, maintenance or postoperative analgesia.	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: Intravenous injection：Bolus intravenous injection before skin incision, the dose is 0.1~0.25 mg/kg; Bolus intravenous injection (dose 0.1~0.25 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.; Intramuscular injection：The dose is 2~4 mg/kg.; Other Names: Conventional therapy + S-ketamine; Conventional therapy + Esketamine
Active Comparator: Control group; Patients who undergo conventional therapy without S (+)-Ketamine hydrochloride injection during perioperative period.	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
The area under the broken line of FLACC scale score	Only for children aged 0~7 years. The score of FLACC Scale is 0-10, the higher the score, the more severe the pain.	Hour 0-48 after surgery
The area under the broken line of Numerical Rating Scale score	Only for children aged 8~17years. The score of Numerical Rating Scale(NRS) is 0-10, the higher the score, the more severe the pain.	Hour 0-48 after surgery
Opioid consumption	Total opioid consumption(conversion to equivalent morphine)	Hour 0-48 after surgery

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
FLACC scale score	Only for children aged 0~7 years. The score of FLACC Scale is 0-10, the higher the score, the more severe the pain. 8≤Age ≤17 years: NRS pain score at 2h, 4h, 24h, 48h after surgery.	Hour 0-48 after surgery
Numerical Rating Scale score	Only for children aged 8~17years. 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 or guardian's requirements in addition to routine postoperative analgesia.	Hour 0-48 after surgery
The incidence of rescue analgesia	Rescue analgesia refers to the analgesia according to the patient's or guardian's requirements in addition to routine postoperative analgesia.	Hour 0-48 after surgery
Recovery time	The time from the end of the operation to recovery(can be awakened)	Day 0
The incidence of emergence delirium	Only for children aged 0-7 years. Evaluating by the Pediatric Emergence Delirium Rating Scale(PAED) ,the score of the scale is 0~20, when the total score is greater than 10, it is considered that the child has delirium.The scale will be evaluated 10minutes, 20minutes, 30minutes after extubation.	Day 0
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 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
Children's Depression Inventory(CDI) score	Only for children aged 8~17.Children's Depression Inventory(CDI) scale include 27 questions ,from 0 to 54pionts, the higher the score, the more severe the depressive symptoms.	Hour 48 after surgery
Hospital Anxiety and Depression Scale(HAD）score	Only for children aged 14~17.Hospital Anxiety and Depression Scale(HAD）include anxiety measure(7 questions,0-21pionts) and depression measure(7 questions,0-21pionts),the higher the score, the more severe the symptoms.	Hour 48 after surgery
Pharmacoeconomic indicators	Calculating incremental cost-effectiveness ratio （ICER）based on cost-effectiveness analysis.	Hour 48 after surgery

Collaborators and Investigators

• Sponsor: Chinese PLA General Hospital
• Collaborators: Shanghai Children's Medical Center; Beijing Children's Hospital; Southern Medical University, China; Hunan Children's Hospital
• Investigators: Study Chair: Weidong Mi, MD, Chinese PLA General Hospital

Publications and helpful links

General Publications

• Wang H, Duan C, Zhang J, Qu S, Sun Y, Zhou L, Yang L, Lan C, Mi W, Chen P. Evaluation of the effect of perioperative administration of S(+)-ketamine hydrochloride injection for postoperative acute pain in children: study protocol for a prospective, multicenter, randomized, open-label, parallel-group, pragmatic clinical trial. Trials. 2022 Jul 23;23(1):586. doi: 10.1186/s13063-022-06534-z.

Study record dates

Study Major Dates

• Study Start (Actual): April 20, 2022
• Primary Completion (Estimated): December 1, 2024
• Study Completion (Estimated): December 4, 2024

Study Registration Dates

• First Submitted: April 2, 2021
• First Submitted That Met QC Criteria: April 3, 2021
• First Posted (Actual): April 8, 2021

Study Record Updates

• Last Update Posted (Actual): March 8, 2024
• Last Update Submitted That Met QC Criteria: March 6, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Nervous System Diseases; Pain; Neurologic Manifestations; Sensation Disorders; Somatosensory Disorders; Acute Pain; Hyperalgesia; 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-C

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