Clinical trial NCT06531369: Flumazenil Antagonism of Remimazolam in Kidney Transplant Patients
Official title: Application of Flumazenil to Antagonize Remimazolam and Evaluation of Remimazolam Plasma Concentration in Kidney Transplant Patients: A Randomized Controlled Trial
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE1
Conditions: Flumazenil to Antagonize Remimazolam
Remimazolam
Renal Transplantation
Keywords: Flumazenil
Remimazolam
renal transplantation
Lead sponsor: Qianfoshan Hospital
Sponsor class: OTHER
First posted: 2024-08-01
Enrollment: 60
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: To investigate the effect of different doses of flumazenil antagonism on remimazolam plasma concentration in patients undergoing renal transplantation under general anesthesia.

Detailed description: During the surgery, other anesthetics, intraoperative monitoring, fluid management, and postoperative pain management were implemented according to a unified standard.

1. Intraoperative Monitoring All study participants underwent the following routine intraoperative monitoring: blood pressure, electrocardiogram, pulse oximetry, end-tidal CO2 pressure, body temperature, and depth of anesthesia monitoring. Additional monitoring such as central venous pressure, invasive continuous arterial blood pressure, and cardiac output was selected based on clinical needs and the attending anesthesiologist's judgment.
2. Anesthetic Regimen

   All study participants underwent general anesthesia with endotracheal intubation and received total intravenous anesthesia with remimazolam. For anesthesia induction, it was recommended to administer remimazolam at a rate of 6-12 mg/kg/h until loss of consciousness; for maintenance, it was recommended to administer at a rate of 0.5-2.0 mg/kg/h. At the end of anesthesia:

   C Group: Immediately after surgery, an equal volume of saline (equal to the volume of 0.5 mg flumazenil) was administered, followed by an equal volume of saline (equal to the volume of 0.3 mg flumazenil) 25 minutes later.

   R1 Group: Immediately after surgery, 0.5 mg flumazenil was administered, followed by an equal volume of saline (equal to the volume of 0.3 mg flumazenil) 25 minutes later.

   R2 Group: Immediately after surgery, 0.5 mg flumazenil was administered, followed by 0.3 mg flumazenil 25 minutes later.

   None of the three groups used inhalation anesthetics such as sevoflurane, or other intravenous sedatives such as midazolam, dexmedetomidine, or etomidate. Intraoperative analgesics were administered with remifentanil via continuous intravenous infusion. Muscle relaxants included cisatracurium, with a single intravenous injection of cisatracurium 0.2 mg/kg for induction to meet muscle relaxation conditions for tracheal intubation, and intermittent single intravenous bolus of cisatracurium 0.05 mg/kg to maintain muscle relaxation as needed for the surgery.
3. Depth of Anesthesia Management Narcotrend was measured as a baseline value within 60 minutes before administration, and intraoperative depth of anesthesia monitoring was conducted using Narcotrend. The dose of remimazolam was adjusted according to hemodynamics to ensure that the patient's anesthesia depth (Narcotrend Index, NCI) was maintained between 27 and 60. (If the NCI value could not be maintained at ≤ 60 or there were signs of potential inadequate anesthesia (e.g., coughing, sweating, and patient movement), and the maximum bolus and infusion doses of remimazolam had been administered, rescue medications such as midazolam or propofol were allowed.)
4. Blood Pressure Management Intraoperative blood pressure control aimed to maintain a mean arterial pressure (MAP) of no less than 65 mmHg, which was the minimum blood pressure tolerated by the anesthesiologist during surgery, not the target value. Higher or lower intraoperative blood pressure management targets could be adopted based on the participant's condition and/or the surgeon's requirements. The use of vasoactive drugs was minimized. If vasoactive drugs were needed, ephedrine 5 mg (maximum dose not exceeding 30 mg) and norepinephrine 10 µg intravenous bolus or continuous infusion were used. Norepinephrine was prepared and used as follows: 2 mg of norepinephrine bitartrate was diluted in 100 mL of saline to a concentration of 20 µg/mL, with an initial dose of 0.01 µg/kg/min. The dose was adjusted in real-time based on intraoperative blood pressure, using the minimum amount of drug necessary to maintain the target MAP. In case of severe bradycardia (\<40 beats/min), the norepinephrine infusion rate could be reduced, and an appropriate dose of atropine could be administered intravenously based on the anesthesiologist's judgment.
5. Respiratory Management A lung-protective ventilation strategy was recommended during surgery: setting a tidal volume of 6-8 mL/kg, an inspiratory-expiratory ratio of 1:2, and adjusting positive end-expiratory pressure (PEEP) to 5-10 cmH2O, maintaining end-tidal CO2 pressure between 35-45 mmHg, and using periodic lung recruitment maneuvers. Spontaneous breathing was restored as soon as possible at the end of surgery, and the endotracheal tube was removed.
6. Fluid Management Crystalloids were the primary fluids recommended during surgery, following a moderately liberal fluid management strategy.
7. Other Management Points Comprehensive warming measures were recommended during surgery to maintain core temperature at 37°C. Blood transfusions were recommended based on bleeding and arterial blood gas analysis to maintain hemoglobin levels at ≥70 g/L. Postoperative pain management was selected based on the participant's preoperative preferences and the anesthesiologist's judgment to provide the best pain relief for the participant.
8. Postoperative Management C Group: Immediately after surgery, an equal volume of saline (equal to the volume of 0.5 mg flumazenil) was administered, followed by an equal volume of saline (equal to the volume of 0.3 mg flumazenil) 25 minutes later.

R1 Group: Immediately after surgery, 0.5 mg flumazenil was administered, followed by an equal volume of saline (equal to the volume of 0.3 mg flumazenil) 25 minutes later.

R2 Group: Immediately after surgery, 0.5 mg flumazenil was administered, followed by 0.3 mg flumazenil 25 minutes later.

Arterial blood samples of 3 mL were collected in plastic tubes containing EDTA K3 (Becton Dickinson, Germany) at T1 (end of surgery), T2 (25 minutes after the end of surgery), and T3 (50 minutes after the end of surgery). The arterial catheter was flushed with 2 mL of saline after each sample collection. Samples were kept on ice water and centrifuged at approximately 2000 rpm at 4°C for 10 minutes within 40 minutes of collection. Plasma was separated into polypropylene tubes (Nunc cryogenic vial cryo tubes, Thermo Fisher Scientific, USA) within 15 minutes and stored at -70°C. The sample collection time was recorded. The samples were sent to a third-party testing company for analysis within two months of collection.

Data recorded included the time to eye-opening, extubation time, the amount of remimazolam used, intraoperative analgesic use, hemodynamic parameters at T0 (admission), T1, T2, and T3, MMSE scores 24h and 72h before and after surgery, Narcotrend values at T0, T1, T2, and T3, PACU stay time, and the incidence of nausea and vomiting during PACU stay; postoperative complications such as atelectasis, cardiovascular and cerebrovascular events (stroke, myocardial infarction), all-cause mortality within 30 days postoperatively, total length of hospital stay (days) for survivors within 30 days postoperatively, and unplanned readmissions within 30 days postoperatively.

Eligibility criteria: Inclusion Criteria:

* Age ≥ 18 years and \< 65 years
* Patients undergoing elective kidney transplant surgery
* Signed the informed consent for the clinical study

Exclusion Criteria:

* Liver decompensation (Child B/C)
* History of liver transplant
* Previous allergies or other serious adverse reactions to narcotic drugs
* Intraoperative depth monitoring of anesthesia is not expected
* Preoperative ASA rating of 5
* Received general anesthesia in the 30 days prior to surgery or plan to receive it again within 30 days
* Plan to extend airway protection or mechanical ventilation support time after surgery
* Previous participation in this study

Primary outcomes:
measure: Plasma Concentration of Remimazolam
timeFrame: T1 (immediately at the end of surgery)
measure: Plasma Concentration of Remimazolam
timeFrame: T2 (25 minutes after the end of surgery)
measure: Plasma Concentration of Remimazolam
timeFrame: T3 (50 minutes after the end of surgery)
Secondary outcomes:
measure: Record eye opening time and extubation time
timeFrame: after surgery,an average of 30 minutes
measure: remimazolam usage
timeFrame: immediately at the end of surgery
measure: The amount of analgesic drugs used during operation
timeFrame: 3 days after surgery
measure: Heart Rate (HR)
timeFrame: T0（Entering the Operating Room, Before Anesthesia）
measure: Blood Pressure (BP)
timeFrame: T0（Entering the Operating Room, Before Anesthesia）
measure: Mean Arterial Pressure (MAP)
timeFrame: T0（Entering the Operating Room, Before Anesthesia）
measure: Oxygen Saturation (SpO2)
timeFrame: T0（Entering the Operating Room, Before Anesthesia）
measure: Heart Rate (HR)
timeFrame: T1(immediately at the end of surgery)
measure: Blood Pressure (BP)
timeFrame: T1(immediately at the end of surgery)
measure: Mean Arterial Pressure (MAP)
timeFrame: T1(immediately at the end of surgery)
measure: Oxygen Saturation (SpO2)
timeFrame: T1(immediately at the end of surgery)
measure: Heart Rate (HR)
timeFrame: T2（25 minutes after the end of surgery)
measure: Blood Pressure (BP)
timeFrame: T2（25 minutes after the end of surgery)
measure: Mean Arterial Pressure (MAP)
timeFrame: T2（25 minutes after the end of surgery)
measure: Oxygen Saturation (SpO2)
timeFrame: T2（25 minutes after the end of surgery)
measure: Heart Rate (HR)
timeFrame: T3（50 minutes after the end of surgery)
measure: Blood Pressure (BP)
timeFrame: T3（50 minutes after the end of surgery)
measure: Mean Arterial Pressure (MAP)
timeFrame: T3（50 minutes after the end of surgery)
measure: Oxygen Saturation (SpO2)
timeFrame: T3（50 minutes after the end of surgery)
measure: Mini-Mental State Examination （MMSE )scores were obtained before, 24h and 72h after surgery
timeFrame: Entering the Operating Room, Before Anesthesia
measure: Mini-Mental State Examination （MMSE ）scores
timeFrame: 24h after the end of surgery
measure: Mini-Mental State Examination （MMSE ）scores
timeFrame: 72 h after the end of surgery
measure: Bispectral Index (BIS)
timeFrame: T0（Entering the Operating Room, Before Anesthesia）
measure: Bispectral Index (BIS)
timeFrame: T1(immediately at the end of surgery)
measure: Bispectral Index (BIS)
timeFrame: T2（25 minutes after the end of surgery)
measure: Bispectral Index (BIS)
timeFrame: T3 (50 minutes after the end of surgery)
measure: Duration of Post-Anesthesia Care Unit (PACU) Stay
timeFrame: Before Leaving PACU Post-Surgery
measure: Occurrence of nausea
timeFrame: 3 days after surgery
measure: Occurrence of vomiting
timeFrame: 3 days after surgery
measure: Number of Participants with Postoperative Pulmonary Atelectasis, Cardiovascular and Cerebrovascular Adverse Events
timeFrame: 30 days after surgery
measure: All-cause death within 30 days after surgery
timeFrame: 30 days after surgery
measure: Total hospital stay for survivors 30 days after surgery
timeFrame: 30 days after surgery
measure: Unplanned second hospital admission within 30 days after surgery
timeFrame: 30 days after surgery
Other outcomes:
Locations:
Study officials:
References: