Comparison of hypotension between propofol and remimazolam-propofol combinations sedation for day-surgery hysteroscopy: a prospective, randomized, controlled trial

Abstract

Background

A combination of remimazolam and propofol could produce more stable sedation. A good medication regimen should consider not only efficacy but also safety, especially hypotension. The aim of the current study was to compare the incidence and amount of hypotension by propofol versus remimazolam-propofol combinations in day-surgery hysteroscopy.

Methods

Patients were randomly assigned to receive either propofol (Group P, n = 125) or remimazolam-propofol combinations (Group RP, n = 125) at a 1:1 ratio. Intravenous injection of sufentanil 0.1ug/kg were administered before sedative medication. In group P, a bolus of 2.5 mg/kg propofol was administered. In group RP, intravenous anesthesia was commenced with 0.125 mg/kg remimazolam and 1 mg/kg propofol. After loss of consciousness, propofol was maintained at 6 mg/kg/h. The primary outcomes were the incidence and amount of hypotension during surgery. Hypotension was defined as a MAP less than 65mmHg for at least 1 min. The amount of hypotension was assessed by time-weighted average intraoperative MAP under a threshold of 65 mmHg. The secondary outcomes were various anesthesia related parameters and some adverse events.

Results

In group P, 25 patients (20.0%) experienced hypotension during hysteroscopy compared with 9 patients (7.2%) in group RP, for a difference of 12.8% (RR 2.778, 95%CI [1.352–5.709]). The combination of remimazolam and propofol resulted in significantly lower TWA (Time Weighted Average) threshold 0.14 (0.10–0.56) mmHg in group RP compared to 0.31 (0.15–0.67) mmHg in group P. The total dose of propofol was nearly double in group P compared to group RP. A significantly higher frequency of injection pain and low oxygen saturation was observed in the group P than that of the group RP. Hiccup was observed only in group RP. The incidences of body movement, bradycardia and vomiting were no significant difference between groups.

Conclusion

The incidence and amount of hypotension by remimazolam-propofol combinations was significantly less than that by propofol sedation in day-surgery hysteroscopy. The optimization of medication regimen would attenuate the harm of hypotension and contribute to patients’ rapid recovery in day surgery.

Trial registration

Chinese Clinical Trial Registry, ChiCTR2400079888 (date: 15/01/2024),

Background

Propofol combined with opioids remains the most widely intravenous anesthesia for day surgery. Because of narrow therapeutic index, propofol may induce significant hemodynamic and respiratory depression [1]. By pooling individual patient data from five trials and a clinical database, Sneyd and his colleagues established that hypotension was common during propofol sedation for colonoscopy [2]. Because of the stronger stimulation on cervix dilation and uterine cavity scratching/clamping, deeper sedation was needed for hysteroscopy. Longer periods of propofol sedation and large propofol doses were associated with longer-lasting and more profound hypotension [2]. Remimazolam is an ultra-short-acting benzodiazepine with characteristics of rapid onset and offset, short duration, and predictable recovery times [3]. It had been widely validated the efficacy and safety profile in both healthy and high-risk patients with minimal respiratory depression and less pronounced hemodynamic changes [4, 5]. Remimazolam could effectively lower the incidence of hypotension than propofol in hysteroscopy but with more body movement and longer recovery time [6].

A combination of remimazolam and propofol was recommended to produce more stable sedation. We had completed the dose finding study of remimazolam combined with propofol for intravenous sedation during day-surgery hysteroscopy [7]. The combination of 0.125 mg/kg remimazolam and 1 mg/kg proporfol had an advantage in reducing adverse events. A good medication regimen should consider not only efficacy but also safety, especially hypotension. The aim of the current study was to compare the incidence and amount of hypotension by propofol versus remimazolam-propofol combinations in day-surgery hysteroscopy.

Methods

Ethics approval and consent to participate

This prospective, randomized, controlled, double-blind trial was approved by the Ethical Committee of Women’s Hospital, Zhejiang University School of Medicine (Hangzhou, China) (No. IRB-20230261-R) and was registered at the Chinese Clinical Trials.gov (No. ChiCTR2400079888, date: 15/01/2024). This trial was conducted from Jan 15, 2024 to Apr 30, 2024 in Women’s Hospital Zhejiang University School of Medicine in Hangzhou. Written informed consent was obtained from all patients before enrollment. The principles of Declaration of Helsinki were followed for this study. This manuscript adheres to the applicable CONSORT guidelines.

Study population

Patients were eligible if they met the inclusion criteria: (1) scheduled to hysteroscopy requiring intravenous anesthesia; (2) American Society of Anesthesiologists (ASA) physical status I-II; (3) aged 20–45 years; (4) body mass index (BMI) 18–25 kg/m². Patients were excluded if they had any of following conditions: (1) cardiopulmonary disease; (2) alcohol abuse, liver and kidney dysfunction; (3) chronic use of tranquillizers/opioids/antidepressants; (4) anesthetic drug allergy; (5) difficulty in cervical dilatation which was defined as the duration of cervical dilatation > 5 min; (6) obstructive sleep apnea-hypopnea syndrome (OSAHS); (7) participating in other clinical studies; (8) other reasons that are not appropriate for clinical study.

Randomization and blinding

The simple randomization was chosen in our trial which was performed using a computer-generated random numbers table to ensure that each group contained 125 subjects. Randomized results were sealed in sequentially numbered envelopes until the end of the study. Sealed and numbered envelopes were handed to an anesthesiologist who was not involved in this study performed the anesthesia procedure. A blinded investigator who was not directly involved in intraoperative anesthesia collected data. The surgeons and patients were all blinded to the grouping assignments.

Anesthesia and monitoring

The intramuscular injection of phloroglucinol (80 mg) was used for cervical ripening for each patient at 2 h before operation. All the patients had routine noninvasive monitoring of blood pressure (1 min cycle), electrocardiogram (ECG), and pulse oximetry (SpO₂) in the operating room during the whole duration of hysteroscopy. In addition, end-tidal carbon dioxide monitoring measured respiratory rate (RR). Spectral entropy (SE) measured the depth of anesthesia by monitor (CARESCAPE Monitor B650, GE Healthcare, Helsinki, Finland). All patients inhaled oxygen (5 L/min) through a Venturi oxygen mask.

Patients were randomly assigned to receive either propofol (Group P, n = 125) or remimazolam-propofol combinations (Group RP, n = 125) at a 1:1 ratio. Intravenous injection of sufentanil 0.1ug/kg, dexamethasone 5 mg and palonosetron 0.25 mg were administered before sedative medication. In group P, a bolus of 2.5 mg/kg propofol (Aspen Pharma Co. LTD., Ireland) was administered. In group RP, intravenous anesthesia was commenced with 0.125 mg/kg remimazolam (Yichang Humanwell Pharmaceutical Co. LTD., China) and 1 mg/kg propofol. The concentrations of propofol and remimazolam were 10 mg/ml and 1.25 mg/ml respectively. The total volumes of induced drugs were 0.2 ml/kg in group RP and 0.25 ml/kg in group P. All drugs were injected by the speed of 600 ml/h. After loss of consciousness, propofol was maintained at 6 mg/kg/h. The surgeon was allowed to start cervical dilation when adequate sedation (SE < 60) was achieved. The cervix was dilated to 1 cm in diameter and hysteroscope with 27-Fr (9 mm) outer sheath was inserted. If patients did not achieve adequate sedation (SE > 60 or body movement), they were given top-up doses of propofol (0.5-1 mg/kg per time) and the top-up interval was more than 1 min. If SE was lower than 40, propofol was suspended till SE > 50. SE was maintained at 40–60 during the operation. After the procedure, patients were transferred to the recovery room. Visual analog scale (VAS) was used to assess pain after surgery. If VAS > 4, ketorolac 30 mg was administered intravenously.

Outcome measures

The primary outcomes were the incidence and amount of hypotension during surgery. Hypotension was defined as a mean arterial pressure (MAP) less than 65mmHg for at least 1 min [8, 9]. The amount of hypotension was assessed by time-weighted average intraoperative MAP (TWA MAP) under a threshold of 65 mmHg. The measure characterizes both the duration and severity of hypotension. TWA was measured by calculating the area under the threshold (AUT) divided by the total duration of hysteroscopy [10, 11]. The AUT was calculated as the sum of the products of the duration spent below the 65mmHg threshold and the difference between these measurements and the threshold. If MAP < 55mmHg, hypotension was treated by intravenous injection of norepinephrine.

The secondary outcomes were various anesthesia related parameters and some adverse events. The onset time was defined as the time from the end of sedation drugs injection to reach SE < 60. The operation time was defined as the time from the insertion of the speculum to the time of the hysteroscope removal. Recovery time was defined as the time from the stop of propofol injection to the time that the patient was awake and opened eyes. The adverse events include injection pain, low oxygen saturation, jaw thrust, bradycardia, hiccup, body movement, additional medication and vomiting. The injection pain was defined as patients verbally reported their pain by themselves after the first injection. Low oxygen saturation was defined as SpO₂ < 95% which was treated with jaw thrust, mask ventilation, or endotracheal intubation. Jaw thrust was defined as maneuver against the patient’s jaw to prevent the jaw from slipping back and causing an airway obstruction. Bradycardia was defined as heart rate (HR) < 50 beats per minute which was treated by intravenous injection of atropine or norepinephrine. Hiccup was defined as involuntary contractions of the diaphragm and the auxiliary respiratory muscles, mostly in irregular series, followed by glottic closure, thereby producing a typical “hiccupping” inspiration. Body movement was defined as visible autonomous body movement during operation. Additional medication was defined as the top-up drugs to achieve adequate sedation after the initial dose of drugs. Induction was defined as the process from injection of sedation drugs to accomplish cervical dilation. Maintain was defined as the process from end of cervical dilation to finish operation.

Statistical analysis

Based on our preliminary study, the incidence of hypotension in intravenous anesthesia during day-surgery hysteroscopy was 5% in the remimazolam-propofol group and 20% in the propofol group. A sample size of 97 patients per group was required for 90% power with a 0.05 α. Taking into account the 20% loss rate, we needed to enroll 125 patients per group for a total of 250 patients.

Analyses were performed using IBM SPSS Statistics for Windows version 26. The Kolmogorov-Smirnov test was used to determine whether the continuous variables were normally distributed. The non-normally distributed variables were tested by two independent samples nonparametric test (the Mann-Whitney test) and expressed as the median (interquartile range). Enumeration data were presented as count (percentage). The chi-square test was used to compare categorical variables. We estimated the effect of TWA drop using the 2-sample Wilcoxon rank-sum test. This method was appropriate because the TWA drop < 65mmHg exhibits a skewed distribution with many patients having TWA drop of zero. We substituted zeros with small nonzero value for the modeling purposes. Values of P < 0.05 were considered statistically significant.

Results

From January to April 2024, 255 patients were recruited for elective hysteroscopy. 5 patients were excluded due to not meeting the recruitment criteria (n = 2) or enrolled in another trial (n = 3). A total of 250 patients were enrolled and randomly assigned to group P (n = 125) or group RP (n = 125) (Fig. 1).

Fig. 1

Study flowchart

The summary of the demographic data was reported in Table 1. There was no difference in age, weight, height and BMI between the groups (P > 0.05).

Table 1 Demographic data

Changes in MAP during sedation were shown in Fig. 2. More patients experienced periods of hypotension in group P.

Fig. 2

Individual MAP change during procedure time in group P (A) and group RP (B). Reference line (red dotted line) indicates MAP 65mmHg

Primary outcomes

In group P, 25 patients (20.0%) experienced 1 or more hypotensive episodes during hysteroscopy compared with 9 patients (7.2%) in group RP, for a difference of 12.8% (RR 2.778, 95%CI [1.352–5.709], P = 0.003). The combination of remimazolam and propofol resulted in significantly lower TWA threshold in group RP 0.14 (0.10–0.56) mmHg compared to 0.31 (0.15–0.67) mmHg in group P (P = 0.003). In patients experiencing hypotension, the AUT was 6.0 (3.0–13.0) mmHg*min in group P and 3.0 (2.0–11.0) mmHg*min in group RP (Table 2).

Table 2 Primary outcomes

Secondary outcomes

The total dose of propofol was almost twice as much as that in group P compared to group RP (P = 0.000). The total sufentanil dose, operation time and recovery time were similar between the groups (P = 0.0917, 0.367, 0.382 respectively). The onset time had small gap in clinic but statistical significance between groups (P = 0.000) (Table 3).

Table 3 Various anesthesia related parameters

A significantly higher frequency of injection pain was observed in the group P than that of the group RP (P = 0.000). Low oxygen saturation was observed in 12/125 (9.6%) of patients sedated with propofol alone versus 2/125 (1.6%) of patients sedated with combination (P = 0.006). Compared to zero in group RP, 4/125 (3.2%) of patients appeared the oxygen saturation below 90 in group P. The need for jaw thrust was much higher in the group P (P = 0.018), and there were no patients required endotracheal intubation. Bradycardia occurred on two patients (1.6%) in group P but none in group RP, similar to vomiting (P = 0.498). Hiccup was observed only in 7/125 (5.6%) of patients sedated with remimazolam (P = 0.014). The incidence of body movement and the need of additional medicine during hysteroscopy were 18.4% versus 20.0% (P = 0.748) and 44.0% versus 50.4% (P = 0.311) respectively between groups. Whether in induction or in maintain time, the incidences were no significant difference (Table 4).

Table 4 Adverse events

Discussion

We found that the incidence and amount of hypotension by remimazolam-propofol combinations was significantly less than that by propofol sedation in day-surgery hysteroscopy. Accompanying with less respiratory depression and injection pain, the remimazolam-propofol combinations was equivalent to propofol in terms of body movement and depth of anesthesia during whole operation. It confirmed that remimazolam combined with propofol maybe a good choice to improve safety in hysteroscopy [7, 12].

Clinical cohort studies had shown intraoperative hypotension in noncardiac surgery to be associated with unfavourable outcomes [9]. Increased time with MAP < 65mmHg or any exposure to MAP < 55mmHg was significantly associated with moderately- or highly-elevated postoperative risk [13]. Given the potentially avoidable nature of the hazard and the extent of the exposed population, hypotension in the operating room is a serious public health issue and should not be ignored in any age group [14].

Hysteroscopy is an endoscopic procedure and has become the gold standard in the diagnosis and treatment of intrauterine pathological conditions such as endometrial polyps, intrauterine adhesions, uterine malformations, and abnormal uterine bleeding. Hysteroscopy can be performed under paracervical block, regional anesthesia and general anesthesia [15]. Procedural pain and uncomfortable experience are common in paracervical block. Longer recovery period and higher incidence of hypotension are familiar with regional anesthesia, especially in spinal anesthesia [16, 17]. Rapid recovery, comfortable experience and cost-effectiveness make the intravenous sedation and anesthesia more suitable for day-surgery hysteroscopy. Therefore, hysteroscopy with propofol sedation has become very common, strong demand suggests that the volume of this procedure is likely to continue increasing. Meta-analysis of 18 RCTs identified an increased risk ratio for the development of hypotension in procedures where propofol was used compared with other hypnotics.² Association of intraoperative hypotension with myocardial injury, acute kidney injury and mortality were confirmed during noncardiac surgery [8, 14]. Futier et al. proved in an RCT that maintaining a higher MAP during abdominal surgery reduced the risk of postoperative organ dysfunction [18]. Hypotension during procedural sedation is common and worth a mention.

In our study, a significantly higher frequency of hypotension was observed in patients sedated with propofol (20%) than that with remimazolam-propofol combinations (7.2%). We compared the frequency of hypotension with other similar studies. A non-inferiority trial of remimazolam in hysteroscopy shown that hypotension was 2.4% in the remimazolam group compared with 12.2% in the propofol group [19]. The rates were very low. Some reason was the different definition of hypotension. Hypotension in this trial was defined as systolic blood pressure lower than 90mmHg. Another reason was that their sedation target was a Modified Observer’s Assessment of Alertness/Sedation score of 2 or lower and accompanied with quite a few body movements [19]. Another trial of remimazolam combined with low-dose propofol in hysteroscopy displayed that incidences of hypotension were 42.2%, 9.4% and 15.4% in group propofol, remimazolam and combinations respectively [12]. Hypotension in this trial was defined as less than 20% of basal blood pressure. Pre-operative blood pressure readings were often elevated due to patients experiencing anxiety. This may partly explain their data higher than us. Remimazolam at doses from 0.1 to 0.2 mg/kg reduced the EC50 of propofol inhibiting response to cervical dilation [20].

Postoperative injury is a function of both time spent having hypotension and depth of hypotension. TWA is a more valuable indicator which can represent both the duration and severity of hypotension [11]. The TWA < 65 of 0.31 mm Hg in the group P means that the average patient had an exposure 0.31 mm Hg below 65 mm Hg throughout surgery. With an average case duration in the study of 12 min, a TWA MAP of 0.31 corresponds to 0.31 mm Hg times 12 min = 3.72 mm Hg × minutes. In this example, 3.72 mmHg·minutes could refer to a patient who spent nearly 1 min at 61 mm Hg. In our study, the TWA in group RP was nearly halved in group P. Although the differences in TWA were small but few minutes of extra hypotension is associated with worse outcome. A single minute at a MAP of 50 mmHg increases the risk of mortality 5% [21]. Patient benefit might be derived from not only avoiding more severe hypotension below an MAP of 65 mm Hg, but also minimizing extended periods at an MAP between 60 and 70 mm Hg, a pressure range traditionally considered only mildly hypotensive and not perceived as posing a hazard for the patient.

We defined hypotension as MAP < 65 mmHg. The most widely used non-invasive method for measuring blood pressure is the automated oscillometry in low-risk operation patients. This device detects the maximum blood pressure oscillations from the arterial blood flow as mean arterial pressure, which is then converted into the projected systolic and diastolic blood pressure by utilizing standard proprietary algorithms [22]. The MAP is the most reliable index of the oscillometric blood pressure measurement device and correlate well with the invasive intra-arterial readings [23]. Although intraoperative hypotension has various definitions, MAP < 65 mmHg has the connection with worse outcomes in several analyses [8, 13, 24]. Based on these studies, in 2019 Perioperative Quality Initiative consensus statement concluded with the notion that anesthesiologists should maintain a MAP threshold of greater than 60 to 70 mm Hg during surgery [9]. Compared to relative thresholds, absolute thresholds are easier to make decision and avoid interferences of anxiety pre-operation.

Some adverse events were obviously difference between propofol and remimazolam-propofol combinations. Propofol was significantly associated with a much higher risk of injection pain compared with remimazolam which causes patients discomfort and anxiety. Explanations for pain on propofol injection include phenol-associated irritation of the skin and mucous membrane, vein endothelium, and delayed pain because of the release of mediators such as kininogen from the kinin cascade [25]. The frequency and degree of low oxygen saturation were more severe by propofol. There were 4(3.2%) patients suffering SpO₂ < 90% in group P but none in group RP. Hiccup occurred frequently in patients who received remimazolam which might last for several seconds to minutes. A rapid administration of remimazolam is more likely to elicit episodes of hiccup in healthy patients than slow infusion [26]. Even though remimazolam induced hiccup is self-limiting, this side-effect should be considered in patients who are at risk of regurgitation and aspiration. By the standard of no movement and no requirement for rescue doses during cervical dilation, the efficacy was 88% by propofol verse 80.8% by remimazolam-propofol combinations. Our regimen was equivalent to propofol in terms of body movement and depth of anesthesia during whole operation.

There were also several limitations. First, we only included patients with BMI18-25 and age 20-45y, obese and old patients were not included. The incidence of hypotension was higher than that in normal patients, which needs further study. Second, we chose the fixed dosage of propofol and remimazolam by previous study and preliminary experiment. Further large-sample clinical studies are needed to confirm whether other combinations could improve outcomes in population. Third, our study was conducted at a single tertiary university hospital and all patients were women who underwent hysteroscopy at the day surgery center. The surgeons have rich clinical experience and are familiar with the operation. The results of this study might be different in lower-level hospitals due to technique differences.

Conclusion

The incidence and amount of hypotension by remimazolam-propofol combinations was significantly less than that by propofol sedation in day-surgery hysteroscopy. The optimization of medication regimen would attenuate the harm of hypotension and contribute to patients’ rapid recovery in day surgery.