Immunoinflammatory Regulation of Esketamine in Septic Patients

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Esketamine, Sepsis, Inflammatory Response, Immunosuppression

Intervention / Treatment
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* Drug: Esketamine hydrochloride


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: esketamine plus propofol<br>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<br>* 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.<br>|
| No Intervention: propofol<br>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?
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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 |
| --- | --- | --- |
| 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 | 0 hour 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Esketamine, Sepsis, Inflammatory Response, Immunosuppression