Half effective dose of rimazolam combined with a subanesthetic dose of esketamine inhibiting response to gastroscopy insertion in elderly patients

doi:10.21203/rs.3.rs-2421518/v1

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Half effective dose of rimazolam combined with a subanesthetic dose of esketamine inhibiting response to gastroscopy insertion in elderly patients

https://doi.org/10.21203/rs.3.rs-2421518/v1

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Objective To investigate the half effective dose of rimazolam inhibiting response to gastroscopy insertion when combined with a subanesthetic dose of esketamine in elderly patients.

Methods Twenty-six elderly patients, of any gender, aged 65-73 years, with body mass index 19-26 kg/m2 and ASA physical state I or II, who underwent painless gastroscopy in Cangzhou Central Hospital from January to May 2022 were selected. Intravenous esketamine 0.25 mg/kg and test dose rimazolam were administered sequentially, and the initial dose of rimazolam was 0.2 mg/kg. The dose of the next patient was determined according to the modified sequential method. If the patient had choking or somatic movement reaction when the gastroscope was placed, it was judged as positive, and the dose of rimazolam in the next patient was increased by one gradient; otherwise, the dose of rimazolam in the next patient was decreased by one gradient, and the dose of adjacent rimazolam was graded to 0.01 mg/kg according to the equal difference method.Termination of the study at the presence of seven positive-negative reaction crossover points. Probit analysis was used to calculate the median effective dose(ED₅₀)and the corresponding 95% confidence interval (CI)． The occurrence of adverse effects such as dizziness, nausea and vomiting, muscle twitching, hypoxemia, hypotension, bradycardia, and postoperative cognitive impairment were recorded.

Results The ED50 of rimazolam combined with esketamine 0.25 mg/kg inhibiting response to gastroscopy insertion in patients was 0.177 mg/kg (95% CI: 0.161-0.184mg/kg). The total dose of remimazolam was (11.4±3.6) mg, the gastroscope diagnosis and treatment time was (7.5±2.5), the recovery time was (10.2±3.8) min and the stay time in the resuscitation room was (8.4±3.2) min. Postoperative dizziness occurred in 1 case, postoperative weakness in 1 case, and postoperative nausea and vomiting in 1 case; no other adverse reactions were found.

Conclusion The ED₅₀ of rimazolam combined with esketamine 0.25 mg/kg inhibiting response to gastroscopy insertion in elderly patients was 0.177 mg/kg, with no significant circulatory and respiratory adverse effects.

Health sciences/Health occupations

Health sciences/Medical research

Rimazolam

Esketamine

Half effective dose

Gastroscopy Dose-response relationship

With the increasing development of painless upper gastrointestinal endoscopy techniques for patients, safe and comfortable anesthesia is an important guarantee for endoscopic treatment ^[1]. Propofol is a commonly used anesthetic sedative drug in painless gastroscopy, however, it is likely to cause hypotension, slowed heart rate, and other adverse effects ^[2], so it is urgent to explore the appropriate sedative drug and dose in clinical work, so as to improve drug safety. Remazolam mesylate is a new benzodiazepine sedative that agonizes GABAa ^[3] and is widely used in patients undergoing gastrointestinal endoscopy with safe and effective anesthesia ^{[4, 5]}. Essiac ketamine is a new intravenous anesthetic drug with a short awakening time and rapid recovery of orientation in short anesthesia for rapid treatment such as painless colonoscopy, which has obvious advantages ^[6]. It has been shown ^[7] that propofol compounded with a small dose of esketamine during painless gastroscopy can suppress the gastroscopic placement response with high quality of awakening and no significant adverse effects. In contrast, the appropriate dose of rimazolam combined with a subanesthetic dose of esketamine in painless gastroscopy consultation is less studied. Therefore, this study evaluated the half effective dose (ED₅₀) of rimazolam with a subanesthetic dose of esketamine for sedation in elderly patients undergoing painless gastroscopy to provide a reference for rational clinical use.

General Information The study was a prospective study of sequential design, approved by the hospital ethics committee (2020-024-01), and informed consent was signed by the patients. This article was registered in the China Clinical Trials Registry(ChiCTR2100044459,18/03/2021).Twenty-six elderly patients, regardless of gender, aged 65–73 years, with body mass index 19–26 kg/m² and ASA grade I or II, who underwent painless gastroscopy in Cangzhou Central Hospital from January to May 2022 were included. Exclusion criteria: allergy to benzodiazepines, history of long-term sedative and analgesic drugs, history of drug or alcohol abuse, myasthenia gravis, morbid obesity, severe depressive states, severe cardiac, pulmonary, renal and hepatic abnormalities, gastrointestinal obstruction with gastric content retention.

Anesthesia method Preoperative fasting and no preoperative medication.MAP, SpO₂, HR, and respiratory rate (RR) were routinely monitored after admission to the endoscopy room, and the average of three measurements was taken as the base value respectively. Oxygen was administered continuously by nasal cannula with an oxygen flow rate of 4 L/min, forearm venous access to the upper extremity was opened, 15 ml/(kg·h) of sodium lactate Ringer injection was administered, and the modified alertness/sedation score (MOAA/S) was measured in the left lateral position ^[5]. The study was performed by the same senior attending anesthesiologist with extensive clinical experience, and the gastroscopy was performed by the same skilled senior physician. All patients received a uniform intravenous infusion of esketamine 0.25 mg/kg, and 30 s later a preset dose of rimazolam (batch number: 220310AU, State Drug Administration: H20190034) was administered intravenously, and the gastroscope was placed by the physician for examination after the patient's eyelash reflex disappeared, there was no somatic motor response and the MOAA/S was < 1 score (Table 1). The dose of rimazolam was determined by the modified sequential method, and the initial dose was set at 0.2 mg/kg based on the results of the pretest and the study by Borkett et al ^[8]. The dose of rimazolam in the next patient was determined according to whether the patient choked or had a somatic motor response when the gastroscope was placed through the pharynx. If the patient had choking or somatic movement reaction when the gastroscope was placed, it was judged as positive, then the dose of rimazolam was increased by one gradient in the next patient; otherwise, the dose of rimazolam was decreased by one gradient in the next patient, and the dose of adjacent rimazolam was graded to 0.01 mg/kg according to the equivocal method. The study was terminated at the occurrence of seven positive-negative reaction crossover points. When choking or somatic movement reaction occurs during gastroscopy, 2.5 mg of rimazolam is administered intravenously as remedial anesthesia until the choking or somatic movement reaction is negative; the remedial anesthesia can be repeated until the gastroscopy can be completed.

Observed indicators SpO₂, HR, RR, and MOAA/S scores were observed and recorded immediately after the patients were admitted to the gastroscopy room, immediately after the injection of esketamine, immediately after the injection of remazolam, when the endoscope was placed in the pharynx, 5 min after the endoscope was placed, when the endoscope was withdrawn from the pharyngeal cavity and immediately when the patients were awakened. Patients' time to wakefulness (last intravenous rimazolam injection until MOAA/S > 4 scores), recovery room stay, and adverse effects such as dizziness, nausea, vomiting, muscle twitching, hypoxemia (SpO₂ ≤ 90% and able to recover after improving airway patency and increasing inhaled oxygen flow), choking, hypotension, bradycardia, and postoperative cognitive impairment were recorded.

The logarithm of each dose of rimazolam (lgx) and the number of effective cases at that dose (n), the rate of negative somatotropic response at the placement of the gastroscope (P), and the difference between the logarithms of two adjacent doses (d) were recorded. The ED₅₀ of rimazolam and its 95% confidence interval(CI) were calculated according to the probability unit method.

Logarithmic values of ED₅₀:lgED₅₀=∑nlgx/∑n

ED₅₀ of Logarithmic values of ED₅₀:(lgED₅₀-1.96SlgED₅₀, lgED₅₀ + 1.96SlgED₅₀)

The result of the calculation was taken as the ED₅₀ and its 95% CI by taking the opposite number.

Intravenous ephedrine 5–10 mg in case of hypotension (≥ 20% decrease in MAP from basal values) during anesthesia; Intravenous atropine 0.2 ~ 0.5mg in case of bradycardia (HR < 50 beats/min or ≥ 20% lower than the basal value); In case of hypoxemia, the jaw was supported, the oxygen flow was increased and oxygen was administered, and assisted ventilation was performed as appropriate; in case of postoperative nausea and vomiting, 5 mg of azelastine was given intravenously.

Statistical processing

SPSS 17.0 software was used for statistical analysis, and normally distributed measures were expressed as (x̄± s), and count data were expressed as frequencies. The ED₅₀ of rimazolam and its 95% confidence interval(CI) were calculated according to the probability unit method.GraphPadPrism 5 software was applied to produce sequential test plots and dose-effect fitting curves. Two-sided test, test level α = 0.05.

General information: 26 patients were included in this study, including 12 males and 14 females, aged 65–73(69 ± 4) years, with body mass index 19–26(23 ± 4) kg/m².The total dose of rimazolam drug was 9.4 ~ 19.7 (11.4 ± 3.6) mg, gastroscopy consultation time was 4.3 ~ 11.2 (7.5 ± 2.5) min, awake time was 5.4 ~ 19.8 (10.2 ± 3.8) min, and recovery room dwell time was 6.2 ~ 13.6 (8.4 ± 3.2) min.

Sequential test results: 26 patients completed the test, including 14 negative cases and 12 positive cases. For the probability regression analysis of the sequential test results, the log dose-response regression equation resulted in Y = 12.679 + 16.425X, R² = 0.958. The goodness of fit of this equation was tested and P = 0.956, indicating a good fit. The ED₅₀ of rimazolam compounded with 0.25 mg/kg esketamine intravenously to inhibit the response to gastroscopy placement in elderly patients was 0.177mg/kg(95%CI: 0.161 ~ 0.184mg/kg). The sequence test diagram and the fitting curve of the volume-effect relationship are shown in Figs. 1 and 2.

Occurrence of adverse reactions: None of the patients had adverse reactions such as hypoxemia, choking, hypotension, slowed heart rate, muscle twitching, and postoperative cognitive impairment,no increase in respiratory secretions seen. One patient had postoperative dizziness, another patient had postoperative weakness, and one patient had postoperative nausea and vomiting.

At present, the most direct method in the diagnosis and treatment of esophageal, gastric, and duodenal diseases is gastroscopy, and the increasing number of elderly patients undergoing gastroscopy, their physical functions are reduced and their tolerance to anesthesia is low, and in the clinical painless gastroscopy operation is often combined with sedative and analgesic drugs intravenous anesthesia, so that the patient is treated with preserved autonomic breathing, which can provide a good treatment environment for the endoscopist ^[9]. Therefore, this study intends to investigate the application study of rimazolam compounded with a subanesthetic dose of esketamine in painless gastroscopy consultation and to determine the ED₅₀ of rimazolam.

ED₅₀ is a reliable indicator for studying the dose-effect relationship of a drug in clinical settings, and more accurately reflects the changing relationship between drug dose and effect ^[10].In contrast, the present study used the classical sequential method to determine the drug ED₅₀, which saves sample size, and the equal difference increase and decrease method to determine the drug dose ^[11], which is easy to calculate the drug dose for the next subject.

Rimazolam is a benzodiazepine sedative-hypnotic drug that acts on GABAa receptors, which inhibits neuronal excitability and reduces the activity of the organism, providing sedative and amnesic effects, and is indicated for short procedures ^[4]; Its metabolites in vivo are not pharmacologically active, so rimazolam has rapid onset and expiration, short awakening time, and mild respiratory and circulatory depression ^{[12, 13]}. And it has been shown ^{[8, 13]} that rimazolam is safe and effective in endoscopy with satisfactory sedation and the patient wakes up soon after the examination to avoid adverse effects such as depression of the patient's breathing and circulation due to excessive sedation. Zhou et al ^[14] also pointed out that age is not an influencing factor in the pharmacokinetics of rimazolam, so it is suitable for anesthetic sedation in elderly patients and has a wide clinical use prospect.

Individual doses vary widely when rimazolam is used alone, and sedation is often inadequate ^[15], requiring the use of other adjunctive medications. Kops et al ^[16] showed that the sedative and analgesic effects of both drugs had a strong synergistic effect when rimazolam was administered at the same time as the analgesic drug. Essiac ketamine, a pure dextroisomer of ketamine (S(+)-ketamine), has a shorter awakening time, greater analgesic effect and higher anesthetic potency compared to ketamine ^[17]. Therefore, the anesthetic regimen of rimazolam compounded with esketamine was chosen for this study, thus providing sedation and analgesia while reducing the occurrence of adverse effects such as respiratory depression and hypotension. The stimulation of the gastroscopy operation is mainly caused by the initial endoscope tip entering the esophagus through the patient's throat, causing the patient's nausea, vomiting, choking, and other stress reactions. In this study, by giving esketamine 0.25 mg/kg intravenously in advance, followed by a preset dose of rimazolam intravenously, the analgesic effect was perfected and the neuro-endocrine stress response was suppressed, while a good sedation requirement was achieved by synergistic rimazolam onset, and the stress response to the throat and cough reflex during gastroscopy placement were effectively suppressed.

All 26 patients in this study completed the trial, of which 14 were negative and 12 were positive. All patients, including those under remedial anesthesia, successfully completed the gastroscopic consultation under rimazolam compounded with a subanesthetic dose of esketamine. The ED₅₀ of rimazolam compounded with 0.25 mg/kg esketamine for suppression of somatotropic response in gastroscopy consultation in elderly patients was 0.177 mg/kg. In contrast, Sun Hu et al ^[4] determined that the ED₅₀ of rimazolam to inhibit gastroscopic placement response when combined with sufentanil was 0.14 mg/kg, and the difference in results may be due to:(1) Although both experiments used MOAA/S rating and no obvious somatic movement response as the criteria for judging the depth of anesthesia, in this experiment the MOAA/S score < 1 after the surgeon placed the gastroscope, while Sun Hu et al. used MOAA/S score ≤ 2 as the criterion for judging the effectiveness of perioperative sedation in their study;(2)There were also differences in the type of adjuvant medication, the timing of medication administration and timing of surgery initiation between the two experiments. Also, this study found that the total dose of rimazolam administration and the duration of wakefulness were large compared to those reported by Chen et al ^[18], the possible reasons for this being: Chen et al. used 2% lidocaine for surface anesthesia along with a compound fentanyl dose of 0.5 µg/kg in their study, whereas no surface anesthesia was done in this trial, and the esketamine dose was larger relative to the fentanyl dose reported by Chen et al ^[18], thereby increasing the total dose of rimazolam used and the time to awaken from anesthesia.

Compared with the basal value, there was no significant change in the patient's perioperative SpO₂, no prolongation of QT interval or other arrhythmias were found in the ECG, and the heart rate did not fall below 50 beats/min during the operation, and there was transient hypertension in MAP after intravenous esketamine infusion, but the increase in blood pressure fluctuated within 20% and remained within the normal range, indicating that the sympathomimetic properties of esketamine caused excitation of the cardiovascular sympathetic nervous system. It further indicates that the combination of rimazolam and esketamine can be used for gastroscopy in elderly patients with smooth intraoperative respiratory and circulatory systems, reduced dosage of sedative drugs and low incidence of adverse effects, and is suitable for painless gastroscopy.In this study, no postoperative cognitive impairment and no increase in respiratory secretions were observed in patients with subanesthetic doses of esketamine combined with rimazolam, probably because esketamine itself has low adverse effects, only subanesthetic doses were used in the experiment, and the side effects associated with esketamine were attenuated by the action of rimazolam on GABAa receptors. One patient experienced postoperative dizziness and recovered on his own after resting in the recovery room; one patient reported weakness of the limbs, but his vital signs were stable and he was discharged after resting without special treatment; one patient experienced postoperative nausea and vomiting, and was given azathioprine and returned successfully. All patients in this trial were given esketamine 0.25 mg/kg intravenously before placement of the gastroscope. It is not clear whether dizziness, nausea and vomiting, and weakness are related to the dose of esketamine used and may be related to the sample size of this study.

The shortcomings of this study are that this study only used MOAA/S and patient's body movements as criteria to determine whether sedation was satisfactory or not, and did not monitor patients' depth of anesthesia, so whether this has any effect on the accuracy of the results should be further investigated; whether smaller doses of esketamine can further reduce the effective dose of rimazolam remains to be studied.

In conclusion, the ED₅₀ of rimazolam compounded with esketamine 0.25 mg/kg to inhibit the response to gastroscopy placement in elderly patients was 0.177 mg/kg with few circulatory and respiratory complications, which is worthy to be widely used in elderly patients undergoing painless gastroscopy.

Mean Arterial Pressure (MAP), Heart Rate (HR), Pulse Oximetry (SpO2), Respiration rate(RR), Electrocardiogram (ECG), Modified observer's assessment of alert/sedation(MOAA/S)

Acknowledgements

A special thanks to the health nurses at the Department of Anesthesiology， Cangzhou Central Hospital China, for their involvement in the study.

Author information

Affiliations

Department of Anesthesiology， Cangzhou Central Hospital， Cangzhou， China. Yu Jian, Sun Liang, Zhang Haidong, Zhu Chunhua& Qi Yingkai

Contributions

Yu Jian designed the study and analysed and interpreted the data. Sun Liang collected the data. Zhu Chunhua and Qi Yingkai wrote the first draft of the manuscript. All authors read, critically revised, and approved the final manuscript.

Corresponding author

Correspondence to Yu Jian.

Email：[email protected]

Ethics declarations

This study was approved by the Medical Ethics Committee of the Cangzhou Central Hospital (2020-024-01), and informed consent was signed with the family. This article was registered in the China Clinical Trials Registry(ChiCTR2100044459,18/03/2021).All methods were performed in accordance with relevant guidelines and regulations.

Data availability

The datasets analyzed during the current study are available from the corresponding author upon reasonable request.

Competing interests

The authors declare no competing interests.

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Table 1 Modified alertness/sedation (MOAA/S) scoring criteria

Rating	Patient response
5 points	Normal response to a normal call for name
4 points	Slow to respond to normal name calls
3 points	Responds to loud and/or repeated calls for name
2 points	Responds to slight pushing or vibration of the body
1 point	Responsive to painful stimuli (squeezing at the trapezius site)
0 points	No response to painful stimuli

No competing interests reported.

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Half effective dose of rimazolam combined with a subanesthetic dose of esketamine inhibiting response to gastroscopy insertion in elderly patients

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Acknowledgements

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Contributions

Yu Jian designed the study and analysed and interpreted the data. Sun Liang collected the data. Zhu Chunhua and Qi Yingkai wrote the first draft of the manuscript. All authors read, critically revised, and approved the final manuscript.

Corresponding author

Ethics declarations

Data availability

Competing interests

References

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