Interactions Between Remimazolam and Propofol in Combination With Sufentanil for Anesthesia During Gastroscopy

doi:10.21203/rs.3.rs-1035688/v1

PDF

Research Article

Interactions Between Remimazolam and Propofol in Combination With Sufentanil for Anesthesia During Gastroscopy

https://doi.org/10.21203/rs.3.rs-1035688/v1

This work is licensed under a CC BY 4.0 License

Version 1

posted 08 Nov, 2021

You are reading this latest preprint version

Background

This study was conducted to determine how remimazolam and propofol interact when given with sufentanil.

Methods

In this single-arm study, patients were assigned to one of five groups. The sample size was not determined in advance. When the median effective dose(ED₅₀) and 95% confidence intervals were calculated, participants were stopped. The study included 159 patients who were scheduled for a gastrointestinal endoscopic examination and had an American Society of Anesthesiologists physical status of I/II. Patients were intravenously administered sufentanil (0.1 µg/kg), along with different doses of remimazolam and propofol depending on the group to which they were assigned. The endpoint for an effective response was the disappearance of the bilateral eyelash reflex. The up-and-down method was used to determine the ED₅₀ within each treatment group. The ED₅₀ deviations from the additive line were analyzed using isoradiometric analysis. The interaction coefficients were calculated by algebraic analysis. Interval estimation is used in statistical inference.

Results

In combination with sufentanil, the ED₅₀ of remimazolam and propofol was determined to be 0.065 (0.057-0.074) mg/kg and 0.657 (0.590-0.724) mg/kg, respectively. After sufentanil administered, when 0.25, 0.5, and 0.75 ED₅₀ remimazolam were given in combination with propofol, the interaction coefficients were 1.03,1.2and 1.08, respectively.

Conclusions

The dose of propofol with remimazolam may need to be reduced regardless of the additive or synergistic effect. There was a strong synergistic effect when the dose ratio of the two drugs was about 6:1 in mg/kg.

Trial registration:

The project was retrospectively registered on October 26, 2021 in Chinese clinical trial center with the registration number of ChiCTR2100052425.

Anesthesiology & Pain Medicine

Drug synergism

Gastroscopy

Propofol

Remimazolam

Sufentanil

Remimazolam, a novel short-term sedative and anesthetic benzodiazepine, is effective and safe; however, it is metabolized faster than midazolam [1]. Midazolam acts synergistically with propofol in inducing anesthesia [2, 3]. Synergistic effects have been reported when midazolam and propofol were used in combination with alfentanil [4].Sufentanil is a commonly used analgesic in gastroscopy [5]. The duration of gastrointestinal endoscopy is short, which is convenient to observe drug effects and potential adverse reactions.

Rememazolam, currently used as painless gastroenteroscopy anesthetic, can be possibly used in combination with propofol and potent opioids for anesthesia induction in other clinical conditions. To use drugs accurately, we need to see if there is any synergy between remimazolam and propofol, and if so, what the synergy coefficient is.

We intend to evaluate the interaction between remimazolam and propofol when combined with sufentanil by isoradiometric analysis. To minimize the discomfort of patients, we believe that the disappearance of eyelash reflex is the endpoint of anesthesia induction [6]. Before inserting the endoscope, propofol was given immediately to deepen the anesthesia according to the ongoing examination or operation.

Patients

The study was approved by the Clinical Investigation Committee of Hainan Medical University's Second Affiliated Hospital. The up-and-down method can significantly reduce the number of subjects required for the study [7, 8,]. The sample size was not determined in advance because this was an adaptive clinical study, and it was adjusted based on certain criteria. [9]When the ED₅₀ and 95% confidence intervals were calculated, participants were stopped.

Patients were excluded from the study if they had: 1. anemia (hemoglobin < 90 g/L), 2. albumin levels < 30 g/L, 3. platelet count < 50×10⁹ /L, 4. anticipated difficult airway, 5. obvious respiratory or circulatory dysfunction before the procedure, 6. severe neuropsychiatric disease, 7. allergies or contraindications for the use of benzodiazepines, opioids, propofol, flumazenil, naloxone or other drugs and their components, and 8. taken similar drugs recently.

Patients who had an American Society of Anesthesiologists physical status of I/II and were scheduled for gastrointestinal endoscopy were included in the study, and they all gave their informed consent.

Intervention and Measurements

Patients were assigned to group A (administered remimazolam in combination with 0.1 µg/kg sufentanil), B (administered propofol in combination with 0.1 µg/kg sufentanil), C (administered propofol in combination with 0.1 µg/kg sufentanil and 0.25 median effective dose (ED₅₀) remimazolam), D (administered propofol in combination with 0.1 µg/kg sufentanil and 0.5 ED₅₀ remimazolam), or E (administered propofol in combination with 0.1 µg/kg sufentanil and 0.75 ED₅₀ remimazolam).

An intravenous line was secured in the waiting area. The patient’s blood pressure, electrocardiogram, and oxygen saturation were monitored after entering the endoscopy suite. The administration time was determined based on the results of a pretest.

The patients were intravenously administered 0.1 µg/kg sufentanil (01A10011, Sichuan Renfu, China) over 10 s, and the cannula was flushed with saline (5 mL). After 90 seconds, the drug was administered according to the dose required by the grouping.

Remimazolam (201114AK, Jiang Su Heng Rui, China) was diluted to 0.5 mg/mL with normal saline. A dose-proportional to the patient’s body weight was administered intravenously over 10 s, and the cannula was flushed with 5 mL normal saline.

Propofol (2011171, Si Chuan Guor Rui, China) was diluted to 1, 2, and 10 mg/mL with normal saline and was administered 20 s after the administration of remimazolam. The observation time was 1 min after the administration of propofol.

To minimize any discomfort to patients, the disappearance of the eyelash reflex was considered the endpoint for anesthesia induction. Propofol was given shortly before endoscopy to deepen the anesthesia based on the procedure.

For the up-and-down method [10], the first patient in a group was administered a dose of the drug that was close to the ED₅₀. If the first patient lost consciousness, the second patient was administered a smaller dose; if the first patient did not lose consciousness, the second was given a higher dose. As the procedure was repeated with more patients, the mean of the doses administered tended towards the ED₅₀ value. According to references [11] and pre-experimental results, the increment/decrement ratio was determined to be 1:0.8.

Statistical analysis

Age and weight are presented as medians and interquartile ranges. Using SPSS version 22 (IBM Corporation, USA), the ED₅₀ and 95% confidence intervals were calculated by probit regression analysis [10]. Interval estimation is used in statistical inference.

The statistical significance of ED₅₀ deviation from the additive line was analyzed using isoradiometric analysis. The equation of the additive line was obtained using the ED₅₀ values of remimazolam (0.065 mg/kg) and propofol (0.657 mg/kg) (Fig. 1). This was calculated as: Y = −10.108x + 0.657.

The lower limits of the 95 % CIs of the ED₅₀s of remimazolam (0.057 mg/kg) and propofol (0.59 mg/kg) were used to calculate the lower limit of the additive line's 95% CI. The equation for this was found to be: Y = −10.351x + 0.59.

The upper limits of the 95% CIs of the ED₅₀s of remimazolam (0.074 mg/kg) and propofol (0.724 mg/kg) were used to calculate the upper limit of the 95% CI additive line. The equation for this was found to be: Y = −9.7838x + 0.724.

The interaction coefficients were calculated by algebraic analysis.

A total of 159 patients were included in the study based on the inclusion and exclusion criteria. The number of patients in group A-E was 27, 34, 29, 39, and 28 respectively. There were no significant differences in the age and weight of patients in the five groups (TableⅠ).

Table I. Dose gradients of remimazolam and propofol and patients' baseline characteristics.

Group	Remimazolam (mg/kg)	Propofol (mg/kg)	n	No eye opening	Age [y, Q2(IQR)]	Weight [kg, Q2(IQR)]
A	0.1	0	2	2	54(17)	57(14)
	0.08	0	6	5
	0.064	0	12	7
	0.051	0	7	0
B	0	0.9	5	5	51(17.5)	61(21)
	0	0.72	14	10
	0	0.58	12	3
	0	0.46	3	0
C	0.016	0.62	7	7	53.5(13.8)	55.5(17.5)
	0.016	0.49	13	6
	0.016	0.39	7	2
	0.016	0.32	2	0
D	0.033	0.31	2	2	50.5(20.8)	57.3(14)
	0.033	0.25	9	8
	0.033	0.20	15	9
	0.033	0.16	11	2
	0.033	0.13	2	0
E	0.049	0.15	6	6	51.5(16.8)	60(15.5)
	0.049	0.12	12	6
	0.049	0.10	8	3
	0.049	0.08	2	0

Patients in group A were administered remimazolam in combination with 0.1 µg/kg sufentanil to determine the ED₅₀ of remimazolam in this combination. Intra-group remimazolam efficacy measurements were carried out with a 1:0.8 increments/decrement ratio. In the pretest, the ED₅₀ of remimazolam was estimated to be 0.08 mg/kg; hence, this was taken as the intermediate dose. Doses of 0.125, 0.1, 0.08, 0.064, and 0.051 mg/kg were chosen for evaluation (Table 1). The ED₅₀ of remimazolam was found to be 0.065 mg/kg (CI: 0.057−0.074 mg/kg) in combination with 0.1 µg/kg sufentanil.

Patients in group B were administered propofol in combination with 0.1 µg/kg sufentanil for the determination of propofol ED₅₀ in this combination. Naguib and coworkers reported that propofol has an ED₅₀ value of 0.9 mg/kg in this combination [12]. Based on these data and using the 1:0.8 increment/decrement ratio, the selected doses of propofol were 1.41, 1.13, 0.9, 0.72, 0.58, and 0.46 mg/kg (Table 1). The ED₅₀ of propofol was found to be 0.657 mg/kg (CI: 0.59−0.724 mg/kg) when used in combination with 0.1 µg/kg sufentanil(Fig. 1).

The ED₅₀ of propofol was determined in groups C-E using the same method as group B. Thus, the ED₅₀ of propofol in combination with 0.1 µg/kg sufentanil and doses of 0.25, 0.5, and 0.75 ED₅₀s of remimazolam were evaluated.

Group C patients were administered 0.1 µg/kg sufentanil, 0.25 ED₅₀ (0.016 mg/kg) remimazolam, and varying propofol doses. The propofol 0.75 ED₅₀ (0.49 mg/kg) was chosen as the central point. The propofol ED₅₀ value was 0.476 mg/kg (CI: 0.411–0.545 mg/kg)

Group D patients were administered 0.1 µg/kg sufentanil, 0.5 ED₅₀ (0.033 mg/kg) remimazolam, and varying propofol doses. The 0.5 The ED₅₀ of propofol (0.25 mg/kg) was used as the central point. The propofol ED₅₀ value was 0.194 mg/kg (CI: 0.171−0.217 mg/kg).

Group E patients were administered 0.1 µg/kg sufentanil, 0.75 ED₅₀ (0.049 mg/kg) remimazolam, and varying propofol doses. The 0.25 The ED₅₀ of propofol (0.15 mg/kg) was used as the central. The propofol ED₅₀ value was 0.114 mg/kg (CI: 0.095−0.132 mg/kg).

An isoradiometric diagram (Fig. 2) and algebraic analysis (Table Ⅱ) showed that the synergistic coefficients of remimazolam and propofol were 1.03, 1.26, and 1.08with doses of remimazolam equivalent to 0.25, 0.5, and 0.75 ED₅₀s, respectively, in combination with sufentanil (0.1 µg/kg). The synergy coefficient of group E was 1.08, but the 95% CI of the propofol dose was within the 95% CI of additive action (Fig. 2).

Table II. Interactions of remimazolam and propofol, in combination with 0.1 μg/kg sufentanil, evaluated through observation of eyelash reflex inhibition.

Group	Remimazolam			Propofol		Coefficient sum	Expected value of additive action	Interaction coefficient
Group	ED50 coefficient		ED50 (mg/kg)	ED50 coefficient	ED50 (mg/kg)	Coefficient sum	Expected value of additive action	Interaction coefficient
A	1	0.065 (0.057-0.074)		0	0	1	1	1
B	0	0		1	0.657 (0.590-0.724)	1	1	1
C	0.25	0.016		0.725	0.476 (0.411-0.545)	0.975	1	1.03 (p=0.154)
D	0.5	0.033		0.295	0.194 (0.171-0.217)	0.795	1	1.20 (p=0.000)
E	0.75	0.049		0.174	0.114 (0.095-0.132)	0.924	1	1.08 (p=0.000)
The table shows median effective dose (ED50) equivalent doses of remimazolam and propofol in combination with 0.1 μg/kg sufentanil.

Drug synergism is attributed to pharmacodynamic or pharmacokinetic interactions [13]. When 0.5ED₅₀ remimazolam was combined with propofol, it produced a synergistic effect in group D. As the metabolic pathways of remimazolam and propofol are different, there is no metabolic interference, suggesting that this synergy occurs after the two drugs bind to the receptor.

Remimazolam and propofol showed an additive effect only in groups C and E. At 0.25ED₅₀, the plasma drug concentration of remimazolam or propofol was near the threshold concentration. Since both the drugs metabolize rapidly, the effects were short-lived. Before the synergistic effect can be observed, the drug will be eliminated. The occupied receptor is less and the efficacy is weakened, so it only shows additive effect.

The interaction coefficient of the combination was the highest at a dose equivalent to 0.5 ED₅₀ of remimazolam. As shown in Table 2, the dose of remimazolam divided by the dose of propofol in group D is about 1:6. This implies that there is a synergistic effect when the dose ratio of remimazolam and propofol is about 1:6 mg/kg.

Table 2

Interactions of remimazolam and propofol, in combination with 0.1 g/kg sufentanil, evaluated through observation of eyelash reflex inhibition.
Table 1. Dose gradients of remimazolam and propofol and patients' baseline characteristics.
Group	Remimazolam (mg/kg)	Propofol (mg/kg)	n	No eye opening	Age [y, Q2(IQR)]	Weight [kg, Q2(IQR)]
A	0.1	0	2	2	54(17)	57(14)
	0.08	0	6	5
	0.064	0	12	7
	0.051	0	7	0
B	0	0.9	5	5	51(17.5)	61(21)
	0	0.72	14	10
	0	0.58	12	3
	0	0.46	3	0
C	0.016	0.62	7	7	53.5(13.8)	55.5(17.5)
	0.016	0.49	13	6
	0.016	0.39	7	2
	0.016	0.32	2	0
D	0.033	0.31	2	2	50.5(20.8)	57.3(14)
	0.033	0.25	9	8
	0.033	0.20	15	9
	0.033	0.16	11	2
	0.033	0.13	2	0
E	0.049	0.15	6	6	51.5(16.8)	60(15.5)
	0.049	0.12	12	6
	0.049	0.10	8	3
	0.049	0.08	2	0

According to group D data in Table 2, the synergy coefficient is 1.25. It can be understood that if a patient changes from the original propofol requirement of 1 mg/kg to combined medication, the same effect can be achieved with only 0.3 mg/kg propofol with 0.05 mg/kg remimazolam.

As there were other adjacent dose ratios, this may lead to a stronger synergy. Therefore, further experiments are required to probe the effects of adjacent does ratios. The disappearance of the eyelash reflex is only one of the common endpoints in clinical anesthesia. The interaction of other clinical endpoints needs to be further studied and determined. The occurrence of side effects also need be observed simultaneously.

Ethics approval and consent to participate

The study was approved by the Clinical Investigation Committee of Hainan Medical University's Second Affiliated Hospital (number/ID was LW2021001). All participants signed informed consent. All methods were performed in accordance with the relevant guidelines and regulations.

Consent for publication

“Not applicable”

Availability of data and materials

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Competing interests

The authors certify that there is no conflict of interest with any financial organization regarding the material discussed in the manuscript.

Funding

This study is supported by the Hainan Provincial Health Commission (20A200247) and Project supported by Hainan Province Clinical Medical Center.

Authors' contributions

Song Lyu and Qingchun Deng contributed equally to the preparation of this manuscript.They have given substantial contributions to the conception or the design of the manuscript, analysis and interpretation of the data. All authors have participated to drafting the manuscript. All authors read and approved the final version of the manuscript.

Acknowledgements

Participating Investigator: The authors acknowledge Hu Sun who served as scientific advisor.

Pastis NJ, Yarmus LB, Schippers F, Ostroff R, Chen A, Akulian J, Wahidi M, Shojaee S, Tanner NT, Callahan SP, Feldman G, Lorch DG Jr, Ndukwu I, Pritchett MA, Silvestri GA; PAION Investigators. Safety and efficacy of remimazolam compared with placebo and midazolam for moderate sedation during bronchoscopy. Chest 2019;155(1):137–46. https://doi.org/10.1016/j.chest.2018.09.015.
Ong LB, Plummer JL, Waldow WC, Owen H. Timing of midazolam and propofol administration for co-induction of anaesthesia. Anaesth Intensive Care 2000;28(5):527(31. https://doi.org/10.1177/0310057X0002800507.
Pace NL, Stylianou MP. Advances in and limitations of up-and-down methodology: a précis of clinical use, study design, and dose estimation in anesthesia research. Anesthesiology 2007;107(1):144(52. https://doi.org/10.1097/01.anes.0000267514.42592.2a.
Vinik HR, Bradley EL Jr, Kissin I. Triple anesthetic combination: propofol-midazolam-alfentanil. Anesth Analg 1994;78(2):354–8. https://doi.org/10.1213/00000539-199402000-00026.
Zhang L, Bao Y, Shi D. Comparing the pain of propofol via different combinations of fentanyl, sufentanil or remifentanil in gastrointestinal endoscopy. Acta Cir Bras 2014;29(10):675–80. https://doi.org/10.1590/s0102-8650201400160008.
Xu Y, Song X, Zhang G. ED50 of dexmedetomidine nasal drip in induction of hypnosis in children during computed tomography. Zhonghua Yi Xue Za Zhi 2014;94(24):1886–8. https://doi.org/10.3760/cma.j.issn.0376-2491.2014.24.012
Short TG, Plummer JL, Chui PT. Hypnotic and anaesthetic interactions between midazolam, propofol and alfentanil. Br J Anaesth 1992;69(2):162–7. https://doi.org/10.1093/bja/69.2.162.
Chinta SS, Schrock CR, McAllister JD, Jaffe DM, Liu J, Kennedy RM. Rapid administration technique of ketamine for pediatric forearm fracture reduction: a dose-finding study. Ann Emerg Med 2015;65(6):640–8.e2. https://doi.org/10.1016/j.annemergmed.2014.12.011.
Yu J, Xiang B, Song Y, Chen H, Li Y, Liu C. ED50 of propofol in combination with low-dose sufentanil for intravenous anesthesia in hysteroscopy. Basic Clin Pharmacol Toxicol 2019;125(5):460(5. https://doi.org/10.1111/bcpt.13280.
Pace NL, Stylianou MP. Advances in and limitations of up-and-down methodology: a précis of clinical use, study design, and dose estimation in anesthesia research. Anesthesiology 2007;107(1):144(52. https://doi.org/10.1097/01.anes.0000267514.42592.2a.
Dixon WJ. The up-and-down method for small samples. J Am Stat Assoc 1965;60:967–78. https://doi.org/10.1080/01621459.1965.10480843.
Naguib M, Samarkandi AH, Moniem MA, Mansour EE, Alshaer AA, Al-Ayyaf HA, Fadin A, Alharby SW. The effects of melatonin premedication on propofol and thiopental induction dose-response curves: a prospective, randomized, double-blind study. Anesth Analg 2006;103(6):1448–52.
Pemovska T, Bigenzahn JW, Superti-Furga G. Recent advances in combinatorial drug screening and synergy scoring. Curr Opin Pharmacol 2018;42:102–10. https://doi.org/10.1016/j.coph.2018.07.008.

No competing interests reported.

PDF

Version 1

posted 08 Nov, 2021

You are reading this latest preprint version

Interactions Between Remimazolam and Propofol in Combination With Sufentanil for Anesthesia During Gastroscopy

Status:

Version 1

Abstract

Background

Methods

Results

Conclusions

Trial registration:

Figures

Background

Methods

Patients

Intervention and Measurements

Statistical analysis

Results

Discussion

Conclusions

Declarations

References

Additional Declarations

Status:

Version 1