Introduction
Cerebrovascular bypass surgery is performed to prevent further episodes of stroke in patients with moyamoya disease [1]. During this procedure, a decline in arterial blood pressure (BP) may lead to decreased cerebral blood flow (CBF) and cerebral perfusion pressure (CPP) that in turn can cause cerebral ischemia and infarction [2,3]. Therefore, CPP in these patients should be strictly controlled perioperatively. Previous investigators have recommended maintaining an intraoperative mean arterial pressure higher than the preoperative pressure for patients undergoing cerebrovascular bypass surgery [3].
During general anesthesia, induction is typically achieved with propofol, whereas maintenance relies on inhalational anesthetics, such as sevoflurane or desflurane. Both propofol and desflurane can cause significant hemodynamic instability through various mechanisms. Propofol-induced hypotension occurs through multiple mechanisms, including a decrease in systemic vascular resistance by inhibiting sympathetic vasoconstrictor nerve activity [4], causing myocardial depression, and inhibiting catecholamine release that reduces vascular tone [5]. Similarly, desflurane produces hypotension primarily by dilating arteriolar resistance vessels, leading to reduced systemic vascular resistance [6]. A previous study indicated that the occurrence rate of hypotension after propofol administration ranges between 25% and 67.5%, independent of the cardiopulmonary condition [7]. The hemodynamic effects of these anesthetics are particularly concerning in cerebrovascular bypass surgery. In patients with moyamoya disease, where CBF is already compromised due to progressive stenosis of the internal carotid arteries, anesthesia-induced hypotension can further reduce CPP and potentially lead to ischemic complications [8]. Furthermore, propofol and desflurane not only affect systemic BP but also reduce CBF [9].
Remimazolam, an ultra-short-acting sedative, was recently introduced and approved for procedural sedation and general anesthesia in Korea [10,11]. Recent clinical evidence demonstrates the favorable hemodynamic profile of remimazolam in various surgeries. In patients undergoing cardiac surgery, it has been reported that this new drug provides greater hemodynamic stability than propofol, as indicated by a lower occurrence rate of hypotension and evidence of a reduced need for vasoactive agents [12,13]. In patients undergoing neurosurgery, remimazolam maintains stable BP more effectively than propofol and sevoflurane [14,15]. Additionally, remimazolam is associated with lower rates of hypotension than desflurane [16]. However, reports on the effect of remimazolam on hemodynamic stability in patients undergoing cerebrovascular bypass surgery are lacking.
Therefore, we hypothesized that remimazolam anesthesia offers more hemodynamic stability than propofol-induced and desflurane-maintained anesthesia for patients undergoing cerebrovascular bypass surgery who are vulnerable to hypotension and cerebral ischemia. This study aimed to compare the effects of anesthesia between remimazolam and propofol/desflurane on the occurrence of hypotension and the need for vasoactive agents in patients with moyamoya disease undergoing cerebrovascular bypass surgery.
Materials and Methods
Ethical approval
This study was a prospective, single-center, randomized controlled trial. The protocol was approved by the Institutional Review Board of Seoul National University Bundang Hospital (B-2209-779-003) and was registered at ClinicalTrials.gov (NCT05557253) prior to patient enrollment. Written informed consent was obtained from all patients before surgery. The study was conducted in accordance with the guidelines of the Declaration of Helsinki, 2013.
Patients
Adult patients (age > 19 years) who were scheduled to undergo elective cerebrovascular bypass surgery with an American Society of Anesthesiologists (ASA) physical status I–III between October 20, 2022, and August 17, 2023, were enrolled in this study. Patients were excluded from the study if they refused to participate, had an ASA physical status of IV, had a body mass index < 18.5 or > 35.0 kg/m2, or had a history of allergy to benzodiazepines. Additionally, patients with conditions such as acute narrow-angle glaucoma, shock, coma, acute alcohol addiction, obstructive sleep apnea, dependency on alcohol or drugs, severe acute respiratory insufficiency, hypersensitivity to Dextran 40 (an excipient in the solution of remimazolam), or pregnancy were excluded.
Randomization and grouping
Patients were randomly allocated to the remimazolam or control group in a 1:1 ratio using computer-generated random sequences (random allocation software, version 1.0, Isfahan University of Medical Sciences). Random sequences were sealed in an opaque envelope and opened by the nurse who prepared the drug. In the remimazolam group, general anesthesia was induced and maintained with remimazolam (6–12 mg/kg/h for induction and 1–2 mg/kg/h for maintenance). In the control group, anesthesia was induced with propofol (1.5–2 mg/kg) and maintained with desflurane (inspired concentration 6–8 vol%, up to 1 minimum alveolar concentration). In both groups, the rate of remimazolam infusion or concentration of inspired desflurane was adjusted to maintain a patient state index of 25–50 that indicates an optimal hypnotic state for general anesthesia, as measured using an SEDLine monitor (SEDLineTM, Masimo). The blinding of the attending anesthesiologists who performed the anesthesia was not possible; however, all patients, the neurosurgeon, and the outcome investigators were blinded to the assigned group.
Anesthesia
Upon arrival at the operating theater, standard monitoring, including pulse oximetry, electrocardiography, non-invasive BP, and patient state index, was performed. After premedication with glycopyrrolate 0.2 mg, remifentanil was administered using target-controlled infusion with an effect-site concentration of 3.0 ng/ml. Anesthesia was induced and maintained according to the respective protocols in each group.
After loss of consciousness, patients were administered rocuronium (0.6 mg/kg) for neuromuscular blockade and intubated with a video-laryngoscope (KoMAC Co.) using a plain endotracheal tube (TaperGuard®, Covidien). Tubes with inner diameters of 7.5 and 7.0 mm were used for male and female patients, respectively. After intubation, patients were mechanically ventilated with an inspired oxygen fraction of 0.5, a fresh gas flow of 2 L/min, a tidal volume of 6–8 ml/kg of ideal bodyweight, and a positive end-expiratory pressure of 5 cmH2O. The respiratory rate was adjusted to maintain partial pressure of carbon dioxide at 35–40 mmHg. Fluid management was conducted using goal-directed therapy based on a pulse pressure variation of ≤ 13. Core body temperature was maintained at 36.0–37.0°C using a forced-air warming device (Bair HuggerTM, 3M). Hematocrit levels were maintained above 30% by administering packed red blood cell transfusion, when necessary. A catheter was inserted into the radial artery to monitor and manage arterial BP during surgery. The intraoperative hemodynamic goal was to maintain systolic BP (SBP) above the lower limit of target SBP (SBPlower limit). SBPlower limit was determined as the median value of the SBP measured from the day before surgery until the morning of surgery. The upper limit of target SBP (SBPupper limit) was determined based on SBPlower limit within a defined range. Specifically, if SBPlower limit was 120 mmHg, SBPupper limit was set to 150 mmHg, and if SBPlower limit was 130 mmHg, SBPupper limit was set to 160 mmHg. If the intraoperative SBP was lower than SBPlower limit, the effect-site concentration of remifentanil was decreased by 1 ng/ml, and the patient was treated with either ephedrine 5 mg (for heart rates < 60 bpm) or phenylephrine 20–30 μg (for heart rates > 60 bpm). If the intraoperative SBP did not recover within 5 min, the effect-site concentration of remifentanil further decreased by 1 ng/ml, and a continuous infusion of norepinephrine was initiated at 0.02 μg/kg/min. We increased the effect-site concentration of remifentanil by 1 ng/ml when either SBP was higher than SBPupper limit or the heart rate exceeded 100 bpm. The effect-site concentration of remifentanil and the rate of norepinephrine infusion were adjusted within the range of 0–5 ng/ml and 0.02–0.2 μg/kg/min, respectively, according to intraoperative SBP.
No additional anesthetic agents, analgesics, brain relaxation agents, or diuretics were administered during surgery beyond those mentioned above.
Surgery
An experienced neurovascular surgeon performed all bypass surgeries [17,18]. The combined bypass procedure was commenced by making a question mark-shaped skin incision, after which the scalp was retracted to harvest the superficial temporal artery. Subsequently, a craniotomy was performed and the dura opened. The posterior parietal artery or the angular artery of the middle cerebral artery (M4) was selected as the recipient artery, following which superficial temporal artery-M4 anastomosis was performed. After the direct bypass, an indirect bypass was performed via encephalo-duro-galeo-synangiosis. In cases where a suitable recipient artery was not present, only an indirect bypass was performed. This was performed using the superficial temporal artery and surrounding galea to complete encephalo-duro-arterio-synangiosis.
After surgery, all patients underwent mobile brain computed tomography (CT) before discharge from the operating room and were transferred to the intensive care unit (ICU) while still intubated. In patients undergoing a combined bypass procedure, perfusion CT was performed on postoperative day (POD) 4, while in patients undergoing an indirect bypass procedure, CT and/or magnetic resonance imaging (MRI) was performed if neurologic deterioration was suspected.
Outcome measures
The primary outcome was the occurrence of an intraoperative decrease in mean BP (MBP) > 20% (MBP20) from baseline MBP that was calculated as the average of MBP measurements from the day before surgery to the day of surgery. The secondary outcomes included total duration of MBP20, lowest MBP, generalized average real variability (ARV) of MBP, the occurrence and total duration of decreased SBP > 20% (SBP20) from SBPlower limit, the occurrence and total duration of decreased SBP > 10% (SBP10) from SBPlower limit, the occurrence of an increase in SBP > 10% or 20% from SBPupper limit, ARV of SBP, bradycardia (heart rate < 40 bpm), tachycardia (heart rate > 100 bpm), lowest and highest intraoperative SBPs, need for vasoactive agents, intraoperative remifentanil consumption, and postoperative clinical outcomes.
We conducted an additional sub-period analysis to evaluate the occurrence and duration of hypotension (MBP20, SBP20, and SBP10) separately during the induction and maintenance phases. The ARV index was calculated using the following formula [19].
where T represents the time from the first to the last BP measurements during surgery and K represents the measurement order.
Postoperative clinical outcomes included the need for vasoactive or antihypertensive agents during ICU stay, duration of mechanical ventilation after surgery, duration of ICU stay, length of hospital stay, acute infarct, hemorrhage, cerebral edema, new-onset neurologic deficit, and 30-day mortality. Acute infarct or hemorrhage was diagnosed via CT or MRI only if the radiological finding appeared acutely and was accompanied by clinical symptoms such as aphasia or weakness. Postoperative clinical outcomes, except 30-day mortality, were observed until discharge.
Statistical analysis
The sample size was determined based on a prior study that reviewed and analyzed patients with moyamoya disease undergoing bypass surgery [20]. In that study, the occurrence of hypotension during surgery was 92%. We considered a 30% reduction in the occurrence of hypotension to be clinically significant. To achieve this, considering α = 0.05 and β = 0.2 and accounting for a drop-out rate of 15%, 36 patients were required in each group.
Categorical variables are presented as numbers with percentages and were examined using chi-squared or Fisher’s exact tests. For continuous variables, the Shapiro–Wilk test was performed to assess normal distribution. Values are presented as mean with standard deviation (normal distribution) or medians with interquartile ranges (non-normal distribution). We performed Student’s t-test (normal distribution) or the Mann–Whitney U test (non-normal distribution) for statistical analyses. SPSS® Statistics for Windows, version 27 (IBM), was used for all statistical analyses. A P value < 0.05 was considered statistically significant.
Results
Participants
From October 2022 to August 2023, 83 patients were scheduled to undergo cerebrovascular bypass surgery. Of these, 11 were excluded in total, either for a body mass index > 35 kg/m2 (n = 5) or refusal to participate in the study (n = 6). Therefore, 72 patients were randomly allocated to one of the two groups. Subsequently, one patient in the remimazolam group withdrew consent, and six patients (four in the remimazolam group and two in the control group) were excluded from the analysis due to intracranial artery stenosis, leaving 65 patients with moyamoya disease in the final analysis (Fig. 1). We adhered strictly to the study protocol for all patients throughout the study period. The demographic and intraoperative characteristics of the patients are summarized in Table 1. None of the included patients had comorbidities, such as angina and coronary artery disease, that increased cardiovascular risk. Pre- and intraoperative variables were comparable between the two groups, except urine output (520 [350, 930] vs. 1385 [1095, 1764] ml in the remimazolam and control groups, respectively, P < 0.001).
Occurrence of hypotension
Fig. 2 shows the occurrence rates of hypotension during the induction and maintenance phases of anesthesia, as well as the overall rates, in the two groups. Hypotension rates were significantly lower in the remimazolam group than in the control group for all definitions (MBP20, P = 0.005; SBP20, P < 0.001; SBP10, P < 0.001). Sub-period analysis revealed that hypotension occurred less frequently in the remimazolam group in both induction (MBP20, P = 0.017; SBP20, P = 0.033; SBP10, P = 0.018) and maintenance (MBP20, P = 0.034; SBP20, P < 0.001; SBP10, and P < 0.001) phases than in the control group.
Duration of hypotension
The duration of hypotension was significantly shorter in the remimazolam group than in the control group (MBP20: 0 [0, 10] vs. 7.5 [1.25, 25] min, P = 0.008; SBP20: 0 [0, 0] vs. 5 [0, 10] min, P < 0.001; SBP10: 5 [0, 10] vs. 22.5 [6.25, 30] min, P < 0.001). Fig. 3 demonstrates that the duration of hypotension was significantly shorter in the remimazolam group than in the control group in both induction (MBP20, P = 0.017; SBP20, P = 0.035; SBP10, P = 0.013) and maintenance (MBP20, P = 0.039; SBP20, P < 0.001; SBP10, P < 0.001) phases.
Other intraoperative hemodynamic variables
Table 2 shows the other intraoperative hemodynamic variables, vasoactive agents’ usage, and intraoperative remifentanil consumption. The number of hypotension, MBP20, was significantly lower in the remimazolam group than in the control group (0 [0, 1] vs. 1 [0.25, 2.75], P = 0.014). The lowest MBP was higher in the remimazolam group than in the control group (78 [73, 84] vs. 69.5 [66.25, 75.8] mmHg, P < 0.001). The ARV of MBP was lower in the remimazolam group (1.42 ± 0.49 vs. 1.66 ± 0.52 mmHg/min, P = 0.036) than in the control group.
The number of SBP20 and SBP10 were significantly lower in the remimazolam group (0 [0, 0] vs. 1 [0, 1], P < 0.001; 1 [0, 2] vs. 3 [1, 5], P < 0.001) than in the control group. No significant difference was observed in the occurrence of increase in SBP between the two groups. In contrast, the lowest SBP in the remimazolam group was significantly higher than that in the control group (110 [104.5, 117] vs. 99 [93, 104] mmHg, P < 0.001). Additionally, the ARV of SBP was significantly lower in the remimazolam group than in the control group (1.78 ± 0.64 vs. 2.18 ± 0.75 mmHg/min, P = 0.032). The occurrence of tachycardia was significantly lower in the remimazolam group than in the control group (32.3% vs. 58.8%, P = 0.032).
Patients in the remimazolam group received less phenylephrine (20 [0, 65] vs. 100 [60, 130] μg, P < 0.001) and norepinephrine (162 [0, 365.5] vs. 1335 [998.5, 1637.5] μg, P < 0.001) than those in the control group. In contrast, remifentanil consumption was significantly higher in the remimazolam group than in the control group (1750 [1454.5, 2184.5] vs. 531 [431, 746.5] μg, P < 0.001).
Postoperative clinical outcomes
As shown in Table 3, there were no significant differences in postoperative clinical outcomes between the two groups. In addition, two patients (one in each group) had postoperative hemorrhage on POD 3 and 8, respectively that was thought to be caused by hyperperfusion syndrome after a direct bypass procedure. Both patients underwent emergency surgery to remove intracranial hemorrhage.
Discussion
This study was performed to evaluate a novel approach for maintaining stable hemodynamics during cerebrovascular bypass surgery, especially in patients vulnerable to hypotension. To the best of our knowledge, this is the first randomized clinical trial to compare the hemodynamic stability of remimazolam and propofol-induced and desflurane-maintained anesthesia in patients undergoing cerebrovascular bypass surgery. The results showed that patients in the remimazolam group had a reduced occurrence and duration of hypotension, BP variability, and need for vasoactive agents to maintain BP. However, no significant difference was observed in postoperative clinical outcomes between the two groups.
Compared with propofol-induced and desflurane-maintained anesthesia, remimazolam ensured intraoperative hemodynamic stability by reducing the occurrence and duration of hypotension. During surgery, BP maintenance is strictly necessary to prevent further cerebral ischemia and infarction due to decreased CBF [21]. A recent review article recommended maintaining SBP within 10%–20% of preoperative baseline SBP [21]. At our institution, intraoperative SBP is strictly maintained in the range of 120–150 mmHg or 130–160 mmHg according to the median preoperative baseline SBP [18,22,23]. The most remarkable result to emerge from the data was that the occurrence of hypotension, defined as a decrease in MBP, remained significantly lower in the remimazolam group, despite the fact that the aim of intraoperative BP management was to maintain SBP. The definition of hypotension varies widely across the literature [24]. In our study, we assessed hemodynamic variables using three different thresholds—MBP20, SBP20, and SBP10. Remimazolam consistently promoted hemodynamic benefits across all these measures. Furthermore, the occurrence, as well as the duration, of hypotension was lower in the remimazolam group. A previous cohort study indicated that both the occurrence and duration of hypotension could predict poor neurological outcomes [25]. Therefore, the shorter duration of hypotension observed with remimazolam may further support its hemodynamic advantages. These findings correlate well with the findings of previous studies. Recent meta-analyses have indicated that remimazolam is superior to propofol in maintaining hemodynamic stability [26–28]. Additionally, remimazolam has demonstrated better hemodynamic stability than inhalational anesthetics, such as sevoflurane [29,30]. Several possible mechanisms may explain the hemodynamic stability observed with remimazolam. First, remimazolam increases intracellular calcium concentration in endothelial and neuronal cells that may help maintain vascular tone [31]. Second, it maintains systemic vascular resistance and has minimal impact on cardiac systolic function [32].
Several studies also support the role of remimazolam in patients with cerebrovascular disease. Two randomized controlled trials included patients undergoing cerebrovascular procedures and concluded that remimazolam was effective in maintaining stable hemodynamics [33,34]. Unlike our study, these studies focused on patients undergoing endovascular procedures and compared remimazolam with propofol-based anesthesia. To the best of our knowledge, this study is the first to demonstrate hemodynamic stability with remimazolam in neurosurgical anesthesia and to suggest it as an alternative to propofol-induced and desflurane-maintained anesthesia.
The remimazolam group required fewer vasoactive agents, such as phenylephrine and norepinephrine, than the control group. Although the association between vasoactive agents and cerebral hemodynamics remains poorly understood, some studies have warned of their adverse effect [35–37]. Reports have indicated that cerebral oxygenation decreases after the administration of either phenylephrine or norepinephrine [35,36]. In addition, a recent study observed a significant reduction in CBF following norepinephrine infusion in healthy volunteers [37]. Given the critical importance of CBF or CPP preservation in patients with moyamoya disease, remimazolam may be regarded as a potentially safe anesthetic agent, since it is capable of reducing the need for vasoactive agents during cerebrovascular bypass surgery.
Meanwhile, the increased urine output in the control group could be attributed to the higher use of norepinephrine during surgery to maintain BP. Norepinephrine can enhance renal blood flow and glomerular filtration rate [38]. Additionally, a previous randomized clinical trial demonstrated that continuous norepinephrine infusion can significantly increase urine output [39].
Our study showed that the remimazolam group achieved more stable BP variability during surgery than the control group. However, BP variability can be influenced by multiple factors, including surgical stress, opioid use, and vasoactive agent use [40]. Administration of remifentanil, known to stimulate the parasympathetic nervous system and cause vasodilation [41,42], can lead to hypotension in a dose-dependent manner [43]. Accordingly, the effect-site concentration of remifentanil reduced when intraoperative SBP was lower than SBPlower limit in this study. Therefore, lower doses of remifentanil and higher doses of vasoactive agents in the control group may have contributed to higher BP variability. Given that higher intraoperative BP variability is associated with poorer postoperative clinical outcomes [44,45], the lower BP variability observed in the remimazolam group is noteworthy, although further research is needed to clarify the direct effect of remimazolam on BP variability.
While our study demonstrates the hemodynamic advantages of remimazolam, particularly in maintaining BP stability and reducing the requirement for vasoactive agents, potential cardiovascular effects need to be carefully considered. A recent study reported a case of unexpected tachycardia during remimazolam administration [46] that could potentially increase myocardial oxygen demand and pose a risk in patients with cardiovascular diseases [47]. Therefore, despite its hemodynamic benefits, cautious use and close monitoring are recommended, particularly for patients with cardiovascular risk factors.
This study has some limitations. First, we focused on SBP as the primary outcome rather than CPP that may be a more critical parameter in patients undergoing cerebrovascular bypass surgery. Therefore, future studies on the current topic are needed to validate the effect of anesthetics on CPP and provide a more comprehensive understanding of the effect of remimazolam than that of propofol-induced and desflurane-maintained anesthesia. Second, since the primary outcome of this study was the occurrence of intraoperative hypotension, the sample size was calculated based on this occurrence. Consequently, it may have been underpowered for detecting significant differences in clinical outcomes. A larger sample size is needed to evaluate the patient-centered outcomes. Third, blinding the attending anesthesiologist to the group allocation was not possible; therefore, potential bias cannot be ruled out. However, hemodynamic management was performed according to a pre-defined protocol, and outcome variables were measured objectively. Fourth, we compared the hemodynamic stability of remimazolam and propofol/desflurane. However, a variety of anesthetics is available, and our findings may not be generalizable to other anesthetics. Further studies are needed to determine if the hemodynamic stability observed with remimazolam compared with that achieved with propofol/desflurane can be generalized to other anesthetics.
In conclusion, the use of remimazolam during cerebrovascular bypass surgery showed intraoperative hemodynamic stability, as indicated by the reduced occurrence of BP decline and need for vasoactive agents to maintain BP. The potential of remimazolam as a preferred anesthetic in cerebrovascular bypass surgery seems to be promising, but further extensive research is imperative to validate these observations and explore potential neuroprotective effects and other long-term consequences of remimazolam use.
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