Adjunctive Esketamine for Analgesia in Mechanically Ventilated Septic Shock Patients

Adjunctive Esketamine for Analgesia in Mechanically Ventilated ICU Septic Shock Patients

Sedation and analgesia in patients with sepsis and hemodynamic instability may be challenging in the ICU. Opioids and propofol can further exacerbate tissue infusion in septic shock by reducing cardiac contractility, increasing vasodilation, and reducing respiratory drive. Ketamine is an NMDA receptor antagonist, which has no effect on respiratory drive and has diastolic airway smooth muscle and anti-inflammatory properties. Esketamine is a dextrorotatory cleavage twice as potent and reduces the incidence of dose-dependent side effects of ketamine. Although it has been successfully used in burn patients undergoing multiple operations and anesthesia-related maintenance analgesia, it has not been reported in ICU septic shock patients undergoing mechanical ventilation. The purpose of this study was to explore the use of esketamine in mechanically ventilated ICU septic shock patients in a single-center randomized controlled trial.

Study Overview

• Status: Recruiting
• Conditions: Septic Shock; Mechanical Ventilation Complication
• Intervention / Treatment: Drug: Remifentanil + propofol; Drug: Saline; Drug: Esketamine; Procedure: Pain and Sedation Assessment

Detailed Description

In order to further clarify whether Esketamine can be used as a conventional continuous intravenous infusion drug in the ICU, further RCT is required. Therefore, this project assumes that low-dose Esketamine has a clear analgesic and sedative effect, and has advantages such as less adverse reactions in hemodynamics, respiratory inhibition, and gastrointestinal peristalsis. It is proposed to complete the following work: on the standard analgesia and sedation scheme (remifentanil+propofol), evaluate the feasibility, effectiveness and safety of the auxiliary analgesia scheme added with esketamine for septic shock patients with mechanical ventilation by whether to load small dose of esketamine for infusion, so as to provide basis for follow-up individualized diagnosis and treatment.

• Study Type: Interventional
• Enrollment (Estimated): 124
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Hongbin Hu, doctor; Phone Number: +86139224837; Email: hobewoos@163.com

Study Locations

• China
  • Guangzhou, China, 510515
    • Recruiting
    • Southern Medical University Nanfang Hospital
    • Contact: Hongbin Hu, doctor; Phone Number: +8613922483752; Email: hobewoos@163.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age ≥ 18;
• A patient diagnosed with septic shock;
• It needs to be treated with analgesics, sedatives, and vasopressors for a period of not less than 48 hours;
• Mechanical ventilation by the ventilator is needed;
• Obtain the informed consent of the human subjects or their legal representatives;

Exclusion Criteria:

• Currently pregnant or breastfeeding;
• Confirmed acute severe intracranial or spinal neurologic diseases caused by vascular, intracranial expansion, or injury;
• History of uncontrolled or malignant hypertension (sustained (>3 hours) heart rate >150 beats/min or systolic blood pressure >180 mmHg); recent history of ketamine use；
• Hearing or vision loss, or any other conditions likely to severely interfere with the collection of research data;
• Long-term use of benzodiazepines or opioids;
• Known allergy to any investigational drug;
• Subject receiving sedative therapy not for tolerance to mechanical ventilation (e.g., seizures);
• Unlikely to require ongoing sedation during mechanical ventilation (e.g., Guillain-Barré syndrome);
• Patients deemed unlikely by the attending physician to be weaned from mechanical ventilation, such as those with diseases/injuries primarily affecting respiratory neuromuscular function and conditions requiring prolonged ventilatory support, which are clearly irreversible (e.g., high spinal cord injury);
• Open eye injury or other ophthalmic diseases;
• Concurrent participation in any other interventional study (any study assigning subjects to different treatment groups and/or conducting unconventional diagnostic or monitoring procedures).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Remifentanil + propofol + esketamine; esketamine (2ml; 50mg), Remifentanil Hydrochloride for Injection (1mg;), propofol injection (50ml; 0.5g; )； The frequency of use is determined by responsible clinicians.All analgesic and sedative drugs used are adjusted according to the actual situation of the patient.	Drug: Remifentanil + propofol; Remifentanil + propofol; Drug: Esketamine; Load dose of 0.25 mg/kg, and the fixed infusion rate of 0.15 mg/kg/h.The load dose will be injected intravenously within 1-2 minutes.Maintain the infusion at a fixed rate of 0.15 mg/kg/h for 72 hours; after 72 hours, change to a fixed rate infusion of 0.06 mg/kg/h. Preparation: 46ml of saline + 4ml of eskeamine.; Other Names: Esketamine Hydrochloride Injection; Procedure: Pain and Sedation Assessment; RASS Score: After randomization success, a baseline Richmond Agitation-Sedation Scale (RASS) score is obtained before administering the investigational drug. Pain assessments are conducted every 1 hour within the first 6 hours after the initiation of the intravenous loading dose of the investigational drug, every 4 hours within the first 24 hours, and subsequently every 8 hours until the end of the study. In addition to the fixed time points mentioned above, researchers may conduct RASS scoring at any time based on the subject's actual condition (excessive or inadequate sedation). (No further RASS scoring is performed once the subject is fully awake.) CPOT Score: CPOT（Critical-Care Pain Observation Tool）Pain assessments are conducted concurrently with RASS scoring.
Placebo Comparator: remifentanil + propofol + saline; Remifentanil Hydrochloride for Injection (1mg;), propofol injection (50ml; 0.5g; )； The amount of saline used is equivalent to the amount of esketamine.All analgesic and sedative drugs used are adjusted according to the actual situation of the	Drug: Remifentanil + propofol; Remifentanil + propofol; Drug: Saline; As a placebo,normal saline at the same dose as esketamine.Saline is also administered intravenously.; Other Names: physiological saline; saline solution; Procedure: Pain and Sedation Assessment; RASS Score: After randomization success, a baseline Richmond Agitation-Sedation Scale (RASS) score is obtained before administering the investigational drug. Pain assessments are conducted every 1 hour within the first 6 hours after the initiation of the intravenous loading dose of the investigational drug, every 4 hours within the first 24 hours, and subsequently every 8 hours until the end of the study. In addition to the fixed time points mentioned above, researchers may conduct RASS scoring at any time based on the subject's actual condition (excessive or inadequate sedation). (No further RASS scoring is performed once the subject is fully awake.) CPOT Score: CPOT（Critical-Care Pain Observation Tool）Pain assessments are conducted concurrently with RASS scoring.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Doses of remifentanil and norepinephrine during mechanical ventilation (total dose/duration of use hours).	Responsible researchers consult the patient's medical record after completing treatment to obtain the dosage and duration of medication.	During mechanical ventilation procedure (From randomization to the seventh day of infusion or ventilator withdrawal, whichever occurs first）

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Duration of mechanical ventilation.	Responsible researchers obtain information by viewing electronic medical records.	From endotracheal intubation to withdrawal from mechanical ventilation, or until 28 days after discharge, death, or randomization in the ICU, whichever occurs
Propofol dosage (total dose/duration of use) during mechanical ventilation.	Responsible researchers consult the patient's medical record after completing treatment to obtain the dosage and duration of medication.	During mechanical ventilation procedure (From randomization to the seventh day of infusion or ventilator withdrawal, whichever occurs first）
The proportion of patients meeting the RASS sedation and CPOT pain goals during mechanical ventilation.	Professionally trained researchers perform RASS and COPT scores on patients at specific time points.	up to 28 days
The incidence of delirium, i.e. the positive rate of CAM-ICU.	The occurrence of delirium in patients will be recorded by clinicians or nurses on medical records, and researchers will summarize the occurrence of delirium (such as the time of occurrence, duration, treatment measures, etc.)Patients will be evaluated using CAM-ICU by clinicians or nurses.	up to 28 days
Incidence of adverse events.	The occurrence of adverse events during the hospital period will be recorded in the medical record by the clinician or nurse, and the researcher will obtain the occurrence of adverse events (event type, time, treatment, results, etc.) through the medical record.	up to 28 days
The mortality rate	Researchers obtain it through the hospital electronic system.	up to 28 days
Mechanical ventilator free days.	Responsible researchers obtain information by viewing electronic medical records.	Days to 28
Length of ICU stay.	Researchers obtain it through the hospital electronic system.	up to 28 days

Collaborators and Investigators

• Sponsor: Nanfang Hospital, Southern Medical University

Study record dates

Study Major Dates

• Study Start (Actual): May 31, 2023
• Primary Completion (Estimated): October 31, 2024
• Study Completion (Estimated): October 31, 2024

Study Registration Dates

• First Submitted: March 20, 2023
• First Submitted That Met QC Criteria: May 1, 2023
• First Posted (Actual): May 3, 2023

Study Record Updates

• Last Update Posted (Estimated): November 22, 2023
• Last Update Submitted That Met QC Criteria: November 20, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: sedation; analgesia; Esketamine; Vasoactive drugs
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Sepsis; Shock, Septic; Shock; Physiological Effects of Drugs; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Analgesics, Opioid; Narcotics; Psychotropic Drugs; Antidepressive Agents; Hypnotics and Sedatives; Remifentanil; Propofol; Esketamine
• Other Study ID Numbers: NFEC-2022-394

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

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