Comparative Efficacy of Remimazolam Versus Propofol in Meningioma Surgery with Scalp Nerve Block

Introduction

As an important treatment in the field of neurosurgery, craniotomy has extremely high demands on anesthesia and analgesia [1]. Its specificity lies in the need to balance the depth of intraoperative analgesia with the recovery of postoperative consciousness and motor response monitoring, while hemodynamic fluctuations can directly threaten the balance of oxygen supply to fragile brain tissues by altering the high intracranial pressure, such as exacerbation of cerebral edema by blood pressure, and induction of cerebral ischemia by hypotension. However, traditional general anesthesia regimens, such as propofol combined with opioid drugs, have significant limitations: propofol can easily cause dose-dependent blood pressure drop and heart rate suppression, increasing the risk of cerebral hypoperfusion, and delayed postoperative recovery can mask early identification of complications, such as intracranial hematoma [2]. In addition, relying solely on systemic analgesics often requires increasing the dosage to control severe pain after craniotomy, which can lead to adverse reactions, such as respiratory depression, nausea, and vomiting, and prolong the rehabilitation period [3]. During surgery, patients experience physical trauma, postoperative pain, and discomfort. This pain not only affects the patient’s sleep quality and psychological state, but also triggers a series of complications, such as elevated blood pressure and accelerated heart rate, which increases the risk of postoperative rebleeding and affects the patient’s recovery. Effective pain management is the key to postoperative recovery for patients undergoing craniotomy. As a new ultra-short-acting benzodiazepine, remimazolam is characterized by fast onset of action and rapid recovery [4]. By acting as an orthosteric modulator of γ-aminobutyric acid A (GABAA) receptors, remazolam produces a sedative effect, along with rapid decompression, which can help reduce patients’ tension and anxiety and maintain good hemodynamic stability [5]. At the same time, it is widely used in clinical practice for general anesthesia induction and maintenance, intraoperative sedation, painless outpatient induced abortion, fiberoptic bronchoscopy, and gastroscopy sedation. Since the approval of remifentanil for induction and maintenance of general anesthesia in 2020, an increasing amount of data indicate that remifentanil has an advantage over propofol in providing more stable hemodynamics [6]. In addition, flumazenil completely antagonizes mirtazapine and has demonstrated a high clinical safety profile, considering its metabolic pathway. In addition, selective scalp nerve block is used as a local anesthetic technique to provide precise and effective analgesia during craniotomy. By targeting and blocking sensory nerves, this technique reduces the dose of general anesthetics, avoids dramatic circulatory fluctuations, and creates conditions for rapid postoperative awakening, to assess neurological function [7]. Blockade of scalp nerves by local anesthetics can contribute to the reduction of intraoperative and postoperative pain, while adverse effects, such as circulatory fluctuations caused by increasing the dose of general anesthetics, can be avoided with this strategy [8]. In addition to improving surgical safety, this type of anesthesia can promote the postoperative recovery of patients; therefore, we selected 300 patients with meningioma who underwent craniotomy with selective scalp nerve block for this experiment. The aim is to evaluate the effectiveness of scalp nerve block in reducing postoperative pain and affecting the dosage or recovery outcomes of remifentanil.

Material and Methods

GENERAL INFORMATION:

Participants in this study were 300 patients with meningiomas (January 2023–December 2023) who underwent craniotomy at our hospital. Based on the results of the pre-pre-test, the difference in visual analog scale (VAS) scores between the mirtazapine and propofol groups at 24 h after surgery was expected to be 1.5 points (standard deviation 2.0). An alpha error level of 0.05 (2-tailed test) and a beta error level of 0.2 (80% test efficacy) were set, and a minimum of 138 samples per group was calculated using G*Power 3.1 software. Considering a 20% dropout rate, it was finalized that 150 patients were included in each group. Patients were randomized into experimental and control groups using a random number table and the residual grouping method. We compared the general data and there were no statistical differences (all P>0.05, Table 1), indicating that the groups were comparable.

In this study, the following standardized measures were taken to ensure the consistency of nerve block techniques. All nerve block operations were performed by a team of anesthesiologists who had passed the unified training and examination. Preoperative 3-dimensional CT image reconstruction was used to clarify the anatomical landmarks of the patient’s cranial bones, and intraoperative high-frequency ultrasound guidance was used to locate the key nerve. The injection parameters were strictly standardized: a 22G block needle was used for in-plane injection at a 45° angle, and a pre-cooled 0.5% mixture of ropivacaine and lidocaine was injected at a uniform rate of 0.1 mL/s. Before injection, blood was withdrawn to make sure that there was no blood, and a neurostimulation device was used to verify the areas of sensory abnormality after the injection at each target point. The block plane was assessed by an independent evaluator 30 min after surgery, by cold sensory testing and pinprick sensation, to ensure that the sensory block covered the 3-cm area extending from the surgical incision. All operation videos were uploaded to the quality control platform, and double-blind evaluation was performed by 2 senior pain physicians. The operation pass rate must reach 100% to be included in the data analysis.

Eligible participants were those with 1) confirmation of meningioma by preoperative evaluation, and scheduled for elective craniotomy; 2) American Society of Anesthesiologists grade II to III; 3) normal indexes of liver, spleen, and kidney; 4) clear consciousness and high cooperation (defined as the ability to correctly understand and complete research processes, such as postoperative VAS scoring and cooperation with neurological function assessment); and 5) provided written informed consent (by either the patients themselves or their families). We excluded those 1) with severe abnormalities of heart, liver, kidney, lung, and other organs; 2) taking sedative drugs for a long time before the study, accompanied by strong cognitive impairment, inability to communicate well; 3) with previous history of head surgery; 4) with severe coagulopathy; and 5) with target drug allergy.

BLINDED IMPLEMENTATION:

This study used a single-blind design. 1) The outcome assessors (postoperative pain scores, laboratory index testers) were unaware of the grouping information. 2) The surgical team was aware only of the category of the anesthetic regimen (benzodiazepines/propofol), and did not have the specific drug details. 3) Blinded coding was used to process the grouping information during the data analysis phase.

METHODS:

The peripheral venous access was established in the study participants after admission to the hospital, with routine monitoring of vital signs simultaneously.

In the control group, anesthesia was induced with propofol (1.0–2.0 mg·kg⁻¹), sufentanil (0.5μg·kg⁻¹), and cisatracurium (0.15 mg·kg⁻¹). Tracheal intubation was made when the bispectral index <60, and all patients were qualified for tracheal intubation. During the maintenance phase of anesthesia, propofol (5–8 mg·kg⁻¹·h⁻¹), remifentanil (10–15 μg·kg⁻¹·h⁻¹), and cisatracurium were continuously injected, accompanied by the inhalation of 0.5% to 1.5% sevoflurane. The bispectral index value was controlled to 40 to 60, and the PET_CO2 value was adjusted between 30 and 35 mmHg. At 10 min before skin incision, 0.5% ropivacaine (Guangdong Jiabo Pharmaceutical Co, Ltd, Chinese Medicine approval No. H20113381, specification: 10 mL: 75 mg) and lidocaine (Sinopausal Rongseng Pharmaceutical Co, Ltd, Sinopausal approval No. H20043676, 5 mL: 0.1 g) mixed at a ratio of 1: 1 (20 mL in total) were injected, to perform scalp nerve block on supraorbital, zygomaticotemporal, auriculotemporal, greater, and lesser occipital nerves. The doses at each region were 2 mL, 3 mL, 5 mL, 5 mL and 5 mL, respectively.

The anesthesia regimen of the experimental group was 0.3 mg/kg remimazolam, 0.3 mg/kg sufentanil, and 0.15 mg/kg cisatracurium for anesthesia induction, and the other operations were the same as in the control group.

After the operation, patients should wait for the indication of extubation; for example, there was no laryngeal edema in the cuff leak trial, the patient could spontaneously expectorate, and the indexes of blood gas analysis basically recovered. In our study, patients could be subjected to endotracheal tube removal and be returned to the ward if the patient could breathe spontaneously, was conscious, and had recovered muscle strength.

All surgical procedures for each patient in both groups were performed by the same anesthesiologist.

ANALGESIC EVALUATION: By using the VAS [9], this study evaluated the pain of patients immediately after extubation and at 2, 8, 12, and 24 h after surgery. The VAS score ranged between 0 and 10, and increased if the degree of pain was aggravated, with 0 points indicating no pain, 3 or less for mild, 4–6 for moderate, and 7–10 for severe.

INDICATORS OF BRAIN INJURY: The central nervous system specific protein (S100-β) [10] was measured at 2, 8, 12, and 24 h after surgery. Each patient underwent enzyme-linked immunosorbent assay. More serious brain injury might be determined if patients had higher values.

LEVELS OF INFLAMMATORY FACTORS:

This study further measured and compared the levels of several clinical markers related to the response of inflammation in patients after treatment.

ADVERSE REACTIONS:

Relevant adverse events included nausea, shivering, hypotension, and respiratory depression. Corresponding incidence rates were compared in patients from both groups.

Circulatory indexes were measured at different time periods in the process of anesthesia. In this study, we monitored and recorded heart rate (HR), diastolic blood pressure (DBP), and systolic blood pressure (SBP) for each patient before anesthesia, and 5 min, 10 min, and 20 min after induction.

STATISTICAL METHODS:

For analysis in SPSS 26.0 software, the measurement data (%) were analyzed by the chi-square test; while the counting data (χ̄±s, in accordance with the normal distribution) were subjected to variance analysis and the t test. This study identified statistical difference based on a value of P<0.05. Longitudinal data analysis involving multiple time points, such as VAS scores, S100-β, and inflammatory factors, were tested using a linear mixed effects model for overall analysis. When a significant interaction between time and group was found, Bonferroni correction was further used for pairwise comparisons after adjustment, with a significance level of α=0.05/number of comparisons.

Results

PAIN DETERMINATION BASED ON VAS SCORES:

After Bonferroni correction, there was no statistically significant difference in VAS scores immediately after extubation (P>0.05). While at different time periods after surgery (Table 2), corresponding values of patients from the group provided with remimazolam + selective scalp nerve block were lower than those of the controls receiving propofol + selective scalp nerve block (all P<0.05).

BRAIN INJURY COMPARISON BASED ON PLASMA S100-β VALUES:

At different time periods after surgery, as shown in Table 3, plasma S100-β values of patients from the group receiving remimazolam + selective scalp nerve block were much lower than those of the controls receiving propofol + selective scalp nerve block (all P<0.05).

INTER-GROUP COMPARISON OF INFLAMMATORY FACTOR LEVELS:

After Bonferroni correction, statistical comparison, as shown in Table 4, revealed lower levels of inflammatory factors in patients from the group receiving remimazolam + selective scalp nerve block than in the controls receiving propofol + selective scalp nerve block (all P<0.05).

INTER-GROUP COMPARISON OF ADVERSE REACTIONS:

After Bonferroni correction, as shown in Table 5, adverse reactions occurred in 2.67% of patients from the group receiving remimazolam + selective scalp nerve block, and in 13.33% of the controls receiving propofol + selective scalp nerve block, with a higher rate in the control group (P<0.05).

COMPARISON OF CIRCULATORY INDEXES OF PATIENTS AT DIFFERENT ANESTHESIA NODES:

After receiving the corresponding anesthesia induction, average SBP, DBP, and HR values of both groups were much lower at 5 min, 10 min, and 20 min after anesthesia than those before anesthesia, with higher values in patients receiving remimazolam + selective scalp nerve block (P<0.05; Table 6).

In addition, in this study, we found that the overall incidence of adverse events in the experimental group was significantly lower than that in the control group (4/150 vs 20/150), with respiratory depression (SpO₂ <90% lasting >30 s) rates of 1.33% (2/150) and 6.67% (10/150), respectively.

Discussion

For patients undergoing craniotomy, higher requirements [11] are put forward for effective implementation of sedation and analgesia, to better form effective treatment and create good treatment conditions. Remimazolam is a new ultra-short-acting benzodiazepine that exerts a sedation role by acting on GABAA receptors. It is highly soluble in water and can be metabolized through carboxyesterase in tissues, giving remimazolam properties of rapid sedation and anesthesia effect, as well as quick recovery. Remimazolam has little effect on respiratory depression and hemodynamics, and is especially suitable for elderly and hemodynamically unstable patients. In addition, its metabolites have no pharmacological activity, which can avoid drug accumulation and improve the safety of use. Compared with other sedative drugs, remimazolam has a fast metabolism and rapid disappearance of sedation, which can accelerate postoperative awakening and shorten the recovery time postoperatively. Selective scalp nerve block is a regional block of nerves innervating the scalp through the application of local anesthetics to reduce pain and stress response during surgery. Compared with general anesthesia, the proposed technique can more accurately control the region under anesthesia, reduce the systemic dosage of anesthetic drugs, and reduce drug-related adverse reactions [12]. In this study, although the results of S100-β as a marker of brain injury showed a statistical difference between the experimental group and the control group, it is important to note the limitations of its clinical interpretation. S100-β is an astrocyte-specific protein, the serum concentration of S100-β is usually less than 0.1 μg/L in healthy adults, and its elevated level can be seen in the disruption of the blood-brain barrier or glial injury [13]. Due to surgical trauma, S100-β concentration usually briefly increases after craniofacial surgery, such as reaching 0.5 to 2.0 μg/L within 24 h after craniotomy, but continues to rise (>5 μg/L) or remains more than twice the baseline level 48 h after surgery, which may be related to secondary brain injury or poor prognosis, such as cognitive impairment or long-term neurological deficits. The present study did not provide patients’ preoperative baseline values to distinguish whether the postoperative elevation was a physiologic response to the surgery itself, such as transient blood-brain barrier opening caused by dural incision, or a pathologic injury, and it did not explicitly report the range of the specific values detected, such as whether the experimental group had recovered to a near-normal level at 24 h after the surgery. Although the significantly lower S100-β levels in the experimental group than in the control group may suggest milder brain tissue stress, the clinical significance of the test needs to be confirmed in conjunction with imaging or neurologic assessment (Glasgow prognostic score), as biomarker changes alone may not be sufficient to independently determine the extent of injury or prognosis. Future studies should supplement baseline testing and establish thresholds for association with clinical outcomes to enhance the clinical guidance of the conclusions.

In our investigation, patients receiving remimazolam + selective scalp nerve block had lower postoperative VAS values at different time periods than those undergoing propofol + selective scalp nerve block. Moreover, patients receiving remimazolam + selective scalp nerve block exhibited lower post-treatment levels of inflammatory factors. Patients with the experimental plan also had much lower plasma S100-β values at different time periods after surgery. In addition, compared with a rate of 13.33% in patients giving propofol + selective scalp nerve block, adverse reactions occurred in only 2.67% of patients receiving remimazolam + selective scalp nerve block. Also, after receiving the corresponding anesthesia induction, SBP, DBP, and HR values in the 2 groups were significantly lower at 5 min, 10 min, and 20 min after anesthesia than those before anesthesia, with even lower levels detected in patients receiving remimazolam + selective scalp nerve block. The main reasons for the above trends are as follows. First is the improvement in the effect of anesthesia. The combination of remimazolam and selective scalp nerve block can play a synergistic role to enhance the anesthetic effect. The general sedative effect of remimazolam combined with local anesthetic effect of scalp nerve block can significantly reduce the pain and anxiety of patients [14]. Second is the relief of stress response. Craniotomy is a strong stressor for patients. The sedative effect of remimazolam can reduce the tension and anxiety of patients, as well as the secretion of stress hormones. Selective scalp nerve block can reduce the pain stimulation during the operation, which may facilitate a reduction in stress response and an improvement in circulatory indexes. Third is acceleration of postoperative recovery. The rapid recovery property of remimazolam combined with local effect of scalp nerve block can accelerate postoperative awakening and shorten patients recovery duration [15]. At the same time, on the basis of reduced dosage of general anesthetics, it also alleviates or suppresses postoperative nausea, vomiting, and other adverse reactions.

Conclusions

In conclusion, remimazolam combined with selective scalp nerve block is feasible for reducing pain, decreasing plasma S100-β, and alleviating inflammation for patients undergoing craniotomy, thereby decreasing the occurrence of adverse reactions.

However, this study still has certain limitations. Although multiple comparison correction was used, it should be noted that the Bonferroni method is relatively conservative and can increase the risk of class II errors. Future research could adopt more flexible false discovery rate methods or controls for multiple test problems, by reducing the number of repeated measurements during the design phase. Other limitations of this study are as follows. First, as a single center study, although we controlled for patient heterogeneity through strict inclusion and exclusion criteria, the extrapolation of the research results can be influenced by differences in surgical habits and anesthesia team experience among medical institutions. For example, there can be differences in the details of scalp nerve block techniques (such as ultrasound-guided usage rate) and postoperative pain management plans among different centers, which can affect the universality of intervention effectiveness. In the future, multicenter and large sample studies will be needed to verify the broad applicability of the conclusions. Second, although there was no statistically significant difference in baseline characteristics between the 2 groups, ANCOVA and other statistical methods were not used to correct for potential confounding factors, such as surgical time, tumor volume, and surgeon and anesthesiologist variability. Especially when comparing biomarkers, such as S100-β, the location of meningiomas can affect the degree of surgical trauma, leading to confounding effects. It is suggested to establish a predetermined covariate adjustment model in future research to improve the credibility of the results.