Effect of remimazolam versus propofol on inferior vena cava collapse index during general anesthesia induction: a randomized controlled trial

1. Introduction

Hypotension during surgery may lead to postoperative myocardial injury, acute kidney injury and other adversities [1, 2, 3]. Recent studies show that more than half of intraoperative hypotensive events happen postinduction [4]. Propofol is the most employed intravenous anesthetic which causes postinduction hypotension [4, 5]. Remimazolam is a novel benzodiazepine that acts on ester-based gamma-aminobutyric acid type A receptor and shows rapid induction and recovery [6]. It may offer favorable pharmacological profile for cardiovascular stability, and thus exhibit reduced hypotension risk in the induction and maintenance phases of anesthesia compared to propofol [7, 8]. However, the reasons for greater remimazolam hemodynamic stability remain unclear. Hypotension can be caused by decrease in sympathetic tone, in preload and afterload, or by direct myocardial depression [9]. Preload related blood volume status can be assessed by ultrasonographic measurements of the diameter of inferior vena cava (IVC) and associated collapsibility indices, which provide accurate and rapid information of postinduction hypotension risk [10]. Current guidelines in America and Europe suggest that IVC diameter ≤2.1 cm and collapsibility >50% indicate right atrial pressure (RAP) of 0–5 mmHg, while diameter >2.1 cm with <50% collapse demonstrates RAP of 10–20 mmHg. A mean pressure value of 8 mmHg is used if the clinical picture does not fit these criteria [11]. Limited studies describe whether these two anesthetics affect preload. This study was thus designed to test the hypothesis in randomized clinical trial if the remimazolam usage for anesthesia induction compared to propofol would reduce the inferior vena cava collapse index (IVC-CI).

2. Materials and methods

3. Results

Patients were enrolled between 01 June 2023 and 30 November 2023 at Wenzhou People’s Hospital. A total of 60 patients consented among the 67 patients screened for eligibility. They were randomly assigned to receive remimazolam (n = 30) or propofol (n = 30). One patient in the propofol group was excluded because of the surgery cancellation. Six patients had poor IVC visualization wherein 2 cases were in remimazolam group and 4 in propofol group. Finally, the data of 59 patients in modified intention-to-treat analysis set were analyzed (Fig. 1). The baseline characteristics of patients were similar for the two groups and provided in Table 1.

Fig. 1.The study flow diagram.

Primary and secondary outcomes are given in Table 2 and Fig. 2. The primary outcome of IVC-CI after anesthesia induction did not differ when accounting for missing data using multiple imputations between the two groups, i.e., 25.5% (5.3) in remimazolam group and 26.1% (5.5) in propofol group (adjusted mean difference, −0.6% (95% CI, −4.5 to 3.3), p = 0.755) (Table 2). The dIVCmin (adjusted mean difference, 0 mm (95% CI, −0.12 to 0.13); p = 0.960) and dIVCmax (adjusted mean difference, −0.04 mm (95% CI, −0.21 to 0.14), p = 0.693) after the anesthesia induction were not different for remimazolam and propofol groups. MAP (adjusted mean difference, 5.6 mmHg (95% CI, 1.8 to 9.3), p = 0.005) and HR (adjusted mean difference, 7.9 bpm (95% CI, 5.2 to 10.6), p < 0.001) after anesthesia induction were higher in the remimazolam group compared to propofol. There was no significant difference in BIS values for the two groups after anesthesia induction (adjusted mean difference, 1.7 (95% CI, −1.0 to 4.4), p = 0.215).

Fig. 2.Primary and secondary outcomes. IVC-CI: Inferior vena cava collapse index; dIVCmin: the minimum diameters of inferior vena cava; dIVCmax: the maximum diameters of inferior vena cava; MAP: mean arterial pressure; HR: heart rate; BIS: bispectral index.

Adverse events are provided in Table 3. After the anesthesia induction, 2 (6.7%) and 9 (31.0%) patients in remimazolam and propofol groups, respectively, experienced hypotension (p = 0.016). Injection pain happened in 0 patients of remimazolam group and 11 (37.9%) of propofol group (p < 0.001). No cases of agitation, bradycardia, reflux aspiration, or bronchospasm were observed.

4. Discussion

In this randomized clinical trial, the remimazolam usage for anesthesia induction compared to propofol did not reduce IVC-CI. The dIVCmax, dIVCmin and BIS values had no significant difference. Remimazolam resulted in higher HR and MAP compared to propofol after the anesthesia induction, with lower incidence of postinduction hypotension.

Ultrasonographic evaluation of IVC had been used as the non-invasive technique for central venous pressure (CVP) assessment because of wide availability, low cost and easier use [15]. Volume status estimation was made by measuring the dynamic respiratory fluctuations in various clinical settings. Dynamic parameters indicated heart-lung interactions which varied according to the cardiac and respiratory cycles. In this study, patients were spontaneously breathing before the anesthesia induction. In this state, negative intrathoracic pressure increased the venous flow to heart and reduced the IVC diameter. At the end expiration, intrathoracic pressure was increased to zero which decreased the venous return and maximized IVC diameter. This had been defined as IVC-CI. IVC-CI was calculated by the following formula: IVC-CI = (dIVCmax − dIVCmin)/dIVCmax × 100% [12]. The mechanical ventilation reversed the cycle. The positive intrathoracic pressure decreased venous flow to the heart and increased IVC diameter during inspiration. End-expiration intrathoracic pressure was decreased to zero which increased the venous flow and reduced IVC diameter. This was defined as distensibility index (IVC-DI). IVC-DI = (dIVCmax − dIVCmin)/dIVCmin × 100% [12]. Positive pressure ventilation increased the intrathoracic pressure, decreased systemic venous return, and increased venous blood volume in the IVC. This effect resulted in IVC-CI reduction following the induction of both drugs as compared to baseline measurements. The convention to normalize by end-expiratory diameter, IVC-CI for spontaneous breathing and IVC-DI for ventilated breathing used in some studies did not allow the data comparison between ventilated and spontaneously breathing encounters. IVC-CI and IVC-DI could be interconverted: IVC-CI = IVC-DI/(1 + IVC-DI) [12]. IVC-CI was calculated for all the patients if ventilated or not, to ensure consistency and convenience.

This was the pioneering study to utilize IVC-CI for examining hemodynamic mechanism of propofol and remimazolam. Several mechanisms led to the hypotension including decreased myocardial contractility, venous return, and vascular resistance in systemic circulation [9]. A previous study suggested that remimazolam prevented hypotension because of better preservation of cardiac output as well as the product of cardiac output and systemic vascular resistance [14]. However, it did not explore the impact of cardiac preload. A patient with large IVC-CI might be a small CVP, and small IVC-CI might be a large CVP [11]. IVC-CI could assess the relative intravascular volume and explain the hypotension cause [12]. It was shown that the volume responsiveness was predicted with similar accuracy during spontaneous breathing (pooled sensitivity 71%, specificity 81%) and mechanical ventilation (pooled sensitivity 75%, specificity 82%) [12]. The results herein exhibited that there was no difference in IVC-CI between the two anesthetics. The reasons could be that both drugs did not dilate the venous and caused the same degree of venous dilatation. Venous dilation had been a cause of propofol-induced hypotension [16]. Zucker et al. [17] demonstrated that propofol anesthesia reduced mean systemic filling pressure which led to the conclusion that propofol-induced hypotension was mitigated by preload reduction as the result of decreased venous vasomotor tone. It was thus concluded herein that remimazolam caused the same venous dilatation as that of propofol. In this study, the insertion of laryngeal mask airway and intravenous administration of penehyclidine hydrochloride were used to mitigate the HR impact. Remimazolam led to higher HR and MAP than propofol. Patients could compensate for the reduced preload or significant vasodilation by increasing the heart rate to increase the cardiac output and perfusion [9]. The blood pressure stability after remimazolam induction could be attributed to less pronounced inhibition of the sympathetic nervous system. It was anticipated that patients receiving rehydration therapy before anesthesia induction would have more benefit.

A previous study compared remimazolam and propofol for total intravenous anaesthesia in urological surgery patients. Remimazolam had non-inferior efficacy as of propofol with lower incidence of hypotension during anaesthesia [18]. Another study evaluating the quality of recovery in urological surgery patients showed that MAP and HR were higher in remimazolam group compared to propofol group after the anesthesia induction [19]. Zhang et al. [20] compared the efficacy and safety of remimazolam besylate versus propofol. A total of 82 patients undergoing hysteroscopy were included in this study. Remimazolam had low incidence of hypotension. Liu et al. [21] evaluated the impact of remimazolam anesthesia induction on hemodynamics in the patients of valve replacement surgery. It was found that the hypotension and cumulative norepinephrine doses used per patient were lower in the remimazolam group than in propofol. A recent European multicenter trial in large population of patients with major comorbidities (ASA physical status of 3 or 4) depicted same results [22]. Consistent with the literature, this study also found that the participants receiving remimazolam for anesthesia induction also had stable hemodynamics. This outcome was contrary to that of Sekiguchi et al. [23], who found that hemodynamics were not different for remimazolam and target-controlled propofol groups during anesthesia induction. They concluded that the choice and dosage of anesthetics were important for hemodynamic stability. Propofol often caused injection pain which negatively impacted the patient experience. This study found that remimazolam did not induce injection pain. It might thus be more feasible for clinical applications.

This study had certain limitations. First, the impact of anesthetics on vascular volume was exclusively assessed by IVC ultrasound. Future studies should consider the addition of echocardiography to evaluate anesthetics effects on cardiac function [24]. Second, patients in this study were young, and relatively thin with ASA physical status of 1 or 2. Results could be different in obese individuals, elderly or those with major comorbidities. Replication studies should thus be conducted for these groups. Finally, 6 patients obtained poor IVC visualization in this study. There were several other factors which could reduce visualization including obesity, abdominal distention, gas in the bowel, and subcutaneous emphysema. Expanding ultrasound window and technique repertoires might overcome the visual limitations [25].

5. Conclusions

The remimazolam usage for anesthesia induction as compared to propofol did not significantly reduce IVC-CI. Remimazolam caused same venous dilatation as that of propofol.

Availability of data and materials

The data presented in this study are available on reasonable request from the corresponding author.

Author contributions

HBC and QZ—designed the research study. HBC, QZ, YYZ and JCX—performed the research. JJC—analyzed the data. HBC and ZYJ—wrote the manuscript. All authors read and approved the final manuscript.

Ethics approval and consent to participate

The research protocol was approved by the Clinical Research Ethics Committee of Wenzhou People’s Hospital (No. 2023-031) and was prospectively registered on www.chictr.org.cn/ (ChiCTR2300070911). Enrolled participants provided written informed consent.

Acknowledgment

Not applicable.

Funding

This research received no external funding.

Conflict of interest

The authors declare no conflict of interest.