Esketamine Induction Intubation in ICU Patients.

Union Hospital, Tongji Medical College, Huazhong University of Science and Technology

Status and phase: Completed; Early Phase 1

Conditions: Critically Ill Patients

Treatments: Drug: Esketamine Hydrochloride 28 Mg in 0.2 mL NASAL SOLUTION [Spravato]; Drug: midazolam, fentanyl

Study type: Interventional

Funder types: Other

Identifiers

NCT05464979

ZJC202203

Details and patient eligibility

About

Intubation in the intensive care unit (ICU) is usually an emergency. Pathophysiological changes such as shock, respiratory failure, and metabolic acidosis in critically ill patients can significantly increase the incidence of adverse events during intubation.

Studies have shown that esketamine has no significant effect on body metabolism, endocrine system, liver, kidney, intestinal function and coagulation function. In terms of drug metabolism, esketamine has high bioavailability, short half-life, faster and more comfortable recovery of patients, and not only has the advantage of providing stable hemodynamics during endotracheal intubation, but also counteracts the respiratory depression caused by opioids. In addition, esketamine has antidepressant and anti-inflammatory properties. The investigators also found that combined prophylactic and therapeutic use of esketamine could attenuate systemic inflammation and inflammatory multi-organ injury in mice after CLP-induced lethal sepsis.

This project aims to study the clinical effect of esketamine induction intubation and conventional induction intubation in ICU patients.

Full description

Esketamine is the S-enantiomer of ketamine and has been approved for clinical use by the National Medical Products Administration (NMPA) in 2019. Studies have shown that esketamine has no significant effect on metabolism, endocrine system, liver, kidney, intestinal function and coagulation function. It is mainly used in combination with sedatives (such as propofol, etc.) or alone to induce and implement general anesthesia. The phase III clinical study on the application of esketamine in the induction and maintenance of general anesthesia in laparoscopic surgery showed that the recovery time of the esketamine group was significantly shorter than that of the ketamine group when the same clinical anesthesia effect was achieved. Esketamine has the effect of dissociative anesthesia, which can maintain better spontaneous breathing of patients while satisfying outpatient examinations or operations, and this feature helps maintain circulatory stability, especially in patients with shock. Esketamine has sympathomimetic properties. In patients with potentially unstable cardiac disease (eg, septic cardiomyopathy), esketamine is the preferred choice for induction of anesthesia, especially in combination with midazolam. Esketamine is also the preferred choice for anesthesia induction in patients with bronchospasm, which can protect patients from bronchospasm during induction.

Studies have found that esketamine has antidepressant and anti-inflammatory effects in addition to its analgesic, sedative and anesthetic effects. Clinical studies have shown that esketamine (0.25 mg/kg, 40 min infusion time) can rapidly improve the depressive symptoms of patients with treatment-resistant depression. The antidepressant effects of esketamine may be closely related to its anti-inflammatory effect. During cardiopulmonary bypass surgery, anesthesia induction was supplemented with 1-3 mg/kg esketamine, anesthesia maintenance was supplemented with 2-3 mg/kg/h esketamine, anesthesia maintenance time was 283 minutes, the total amount of esketamine was 1580mg on average. Esketamine decreased plasma levels of IL-6 (6 h after opening the aorta) and IL-8 (1 and 6 h after opening the aorta) and increased plasma levels of IL-10 (1 h after opening the aorta). In the investigators' preliminary study on the role of esketamine in systemic inflammation induced by lipopolysaccharide (LPS), the investigators found that in systemic LPS (5 mg/kg)-induced systemic inflammation model, esketamine (10 mg/kg, IP) was administrated twice 24 hours before LPS administration and 10 minutes after LPS administration. The plasma levels of IL-6, IL-17A and interferon γ (IFN-γ) were significantly decreased 24 h after LPS administration in mice. However, the efficacy and safety of esketamine for tracheal intubation in ICU patients is still unclear, and no relevant clinical studies have been reported.

The investigators will include adult patients subjected to tracheal intubation in the ICU strictly according to the inclusion and exclusion criteria to investigate the efficacy and safety of esketamine for tracheal intubation in ICU patients.

Enrolled patients were randomly assigned to two groups: the esketamine intubation group and the conventional intubation group. In esketamine intubation group, esketamine at 0.5-1.0 mg/kg BW and rocuronium bromide at 0.6 mg/kg BW was given intravenously for induction intubation. In conventional intubation group, Midazolam at 0.1mg/kg BW, fentanil citrate at 1ug/kg BW, rocuronium bromide at 0.6mg/kg BW was given intravenously for induction intubation.Both groups were given roccuronium bromide (0.6 mg/kg) before intubation. Sufentanil citrate (0.08-0.15 μg/kg/h) combined with remimazolam besylate (0.15-0.25 mg/kg/h) was administered intravenously to sustain a Critical-Care Pain Observation Tool (CPOT) score 0 and a Richmond Agitation and Sedation Scale (RASS) score between -3 and 0 following intubation. Before induction, monitors were applied:

continuous electrocardiograph (ECG), continuous pulse oximetry, invasive blood pressure monitor through a 20-G radial arterial catheter connected to a pressure transducer placed at the level of the heart.

Five tubes of venous blood were collected and sent to the laboratory and immunology department of Union Hospital affiliated to Tongji Medical College, Huazhong University of Science and Technology, before intubation, and five tests including blood routine, coagulation, liver function, kidney function, electrolytes, C-reactive protein, myocardial enzyme, BNP, lymphocyte subsets and cytokines were performed.

If the adverse events of esketamine appear during the study, patients or authorized client withdraw from the study actively, or drugs that seriously affect systemic inflammation and immune function (such as non-steroidal anti-inflammatory drugs, immunosuppressants, immunoenhancers, high doses of hormones (more than 10mg prednisolone per day or equivalent dose of other hormones, etc.) were used in clinical treatment, the study will be terminated. In this study, adverse reactions were evaluated daily after inclusion.

Enrollment: 80 patients

Sex: All

Ages: 18 to 80 years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Patients aged ≥ 18 years old without restriction of gender, race, religion, creed or nationality;
• No use of sedatives within the half-life of their elimination before inclusion；
• Patients and/or their family members know and agree to participate in the trial.

Exclusion criteria

• Age <18 years,Allergy to esketamine or midazolam;
• Endotracheal tract required intubation without notsedative drugs, such as cardiac arrest、neurologic dysfunction or the need for awake intubation
• Patients with suspected elevated intracranial pressure;
• Bradycardia (heartrate (HR) less than 50 beats / min) or atrioventricular block；
• Untreated or undertreated hyperthyroid patients;
• Chronic kidney disease;
• Severe chronic liver disease (child-Pugh: Grade C);
• Alcohol or opioid dependence, mental illness, or severe cognitive impairment;
• Pregnancy or lactation;
• Lack of informed consent.

Trial design

Primary purpose: Screening

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Double Blind

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80 participants in 2 patient groups, including a placebo group

Esketamine intubation group

Experimental group

Description:

Esketamine at 0.5-1.0 mg/kg BW and rocuronium bromide at 0.6 mg/kg BW was given intravenously for induction intubation. After the intubation was completed, sufentanil citrate (0.08-0.15 μg/kg/h) combined with remimazolam besylate (0.15-0.25 mg/kg/h) was administered intravenously to sustain a Critical-Care Pain Observation Tool (CPOT) score 0 and a Richmond Agitation and Sedation Scale (RASS) score between -3 and 0 following intubation.

Treatment:

Drug: Esketamine Hydrochloride 28 Mg in 0.2 mL NASAL SOLUTION [Spravato]

Conventional intubation group

Placebo Comparator group

Description:

Midazolam at 0.1mg/kg BW, fentanyl at 1ug/kg BW, rocuronium bromide at 0.6mg/kg BW was given intravenously for induction intubation; After the intubation was completed, sufentanil citrate (0.08-0.15 μg/kg/h) combined with remimazolam besylate (0.15-0.25 mg/kg/h) was administered intravenously to sustain a Critical-Care Pain Observation Tool (CPOT) score 0 and a Richmond Agitation and Sedation Scale (RASS) score between -3 and 0 following intubation.

Treatment:

Drug: midazolam, fentanyl