Immunoinflammatory Regulation of Esketamine in Septic Patients

Effects of Esketamine Combined With Propofol for Sedation on Systemic Inflammation and Immune Function in Septic Patients in the ICU: a Single-center, Non-blind, Prospective Randomized Controlled Trial

Studies have shown that excessive systemic inflammatory response and concomitant immunosuppression are the main cause of early death in patients with sepsis. Therefore, it is very important to reduce excessive inflammation and improve immunosuppression in the acute phase of sepsis. Clinical studies have shown that esketamine combined with propofol for sedation has been proven to be safe and effective for septic patients in the ICU due to its cardiovascular stability. Previous studies have demonstrated that esketamine has anti-inflammatory effects against depression and surgical stress. Our preliminary experimental studies have found that esketamine had strong anti-inflammatory effects in the acute phase of sepsis. However, it is not clear whether esketamine could reduce excessive inflammation and improve immunosuppression in septic patients primarily sedated with a continuous infusion of propofol.

This intervention study is to investigate whether three consecutive days of intravenous esketamine infusions via infusion pump (0.07 mg/kg/h) could reduce excessive inflammation and improve immunosuppression in septic patients requiring mechanical ventilation in the ICU under sedation primarily with propofol.

Study Overview

• Status: Recruiting
• Conditions: Sepsis; Inflammatory Response; Immunosuppression; Esketamine
• Intervention / Treatment: Drug: Esketamine hydrochloride

• Study Type: Interventional
• Enrollment (Estimated): 100
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Jiancheng Zhang, PhD, MD; Phone Number: +8613554105815; Email: zhjcheng1@126.com

Study Locations

• China
  • Hubei
    • Wuhan, Hubei, China, 430022
      • Not yet recruiting
      • Department of Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology
      • Contact: Jiancheng Zhang, PhD, MD; Phone Number: +8613554105815; Email: zhjcheng1@126.com
    • Wuhan, Hubei, China, 430022
      • Recruiting
      • Department of Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology
      • Principal Investigator: Jiancheng Zhang, Dr.
      • Contact: Jiancheng Zhang, Dr.; Phone Number: +8613554105815; Email: zhjcheng1@126.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 18 years old ≤ age ≤60 years old;
• SOFA score ≥2;
• Mechanical ventilation should be required for at least 24 hours when included in the study;
• Informed consent is obtained.

Exclusion Criteria:

• Age < 18 years old or ≥ 60 years old;
• Previous solid organ or bone marrow transplantation;
• Autoimmune diseases (rheumatoid arthritis, systemic lupus erythematosus, etc.), or hematologic malignancies (leukemia and lymphoma, etc.);
• Received radiotherapy or chemotherapy within the past 30 days, or received immunosuppressant drugs (tripterygium wilfordii, mycophenolate mofetil, cyclophosphamide, FK506, etc.), or continuous treatment with prednisolone more than 10 mg/day (or equivalent doses of the other hormones);
• Unstable angina pectoris or myocardial infarction in the past six months;
• Acute brain injury (traumatic brain injury, subarachnoid hemorrhage, acute ischemic stroke, acute intracranial hemorrhage, acute intracranial infection, etc.);
• Poorly controlled hypertension and congestive heart failure;
• Increased intraocular or intracranial pressure;
• Chronic kidney disease, received continuous renal replacement therapy in the past 30 days, or acute renal failure requiring CRRT;
• Severe chronic liver disease (Child-Pugh class B or C);
• Alcohol dependence, mental illness or severe cognitive impairment;
• Pregnancy or lactation;
• Informed consent is not obtained.

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
Experimental: esketamine plus propofol; After inclusion, patients are sedated primarily with propofol (0-3 mg/kg/h) using a microinfusion pump and adjusted according to the depth of sedation (Richmond Agitation Sedation Scale (RASS): 0 to -2). After inclusion, septic patients will be received a single intravenous injection of esketamine (0.7 mg/kg), and then followed by an intravenous administration of esketamine (0.07 mg/kg/h) with an infusion pump for three consecutive days.	Drug: Esketamine hydrochloride; After inclusion, septic patients will be received a single intravenous injection of esketamine (0.7 mg/kg), and then followed by an intravenous administration of esketamine (0.07 mg/kg/h) with an infusion pump for three consecutive days.
No Intervention: propofol; After inclusion, patients are sedated primarily with propofol (0-3 mg/kg/h) using a microinfusion pump and adjusted according to the depth of sedation (Richmond Agitation Sedation Scale (RASS): 0 to -2).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Serum concentration of inflammatory cytokines (0 h)	Interleukin (IL)-6, tumor necrosis factor (TNF)-α, IL-2, IL-4, IL-10, IL-17A, and interferon (IFN)-γ	0 hour after study inclusion
Serum concentration of inflammatory cytokines (48 h)	IL-6, TNF-α, IL-2, IL-4, IL-10, IL-17A, and IFN-γ	48 hours after study inclusion
Serum concentration of inflammatory cytokines (72 h)	IL-6, TNF-α, IL-2, IL-4, IL-10, IL-17A, and IFN-γ	72 hours after study inclusion
Absolute number of lymphocyte subsets in the peripheral blood (0 h)	CD3(+), CD3(+) CD4(+), CD3(+) CD8(+), CD3(-) CD16(+) CD56(+) , and CD19(+) cells	0 hour after study inclusion
Absolute number of lymphocyte subsets in the peripheral blood (48 h)	CD3(+), CD3(+) CD4(+), CD3(+) CD8(+), CD3(-) CD16(+) CD56(+) , and CD19(+) cells	48 hours after study inclusion
Absolute number of lymphocyte subsets in the peripheral blood (72 h)	CD3(+), CD3(+) CD4(+), CD3(+) CD8(+), CD3(-) CD16(+) CD56(+) , and CD19(+) cells	72 hours after study inclusion
ICU length of stay	Length of stay in the ICU	up to 8 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Acute physiology and chronic health evaluation (APACHE) Ⅱ score	0-67, higher scores correspond to more severe disease and a higher risk of death	0 hour after study inclusion
Serum concentration of atrial natriuretic peptide (ANP) (0 h)	ANP is secreted primarily by atrial cardiomyocytes	0 hour after study inclusion
Serum concentration of atrial natriuretic peptide (ANP) (48h)	ANP is secreted primarily by atrial cardiomyocytes	48 hours after study inclusion
Serum concentration of atrial natriuretic peptide (ANP) (72h)	ANP is secreted primarily by atrial cardiomyocytes	72 hours after study inclusion
Acute physiology and chronic health evaluation (APACHE) Ⅱ score	0-67, higher scores correspond to more severe disease and a higher risk of death	24 hours after study inclusion
Acute physiology and chronic health evaluation (APACHE) Ⅱ score	0-67, higher scores correspond to more severe disease and a higher risk of death	48 hours after study inclusion
Acute physiology and chronic health evaluation (APACHE) Ⅱ score	0-67, higher scores correspond to more severe disease and a higher risk of death	72 hours after study inclusion
Sequential organ failure assessment (SOFA) score	0-43, higher scores correspond to more severe sepsis	0 hour after study inclusion
Sequential organ failure assessment (SOFA) score	0-43, higher scores correspond to more severe sepsis	24 hours after study inclusion
Sequential organ failure assessment (SOFA) score	0-43, higher scores correspond to more severe sepsis	48 hours after study inclusion
Sequential organ failure assessment (SOFA) score	0-43, higher scores correspond to more severe sepsis	72 hours after study inclusion
Mechanical ventilation time after inclusion	Patients requiring mechanical ventilation after study inclusion	Up to 8 weeks
Total hospital length of stay	Total length of hospital stay	Through study completion, an average of 2 year
Infection complications	Pulmonary infection, urinary tract infection, bloodstream infections, etc	Through study completion, an average of 2 year
In-hospital mortality	Mortality rates for the entire period of hospitalization	Through study completion, an average of 2 year
90-day readmission rate	Percentage of readmission to hospital within 90 days of study inclusion	Through study completion, an average of 2 year
CCL1 expression in alveolar macrophages (0 h)	CCL1 expression in alveolar macrophages collected from bronchoalveolar lavage fluid	0 hour after study inclusion
CCL1 expression in alveolar macrophages (24 h)	CCL1 expression in alveolar macrophages collected from bronchoalveolar lavage fluid	24 hours after study inclusion
CCL1 expression in alveolar macrophages (72 h)	CCL1 expression in alveolar macrophages collected from bronchoalveolar lavage fluid	72 hours after study inclusion
expression of WNT pathway proteins in alveolar macrophages (0 h)	Wnt5a, FZD5, b-catenin, Lef1 expression in alveolar macrophages collected from bronchoalveolar lavage fluid	0 hour after study inclusion
expression of WNT pathway proteins in alveolar macrophages (24 h)	Wnt5a, FZD5, b-catenin, Lef1 expression in alveolar macrophages collected from bronchoalveolar lavage fluid	24 hours after study inclusion
expression of WNT pathway proteins in alveolar macrophages (72 h)	Wnt5a, FZD5, b-catenin, Lef1 expression in alveolar macrophages collected from bronchoalveolar lavage fluid	72 hours after study inclusion

Collaborators and Investigators

• Sponsor: Wuhan Union Hospital, China
• Investigators: Principal Investigator: Shiying Yuan, PhD, MD, Wuhan Union Hospital, China

Study record dates

Study Major Dates

• Study Start (Actual): July 28, 2021
• Primary Completion (Estimated): October 30, 2026
• Study Completion (Estimated): October 30, 2026

Study Registration Dates

• First Submitted: March 29, 2021
• First Submitted That Met QC Criteria: April 11, 2021
• First Posted (Actual): April 14, 2021

Study Record Updates

• Last Update Posted (Actual): July 18, 2025
• Last Update Submitted That Met QC Criteria: July 17, 2025
• Last Verified: July 1, 2025

More Information

Terms related to this study

• Keywords: Immunosuppression; Sepsis; Esketamine; Inflammatory Response
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Sepsis; Psychotropic Drugs; Antidepressive Agents; Esketamine
• Other Study ID Numbers: YSY202001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: After the completion of the study, the original data will be sent to the email address: zhjcheng1@163.com, and the password will be provided after the paper is published.
• IPD Sharing Time Frame: Six months after the paper was published
• IPD Sharing Access Criteria: The raw data supporting the conclusions of this manuscript will be made available by the authors, without undue reservation, to any qualified researcher.
• IPD Sharing Supporting Information Type: CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No