Clinical Study of Esketamine in Patients With Sepsis Undergoing Invasive Mechanical Ventilation

A Clinical Study of Esketamine for Sedation, Delirium Prevention and Clinical Outcomes in Septic Patients Under Invasive Mechanical Ventilation

Sepsis is a syndrome of acute organ dysfunction resulting from dysregulated host responses to infection, often leading to severe complications such as acute lung injury and ARDS. ICU patients on mechanical ventilation face multiple noxious stimuli and require effective analgesic and sedative treatments to improve prognosis. The limitations of existing analgesic and sedative drugs are as follows:Opioids (such as remifentanil) have strong analgesic effects but can easily cause adverse reactions such as respiratory depression, hypotension, and gastrointestinal dysfunction.Sedative drugs like midazolam may lead to delirium and gastrointestinal dysfunction.Esketamine exerts its analgesic and sedative effects by non-competitively inhibiting the N-methyl-D-aspartate (NMDA) receptor. It has sympathomimetic activity, which can reduce hemodynamic fluctuations. It also has immunomodulatory effects, which may improve the prognosis of sepsis patients. Currently, esketamine is only used for anesthesia induction in surgery, postoperative analgesia, painless procedures, and as an adjunctive treatment for depression, with limited sample sizes and few reports. There are no large-scale clinical studies on the use of esketamine in sepsis patients undergoing invasive mechanical ventilation, and further verification of its efficacy and safety is needed.

Sepsis is circulatory dysfunction or failure caused by infection. When a pathogen infects the body, the body activates autoimmune mechanisms to eliminate the pathogen. While removing pathogens, it often causes damage to its own capillary endothelium, capillary leakage, coagulation dysfunction, and local inflammatory damage. Acute lung injury is characterized by refractory hypoxemia and respiratory distress, which can further develop into more severe acute respiratory distress syndrome; Patients with pulmonary inflammation characterized by decreased lung compliance and ventilation/flow dysbivie requiring invasive mechanical ventilation to improve oxygen uptake are common in the ICU.ICU mechanically ventilated patients are in a strong stress environment, and invasive mechanically ventilated patients must experience a variety of nociceptive stimuli of different intensities in the process of receiving treatment, such as antiphysiological ventilation mode, restraint and immobilization, tracheal tube stimulation, various puncture operations, wound care, sputum suction, and environmental factors stimuli, etc., on the basis of the influence of the primary disease, these exogenous stimuli can cause strong discomfort in patients and induce severe physical and psychological stress, which is to cause patients to have anxiety, restlessness, Delirium and other important causes of adverse events (1) can even have an adverse effect on clinical prognosis. For patients with respiratory failure and strong compensatory drive for spontaneous breathing, an appropriate depth of analgesia and sedation is required to minimize the patient's excessive spontaneous respiratory drive and reduce stretch damage to lung tissue. Effective analgesia and sedation can reduce the metabolic rate of patients, reduce their oxygen consumption demand, make the changes in oxygen consumption demand of body tissues adapt to the damaged oxygen delivery state as much as possible, and reduce the metabolic burden of various organs, thereby reducing the damage caused by strong pathological factors and creating conditions for the recovery of organ function. Therefore, it is the basic task of critical care to effectively control the disease factors and various injury stimuli caused by intensive medical measures through appropriate analgesia and sedation treatment, and to maintain the comfort and safety of patients with invasive mechanical ventilation.Opioids are one of the powerful central analgesics, which have the advantages of strong analgesic effect, fast onset, strong adjustability, and low price, and are the basic drugs in the pain management of ICU patients. However, the adverse effects of opioids are mainly caused by respiratory depression, a drop in blood pressure, and a decrease in gastrointestinal motility, especially in the elderly. Thus, the use of opioids in patients with sepsis may affect their hemodynamic and gastrointestinal function.The ideal sedative, analgesic or combination regimen requires not only adequate sedation and analgesia, but also rapid onset of action, rapid awakening after discontinuation of the drug, minimal accumulation in the body and minimal circulatory impact, and anti-anxiety and anti-delirium effects. Ketamine is a commonly used anesthetic drug with good sedative and analgesic effects. However, due to the adverse reactions of the drug such as postoperative nightmares and extrapyramidal syndrome, the clinical application of the drug in the late 90s of the 20th century has decreased. Esketamine is a pure dextrarive enantiomer of ketamine, which can be used for analgesia and anesthesia in clinical practice, mainly through non-competitive inhibition of N-methyl-D-aspartate receptors to exert analgesic and sedative effects. The analgesic, sedative, and anesthetic effects of esketamine are dose-dependent, and the anesthesia has a rapid onset and relatively short duration, and its combination with benzodiazepines can greatly reduce the risk of psychotic reactions during awakening. For hemodynamically unstable mechanically ventilated patients, the use of analgesic and sedative drugs often further affects hemodynamic stability, but esketamine can inhibit the reuptake of norepinephrine by sympathetic nerve endings in the body, cause adrenergic hyperactivity, increase the concentration of norepinephrine in the circulatory system, and produce sympathomimetic activity, which can effectively reduce this adverse reaction. Moreover, esketamine does not produce respiratory drive inhibition, and patients can resume spontaneous breathing relatively early, accelerating the weaning process. In addition, esketamine has immunomodulatory effects, which can reduce the level of inflammatory factors and improve the prognosis of patients with sepsis. Therefore, esketamine in patients with sepsis who are invasively mechanically ventilated may have certain advantages in improving hemodynamics and reducing respiratory depression and gastrointestinal adverse effects.Esketamine is currently only used as an adjunct to anesthesia induction during surgery, postoperative analgesia and painless procedures, and depression, with a small sample size and few reports. There are no similar reports on its use in sepsis, so its efficacy and safety need to be further validated in randomized prospective clinical studies.

Inclusion Criteria:

• Meet Sepsis-3.0 diagnostic criteria.
• Age ≥ 18 years.
• Required invasive mechanical ventilation.
• Expected ICU stay ≥ 24 h.

Exclusion Criteria:

• Pregnant or lactating women.
• Pregnant or lactating women.
• Child-Pugh class C or worse.
• Severe renal impairment (Scr > 178 µmol/L or BUN > 9 mmol/L).
• Pre-existing delirium, dementia, or other psychiatric disorder.
• Known allergy to opioids or benzodiazepines.
• Uncontrolled hypertension (SBP > 180 mmHg or DBP > 100 mmHg).
• Preeclampsia/eclampsia.
• Significant ischemic heart disease.
• Severe pulmonary dysfunction.