DOI: https://doi.org/10.21203/rs.3.rs-2130128/v1
Remimazolam confers a lower risk of hypotension than propofol. However, no studies have compared efficacy of remimazolam and propofol administered using target-controlled infusion (TCI). This study aimed to investigate hemodynamic effects of remimazolam and target-controlled propofol in middle-aged and elderly patients during the induction of anesthesia.
Forty adults aged 45–80 years with the American Society of Anesthesiologists Physical Status 1–2 were randomly assigned to remimazolam or propofol group (n = 20 each). Patients received either remimazolam (12 mg/kg/h) or propofol (3 µg/mL, TCI), along with remifentanil for inducing anesthesia. We recorded the blood pressure, heart rate (HR), and estimated continuous cardiac output (esCCO) using the pulse wave transit time. The primary outcome was the maximum change in mean arterial pressure (MAP) after induction. Secondary outcomes included changes in HR, cardiac output (CO), and stroke volume (SV).
MAP tended to decrease after induction of anesthesia in both the groups, without significant differences between the groups (-41.1 [16.4] mmHg and − 42.8 [10.8] mmHg in remimazolam and propofol groups, respectively; mean difference: 1.7 [95% confidence interval: -8.2 to 4.9]; p = 0.613). Furthermore, HR, CO, and SV decreased after induction in both groups, without significant differences between the groups. Remimazolam group had significantly shorter time until loss of consciousness than propofol group (1.7 [0.7] min and 3.5 [1.7] min, respectively; p < 0.001). However, MAP, HR, CO, and SV were not significantly different between the groups despite adjusting time until loss of consciousness as a covariate. Remimazolam group tended to have a lower frequency of hypotension (MAP < 65 mmHg) than propofol group (7 [35%] and 11 [55%] cases, respectively; p = 0.341).
Hemodynamics were not significantly different between remimazolam and target-controlled propofol groups during induction of anesthesia. Thus, the choice, dose, and usage of anesthetics are important for hemodynamic stability while inducing anesthesia. Clinicians should monitor hypotension while inducing anesthesia with remimazolam as well as propofol.
UMIN-CTR (UMIN000045612).
Hypotension during general anesthesia is associated with adverse outcomes [1, 2]. Previous studies suggest that intraoperative hypotension is associated with cardiovascular events and acute kidney injury in patients undergoing non-cardiac surgery [3–5]. Propofol often leads to hypotension during induction of anesthesia, and the risk increases with age [6–9]. Given the risk of perioperative complications in elderly patients [10–12], preventive measures are required against hypotension during general anesthesia.
Remimazolam, an ultra-short-acting benzodiazepine intravenous anesthetic, has an imidazobenzodiazepine skeleton with side chains containing ester bonds in the diazepine ring [13]. Remimazolam may have a favorable profile for circulation with a lower risk of hypotension during induction and maintenance of anesthesia than propofol [14–16]. However, previous studies reporting superiority of remimazolam used bolus doses of 1.5–2.5 mg/kg propofol during induction [14–16], and no study has compared efficacy of remimazolam and propofol administered using target-controlled infusion (TCI). TCI may require a lower dose of propofol to achieve loss of consciousness during induction of anesthesia than manual infusion [17–19]. However, to verify the superiority of remimazolam over propofol, multiple methods used in clinical practice should be employed. Therefore, this study aimed to compare hemodynamics during induction of anesthesia using remimazolam and target-controlled propofol in middle-aged and elderly patients.
This study was reviewed and approved by the Ethics Committee of the Tokushima University Hospital (approval no. 4101). The protocol was registered at the University Hospital Medical Information Network Clinical Trial Registry (UMIN-CTR, UMIN000045612). Prior written informed consents were obtained from all participants. The study complies with the CONSORT statement.
We included 40 patients aged 45–80 years with the American Society of Anesthesiologists Physical Status 1–2 and who underwent surgery under general anesthesia at the Tokushima University Hospital. We excluded patients with the following characteristics: emergency cases, cardiovascular disease, pregnant woman, severe liver dysfunction, dialysis, neurological disorder, intestinal obstruction, drug hypersensitivity, severe lipid metabolism disorder, body mass index (BMI) ≥ 30 kg/m2, or a predicted difficult airway. We also excluded patients who underwent surgeries in the lateral or prone position.
Patients were randomly assigned to the remimazolam or propofol group (n = 20 each) by the sealed envelope system. Patients, but not anesthesiologists, were blinded to the group allocation. Patients received Ringer solution acetate at 500 mL/h rate through a peripheral venous tract larger than 22G. Remimazolam 12 mg/kg/h or propofol 3 µg/mL (effect site concentration) using TCI system (TERFUSION Syringe Pump Type SS3 TCI, TERUMO Corporation, Tokyo, Japan) was administered along with remifentanil 0.3 µg/kg/min for induction of anesthesia. The loss of consciousness was confirmed when the patients failed to respond. Remimazolam was adjusted to 1–2 mg/kg/h and propofol to 2–5 µg/mL by adjusting the bispectral index (BIS) values between 40 and 60 after loss of consciousness. Endotracheal intubation was performed after loss of consciousness using 0.6 mg/kg rocuronium. After intubation, remifentanil was adjusted to 0.1–0.3 µg/kg/min and mechanical ventilation was maintained by adjusting the end-tidal CO2 between 35 and 45 mmHg. The noninvasive blood pressure was measured using an upper arm cuff every 2.5 min. Cardiac output (CO) and stroke volume (SV) were estimated using pulse wave transit time (estimated continuous cardiac output [esCCO], Nihon Koden, Tokyo, Japan). Hypotension (mean arterial pressure [MAP] < 65 mmHg over 2.5 min) was treated using 4–8 mg ephedrine.
Primary outcome measure was the maximum change in MAP after induction. Secondary outcome measures were the maximum change in heart rate (HR), CO, and SV. These hemodynamic changes were also examined after adjusting the time until loss of consciousness. Frequency of hypotension (MAP < 65 mmHg over 2.5 min) was also compared. The observation period was from induction of anesthesia to 10 min after endotracheal intubation.
The study was designed as a superiority trial and the sample size was determined as follows: The effect size was set to 1.0 with reference to previous studies that examined the difference in MAP reduction between remimazolam and propofol [15, 16]. After adjusting the α error to 0.05 and power to 0.8, the sample size was calculated to be 34. Therefore, considering a 10% loss of patients, we selected a sample size of 40 patients (n = 20 per group).
Data are presented as mean (standard deviation or 95% confidence interval [CI]). Numerical variables between the groups were compared using the Welch’s t-test. Analysis of covariance (ANCOVA) was performed to control the effects of covariates. Ratios were compared using the chi-square test or Fisher’s exact test for ≤ 5 cells. All p values were two-sided, and p < 0.05 was considered to be statistically significant. Statistical analyses were performed using EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), a graphical user interface for R version 4.0.1 (The R Foundation for Statistical Computing, Vienna, Austria), that provides statistical functions frequently used in biostatistics [20].
Forty patients who met the eligibility criteria were enrolled to the study between November 2021 and February 2022, and randomly assigned to either the remimazolam or propofol group. All patients completed the protocol and were included in the primary endpoint analysis. Two patients in the propofol group were excluded from CO and SV analyses due to lack of esCCO data (Fig. 1).
Characteristics of patients in the groups are listed in Table 1. All patients in the two groups achieved loss of consciousness with the dose of anesthetics specified in the protocol.
Characteristics | Remimazolam (n = 20) | Propofol (n = 20) |
---|---|---|
Age, years | 67 (10) | 62 (10) |
Sex, male/female | 6/14 | 4/16 |
ASA-PS, 1/2 | 5/15 | 4/16 |
Height, cm | 157.8 (5.7) | 157.5 (6.0) |
Body weight, kg | 59.2 (8.9) | 57.1 (9.4) |
BMI | 23.7 (2.6) | 23.1 (3.7) |
Hypertension, ± | 11/9 | 7/13 |
Antihypertensive drug, ± | 11/9 | 6/14 |
Values are mean (standard deviation, SD) or the number of patients. | ||
n, number; ASA-PS, American Society of Anesthesiologists physical status; BMI, body mass index. |
MAP tended to decrease after induction in both the groups, without significant differences between the groups (-41.1 [16.4] mmHg and − 42.8 [10.8] mmHg in remimazolam and propofol group, respectively; mean difference: 1.7 mmHg [95% CI: -8.2 to 4.9]; p = 0.613). Further, HR, CO, and SV tended to decrease after induction of anesthesia in both the groups, without significant differences between the groups (HR: -9.6 [6.6] bpm and − 13.8 [9.9] bpm, p = 0.129; CO: -18.4 [10.8]% and − 24.6 [12.2]%, p = 0.101; SV: -12.7 [8.4]% and − 10.1 [5.7]%, p = 0.262; in the remimazolam and propofol groups, respectively) (Table 2).
Characteristics | Remimazolam (n = 20) | Propofol (n = 20) | Mean difference (95% CI) | p |
---|---|---|---|---|
MAP changes, mmHg | -41.1 (9.6) | -42.8 (10.8) | -1.7 (-8.2 to 4.9) | 0.613 |
HR changes, bpm | -9.6 (6.6) | -13.8 (9.9) | 4.2 (-1.3 to 9.6) | 0.129 |
CO changes, % | -18.4 (10.8) | -24.5 (12.2) | 6.2 (-1.7 to 13.7) | 0.101 |
SV changes, % | -12.7 (8.4) | -10.1 (5.7) | -2.6 (-7.2 to 2.0) | 0.262 |
Values are the mean (standard deviation, SD). | ||||
n, number; CI, confidence interval; MAP, mean arterial pressure; HR, heart rate; bpm, beats per minute; CO, cardiac output; SV, stroke volume. |
The remimazolam group had a significantly shorter time until loss of consciousness than propofol group (1.7 [0.7] min and 3.5 [1.7] min, respectively; mean difference: 1.8 min [95% CI: 0.8 to 2.6] p < 0.001). The time until loss of consciousness had no significant effect on MAP and SV decline (MAP: F[1, 37] = 0.311, p = 0.580; SV: F[1, 36] = 2.49, p = 0.123), without significant differences between the groups despite adjusting the time until loss of consciousness (MAP: F[1, 37] = 0.535, p = 0.469; SV: F[1, 36] = 3.43, p = 0.072). The time until loss of consciousness significantly affected HR and CO decline after induction of anesthesia (HR: F[1, 37] = 5.00, p = 0.031; CO: F[1, 36] = 9.17, p = 0.005), and the degree of decline increased proportional to time until loss of consciousness. However, changes in HR and CO were not significantly different between the groups despite adjusting time until loss of consciousness (HR: F[1, 37] = 0.011, p = 0.916, CO: F[1, 36] = 0.05, p = 0.824). According to ANCOVA, the time until loss of consciousness and anesthesia group were not significantly associated for all variables (Table 3, Fig. 2).
Characteristics | Estimate | Std. error | 95% CI | p value |
---|---|---|---|---|
MAP changes, mmHg | ||||
Intercept | -42.3 | 3.1 | -48.7 to -35.9 | < 0.001 |
Anesthetic group | -2.8 | 3.9 | -10.9 to 5.1 | 0.469 |
Times until LoC | 0.7 | 1.3 | -1.8 to 3.3 | 0.580 |
HR changes, mmHg | ||||
Intercept | -5.9 | 2.4 | -10.8 to -0.9 | 0.021 |
Anesthetic group | -0.3 | 3.1 | -6.5 to 5.9 | 0.916 |
Times until LoC | -2.1 | 1.0 | -4.2 to 0.2 | 0.031 |
CO changes, % | ||||
Intercept | -11.7 | 3.2 | -18.2 to -5.3 | < 0.001 |
Anesthetic group | 0.9 | 4.1 | -7.4 to 9.2 | 0.82 |
Times until LoC | -3.9 | 1.3 | -6.5 to -1.3 | 0.005 |
SV changes, % | ||||
Intercept | -10.4 | 2.2 | -14.8 to -6.0 | < 0.001 |
Anesthetic group | 5.1 | 2.8 | -0.5 to 10.7 | 0.072 |
Times until LoC | -1.4 | 0.9 | -3.2 to 0.4 | 0.123 |
Std, standard; CI, confidence interval; LoC, loss of consciousness; MAP, mean arterial pressure; HR, heart rate; CO, cardiac output; SV, stroke volume. |
The remimazolam group tended to have a lower frequency of hypotension (MAP < 65 mmHg over 2.5 min) than propofol group (7 cases [35%] and 11 cases [55%], respectively, p = 0.341). Ephedrine was used when hypotension persisted for > 2.5 min; its administration successfully treated postoperative complications related to hypotension, such as myocardial and kidney injuries, in all patients.
The reduction in MAP in the remimazolam and target-controlled propofol groups during induction of anesthesia in middle-aged and elderly patients was not significantly different between the groups, and the mean difference was very small. Moreover, the changes in HR, CO, and SV were not significantly different between the groups. The time until loss of consciousness was significantly shorter in remimazolam group than in propofol group. The time until loss of consciousness had no significant effect on the decrease in MAP and SV. A prolonged time until loss of consciousness correlated with greater degree of decline in HR and CO. Despite adjusting the time until loss of consciousness, MAP, HR, CO, and SV were not significantly different between the groups.
Previous studies have shown that remimazolam administration for induction or maintenance of anesthesia led to a lesser reduction in blood pressure than propofol [14–16], as opposed to results of the present study. Differences in doses and mode of administration of remimazolam and propofol may have influenced the results. For instance, Doi et al. administered remimazolam (6 or 12 mg/kg/h) or propofol (2.0–2.5 mg/kg, bolus) along with remifentanil for inducing anesthesia [14]. Zhang et al. administered remimazolam (0.2–0.4 mg/kg, bolus) or propofol (1.5–2.0 mg/kg, bolus), along with sufentanil for inducing anesthesia [15]. Whereas, Zang et al. administered remimazolam (0.2 mg/kg, bolus) or propofol (1.5–2.0 mg/kg, bolus) for inducing anesthesia [16]. In the present study, we administered remimazolam (12 mg/kg/h) or target-controlled propofol (3.0 µg/mL) along with remifentanil for inducing anesthesia. A 1 min dose of 12 mg/kg/h remimazolam is equivalent to 0.2 mg/kg. As patients required 1.7 (0.7) min to achieve loss of consciousness with remimazolam at 12 mg/kg/h, the dose of remimazolam necessary for loss of consciousness was calculated to be 0.34 (0.14) mg/kg. TCI requires a lower dose of propofol to achieve loss of consciousness than manual infusion [17–19]. Remimazolam and propofol decrease blood pressure in a dose-dependent manner [21–24]. The Food and Drug Administration (FDA) recommends a 1.5 mg/kg maximum dose of propofol for inducing anesthesia in elderly patients [25]. The present study reaffirms that the factors affecting hemodynamics during anesthesia are the choice, dose, and usage of drugs.
In the present study, 35% and 55% of patients in the remimazolam and propofol groups, respectively, experienced hypotension (MAP < 65 mmHg over 2.5 min) during induction of anesthesia, although without significant differences between the groups. The number of cases (n = 40) in the present study may be low to detect a significant difference in the secondary outcome—192 cases (96 per group) would be required to compare the differences between 35% and 55% at α error of 0.05 and power of 0.8. However, even with 192 cases, a significant difference may not be achieved for the degree of MAP reduction (the primary outcome of this study) due to the extremely small mean difference. A previous study reported that MAP below an absolute threshold of 65 mmHg was related to both myocardial and kidney injuries [26]. Thus, hypotension should be closely monitored after induction of anesthesia with both remimazolam and propofol.
This study has some limitations. First, we measured non-invasive blood pressure every 2.5 min. More detailed data would have been obtained if arterial blood pressure was continuously measured, such as by radial artery cannulation. However, invasive methods were not deemed appropriate based on patients’ background. Second, for safety reasons, ephedrine was administered to treat persistent hypotension in the patients. The differences between the two groups could have been more thoroughly examined if the blood pressure was monitored to its lowest level without treatment, although it would have been unethical. Third, remimazolam was continuously administered at 12 mg/kg/h and propofol at 3 µg/mL using the TCI system. Thus, the results may not apply for different doses and drugs. The esCCO was used to estimate CO and SV that may differ from the actual values of CO and SV. However, the trending ability of esCCO has been reported to be clinically acceptable and comparable with the currently available methods using arterial waveform analysis. As esCCO was better at evaluating relative than absolute values, we evaluated CO and SV based on percent changes [27, 28].
In conclusion, no significant differences in hemodynamics were observed after induction of anesthesia with remimazolam or target-controlled propofol. Thus, the choice of drug and its dosage and usage are important for ensuring hemodynamic stability during induction of anesthesia. Clinicians should carefully monitor hypotension while inducing anesthesia with remimazolam or propofol.
TCI, target-controlled infusion; BMI, body mass index; BIS, bispectral index; CO, cardiac output; SV, stroke volume; esCCO, estimated continuous cardiac output; MAP, mean arterial pressure; HR, heart rate; ANCOVA, analysis of covariance; CI, confidence interval.
Ethics approval and consent to participate
This study was approved by the Ethics Committee of the Tokushima University Hospital (approval no. 4101). Written informed consent was obtained from all participants or their parents/guardians. This study was registered at the UMIN-CTR (Number: UMIN000045612, Date of registration: 10/01/2021). All methods were performed in accordance with the Declaration of Helsinki.
Consent for publication
Not applicable.
Availability of data and materials
The datasets used and/or analyzed during the study are available from the corresponding author on reasonable request.
Competing interests
The authors declare that they have no competing interests.
Funding
This work was supported by JSPS KAKENHI Grant Numbers 19K09352, 20K17814.
Authors’ contributions
RS conceived and designed the study; collected, analyzed and interpreted data; and prepared the manuscript draft. MK conceived and designed the study; collected, analyzed and interpreted data; and edited the manuscript. RK, NK, and YS collected, analyzed and interpreted data; and edited the manuscript. KT conceived and designed the study; analyzed and interpreted data; and edited the manuscript. All authors read and approved the final manuscript.
Acknowledgments
This work was supported by JSPS KAKENHI Grant Numbers 19K09352, 20K17814.
We would like to thank Editage (www.editage.com) for English language editing.