Abstract
Background
Hemodynamic instability is common during hepatectomy under general anesthesia combined with thoracic epidural anesthesia, along with intraoperative low central venous pressure (LCVP). We hypothesized that remimazolam-based anesthesia would improve hemodynamic instability compared to propofol-based anesthesia.
Methods
The patients undergoing elective hepatectomy under general anesthesia combined with thoracic epidural anesthesia were enrolled and randomly allocated to either group R (remimazolam anesthesia) or group P (propofol anesthesia). The hemodynamic instability was evaluated by the hemodynamic instability scores (HI-score) at induction period, during hepatectomy and hemostasis. The advanced hemodynamic parameters (cardiac index CI, system vascular resistance index SVRI) were recorded. The secondary outcomes including length of PACU stay, changes in hemoglobin level, major cardiovascular events within postoperative 3 days, length of hospital stay, postoperative ambulation time, and time to first flatus were also documented.
Results
A total of 72 subjects were randomized, and 33 ones under minor hepatectomy surgery in each group were analyzed finally. There was significant hemodynamics instability in both groups, however, the total HI-score was significantly lower in group R (22.8 ± 2.1) than group P (33.0 ± 4.1, P = 0.029). Further analysis demonstrated that the HI-scores were also lower in group R than group P during induction period (11.9 ± 1.0 vs. 22.6 ± 4.2, P = 0.017), hepatectomy period (23.2 ± 3.2 vs. 38.5 ± 6.0, P = 0.027) and hemostasis period (22.2 ± 2.8 vs. 33.5 ± 3.8, P = 0.019). Nevertheless, compared with propofol-based anesthesia, remimazolam-based anesthesia did not reduce incidence of major cardiovascular events and length of hospital stay (P > 0.05).
Conclusions
When compared with propofol-based anesthesia, remimazolam-based anesthesia has better intraoperative hemodynamic stability during minor hepatectomy surgery under combined general-epidural anesthesia. However, this improved hemodynamics may not necessarily translate into better perioperative outcomes.
Trial registration
Registered at ClinicalTrials.gov (Registration No. NCT06565715 Principal investigator Jun Zhang Date of registration 08/21/2024 https://clinicaltrials.gov/study/NCT06565715?term=NCT06565715&rank=1).
Keywords: Remimazolam, Propofol, Minor hepatectomy, Hemodynamics.
Introduction
Hepatectomy serves as the cornerstone treatment for hepatic benign and malignant tumors, yet perioperative hemodynamic management is challenging during hepatectomy. Current clinical practice has indicated that low central venous pressure (LCVP) method combined with hepatic portal occlusion could significantly reduce intraoperative blood loss [1, 2], though the hypovolemic state resulting from LCVP method may exacerbate circulatory instability [3]. This paradox, when combined with anesthetic interventions, leads to increased perioperative vasopressor requirements and potentially increases risks of severe complications like acute kidney injury [3–6].
Propofol, the most widely used intravenous anesthetic agent, predisposes patients to intraoperative hypotension through inhibiting myocardial contractility and decreasing systemic vascular resistance [7, 8]. Thoracic epidural anesthesia further aggravates the hemodynamic fluctuations via cardiac sympathetic blockade [9]. In this context, remimazolam, a novel intravenous benzodiazepine, demonstrates unique hemodynamic advantages. It features rapid onset (1–2 min) and quick metabolism without accumulation [10]. Existing evidences indicate remimazolam (induction dose 6–12 mg/kg/h, maintenance dose 1 mg/kg/h) significantly reduces circulatory fluctuations at equivalent sedative level as propofol [11].
Current researches on remimazolam use, however, present three critical limitations [11–15]: hemodynamic parameters often serve as a secondary endpoint; synergistic effect with epidural anesthesia is lacking; and data in hepatectomy remains insufficient. This study directly compared the hemodynamic data between remimazolam-based anesthesia and propofol-based anesthesia in patients undergoing minor hepatectomy under combined general anesthesia and epidural anesthesia, aiming to identify better anesthesia regimen during liver procedures. We hypothesized that remimazolam-based anesthesia could provide more stable hemodynamics during hepatectomy with LCVP manipulation when compared with propofol-based anesthesia.
Methods
Ethical approval and participants
This single center randomized controlled trial, approved by the Institutional Review Board of Fudan University Shanghai Cancer Center (Approval No. 2406-Exp031) and prospectively registered at ClinicalTrials.gov (Registration No. NCT06565715; Principal investigator: Jun Zhang; Date of registration: 08/21/2024; URL: https://clinicaltrials.gov/study/NCT06565715?term=NCT06565715&rank=1 ). The patients scheduled for partial hepatectomy under combined general anesthesia and thoracic epidural blockade were enrolled between August and October 2024. The written informed consent was obtained from every patient before recruitment. Inclusion criteria were: (1) age ≥ 18 years; (2) American Society of Anesthesiologists (ASA) physical status grade I-III; (3) Child-Pugh class A liver function. Exclusion criteria included: (1) coagulation disorders; (2) history of psychoactive substance dependence; (3) neurological comorbidities; (4) sever cardiopulmonary or kidney diseases; (5) significant cardiac arrhythmias.
Randomization and grouping
The randomization was conducted with MinimPy2 software (version 2.0, OSDN, Columbus, OH, USA) by an independent researcher before anesthetic induction. The eligible patients were randomized to either the remimazolam group (group R) or the propofol group (group P) according to 1:1 principle. The patients in the group R received remimazolam for both induction and maintenance of anesthesia, while those in the group P received propofol anesthesia throughout the procedure.
Intervention protocol
All patients received standard intraoperative monitoring including electrocardiogram, pulse oximetry, invasive radial arterial pressure monitoring, and central venous pressure (CVP) monitoring upon operating room admission. An epidural catheter (19G, Arrow International, USA) was placed at the T8-T9 interspace with 4 cm cephalad advancement to produce a bilateral segmental sensory block to pinprick between T4 and T12 dermatomes. A dual-lumen central venous catheter (7 F, Arrow International, USA) was inserted into the right internal jugular vein, the primary lumen designated for intravenous administration and the secondary lumen dedicated to continuous CVP monitoring. Hemodynamic parameters including cardiac index (CI), stroke volume variation (SVV), and systemic vascular resistance index (SVRI) were continuously monitored using the Picco system (Pulsion Medizintechnik, Germany) through the radial arterial cannula. The Narcotrend index (NCI) was used for monitoring intraoperative depth of anesthesia with Narcotrend® EEG system (MTN Monitor; Narcotrend-Gruppe, Hannover, Germany).
Prior to anesthetic induction, 5 mL of 1% lidocaine was administered epidurally as a test dose followed by 5–8 mL of 0.25% ropivacaine was administered if no adverse reactions (local anesthetic toxicity or subarachnoid blockade signs) were confirmed. Anesthetic induction commenced after 3 min of preoxygenation (100% oxygen, 8 L/min). Group R received intravenous remimazolam 0.3 mg/kg + sufentanil 4 µg/kg, while Group P received propofol 2 mg/kg + sufentanil 4 µg/kg. Both groups received rocuronium 0.6 mg/kg, followed by endotracheal intubation.
Mechanical ventilation was initiated post-intubation with the following initial settings: tidal volume 8 mL/kg (ideal body weight), respiratory rate 12 breaths/min, inspiratory-to-expiratory (I: E) ratio 1:1.5, positive end-expiratory pressure (PEEP) 5 cm H₂O and 40% oxygen in air delivered at a fresh gas flow rate of 2 L/min. Ventilatory parameters were subsequently adjusted to maintain partial pressure of end-tidal CO2 between 35 and 45 mmHg.
For anesthesia maintenance, Group R received continuous 0.2-3 mg.kg⁻¹.h⁻¹ remimazolam infusion while Group P received 4–12 mg.kg⁻¹.h⁻¹ propofol according to depth of anesthesia monitoring, both along with remifentanil target-controlled infusion (effect-site concentration: 1 ng/ml). This study employed strict total intravenous anesthesia throughout the procedure. Intermitted rocuronium 0.15 mg/kg was given to maintain neuromuscular blockade. A supplemental dose of 3–5 mL 0.25% ropivacaine was administered epidurally every hour.
Intraoperatively, hepatic blood flow was controlled using the Pringle maneuver (hepatic inflow occlusion). This involved intermittent clamping with cycles of ≤ 20-minute occlusion followed by 5-minute reperfusion intervals, repeated as necessary. Liver transection was consistently performed using an ultrasonic scalpel. Hemostasis on the liver transection surface was achieved using electrocautery coagulation and suture ligation. For patients requiring additional radiofrequency ablation (RFA), hepatic resection was completed first, followed by meticulous hemostasis of the transection surface before RFA initiation (maximum power: 50 W). Hemodynamic parameters during RFA were categorized under the hemostasis phase. Drains were routinely placed at the conclusion of the surgery. For patients exhibiting a large resection surface area or significant oozing, the raw surface was covered with an absorbable hemostat (SURGICEL Absorbable Hemostat 1952, ETHICON, USA).
During the pre-hepatic resection phase, strict fluid restriction was performed with crystalloid infusion at 1 mL.kg⁻¹.h⁻¹, maintaining CVP < 5 mmHg. If necessary, norepinephrine (NE) was administered to sustain systolic blood pressure ≥ 90 mmHg and urine output > 25 mL/h. Fluid boluses were initiated when stroke volume variation (SVV) exceeded the normal range by 10–20% [16], concurrently supplemented with NE or phenylephrine (PE) to ensure cardiac index (CI) targets: ≥ 2.8 L.min⁻¹.m⁻² for patients aged < 60 years, ≥ 2.6 L.min⁻¹.m⁻² for 60–75 years, and ≥ 2.4 L.min⁻¹.m⁻² for those ≥ 75 years. Following hepatic resection, goal-directed fluid resuscitation protocol was activated to maintain SVV < 12%, while NE or PE support was initiated or escalated when CI remained suboptimal with SVV < 12% [17].
Intraoperative hemodynamic stabilization included a NE bolus (10 µg) followed by continuous infusion (initial rate 0.3 µg.kg⁻¹.h⁻¹) for sustained hypotension (MAP < 65 mmHg for > 1 min), titrated to maintain mean arterial pressure (MAP) ≥ 65 mmHg [18]. Heart rate (HR) < 45 bpm) was treated with 0.5 mg atropine [19]. If blood loss < 20% of estimated total blood volume, 5% albumin was infused according to 1:1 replacement; and if blood loss > 20% of estimated total blood volume, packed red blood cells was transfused to maintain hemoglobin ≥ 7 g/dL. The fresh frozen plasma was infused if necessary.
At skin closure, intravenous anesthetics were discontinued. Epidural analgesia was initiated via connecting to a patient-controlled pump (ropivacaine 300 mg + sufentanil 100 µg + saline 200 mL, basal rate 3.5 mL/h, bolus 3.5 mL, lockout interval 20 min). The patients were transferred into post-anesthesia care unit (PACU) for further monitoring and management after surgical procedure completed.
Data collection
Intraoperative hemodynamic parameters were systematically recorded at predefined time points: pre-induction baseline (T₀), loss of eyelash reflex (T₁), immediately after endotracheal intubation (T₂), and at 1 min (T₃), 5 min (T₄), 10 min (T₅), and every 5 min thereafter (T₆ onward). Measured parameters included systolic blood pressure (SBP), MAP, HR, CI, SVRI, SVV, CVP, NCI, as well as use of vasoactive agents and anesthetic agents. The vital signs, length of stay, and complications in the PACU, as well as gastrointestinal recovery and postoperative complications within 3 days postoperatively. A trained nurse who blinded to study protocol performed intraoperative hemodynamic instability scoring and 3-day postoperative follow-up, and data collection from electronic medical records. The locked database was accessible exclusively to the principal investigator and statistician.
The study design ensured masking of group allocation for postoperative follow-up and data entry personnel, while anesthesia providers, intraoperative care teams, and PACU staff remained aware of group assignments. The anesthesia process was divided into three phases: induction (from anesthetics administration to 15 min post-intubation) [20, 21], hepatectomy (from skin incision to tumor removal), and hemostasis (from liver resection completion to abdominal closure). Primary outcome was hemodynamic instability scores (HI-score) [22] during three distinct surgical phases (induction, hepatectomy, and hemostasis) and comprehensive intraoperative IH-score (total IH-score). Secondary outcomes included: intraoperative blood loss, urine volume and fluid infusion volume; perioperative arterial blood gas; pre- and post-operative differences in hemoglobin; total bilirubin; serum creatinine; alanine aminotransferase (ALT); lactate dehydrogenase (LDH); international normalized ratio (INR); liver lesions characteristics; surgical procedure; extent of hepatectomy; combined use of intraoperative radiofrequency ablation (RFA) (yes/no) and durations of anesthesia and surgery; length of PACU stay; postoperative ambulation time; time to first flatus; postoperative complications, as well as length of hospital stay.
Statistical analysis
We calculated the sample size based on the intraoperative HI-score. In our pilot study, the intraoperative HI-score during hepatectomy was 50 ± 10. It is estimated that the remimazolam group can reduce intraoperative HI-score by 15%. With a significance level α = 0.05, test power 1-β = 0.8, and two-sided comparison, the calculated sample size per group was 28. Considering an estimated 20% dropout rate, the total sample size required is 70 patients.
Statistical analysis was performed using SPSS 26 software. The Shapiro-Wilk test was employed to assess data normality. Normally distributed parameters were expressed as mean ± standard error (x ± SE) and compared using one-way analysis of variance (ANOVA). Vital signs at different time points were analyzed using repeated-measures ANOVA with Bonferroni correction for post-hoc tests. Non-normally distributed data (vasoactive drug consumption) were presented as median [IQR] (interquartile range, IQR) and analyzed using Kruskal-Wallis test. Categorical variables (Sex, ASA classification, Child-Pugh classification, Duration in PACU > 60 min, Duration in PACU > 90 min) were expressed as counts (%) and analyzed using Fisher’s exact test or Chi-square test. P < 0.05 was considered statistically significant.
Results
In the present study, a total of 73 eligible patients were initially screened, and one patient was excluded. The remaining 72 participants were randomized 1:1 into Group R (n = 36) or Group P (n = 36) (Fig. 1). Ultimately, 66 patients were included in the final analysis after exclusions: three major hepatectomy cases from each group. Their demographic characteristics are summarized in Table 1.
Fig. 1.
Study flow diagram. Group R, remimazolam group; Group P, propofol group
Table 1.
Demographic and clinical data
| Group R (n = 33) | Group P (n = 33) | P value | ||
|---|---|---|---|---|
| Age (year) | 57.18 ± 2.1 | 61.61 ± 2.1 | 0.137 | |
| Sex, male, n (%) | 18 (52.9%) | 21 (63.6%) | 0.375 | |
| BMI (kg/m2) | 24.65 ± 0.4 | 24.50 ± 0.5 | 0.808 | |
| ASA classification n (%) | ||||
| I | 0 (0) | 0 (0) | 1.000 | |
| II | 29 (87.9%) | 29 (87.9%) | ||
| III | 4 (12.1%) | 4 (11.1%) | ||
| Child-pugh classification n (%) | ||||
| A | 33 (100%) | 33 (100%) | ||
| Hypertension, n (%) | 11 (33.3%) | 14 (42.4%) | 0.447 | |
| History of cardiovascular and cerebrovascular diseases, n (%) | 2 (6.1%) | 1 (3%) | 1.000 | |
| Diabetes, n (%) | 5 (15.2%) | 6 (18.2%) | 0.741 | |
| Preoperative status | ||||
| Hemoglobin (g/L) | 130.67 ± 2.9 | 131.76 ± 2.7 | 0.784 | |
| Total bilirubin (µmol/L) | 14.52 ± 3.2 | 9.96 ± 1.2 | 0.209 | |
| Serum creatinine (µmol/L) | 65.42 ± 2.6 | 69.82 ± 3.3 | 0.295 | |
| Alanine transaminase (ALT) (U/L) | 32.54 ± 4.8 | 26.85 ± 3.2 | 0.326 | |
| Lactate dehydrogenase (LDH) (U/L) | 207.30 ± 9.7 | 195.18 ± 11.78 | 0.430 | |
| International normalized ratio (INR) | 1.00 ± 0.01 | 1.03 ± 0.01 | 0.092 | |
| Preoperative arterial blood gas analysis | ||||
| PH | 7.426 ± 0.0 | 7.431 ± 0.0 | 0.558 | |
| Lactic acid (mmol/L) | 1.50 ± 0.10 | 1.54 ± 0.10 | 0.777 | |
| PaCO2 (mmHg) | 38.24 ± 0.77 | 39.03 ± 1.4 | 0.623 | |
| PaO2(mmHg) | 84.55 ± 1.67 | 86.47 ± 2.3 | 0.497 | |
| BE (mmol/L) | 0.87 ± 0.4 | 1.84 ± 0.3 | 0.092 | |
| Hemoglobin (g/L) | 123.73 ± 3.0 | 125.81 ± 3.0 | 0.623 | |
| Source of Liver Lesions | ||||
| Malignant n (%) | 27 (81.8%) | 29 (87.9%) | 0.733 | |
| Primary Tumor n/N (%) | 13/27 (48.1%) | 14/29 (48.3%) | 1.000 | |
| Metastatic Tumor n/N (%) | 14/27 (51.9%) | 15/29 (51.7%) | ||
| Benign n (%) | 6 (18.2%) | 4 (12.1%) | 0.733 | |
| Number of liver lesions | ||||
|
1 2 3 > 3 |
19 (57.6%) 2 (6.1%) 4 (12.1%) 8 (24.2%) |
22 (66.7%) 2 (6.1%) 2 (6.1%) 7 (21.2%) |
0.612 1.000 0.672 0.769 |
|
| Partial hepatectomy combined with adjunctive radiofrequency ablation | 7 (21.2%) | 6 (18.2%) | 0.757 | |
The data are presented as mean (standard error, SE) or numbers (%). Group R, remimazolam group; Group P, propofol group; ALT, alanine aminotransferase
Primary outcomes
Hemodynamic instability score
As shown in Table 2; Figs. 2 and 3, the remimazolam group exhibited significantly lower overall hemodynamic instability compared to the propofol group (total HI score: 22.8 ± 2.1 vs. 33.0 ± 4.1, P = 0.029). Further analysis of critical procedural phases showed improved HI scores for remimazolam: during anesthesia induction (11.9 ± 1.0 vs. 22.6 ± 4.2, P = 0.017), hepatectomy (23.2 ± 3.2 vs. 38.5 ± 6.0, P = 0.027), and hemostasis (22.2 ± 2.8 vs. 33.5 ± 3.8, P = 0.019).
Table 2.
Hemodynamic instability scoring system and number of patients experiencing different events across intraoperative phases
| HI-scoring system | Patients experiencing different events across intraoperative phases(n (%)) | |||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Induction period | Hepatectomy period | Hemostasis period | Total | |||||||||||
| Event Type | Score | Group R n = 33 N (%) |
Group P n = 33 N (%) |
P value | Group R n = 33 N (%) |
Group P n = 33 N (%) |
P value |
Group R n = 33 N (%) |
Group P n = 33 N (%) |
P value | Group R n = 33 N (%) |
Group P n = 33 N (%) |
P value | |
| Maximum SBP (mmHg) | ||||||||||||||
| < 160 | 0 | 12 (36.4%) | 15 (45.4%) | 0.617 | 20 (60.6%) | 25(75.8%) | 0.186 | 12 (36.4%) | 10 (30.3%) | 0.602 | 4 (12.1%) | 2 (6.1%) | 0.672 | |
| 160 to 179 | 1 | 10 (30.3%) | 11 (33.3%) | 0.792 | 6 (18.2%) | 2 (6.1%) | 0.258 | 14 (42.4%) | 18 (54.5%) | 0.460 | 10 (30.3%) | 14 (42.4%) | 0.306 | |
| 180 to 199 | 3 | 6 (18.2%) | 6 (18.2%) | 1.000 | 6 (18.2%) | 3 (9.1%) | 0.475 | 4 (12.1%) | 2 (6.1%) | 0.672 | 14 (42.4%) | 12 (36.4%) | 0.614 | |
| ≥ 200 | 7 | 5 (15.2%) | 1 (3.0%) | 0.197 | 1 (3.0%) | 3 (9.1%) | 0.613 | 3 (9.1%) | 3 (9.1%) | 1.000 | 5 (15.2%) | 5 (15.2%) | 1.000 | |
| Time SBP > 160 mmHg (%) | ||||||||||||||
| 0 | 0 | 12 (36.4%) | 15 (45.4%) | 0.617 | 19 (57.6%) | 25 (75.8%) | 0.117 | 12 (36.4%) | 10 (30.3%) | 0.602 | 11 (33.3%) | 12 (36.4%) | 0.796 | |
| 0.1 to 1.0 | 1 | 0 | 0 | 0 | 0 | 2 (6.1%) | 4 (12.1%) | 0.672 | 9 (30.6%) | 11 (33.3%) | 0.592 | |||
| 1.1 to 6.6 | 3 | 13 | 12 (36.4%) | 0.800 | 6 (18.2%) | 5 (15.2%) | 0.741 | 7 (21.2%) | 11 (33.3%) | 0.408 | 6 (18.2%) | 8 (24.2%) | 0.547 | |
| ≥ 6.7 | 7 | 8 (24.2%) | 6 (18.2%) | 0.547 | 8 (24.2%) | 3 (9.1%) | 0.099 | 12 (36.4%) | 8 (24.2%) | 0.422 | 7 (21.2%) | 2 (6.1%) | 0.149 | |
| Minimum MAP (mmHg) | ||||||||||||||
| ≥ 60 | 0 | 25 (75.8%) | 15 (45.4%) | 0.012 | 14 (42.4%) | 12 (36.4%) | 0.614 | 31 (93.9%) | 25 (75.8%) | 0.082 | 17 (50.0%) | 11 (33.3%) | 0.135 | |
| 50 to 59 | 1 | 8 (24.2%) | 14 (42.4%) | 0.117 | 14 (42.4%) | 12 (36.4%) | 0.614 | 2 (6.1%) | 6 (18.2%) | 0.258 | 10 (30.3%) | 14 (42.4%) | 0.306 | |
| 40 to 49 | 3 | 0 | 3 (9.1%) | 0.238 | 4 (12.1%) | 7 (21.2%) | 0.322 | 0 | 2 (6.1%) | 0.492 | 4 (12.1%) | 7 (21.2%) | 0.322 | |
| < 40 | 7 | 0 | 1 (3.0%) | 1.000 | 1 (3.0%) | 2 (6.1%) | 1.000 | 0 | 0 | 2 (6.1%) | 1 (2.8%) | 1.000 | ||
| Time MAP < 60mmHg (%) | ||||||||||||||
| 0 | 0 | 25 (75.8%) | 15 (45.4%) | 0.012 | 14 (42.4%) | 13 (39.4%) | 0.802 | 31 (93.9%) | 25 (75.8%) | 0.082 | 17 (50.0%) | 11 (33.3%) | 0.135 | |
| 0.1 to 1.1 | 1 | 0 | 1 (3.0%) | 1.000 | 5 (13.9%) | 2 (6.1%) | 0.427 | 0 | 1 (3.0%) | 1.000 | 4 (12.1%) | 6 (18.2%) | 0.733 | |
| 1.2 to 4.1 | 3 | 0 | 1 (3.0%) | 1.000 | 7 (21.2%) | 6 (18.2%) | 0.757 | 2(6.1%) | 3 (9.1%) | 1.000 | 6 (18.2%) | 5 (15.2%) | 0.741 | |
| ≥ 4.2 | 7 | 8 (24.2%) | 16(48.5%) | 0.041 | 7 (21.2%) | 12 (27.9%) | 0.174 | 0 | 4 (12.1%) | 0.114 | 6 (18.2%) | 11 (33.3%) | 0.159 | |
| Maximum HR (bpm) | ||||||||||||||
| < 100 | 0 | 30 (90.9%) | 30 (90.9%) | 1.000 | 26 (78.8%) | 31 (93.9%) | 0.073 | 31 (90.9%) | 33 | 0.492 | 21 (63.6%) | 28 (84.8%) | 0.049 | |
| 100 to 119 | 1 | 2 (6.1%) | 2 (6.1%) | 1.000 | 7 (21.2%) | 1 (3.0%) | 0.054 | 2 (9.1%) | 0 | 0.492 | 9 (27.3%) | 3 (9.1%) | 0.108 | |
| ≥ 120 | 3 | 1 (3.0%) | 1 (3.0%) | 1.000 | 0 | 1 (3.0%) | 1.000 | 0 | 0 | 3 (9.1%) | 2 (6.1%) | 1.000 | ||
| ≥ 100 | 3 (9.1%) | 3 (9.1%) | 1.000 | 7 (21.2%) | 2(6.1%) | 0.149 | 2(6.1%) | 0 | 0.492 | 12(36.4%) | 5(15.2%) | 0.049 | ||
| Time HR > 100 bpm (%) | ||||||||||||||
| 0 | 0 | 30 (90.9%) | 30 (90.9%) | 1.000 | 26 (78.8%) | 31 (93.9%) | 0.073 | 31 (93.9%) | 33 | 0.492 | 21 (63.6%) | 28 (84.8%) | 0.049 | |
| 0.1 to 1.0 | 1 | 0 | 0 | 1 (3.0%) | 0 | 1.000 | 0 | 0 | 5 (15.2%) | 4 (12.1%) | 1.000 | |||
| > 1.0 | 3 | 3 (9.1%) | 3 (9.1%) | 1.000 | 6 (18.2%) | 2 (6.1%) | 0.258 | 2 (6.1%) | 0 | 0.492 | 7 (21.2%) | 1 (3.0%) | 0.054 | |
| Minimum HR (bpm) | ||||||||||||||
| ≥ 50 | 0 | 30(90.9%) | 28(84.8%) | 0.708 | 32 (97.0%) | 28 (84.8%) | 0.194 | 32(97.0%) | 31 (93.9%) | 1.000 | 31 (93.9%) | 26 (78.8%) | 0.149 | |
| 40 to 49 | 1 | 3 (9.1%) | 4 (12.1%) | 1.000 | 1 (3.0%) | 5 (15.2%) | 0.194 | 1 (3.0%) | 2 (6.1%) | 1.000 | 2 (6.1%) | 6 (18.2%) | 0.258 | |
| < 40 | 3 | 0 | 1 (3.0%) | 1.000 | 0 | 0 | 1.000 | 0 | 0 | 0 | 1 (3.0%) | |||
| < 50 | 3 (9.1%) | 5 (15.2%) | 0.708 | 1 (3.0%) | 5 (15.2%) | 0.197 | 1 (3.0%) | 2(6.1%) | 1.000 | 2(6.1%) | 7 (21.2%) | 0.149 | ||
| Time HR < 50 bpm (%) | ||||||||||||||
| 0 | 0 | 30(90.9%) | 28(84.8%) | 0.708 | 32 (97.0%) | 28 (84.8%) | 0.194 | 32(97.0%) | 31 (93.9%) | 1.000 | 31 (93.3%) | 26 (78.8%) | 0.149 | |
| 0.1 to 1.7 | 1 | 1 (3.0%) | 0 | 1.000 | 0 | 1 (3.0%) | 1.000 | 0 | 0 | 1 (3.0%) | 1 (3.0%) | 1.000 | ||
| > 1.7 | 3 | 2 (6.1%) | 5(15.2%) | 0.708 | 1 (3.0%) | 4 (12.1%) | 0.355 | 1 (3.0%) | 2 (6.1%) | 1.000 | 1 (3.0%) | 6 (18.2%) | 0.105 | |
| Volume therapy (ml.kg−1.h−1) | ||||||||||||||
| 0 to 84 ml/ | 0 | 6 (18.2%) | 3 (9.1%) | 0.475 | 0 | 1(3.0%) | 1.000 | 0 | 0 | 0 | 0 | |||
| ≤ 6.3 | 2 | 24(72.7%) | 30 (90.9%) | 0.108 | 11 (33.3%) | 6 (18.2%) | 0.159 | 5 (15.2%) | 2 (6.1%) | 0.427 | 10 (30.3%) | 10 (30.3%) | 1.000 | |
| 6.4 to 9.7 | 6 | 3 (9.1%) | 0 | 0.238 | 12 (36.4%) | 17 (51.5%) | 0.215 | 7 (21.2%) | 6 (18.2%) | 0.757 | 13 (39.4%) | 10 (30.3%) | 0.438 | |
| 9.8 to 14.3 | 14 | 0 | 0 | 7 (21.2%) | 8 (24.2%) | 0.769 | 14 (42.4%) | 15 (45.4%) | 0.804 | 9 (27.3%) | 11 (33.3%) | 0.592 | ||
| > 14.3 | 30 | 0 | 0 | 3 (9.1%) | 1 (3.0%) | 0.613 | 7 (21.2%) | 9 (27.3%) | 0.566 | 1 (3.0%) | 2 (6.1%) | 1.000 | ||
| Norepinephrine (ug.kg−1.h−1) | ||||||||||||||
| 0 | 0 | 30 (90.9%) | 23(69.7%) | 0.061 | 25 (75.8%) | 15 (45.4%) | 0.012 | 28 (84.8%) | 21 (63.6%) | 0.049 | 25 (75.8%) | 13 (39.4%) | 0.003 | |
| > 0 to 1.48 | 5 | 3 (9.1%) | 4 (12.1%) | 1.000 | 5 (15.2%) | 7 (21.2%) | 0.523 | 2 (6.1%) | 5 (15.2%) | 0.427 | 5 (15.2%) | 11 (33.3%) | 0.085 | |
| 1.49 to 2.47 | 15 | 0 | 1 (3.0%) | 1.000 | 0 | 1 (3.0%) | 1.000 | 1 (6.1%) | 0 | 1.000 | 2 (6.1%) | 3 (9.1%) | 1.000 | |
| 2.48 to 4.14 | 35 | 0 | 3 (9.1%) | 0.238 | 3 (9.1%) | 3 (9.1%) | 1.000 | 2 (6.1%) | 5 (15.2%) | 0.427 | 1 (3.0%) | 4 (12.1%) | 0.355 | |
| > 4.14 | 75 | 0 | 2 (6.1%) | 0.492 | 0 | 7 (21.2%) | 0.011 | 0 | 2 (6.1%) | 0.492 | 0 | 2 (6.1%) | 0.492 | |
| Phenylephrine (ug.kg−1.h−1) | ||||||||||||||
| 0 | 0 | 25 (75.8%) | 24(72.7%) | 0.778 | 16 (48.5%) | 19 (57.6%) | 0.459 | 32 (97.0%) | 25 (75.8%) | 0.027 | 9 (27.3%) | 13 (39.4%) | 0.317 | |
| > 0.0 to 2.06 | 4 | 4 (12.1%) | 1 (3.0%) | 0.355 | 12 (36.4%) | 10 (30.3%) | 0.602 | 1 (3.0%) | 7 (21.2%) | 0.054 | 24 (72.7%) | 19 (57.6%) | 0.141 | |
| > 2.06 | 12 | 4 (12.1%)4 | 8 (24.2%) | 0.339 | 5 (15.2%) | 4 (12.1%) | 1.000 | 0 | 1(6.1%) | 1.000 | 0 | 1 (3.0%) | 1.000 | |
| Dobutamine (ug.kg−1.h−1) | ||||||||||||||
| 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | |||||
| > 0 to 0.22 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | |||||
| > 0.22 | 3 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | |||||
| Total (0 to 160) | 11.9 ± 1.0 | 22.6 ± 4.2 | 0.017 | 23.2 ± 3.2 | 38.5 ± 6.0 | 0.027 | 22.2 ± 2.8 | 33.5 ± 3.8 | 0.019 | 22.8 ± 2.1 | 33.0 ± 4.1 | 0.029 | ||
The data are presented as numbers (%). HI-score, haemodynamic instability score; HR, heart rate; MAP, mean arterial pressure; SAP, systolic arterial pressure. Group R, remimazolam group; Group P, propofol group
Fig. 2.
Intraoperative hemodynamic instability score. IH-Score, intraoperative hemodynamic instability score; Group R, remimazolam group; Group P, propofol group
Fig. 3.
Norepinephrine and phenylephrine consumption at different stages of the operation. Data were presented as median [IQR]. Group R, remimazolam group; Group P, propofol group
Hemodynamic parameters
SBP
Baseline SBP showed no intergroup differences (P > 0.05). Mean SBP remained comparable between groups during anesthesia induction (115.4 ± 3.1 vs. 112.2 ± 2.1 mmHg, P = 0.385), hepatectomy (115.6 ± 2.4 vs. 114.0 ± 1.9 mmHg, P = 0.064), hemostasis (134.5 ± 3.0 vs. 129.9 ± 2.2 mmHg, P = 0.215), and PACU (129.1 ± 3.5 vs. 133.0 ± 3.1 mmHg, P = 0.403). However, remimazolam exhibited significantly higher SBP at the loss of the eyelash reflex (144.1 ± 4.8 vs. 132.0 ± 3.7, P = 0.045) and 5-min post-induction (115.5 ± 4.4 vs. 103.3 ± 3.1 mmHg, P = 0.021) (Tables 3 and 4).
Table 3.
Hemodynamic parameters during intraoperative stages and PACU
| Time | Group | SBP (mmHg) | MAP (mmHg) | HR (bpm) | CVP (cmH2O) | CI (L/(min*m^2)) | SVRI (dyn·s/cm^5/m^2) | |
|---|---|---|---|---|---|---|---|---|
| Baseline | Group R | 164.6 ± 3.7 | 108.3 ± 2.1 | 74.1 ± 1.8 | 6.0 ± 0.3 | 3.4 ± 0.2 | 2490 ± 107 | |
| Group P | 163.2 ± 3.5 | 105.5 ± 2.0 | 73.8 ± 2.0 | 5.4 ± 0.2 | 3.4 ± 0.1 | 2442 ± 91 | ||
| P value | 0.785 | 0.329 | 0.900 | 0.212 | 0.985 | 0.732 | ||
| Induction period | Group R | 115.4 ± 3.1 | 80.8 ± 2.1 | 74.3 ± 1.7 | 6.1 ± 0.3 | 3.2 ± 0.2 | 2058 ± 93 | |
| Group P | 112.2 ± 2.1 | 77.2 ± 1.5 | 68.8 ± 1.6 | 6.5 ± 0.3 | 2.7 ± 0.1 | 2216 ± 96 | ||
| P value | 0.385 | 0.161 | 0.016 | 0.277 | 0.022 | 0.238 | ||
| Hepatectomy | Group R | 115.6 ± 2.4 | 83.1 ± 1.8 | 73.6 ± 1.6 | 3.5 ± 0.1 | 2.9 ± 0.1 | 2196 ± 99 | |
| Group P | 114.0 ± 1.9 | 80.9 ± 1.4 | 72.2 ± 2.3 | 3.9 ± 0.3 | 2.7 ± 0.1 | 2249 ± 124 | ||
| P value | 0.604 | 0.329 | 0.615 | 0.196 | 0.366 | 0.736 | ||
| Hemostasis | Group R | 134.5 ± 3.0 | 94.3 ± 2.0 | 73.1 ± 1.5 | 6.7 ± 0.4 | 3.1 ± 0.1 | 2286 ± 81 | |
| Group P | 129.9 ± 2.2 | 87.2 ± 1.7 | 69.3 ± 1.6 | 7.3 ± 0.3 | 3.1 ± 0.1 | 2239 ± 124 | ||
| P value | 0.215 | 0.007 | 0.083 | 0.218 | 0.980 | 0.751 | ||
| PACU | Group R | 129.1 ± 3.5 | 96.7 ± 2.5 | 73.5 ± 1.6 | / | / | / | |
| Group P | 133.0 ± 3.1 | 94.8 ± 2.0 | 71.6 ± 1.7 | |||||
| P value | 0.403 | 0.563 | 0.421 | |||||
| Group*Time | P value | 0.511 | 0.189 | 0.093 | 0.058 | 0.075 | 0.159 | |
The data are presented as mean (standard error, SE). PACU, post-anesthesia care unit; Group R, remimazolam group; Group P, propofol group; SBP, systolic blood pressure; MAP, mean arterial blood pressure; HR, heart rate; CVP, central venous pressure; CI, cardiac output index; SVRI, systemic vascular resistance index
Table 4.
Comparison of hemodynamic parameters during the induction period between two groups
| Time | Group | SBP (mmHg) | MAP (mmHg) | HR (bpm) | CI (L/(min*m^2)) | SVRI (dyn·s/cm^5/m^2) |
|---|---|---|---|---|---|---|
| T0 | Group R | 164.6 ± 3.7 | 108.3 ± 2.1 | 74.1 ± 1.8 | 3.4 ± 0.1 | 2490 ± 107 |
| Group P | 163.2 ± 3.5 | 105.5 ± 2.0 | 73.8 ± 2.0 | 3.4 ± 0.1 | 2442 ± 91 | |
| P value | 0.785 | 0.329 | 0.900 | 0.985 | 0.732 | |
| T1 | Group R | 144.1 ± 4.8 | 95.9 ± 2.8 | 78.4 ± 2.0 | 3.5 ± 0.2 | 2153 ± 140 |
| Group P | 132.0 ± 3.7 | 87.1 ± 2.2 | 72.7 ± 2.0 | 3.2 ± 0.1 | 2100 ± 96 | |
| P value | 0.045 | 0.013 | 0.044 | 0.163 | 0.749 | |
| T2 | Group R | 137.7 ± 5.2 | 95.5 ± 3.4 | 84.8 ± 2.3 | 3.8 ± 0.2 | 1956 ± 107 |
| Group P | 129.8 ± 4.4 | 89.4 ± 3.0 | 77.6 ± 1.9 | 3.3 ± 0.2 | 2084 ± 108 | |
| P value | 0.243 | 0.178 | 0.013 | 0.087 | 0.400 | |
| T3 | Group R | 129.5 ± 4.6 | 89.9 ± 2.9 | 81.8 ± 2.2 | 3.5 ± 0.2 | 1978 ± 112 |
| Group P | 122.5 ± 4.0 | 84.0 ± 2.6 | 73.4 ± 2.0 | 2.9 ± 0.1 | 2136 ± 89 | |
| P value | 0.249 | 0.123 | 0.006 | 0.004 | 0.270 | |
| T4 | Group R | 115.5 ± 4.4 | 81.0 ± 3.2 | 72.1 ± 2.1 | 3.0 ± 0.2 | 2105 ± 142 |
| Group P | 103.3 ± 3.1 | 72.8 ± 2.2 | 65.1 ± 1.8 | 2.4 ± 0.1 | 2203 ± 148 | |
| P value | 0.021 | 0.035 | 0.013 | 0.022 | 0.631 | |
| T5 | Group R | 111.2 ± 3.4 | 77.4 ± 2.5 | 66.6 ± 2.4 | 2.7 ± 0.1 | 2133 ± 119 |
| Group P | 107.7 ± 3.5 | 75.3 ± 2.5 | 61.8 ± 1.4 | 2.4 ± 0.1 | 2439 ± 149 | |
| P value | 0.479 | 0.557 | 0.083 | 0.162 | 0.108 | |
| T6 | Group R | 112.1 ± 3.8 | 78.3 ± 2.6 | 66.6 ± 1.8 | 2.7 ± 0.2 | 2224 ± 144 |
| Group P | 110.0 ± 3.6 | 76.3 ± 2.1 | 60.1 ± 1.6 | 2.3 ± 0.1 | 2378 ± 104 | |
| P value | 0.694 | 0.563 | 0.015 | 0.077 | 0.383 | |
| Group*Time | P value | 0.332 | 0.447 | 0.108 | 0.022 | 0.324 |
The data are presented as mean (standard deviation, SD). The induction phase of anesthesia was designated as the period from the initiation of intravenous bolus administration of anesthetic agents to 15 min after completion of tracheal intubation, divided into seven time points: Pre-induction baseline (T₀), loss of eyelash reflex (T₁), immediately after tracheal intubation (T₂), and at 1 min (T₃), 5 min (T₄), 10 min (T₅), and 15 min (T₆) post-intubation. group R, remimazolam group; group P, Propofol group; SBP, systolic blood pressure; MAP, mean arterial blood pressure; HR, heart rate; CVP, central venous pressure; CI, cardiac output index; SVRI, systemic vascular resistance index
MAP
The remimazolam group had significantly more patients maintaining MAP ≥ 60 mmHg during anesthesia induction (25 [75.8%] vs. 15 [45.4%], P = 0.012) (Table 2). The differences in MAP reached significance during hemostasis (94.3 ± 2.0 vs. 87.2 ± 1.7 mmHg, P = 0.007), loss of eyelash reflex (95.9 ± 2.8 vs. 87.1 ± 2.2 mmHg, P = 0.013), and 5-min post-induction (81.0 ± 3.2 vs. 72.8 ± 2.2 mmHg, P = 0.035) (Tables 3 and 4).
HR
During intraoperative period, the remimazolam group demonstrated significantly higher incidence of tachycardia events (HR ≥ 100 bpm) compared to the propofol group (12/33[36.4%] vs. 5/33[15.2%], P = 0.049). However, no significant difference was observed between groups in the incidence of severe tachycardia (HR ≥ 120 bpm) (Table 2). Remimazolam demonstrated a numerically lower, though statistically non-significant, rate of bradycardia (HR < 50 bpm) during the medication period (2/33 [6.1%] vs. 7/33 [21.2%], P = 0.149) (Table 2). The remimazolam group had significantly higher mean HR during induction (74.3 ± 1.7 vs. 68.8 ± 1.6 bpm, P = 0.016), loss of eyelash reflex (78.4 ± 2.0 vs. 72.7 ± 2.0 bpm, P = 0.044), and at multiple post-intubation timepoints (immediately: 84.8 ± 2.3 vs. 77.6 ± 1.9 bpm, P = 0.013; post-1 min: 81.8 ± 2.2 vs. 73.4 ± 2.0 bpm, P = 0.006; post-5 min: 72.1 ± 2.1 vs. 65.1 ± 1.8 bpm, P = 0.013; post-15 min: 66.6 ± 1.8 vs. 60.1 ± 1.6 bpm, P = 0.015) (Tables 3 and 4).
CI
Significant differences emerged at 1-min post-intubation (3.5 ± 0.2 vs. 2.9 ± 0.1 L/(min·m²), P = 0.004) and 5-min post-intubation (3.0 ± 0.2 vs. 2.4 ± 0.1 L/(min·m²), P = 0.022) (Tables 3 and 4).
The remimazolam group had more patients without requiring NE during the whole surgical procedure (25/33 [75.8%] vs. 13/33 [39.4%], P = 0.003), particularly during hepatectomy (25/33 [75.8%] vs. 15/33 [45.4%], P = 0.012) and hemostasis (28/33 [84.8%] vs. 21/33 [63.6%] P = 0.049) (Table 2). Total NE consumption was significantly lower in remimazolam group (median [IQR]: 0 [24] µg vs. 18 [378] µg, P = 0.013), particularly during induction (0 [0] µg vs. 0 [10] µg, P = 0.021) and hepatectomy (0 [13] µg vs. 14 [238] µg, P = 0.013). The proportion of patients without requiring PE was significantly higher in the remimazolam group compared to the propofol group (32/33 [97.0%] vs. 25/33 [75.8%], P = 0.027) during the hemostasis phase rather than during anesthesia induction phase and hepatectomy phase (Figs. 3).
Secondary outcomes
No significant intergroup differences were observed in postoperative outcomes (length of PACU stay; incidences of PACU duration longer than 60–90 min, hemoglobin decline within postoperative 3 days, postoperative delirium and major adverse cardiovascular events; ambulation initiation time, first flatus occurrence as well as length of hospital stay) as shown in Table 5 (all P > 0.05). Notably, both groups had no unplanned ICU admission, unplanned re-operation, and in-hospital mortality during the study period.
Table 5.
The patients’ perioperative outcomes
| Group R (n = 33) | Group P (n = 33) | P value | ||
|---|---|---|---|---|
| Intraoperative blood loss (ml) | 201.82 ± 34.9 | 160.76 ± 11.6 | 0.269 | |
| Intraoperative urine volume (ml) | 460.91 ± 47.0 | 396.97 ± 44.3 | 0.326 | |
| Intraoperative fluid infusion volume (ml) | 1863.64 ± 87.6 | 1925.76 ± 79.5 | 0.601 | |
| Duration of anesthesia (min) | 187.88 ± 8.8 | 181.76 ± 8.6 | 0.620 | |
| Duration of surgery (min) | 146.33 ± 8.7 | 139.79 ± 8.6 | 0.594 | |
| Length of stay in PACU (min) | 52.06 ± 4.3 | 54.88 ± 3.8 | 0.622 | |
| Duration in PACU > 60 min, n (%) | 11 (33.3%) | 12 (36.4%) | 0.796 | |
| Duration in PACU > 90 min, n (%) | 2 (6.1%) | 3 (9.1%) | 1.000 | |
| Postoperative delirium, n (%) | 1 (3.0%) | 0 | 1.000 | |
| Major adverse cardiovascular events within 3 postoperative days | 0 | 0 | ||
| Length of hospital stay (day) | 8.21 ± 0.4 | 8.21 ± 0.3 | 1.000 | |
| Postoperative ambulation time (h) | 29.09 ± 1.7 | 25.45 ± 1.0 | 0.075 | |
| Time to first flatus (h) | 51.64 ± 2.6 | 50.18 ± 2.4 | 0.682 | |
| Postoperative day 1 LDH (U/L) | 413.85 ± 48.4 | 327.61 ± 17.3 | 0.098 | |
|
> 1250, n (%) 500–1250, n (%) 250–500, n (%) |
2 (6.1%) 5 (15.2%) 20 (60.6%) |
0 3 (9.1%) 22 (66.7%) |
0.492 0.708 0.798 |
|
|
Postoperative day 3 LDH (U/L) > 1250, n (%) 500–1250, n (%) 250–500, n (%) |
238.06 ± 17.3 0 1 (3%) 8 (24.2%) |
210.23 ± 11.8 0 0 7 (21.2%) |
0.193 1.000 0.769 |
|
| Postoperative day 1 INR | 1.241 ± 0.03 | 1.258 ± 0.02 | 0.639 | |
| Postoperative day 3 INR | 1.162 ± 0.02 | 1.195 ± 0.01 | 0.209 | |
| The difference between postoperative 1 st day and preoperative day | ||||
| Hemoglobin reduction (g/L) | 10.88 ± 1.4 | 12.24 ± 2.1 | 0.593 | |
| Total bilirubin increase (µmol/L) | 19.40 ± 1.8 | 20.05 ± 1.9 | 0.806 | |
| Serum creatinine increase (µmol/L) | -4.41 ± 1.7 | -3.85 ± 1.3 | 0.797 | |
| ALT increase (U/L) | 236.73 ± 36.9 | 189.68 ± 18.21 | 0.257 | |
| LDH increase (U/L) | 206.55 ± 44.6 | 132.42 ± 19.1 | 0.125 | |
| INR increase | 0.236 ± 0.02 | 0.226 ± 0.02 | 0.731 | |
| The difference between postoperative 3rd day and preoperative day | ||||
| Hemoglobin reduction (g/L) | 23.18 ± 2.7 | 22.29 ± 2.5 | 0.809 | |
| Total bilirubin increase (µmol/L) | 21.33 ± 2.9 | 18.39 ± 2.5 | 0.441 | |
| Serum creatinine increase (µmol/L) | -7.72 ± 1.6 | -7.52 ± 1.0 | 0.915 | |
| ALT increase (U/L) | 211.07 ± 43.2 | 202.49 ± 48.4 | 0.895 | |
| LDH increase (U/L) | 30.76 ± 16.8 | 13.10 ± 16.0 | 0.451 | |
| INR increase | 0.157 ± 0.02 | 0.159 ± 0.02 | 0.956 | |
| The ABG difference between PACU analysis and preoperative analysis | ||||
| PH reduction | 0.064 ± 0.006 | 0.049 ± 0.008 | 0.154 | |
| Lactic acid increase (mmol/L) | 0.076 ± 0.10 | -0.039 ± 0.09 | 0.403 | |
| PaCO2 increase (mmHg) | 4.36 ± 0.8 | 1.72 ± 1.29 | 0.086 | |
| PaO2 reduction (mmHg) | 3.82 ± 2.2 | 4.85 ± 1.9 | 0.647 | |
| BE reduction (mmol/L) | 1.97 ± 0.35 | 2.38 ± 0.44 | 0.465 | |
| Hemoglobin reduction (g/L) | 20.67 ± 3.1 | 27.36 ± 2.8 | 0.113 | |
The data are presented as mean (standard error, SE) or numbers (%). PACU, post-anesthesia care unit; Group R, remimazolam group; Group P, propofol group; ALT, alanine aminotransferase; LDH, Lactate Dehydrogenase; INR, International normalized ratio; ABG, arterial blood gas
Discussion
This prospective randomized controlled trial systematically evaluated the hemodynamic profiles of remimazolam-based anesthesia combined with neuraxial anesthesia in minor hepatectomy. The results revealed that the remimazolam exhibited significantly better hemodynamics when compared with propofol, evidenced by lower HI-scores during anesthetic induction, hepatectomy, and hemostasis. These findings confirmed hemodynamic stability of remimazolam anesthesia.
HI-score system was used for hemodynamics evaluation in the present study. Prior remimazolam studies focused on single hemodynamics parameters [11–15], whereas this trial adopted the multidimensional HI-score system [22] integrating hemodynamic variables, volume therapy, and vasoactive medication into a composite index. The key advantages of HI-score include: (1) detecting latent instability through intervention-weighted scoring (e.g., revealing differences despite nonsignificant intergroup SBP/CI variations); (2) standardized thresholds enabling cross-procedural comparisons; (3) reliance on routine monitoring metrics without specialized equipment.
Hepatectomy procedures were enrolled in this study. Current evidence has indicated that remimazolam anesthesia has significant safety advantages in short-duration surgeries, with lower incidences of hypotension, intervention-required hypotension, and bradycardia compared to propofol anesthesia [23]. However, its application in major surgeries remains controversial. Fechner et al. [15] reported that remimazolam reduced post-induction hypotensive events by 23% and NE demand by 26% in high-risk patients (ASA III–IV) undergoing non-cardiac surgeries ≥ 90 min. Yet, no significant reduction in post-induction hypotension was observed in patients ≥ 80 years old (RR = 0.89, 95% CI 0.72–1.10) [24], suggesting a limited benefit in the elderly population. Notably, unlike our study, Fechner’s study exclusively enrolled ASA III-IV patients, and post-induction hypotension was not a primary outcome. Furthermore, for the incidence of bradycardia during induction and cumulative NE consumption, they did not perform a confounding analysis of fluid management or conduct a comprehensive hemodynamic assessment [24]. In contrast, our research used HI-score as the primary outcome measure and performed a phase-specific evaluation, examining the hemodynamic effects of remimazolam during whole surgical procedure. Additionally, our study employed advanced hemodynamic monitoring, and found improved tissue perfusion evidenced by higher CI at early post-induction period. These findings indicate that remimazolam anesthesia has superior hemodynamic stability during critical phases of hepatectomy surgeries.
Remimazolam has weaker sympathetic inhibition compared to propofol which suppresses the hypothalamic-pituitary-adrenal axis and reduces plasma catecholamines [25, 26]. This may explain a higher HR during induction phase, in the remimazolam group without increased myocardial oxygen consumption-related complications. As an ultra-short-acting benzodiazepine, remimazolam exerts milder suppression on myocardial function and vasoconstriction than propofol [27], a critical advantage in hepatectomy under LCVP strategy and epidural blockade. LCVP reduces intraoperative blood loss by maintaining CVP < 5 mmHg but may induces insufficient intravascular volume. Our results demonstrated that the remimazolam group showed significantly lower total NE consumption compared to the propofol group, while maintaining more higher MAP and CI during the hepatectomy phase, suggesting its superior capacity to stabilize cardiac output against LCVP-induced hemodynamic challenges.
Although intraoperative hypotension and cumulative NE dosage have been independently associated with postoperative acute kidney injury (AKI) [28], and remimazolam’s NE-sparing effect may potentially mitigate α-receptor overactivation risks [29], no significant differences were found between two groups in postoperative recovery parameters and incidences of complications. These findings were consistent with previous studies on cerebrovascular and geriatric hip surgeries [30, 31]. Collectively, remimazolam demonstrated significant intraoperative hemodynamic advantages, nevertheless, it did not substantially improve clinical outcomes in patients undergoing hepatectomy, which may be attributed to standardized fluid management protocol and small sample size.
This study has several advantages in protocol design: (1) establishing the first phase-specific HI-scoring system for hepatectomy; (2) validating remimazolam’s compatibility with neuraxial anesthesia (prior studies focused on general anesthesia only [11, 12]); and (3) implementing NCI-guided sedation depth titration. And limitations include single-center design, small sample size, exclusion of Child-Pugh B/C patients, potential oversight of delayed complications within the 3-day follow-up. While our standardized anesthetic protocol ensured consistency, it did not account for the distinct physiological challenges of major versus minor hepatectomy. Future study should incorporate plasma biomarkers and long-term outcomes in multicenter trials with larger sample size.
Conclusion
This prospective randomized controlled trial demonstrates that in patients undergoing minor hepatectomy under combined general-epidural anesthesia, remimazolam-based anesthesia significantly improved intraoperative hemodynamic stability compared with propofol-based anesthesia. The remimazolam group showed lower hemodynamic instability scores during whole surgical procedure, with more patients maintaining MAP ≥ 60 mmHg and less NE consumption. However, remimazolam anesthesia seems not significantly improve postoperative short-term (3-day) outcomes following hepatectomy.
Acknowledgements
The authors would like to thank nurse Congxia Pan (assisting ethical application) and hepatobiliary surgeon from the Fudan University Shanghai Cancer Center for their help and support on this project.
Author contributions
Q.Y. and H.W. carried out the trial procedures, analysed the data and drafted the manuscript. Y.L. performed the randomization, assisted with the trial procedures, and prepared the manuscript. Z.J., C.L., and Y.L. conceived of the study, and participated in its design and coordination and helped to revise the manuscript. All authors read and approved the final manuscript.
Funding
Grant from Shanghai Municipal Science and Technology Committee (to Jun Zhang, No. 22Y11904200). This work was supported by grants from the Zhejiang Medical Association Medical Support and Assistance Public Welfare Foundation (2020-08 No. 05).
Data availability
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Declarations
Ethics approval and consent to participate
This trial was approved by the Fudan university Shanghai Cancer Center Ethics Committee (Approval No. 2406-Exp031), and written informed consents were obtained from all participating subjects before enrollment. This study adhered to the Declaration of Helsinki and CONSORT guidelines. All methods were performed in accordance with the relevant guidelines and regulations.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Ying Qian, Wenting Hou and Li Yang have contributed equally to this work.
Contributor Information
Nianping Chen, Email: chennianping234@163.com.
Jun Zhang, Email: snapzhang@aliyun.com.
References
- 1.Liu TS, Shen QH, Zhou XY, Shen X, Lai L, Hou XM, Liu K. Application of controlled low central venous pressure during hepatectomy: a systematic review and meta-analysis. J Clin Anesth. 2021;75:110467. [DOI] [PubMed] [Google Scholar]
- 2.Rahbari NN, Koch M, Zimmermann JB, Elbers H, Bruckner T, Contin P, Reissfelder C, Schmidt T, Weigand MA, Martin E, et al. Infrahepatic inferior Vena Cava clamping for reduction of central venous pressure and blood loss during hepatic resection: a randomized controlled trial. Ann Surg. 2011;253(6):1102–10. [DOI] [PubMed] [Google Scholar]
- 3.Lepere V, Vanier A, Loncar Y, Lemoine L, Vaillant JC, Monsel A, Savier E, Coriat P, Eyraud D. Risk factors for pulmonary complications after hepatic resection: role of intraoperative hemodynamic instability and hepatic ischemia. Bmc Anesthesiol. 2017;17(1):84. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Correa-Gallego C, Berman A, Denis SC, Langdon-Embry L, O’Connor D, Arslan-Carlon V, Kingham TP, D’Angelica MI, Allen PJ, Fong Y, et al. Renal function after low central venous pressure-assisted liver resection: assessment of 2116 cases. HPB (Oxford). 2015;17(3):258–64. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Maheshwari K, Turan A, Mao G, Yang D, Niazi AK, Agarwal D, Sessler DI, Kurz A. The association of hypotension during non-cardiac surgery, before and after skin incision, with postoperative acute kidney injury: a retrospective cohort analysis. Anaesthesia. 2018;73(10):1223–8. [DOI] [PubMed] [Google Scholar]
- 6.Pang Z, Liang S, Zhou N, Zhu X, Guo Q, Sessler DI, Zou W. Individualized blood pressure regulation and acute kidney injury in older patients having major abdominal surgery: a pilot randomized trial. Int J Surg. 2025. [DOI] [PMC free article] [PubMed]
- 7.Czajka S, Putowski Z, Krzych LJ. Post-induction hypotension and intraoperative hypotension as potential separate risk factors for the adverse outcome: a cohort study. J Anesth. 2023;37(3):442–50. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Royse CF, Liew DF, Wright CE, Royse AG, Angus JA. Persistent depression of contractility and vasodilation with propofol but not with sevoflurane or desflurane in rabbits. Anesthesiology. 2008;108(1):87–93. [DOI] [PubMed] [Google Scholar]
- 9.Wink J, de Wilde RB, Wouters PF, van Dorp EL, Veering BT, Versteegh MI, Aarts LP, Steendijk P. Thoracic epidural anesthesia reduces right ventricular systolic function with maintained ventricular-pulmonary coupling. Circulation. 2016;134(16):1163–75. [DOI] [PubMed] [Google Scholar]
- 10.Schuttler J, Eisenried A, Lerch M, Fechner J, Jeleazcov C, Ihmsen H. Pharmacokinetics and pharmacodynamics of remimazolam (CNS 7056) after continuous infusion in healthy male volunteers: part I. pharmacokinetics and clinical pharmacodynamics. Anesthesiology. 2020;132(4):636–51. [DOI] [PubMed] [Google Scholar]
- 11.Doi M, Morita K, Takeda J, Sakamoto A, Yamakage M, Suzuki T. Efficacy and safety of remimazolam versus Propofol for general anesthesia: a multicenter, single-blind, randomized, parallel-group, phase iib/iii trial. J Anesth. 2020;34(4):543–53. [DOI] [PubMed] [Google Scholar]
- 12.Ko CC, Hung KC, Illias AM, Chiu CC, Yu CH, Lin CM, Chen IW, Sun CK. The use of remimazolam versus Propofol for induction and maintenance of general anesthesia: a systematic review and meta-analysis. Front Pharmacol. 2023;14:1101728. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Xing Q, Zhou X, Zhou Y, Shi C, Jin W. Comparison of the effects of remimazolam Tosylate and Propofol on immune function and hemodynamics in patients undergoing laparoscopic partial hepatectomy: a randomized controlled trial. BMC Anesthesiol. 2024;24(1):205. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Li HX, Li BL, Wang TH, Xu X, Wang F, Zhang X, Zhang X, Li HY, Mu B, Sun YL, et al. Comparison of the effects of remimazolam Tosylate and propofol on postoperative delirium among older adults undergoing major non-cardiac surgery: protocol for a randomised controlled trial. Bmj Open. 2023;13(5):e71912. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Fechner J, El-Boghdadly K, Spahn DR, Motsch J, Struys M, Duranteau O, Ganter MT, Richter T, Hollmann MW, Rossaint R, et al. Anaesthetic efficacy and postinduction hypotension with remimazolam compared with propofol: a multicentre randomised controlled trial. Anaesthesia. 2024;79(4):410–22. [DOI] [PubMed] [Google Scholar]
- 16.Choi SS, Jun IG, Cho SS, Kim SK, Hwang GS, Kim YK. Effect of stroke volume variation-directed fluid management on blood loss during living-donor right hepatectomy: a randomised controlled study. Anaesthesia. 2015;70(11):1250–8. [DOI] [PubMed] [Google Scholar]
- 17.de Waal E, Frank M, Scheeren T, Kaufmann T, de Korte-de BD, Cox B, van Kuijk S, Montenij LM, Buhre W. Perioperative goal-directed therapy in high-risk abdominal surgery. a multicenter randomized controlled superiority trial. J Clin Anesth. 2021;75:110506. [DOI] [PubMed] [Google Scholar]
- 18.Mets B. Should norepinephrine, rather than phenylephrine, be considered the primary vasopressor in anesthetic practice?? Anesth Analg. 2016;122(5):1707–14. [DOI] [PubMed] [Google Scholar]
- 19.Zheng L, Fang T, Zhang W, Zhang X, Ren Z, Qin W, Liang W, Ma Q, Yin N. Beneficial effects of low-dose intravenous Dexmedetomidine premedication in patient undergoing laparoscopic cholecystectomy under general anesthesia: a prospective, double-blind, randomized controlled trial. Drug Des Devel Ther. 2024;18:443–52. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Hannam JA, Mitchell SJ, Cumin D, Frampton C, Merry AF, Moore MR, Kruger CJ. Haemodynamic profiles of etomidate vs Propofol for induction of anaesthesia: a randomised controlled trial in patients undergoing cardiac surgery. Br J Anaesth. 2019;122(2):198–205. [DOI] [PubMed] [Google Scholar]
- 21.Schonberger RB, Dai F, Michel G, Vaughn MT, Burg MM, Mathis M, Kheterpal S, Akhtar S, Shah N, Bardia A. Association of propofol induction dose and severe pre-incision hypotension among surgical patients over age 65. J Clin Anesth. 2022;80:110846. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Buitenwerf E, Boekel MF, van der Velde MI, Voogd MF, Kerstens MN, Wietasch G, Scheeren T. The haemodynamic instability score: development and internal validation of a new rating method of intra-operative haemodynamic instability. Eur J Anaesthesiol. 2019;36(4):290–6. [DOI] [PubMed] [Google Scholar]
- 23.Barbosa EC, Espirito SP, Baraldo S, Meine GC. Remimazolam versus propofol for sedation in gastrointestinal endoscopic procedures: a systematic review and meta-analysis. Br J Anaesth. 2024;132(6):1219–29. [DOI] [PubMed] [Google Scholar]
- 24.Takaki R, Yokose M, Mihara T, Saigusa Y, Tanaka H, Yamamoto N, Masui K, Goto T. Hypotension after general anaesthesia induction using remimazolam or propofol in geriatric patients undergoing sevoflurane anaesthesia with remifentanil: a single-centre, double-blind, randomised controlled trial. Br J Anaesth. 2024;133(1):24–32. [DOI] [PubMed] [Google Scholar]
- 25.Philip AB, Brohan J, Goudra B. The role of GABA receptors in anesthesia and sedation: an updated review: the role of GABA receptors in anesthesia and sedation. CNS Drugs. 2025;39(1):39–54. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Sahinovic MM, Struys MMRF, Absalom AR. Clinical pharmacokinetics and pharmacodynamics of propofol. Clin Pharmacokinet. 2018;57(12):1539–58. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Hiltebrand LB, Koepfli E, Kimberger O, Sigurdsson GH, Brandt S. Hypotension during fluid-restricted abdominal surgery: effects of norepinephrine treatment on regional and microcirculatory blood flow in the intestinal tract. Anesthesiol. 2011;114(3):557–64. [DOI] [PubMed] [Google Scholar]
- 28.Legrand M, Kothari R, Fong N, Palaniappa N, Boldt D, Chen LL, Kurien P, Gabel E, Sturgess-DaPrato J, Harhay MO, et al. Norepinephrine versus phenylephrine for treating hypotension during general anaesthesia in adult patients undergoing major noncardiac surgery: a multicentre, open-label, cluster-randomised, crossover, feasibility, and pilot trial. Br J Anaesth. 2023;130(5):519–27. [DOI] [PubMed] [Google Scholar]
- 29.Kattan E, Ibarra-Estrada M, Jung C. Knowing the ropes of vasopressor dosing: a focus on norepinephrine. Intens Care Med. 2024;50(4):587–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Fang PP, Hu J, Wei QF, Liang YJ, Fan YG, Shen QY, Lu Y, Liu XS, Maze M. Effect of remimazolam besylate vs Propofol on incidence of postoperative delirium in older patients undergoing hip surgery: a randomized noninferiority trial. Int J Surg. 2025;111(1):1469–72. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Chae D, Kim HC, Song Y, Choi YS, Han DW. Pharmacodynamic analysis of intravenous bolus remimazolam for loss of consciousness in patients undergoing general anaesthesia: a randomised, prospective, double-blind study. Br J Anaesth. 2022;129(1):49–57. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.