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Introduction

The prevalence of diabetes, particularly type 2 diabetes (T2D), is rising globally, posing a significant public health challenge due to its various acute and chronic complications.¹ Among these complications, cardiovascular diseases (CVDs) stand out as the leading cause of death in patients with T2D.² Vascular dysfunctions, including arterial stiffness (AS) and impaired vasodilation, can emerge before the onset of severe CVDs symptoms.³ Therefore, early assessment of AS is particularly important in the management of T2D. The brachial-ankle pulse wave velocity (baPWV) is a simple, effective and non-invasive method for evaluating AS,⁴ and can independently predict cardiovascular risk, providing important evidence for assessing the development of CVDs in individuals.⁵

Insulin resistance (IR) is considered a significant factor to AS and the progression of CVDs.⁶ While the euglycemic hyperinsulinemic clamp (EHC) is considered the gold standard for assessing IR,⁷ its invasive nature, time consuming and requirement for hospitalization limit its practical applicability. The homeostasis model assessment index (HOMA-IR) offers a simpler approach to assessing IR.⁸ However, it presents specific challenges for patients undergoing insulin therapy. Recently, a growing number of non-insulin-based IR surrogate markers have been proposed, including the triglyceride-glucose (TyG) index, triglyceride-to-high-density lipoprotein cholesterol (TG/HDL-c) ratio, and metabolic score for insulin resistance (METS-IR).^9–11 These markers have been associated with various metabolic diseases. One of our previous studies examined their relationship with nonalcoholic fatty liver disease (NAFLD) in patients with T2D, highlighting their clinical relevance in this context.¹² Building on this foundation, our current study shifts the focus toward AS, a distinct yet critical cardiovascular complication in T2D. A more recent development is the natural log transformation of the glucose disposal rate (log_e GDR), a non-insulin-based model to assess insulin sensitivity (IS) in T2D patients.¹³ The log_e GDR is calculated based on body mass index (BMI), triglycerides (TG), the urinary albumin to creatinine ratio (UACR) and γ-glutamyl transferase (GGT), and it has been validated and demonstrated a strong association with CVDs and mortality rates.¹³ Despite these advances, no studies to date have specifically investigated the relationship between the log_e GDR and AS in T2D. Based on the groundwork laid by our earlier research, this study aims to explore the novel association between log_e GDR and AS, offering fresh insights into the complex interplay between IS and vascular health.

The prevalence of non-obese T2D is gradually increasing, particularly in Asian countries.^14,15 Although CVDs and other conditions have traditionally been associated with obesity and being overweight, recent evidence suggests that non-obese T2D patients may have higher all-cause and cardiovascular mortality rates.^16,17 This could be attributed to factors such as increased visceral fat, impaired IS, and heightened inflammatory responses despite a normal BMI.¹⁸ Furthermore, recent studies have reported non-obese T2D patients have a comparable or even higher prevalence of AS compared to their obese counterparts¹⁸ Due to significant differences in metabolic characteristics between obese and non-obese diabetic patients, particularly regarding IS.¹⁹ And research exploring the relationship between IR surrogate markers and AS in non-obese patients with T2D remains limited. Therefore, we aim to analyze the relationship between the log_e GDR and AS in this population.

Methods

Study Design and Population

We retrospectively reviewed the medical records of patients aged ≥ 18 years with T2D from the Department Endocrinology of Linyi People’s Hospital, from January 2020 to March 2023. The exclusion criteria were (1) subjects missing key anthropometric measurements (height and weight); (2) subjects who had severe liver and kidney dysfunctions; (3) subjects with a history of angina, myocardial infarction and cerebrovascular accident; (4) subjects who had not undergone the baPWV tests or whose clinical data were incomplete, including GGT, TG and UACR; (5) subjects with BMI ≥ 24 kg/m². Ultimately, a total of 790 non-obese patients with T2D were eventually included (Figure 1).

Figure 1 The flow chart of study participants selection.

It is important to note that a portion of the participants included in the current study were also part of our previous work, which primarily investigated the association between IR markers and NAFLD in the overall T2D population. In terms of exclusion criteria, the previous study mainly excluded confounding factors that could affect the diagnosis and analysis of fatty liver disease.¹² For the overlapping populations, we further compared differences in baseline characteristics and various IR indices between the two studies, and the results did not show significant differences, suggesting that the results of this study are relatively stable and have some replication.

Demographic Information

The sex, age, diabetes duration and self-reported current cigarette smoking and drinking status were collected.

Physical Examinations

According to unified standards, the height, weight, systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured and collected. The bioelectrical impedance analysis (Omron DUALSCAN HDS-2000, Kyoto, Japan) was used to measure the visceral fat area (VFA) and subcutaneous fat area (SFA).

Each participant’s baPWV was measured using the automated system BP-203RPE III (Omron Healthcare Co., Japan) by trained technicians. The device simultaneously recorded pulse waveforms from the brachial and tibial arteries and automatically calculated baPWV values. Before measurement, participants were required to rest in a supine position for at least 5 minutes to ensure hemodynamic stability. Subsequently, appropriately sized cuffs were placed on both upper arms and ankles, and the device was operated according to standard protocols to obtain waveform signals and compute baPWV values.²⁰ To enhance measurement accuracy, this study analyzed data in cases where there was a significant difference between left and right baPWV values and assessed each side’s baPWV separately. AS was defined as baPWV ≥1800 cm/s.

Laboratory Measurements

Following an overnight fast, blood samples were collected and analyzed in the morning for alanine aminotransferase (ALT), aspartate aminotransferase (AST), GGT, TG, HDL-c, total cholesterol (TC), low density lipoprotein-cholesterol (LDL-c), serum creatinine (Scr), uric acid (UA), Cystatin C (Cys C), hemoglobin (Hb), fasting blood glucose (FBG) and glycosylated haemoglobin (HbA1c), fasting insulin (FINS) and UACR. A comprehensive overview of the tools and methods utilized in this research is available in our earlier publication.¹² Non-obese was defined as BMI < 24 kg/m².

Parameter Calculation

1. BMI = weight (kg) / height² (m²);
2. eGFR = 175 * Scr (mg/dL) ^−1.234 * age ^−0.179 * (0.79, if female);²¹
3. HOMA-IR = FBG (mmol/L) * FINS (µU/mL)/22.5;⁸
4. TyG index = ln [TG (mg/dL) × FBG (mg/dL)/2];¹⁰
5. TG/HDL-c ratio = TG (mmol/L)/HDL-c (mmol/L);¹¹
6. METS-IR = ln [(2*FBG (mg/dL)) + TG (mg/dL)] *BMI)/(Ln [HDL-c (mg/dL)]);⁹
7. Log_e GDR = 5.3505–0.3697 * log_e (GGT, IU/L) – 0.2591 * log_e (TG, mg/dL) – 0.1169 * log_e (UACR, mg/g) – (0.0279*BMI, kg/m²).¹³

Statistical Analysis

Statistical analysis was performed using SPSS 26.0 (SPSS Inc, Chicago, USA) and R (version 4.3.2). Data were presented as means ± SD for normally distributed variables and as medians (interquartile ranges) for non-normally distributed variables. Independent-Samples T test and Mann–Whitney U-test were used for comparisons of normally and abnormally distributed continuous variables between two groups, respectively. Categorical variables were presented as percentage (%) and were compared by Chi-square test. For normally distributed data, an Analysis of Variance (ANOVA) and Student-Newman-Keuls tests were used for multiple and pairwise comparisons between the log_e GDR tertiles groups, while the Kruskal–Wallis one-way ANOVA test was used for abnormally distributed data. Pearson correlation and multiple linear stepwise regression analyses were used to evaluate the independent correlations of baPWV. Univariate logistic regression analysis and directed acyclic graphs (DAG) were used to guide the selection of covariates for AS. The DAG was constructed using the dagitty package. And the identified minimal adjustment set includes age, BMI, diabetes duration, FBG, TG, HOMA-IR, METS-IR, TG/HDL-c ratio and TyG index. Logistic regression analysis was used to analyze the independent correlates of AS. Net reclassification improvement (NRI) analysis was performed using the survIDINRI package in R to assess the incremental predictive value of log_e GDR compared with other IR markers for identifying AS. Statistical differences were defined by P-value (two-tailed) less than 0.05.

Results

Clinical and Biochemical Characteristics

The clinical and biochemical characteristics of the participants are shown in Table 1. A total of 790 non-obese patients with T2D were enrolled in our study. The subjects were divided into two groups including non-AS group (baPWV < 1800cm/s) and AS group (baPWV ≥ 1800cm/s). Compared with the non-AS group, the age, diabetes duration, VFA, SFA, SBP, DBP, AST, GGT, UA, Scr, UACR and Cys C were increased in AS group, but the HbA1c, eGFR, Hb and log_e GDR were markedly reduced (all P < 0.05). There were no obvious differences in BMI, TC, LDL-c, HDL-c, TG, FBG, FINS, ALT, HOMA-IR, TG/HDL-c ratio, TyG index, METS-IR and the percentages of males, smoking and drinking between the two groups (all P > 0.05).

Table 1 Clinical and Biochemical Characteristics by Presence of AS

Then, according to tertiles of log_e GDR, the participants were divided into three groups: T1 (0.25–1.98), T2 (1.98–2.28) and T3 (2.28–3.12) (Table 2). As the log_e GDR tertiles increased, the age, diabetes duration, BMI, VFA, SFA, SBP, DBP, TC, LDL-c, TG, FINS, HbA1c, ALT, AST, GGT, UA, Scr, UACR, Cys C, HOMA-IR, TyG index, TG/HDL-c ratio, METS-IR, baPWV, the percentages of smoking, drinking and AS were gradually decreased, while the HDL-c, Hb and eGFR were gradually elevated (all P < 0.05). The FBG and the percentages of males were no significant different between the three groups (both P > 0.05).

Table 2 Comparison of Variables According to the Tertiles of Loge GDR

Correlation Between baPWV or AS and Each Variable by Univariate Analysis

As shown in Table 3, a Pearson correlation analysis was performed to analyze the association between baPWV and each variable. The results displayed that the baPWV was positively related to age, diabetes duration, VFA, SFA, SBP, DBP, TG, FINS, GGT, UA, UACR, Cys C and TG/HDL-c ratio, while negatively to the Hb, HbA1c, eGFR and log_e GDR (all P < 0.05). BMI, TC, LDL-c, HDL-c, FBG, ALT, AST, HOMA-IR, TyG index and METS-IR were not correlated with baPWV (all P > 0.05).

Table 3 The Correlation Between baPWV or AS and Different Variables by Univariate Analysis

Moreover, univariate regression analysis was conducted to identify the factors associated with AS. The results showed that AS was positively related to the age, diabetes duration, VFA, SFA, SBP, DBP, FINS, AST, UA, UACR, Cys C, and negatively to the Hb, HbA1c, eGFR and log_e GDR (all P < 0.05). No significant relationships existed between AS and BMI, TC, LDL-c, TG, HDL-c, FBG, ALT, GGT, HOMA-IR, TyG index, TG/HDL-c ratio, METS-IR and the percentages of males, smoking and drinking (all P > 0.05).

Independent Variables of baPWV by Multiple Linear Stepwise Regression Analysis

The covariates for multivariate linear regression analysis were determined based on the results of Pearson correlation analysis and previous literature reports. A multiple linear stepwise regression analysis was conducted to analyze the independent correlations of baPWV (Table 4). The age, diabetes duration, VFA, SFA, SBP, DBP, TG, FINS, GGT, UA, UACR, Cys C, TG/HDL-c ratio, Hb, HbA1c, eGFR and log_e GDR were set as the dependent variables based on the results of Pearson correlation analysis, and the results displayed that the age, SBP and log_e GDR fit a regression model (all P < 0.05).

Table 4 Multivariate Linear Regression Analysis with baPWV as the Dependent Variable

Independent Correlations of AS by Logistic Regression Analysis

Finally, AS was served as the dependent variable, and based on the results of univariate logistic regression analysis, the DAG diagram (Figure 2), and previous literature, the following variables were included as independent variables: age, diabetes duration, VFA, SFA, SBP, DBP, FINS, HbA1c, AST, UA, eGFR, UACR, Cys C, Hb, BMI, FBG, TG, HOMA-IR, TG/HDL-c ratio, TyG index, METS-IR, log_e GDR and the percentages of smoking and drinking. A logistic regression analysis was performed to analyze the independent correlates of AS (Table 5), and the results found that after adjusting for the other variables, the log_e GDR (OR: 0.286, 95.0% CI for OR: 0.110–0.743), age (OR: 1.196, 95.0% CI for OR: 1.138–1.258), SBP (OR: 1.053, 95.0% CI for OR: 1.031–1.075) and FBG (OR: 0.886, 95.0% CI for OR: 0.792–0.990) were independently related to AS.

Table 5 The Independent Variables for AS

Figure 2 The DAG of identifying confounding variables.

Predictive Value of IR Markers for AS

To assess the incremental predictive value of various IR markers for AS, NRI analysis was performed based on logistic regression models (Table 6). All models were adjusted for potential confounders, including age, diabetes duration, VFA, SFA, SBP, DBP, FINS, HbA1c, AST, UA, eGFR, UACR, Cys C, Hb, BMI, FBG, TG, smoking and drinking. Building upon the base model without any IR marker, integrating log_e GDR yielded a modest improvement in the model’s ability to reclassify patients with AS (NRI:0.043, 95% CI 0.009–0.079, P = 0.011). In contrast, building upon the base model, integrating other IR markers such as HOMA-IR (NRI:0.007, P = 0.697), TyG index (NRI:0.011, P = 0.356), TG/HDL-c ratio (NRI:0.006, P = 0.317), and METS-IR (NRI: −0.004, P = 0.568) did not significantly improve the predictive performance.

Table 6 Analysis of the NRI for Predicting AS

Discussion

This cross-sectional study of non-obese patients with T2D revealed a significant negative association between the log_e GDR and both baPWV and AS. Increased log_e GDR tertiles corresponded with a significant reduction in baPWV and AS incidence. Furthermore, after adjusting for confounding factors, the log_e GDR was independently associated with baPWV and AS.

IR is common among diabetic patients, leading to endothelial dysfunction and inflammatory responses that contribute to AS and atherosclerosis.²² Although the EHC is considered the gold standard for assessing IS, its complexity, time consuming, and requirement for specialized personnel limit its use in large-scale clinical studies. HOMA-IR is a commonly used and simpler indicator of IR, but it relies on FINS. Previous studies have shown that fluctuations in insulin levels can be significantly influenced by an individual’s glucose tolerance and the effects of treatment. Therefore, FINS levels may not be entirely accurate for patients with T2D undergoing treatment.^23,24 Recently, an increasing number of studies have explored the close association between non-insulin-based IR surrogate indicators and AS across various populations. For instance, a study in a healthy Japanese cohort found a significant correlation between the METS-IR and AS.²⁵ A study involving 1895 participants showed a close correlation between the TyG index and the TG/HDL-c ratio with AS in hypertensive patients, while no such relationship was observed in patients with prehypertension.²⁶ Furthermore, research on patients with T2D had indicated that the TyG index was independently and more strongly associated with the prevalence of increased AS compared to HOMA-IR.²⁰ The relationship between non-insulin-based IR surrogate indicators with AS had also been validated in lean postmenopausal women, Chinese non-hypertensive and older subjects.^27–29

The log_e GDR is a newly developed model for assessing IS in T2D, and it has been validated as a reliable EHC-based surrogate capable of capturing the variability of IS in patients with T2D well.¹³ The inclusion of metabolic components (GGT, UACR, BMI and TG) allows log_e GDR to reflect a more comprehensive metabolic profile and potentially capturing a broader range of pathogenic mechanisms. In our study, we found that it was closely associated with IR markers as well. As the tertiles of log_e GDR increased, significant reductions were observed in other IR markers, suggesting a consistent relationship between log_e GDR and IS. Notably, we found that the log_e GDR was independently related to baPWV and AS. This relationship remains important even after adjusting for other confounding factors including IR markers (HOMA-IR, TG/HDL-c ratio, TyG index, and METS-IR).

The mechanisms potentially linking log_e GDR to AS are likely multifactorial and may involve several key pathways. The components included in the calculation of log_e GDR, including GGT, UACR, BMI and TG, may have been suggested as part of circadian syndrome.³⁰ Recent studies indicate that circadian syndrome may be a better predictor of CVDs risk than metabolic syndrome,³⁰ suggesting that log_e GDR might reflect a disruption in circadian rhythms, potentially influencing cardiovascular health. GGT is a key marker of oxidative stress, promoting endothelial dysfunction by reducing nitric oxide bioavailability and increasing vascular inflammation, both of which contribute to arterial stiffening. TG facilitates lipid accumulation in the vascular wall, leading to foam cell formation and atherosclerosis progression. Elevated TG levels are also associated with increased production of small, dense LDL particles, which enhance oxidative stress and vascular inflammation. UACR reflects endothelial dysfunction and vascular damage, as albuminuria is linked to increased vascular permeability and low-grade inflammation, both contributing to arterial remodeling. Additionally, BMI, particularly in the context of visceral adiposity, is associated with chronic low-grade inflammation and activation of the renin-angiotensin-aldosterone system, further promoting vascular stiffness. These components effectively represent the key metabolic pathways leading to AS, supporting the close relationship between log_e GDR and AS.^31–33

Additionally, AS is a degenerative vascular process that increases with age.³⁴ High SBP levels may damage endothelial function, leading to progressively stiffer arteries.³⁵ Be consistent with the above findings, we found a strong relationship between age and SBP with AS in non-obese patients with T2D. This underscores the importance of managing SBP as a modifiable risk factor for AS, particularly in this population. Interestingly, we observed a negative correlation between AS and FBG, which was inconsistent with most studies that suggested elevated FBG was a significant risk factor for AS.³⁶ The multifaceted influencing factors of AS may help explain this phenomenon. As mentioned earlier, the average age in the AS group was significantly higher than that in the non-AS group, and some studies have suggested that older diabetic patients tend to have better blood glucose control.³⁷

The relationship between the novel IS index log_e GDR and AS has not been extensively studied in the context of non-obese T2D. Our study is the first to observe a strong association between log_e GDR and AS in non-obese patients with T2D, highlighting its potential clinical significance. Although non-obese individuals with T2D may have normal body weight, they can still exhibit significant vascular changes. Since log_e GDR incorporates metabolic parameters including BMI, TG, UACR and GGT, it may reflect a broader metabolic disorder amenable to intervention than other IR markers. Importantly, logₑ GDR demonstrated the highest NRI among the evaluated IR indicators, indicating relatively better discriminatory capacity for AS. However, the overall improvement in risk prediction was modest, suggesting that its incremental value in risk stratification may be limited. Therefore, while logₑ GDR shows potential as a complementary tool for early identification of cardiovascular risk in non-obese T2D patients, its clinical utility should be interpreted with caution. Further prospective studies with larger, diverse cohorts are needed to confirm these findings and to clarify the role of logₑ GDR in improving cardiovascular risk prediction models.

Several limitations of this study should be acknowledged. First, as with all cross-sectional studies, we cannot establish causality between log_e GDR and AS. Longitudinal studies are essential to determine the temporal relationship and causal pathways between these variables. Second, using BMI < 24 kg/m² to define “non-obese” may not perfectly capture individuals with increased visceral adiposity, which is a key driver of metabolic dysfunction. Future studies could consider including measures such as waist circumference or waist-to-hip ratio, which provide more direct insight into visceral fat distribution. Lastly, this study is single-center and based on a small sample size, which may limit the generalizability of the results. Future prospective multi-center studies involving larger populations are needed to confirm these findings and further investigate the underlying mechanisms.

Conclusion

In conclusion, the log_e GDR, as a new simple index of IS, is independently associated with AS in non-obese patients with T2D. Its inclusion in existing risk models modestly improved the identification of arterial stiffness. The potential utility of log_e GDR in cardiovascular risk assessment warrants further investigation and validation in future studies.

Ethics Approval and Consent to Participate

The study was approved by the Human Ethics Committee of the Linyi People’s Hospital. All procedures were performed in accordance with ethical standards laid out in the Declaration of Helsinki. Informed consent was obtained from the patients.

Acknowledgments

Shuwei Shi is currently Department of Endocrinology, Linyi People’s Hospital Affiliated to Shandong Second Medical University, Linyi, China. This study was conducted while she was affiliated with the School of Clinical Medicine, Shandong Second Medical University, Weifang, Shandong, China. Baolan Ji and Guanqi Gao are co-corresponding authors for this study.

Funding

This study was supported by grants from the Postdoctoral Program of Affiliated Hospital of Jining Medical University (JYFY322152).

Disclosure

All authors declare that they have no competing interests in this study.

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Introduction

The advancement of medical technology and evolving healthcare concepts has led to the widespread adoption of day surgery, a new medical service model.¹ Anaesthetic techniques are the cornerstone of day surgery. Therefore, improving anaesthesia concepts and methods is essential to ensure safe and effective outcomes in this setting.

In clinical practice, drugs with complementary effects are often used together. The combination of sedatives and opioids is a standard practice for procedural sedation and general anaesthesia. For example, the combination of propofol with fentanyl, midazolam with fentanyl, and propofol with remifentanil improved efficacy, reducing the dosage of both drugs, and reducing adverse effects.^2–5 However, drug interactions can alter pharmacological outcomes,⁶ making it essential to understand the characteristics of these interactions. Remimazolam, a novel, ultrafast, and short-acting benzodiazepine, gained approval for use in both procedural sedation and general anaesthesia.^7–9 Alfentanil, a fentanyl derivative, is a short-acting μ-opioid analgesic widely used in various clinical settings, including endoscopy, abortion, and general anaesthesia.^10–13

Given the rapid onset and offset of remimazolam and alfentanil, their combination could be an ideal anaesthetic regimen for day surgeries. Despite this potential, only a few studies have explored the remimazolam-alfentanil interaction. Our hypothesis is that alfentanil may enhance the sedative effects of remimazolam during anaesthesia induction in patients undergoing urological day surgery.

Methods

Study Design and Participants

This study was a single-centre, single-blinded, randomised clinical trial. Ethical approval was granted by the Medical Ethics Committee of the First Affiliated Hospital of Guangxi Medical University (identifier: 2022-KY-E-302; Chairperson: Prof. Songqing He) on 13 September 2022 and was registered with the Chinese Clinical Trial Registry (https://www.chictr.org.cn; registration number: ChiCTR2200064130, principal investigator: Xuehai Guan; date of registration: 27 September 2022). Written informed consent was obtained from all patients before enrolment. This trial was performed at the First Affiliated Hospital of Guangxi Medical University in accordance with the Declaration of Helsinki and CONSORT guidelines.

A total of 114 patients, aged 18–65 years, with an American Society of Anaesthesiologists (ASA)physical status I–III, undergoing elective urological day surgery under general anaesthesia, were enrolled. Patients with a history of difficult airway (modified Mallampati class 3–4), asthma, severe hypertension (systolic blood pressure ≥ 180 mmHg or diastolic blood pressure ≥ 110 mmHg), pulmonary heart disease, pulmonary arterial hypertension, cardiac insufficiency, hyperthyroidism, epilepsy, or psychosis were excluded. Further exclusion criteria included allergic reactions to drugs, obesity (body mass index, BMI ≥ 30 kg.m⁻²), pregnancy, and analgesic abuse.

Randomisation and Masking

Enrolled patients were randomly assigned to either the RMZ-AF or AF-RMZ group using a computer-generated randomisation code (EpiCalc 2000 software) in a 1:1 ratio. Randomisation was performed by an independent anaesthesiologist who was only involved in patient assignment and drug preparation. Group assignments were concealed in sealed envelopes. Patients, surgeons, and data collectors were blinded to the group allocation throughout the process, with the allocation only revealed after data collection and analysis were completed.

Anaesthesia Management and Intervention

All patients fasted for 8 h before surgery, with no premedication administered. Upon arrival in the operating room, standard monitoring was initiated, including non-invasive blood pressure measurement, electrocardiography, capnography, pulse oximetry (SpO₂), and bispectral index (BIS). All patients inhaled 100% oxygen through a mask for 3 min before anaesthesia induction. In the RMZ-AF group, anaesthesia was induced using remimazolam tosilate (RMZ; Jiangsu Hengrui Medicine Co., Lianyungang, China; diluted with normal saline to 1 mg mL⁻¹), starting at 6 mg kg⁻¹ h⁻¹ until the BIS reached 40–60 and was maintained between 0.2–2 mg kg⁻¹ h⁻¹. When BIS was within 40–60, alfentanil (AF; 30 µg kg⁻¹ IV; Yichang Humanwell Pharmaceutical Co., Yichang, China) and rocuronium (0.6 mg kg⁻¹ IV; Sinopharm Chemical Reagent Co., Shanghai, China) were administered. In the AF-RMZ group, anaesthesia was induced by using alfentanil (30µg kg⁻¹ IV), followed by remimazolam tosilate, starting at 6 mg kg⁻¹ h⁻¹ until BIS reached 40–60 and was maintained between 0.2–2 mg kg⁻¹ h⁻¹. When BIS was within 40–60, rocuronium (0.6 mg kg⁻¹ IV) was administered. In both groups, a laryngeal mask airway (LMA) was inserted 1 min after rocuronium administration. Anaesthesia was maintained using a combination of remimazolam (0.2–2 mg kg⁻¹ h⁻¹) and alfentanil (1–2 µg kg⁻¹ min⁻¹), adjusted based on the clinical signs and symptoms, BIS values (maintained at a range of 40–60), and the patient’s overall condition. Rocuronium was administered as a repeated bolus dose of 0.1–0.2 mg kg⁻¹ when needed. All patients underwent mechanical ventilation (tidal volume, 8 mL kg⁻¹; respiratory rate: 8–12 breaths min⁻¹; oxygen concentration, 60%; and fresh gas flow, 2 L min⁻¹). All patients with hypotension (a 30% decrease in mean arterial blood pressure (MBP) compared with baseline) were treated with ephedrine at the discretion of the attending anaesthesiologist.

If signs of intraoperative awakening (BIS > 60) were detected, the remimazolam infusion rate was adjusted to 10 mg kg⁻¹ h ⁻¹ for up to 1 min. If awakening signs persisted, remimazolam was discontinued and replaced with propofol. All drugs were discontinued at the end of the surgery, and patients were transferred to the post-anaesthesia care unit (PACU) for recovery.

Outcomes

The primary outcome was the time from remimazolam administration to loss of consciousness (LOC) during anaesthesia induction. The consciousness was assessed by using Modified Observer`s Assessment Alertness/Sedation Scale (MOAA/S; 0, no response after painful trapezius squeeze, defined as LOC; 1, responds only after painful trapezius squeeze; 2, responds only after mild prodding or shaking; 3, response to name spoken loudly and/or repeatedly; 4, response to name spoken in normal tone; 5, response readily to name spoken in normal tone) with 10s interval during anaesthesia induction.

Secondary outcomes included anaesthetic and surgical characteristics, vital signs, and adverse events. The durations of surgery, anaesthesia, and PACU stay, as well as the time of eyes-opening and extubation, were recorded. We recorded the administration of remimazolam and alfentanil at the following time points: from administration to LOC, at BIS ≤ 60, and at the end of surgery. Total administration of rocuronium, ephedrine, and crystalloid infusion volumes were also recorded. Vital signs (mean arterial blood pressure [MBP], heart rate, SpO₂, and BIS) were recorded at the following time points: 5 min before anaesthesia (baseline), at LOC, at BIS ≤ 60, at intubation, at 1 and 5 min after intubation, at the beginning of surgery, at 5 min after surgery, at time of eyes-opening, at time of extubation, and at discharge from the PACU. Adverse events such as hypertension (≥ 30% increase in MBP from baseline), hypotension (≥ 30% decrease in MBP from baseline), bradycardia (<50 beats min⁻¹), tachycardia (>100 beats min⁻¹), injection pain, dysphoria, nausea/vomiting, awareness, delirium, and hiccups were also recorded.

Statistical Analyses

Statistical analyses were performed using GraphPad Prism 9.0 (Dotmatics, Boston, MA, USA). The normality and equality of variances for continuous variables were tested using the Kolmogorov–Smirnov and sphericity tests, respectively. Continuous values with normal distribution and equal variance are presented as means (SD) and were analysed using an unpaired t-test or repeated-measures two-way analysis of variance (ANOVA), followed by Bonferroni’s multiple comparison test. Continuous values with non-normal distribution and unequal variance are presented as medians (interquartile range [IQR]) and were analysed using the Mann–Whitney U-test. Categorical values are presented as numbers (%) and were analysed using Fisher’s exact test. A P-value of <0.05 was considered statistically significant.

This study was designed as a superiority trial. PASS software (version 11.0; NCCS, Utah, USA) was used to calculate the sample size. Preliminary tests showed that the time from remimazolam administration to LOC (mean [SD]) was 106.0 (30.0) s and 123.0 (32) s in the AF-RMZ and RMZ-AF groups, respectively. We calculated that 54 patients per group were required to achieve 80% power at a two-sided alpha of 0.05 to detect a significant difference in the primary outcome. To account for a potential 5% dropout rate, we enrolled 57 patients in each group.

Results

Between September 2022 and December 2023, 171 patients were screened for eligibility. Of these, 30 did not meet the inclusion criteria, 27 declined to participate, while 114 were successfully recruited and randomised into either the RMZ-AF or AF-RMZ group (n=57 per group). A total of 114 patients were included in the analysis (Figure 1). Table 1 presents the patient demographic data. No statistically significant differences were observed between the groups.

Table 1 Baseline Characteristics of Patients

Figure 1 CONSORT diagram for the trial. CONSORT indicates Consolidated Standards for Reporting of Trials.

The time from remimazolam administration to LOC during anaesthesia induction was significantly shorter in the AF-RMZ group than in the RMZ-AF group (87.3 [25.7] s vs 132.3 [32.3] s, P<0.0001, Table 2). Similarly, the time from remimazolam administration to BIS ≤ 60 was significantly shorter in the AF-RMZ group than in the RMZ-AF group (168.2 [58.1] s vs 207.8 [61.6] s, P=0.0006, Table 2).

Table 2 Sedation Characteristics of Patients Receiving Remimazolam Combined with or Without Alfentanil for Anaesthesia Induction

No significant differences were found between groups in terms of anaesthesia duration, surgery duration, eyes-opening time, extubation time, or PACU stay (Table 2). The total administration of remimazolam did not differ significantly between groups (Table 3). However, remimazolam doses were more in the RMZ-AF group than in the AF-RMZ group at LOC (14.7 [12.3, 16.4] mg vs 9.9 [8.5, 11.0] mg, P<0.0001) and at BIS ≤ 60 (21.3 [17.5, 25.1] mg vs 18.4 [13.1, 22.6] mg, P=0.0058). No differences were found between the groups in terms of the total administration of alfentanil, ephedrine, rocuronium, or crystalloid infusion volume.

Table 3 Characteristics of Anaesthesia and Surgery in Patients Receiving Remimazolam Combined with or Without Alfentanil for Anaesthesia Induction

Table 4 presents the incidence of adverse events. Hypotension was the most common adverse event, but no difference was found between the RMZ-AF and AF-RMZ groups (28 [49.1%] vs 22 [38.6%], 95% CI: 1.3 [0.84–2.0], P=0.3454). The incidence of hypertension was 10.5% (n=6) in the RMZ-AF group and 15.8% (n=9) in the AF-RMZ group (95% CI: 1.5 [0.59–3.8], P=0.5808). Tachycardia occurred in 12.3% of patients in both groups. No patients in either group experienced bradycardia, injection pain, dysphoria, nausea/vomiting, awareness, delirium, or hiccups.

Table 4 Incidence of Adverse Event in Patients Receiving Remimazolam Combined with or Without Alfentanil for Anaesthesia Induction

No significant differences were observed in MBP, heart rate, SpO₂, or BIS values at any time point (Figure 2).

Figure 2 Changes in vital signs of patients receiving remimazolam combined with or without alfentanil for anaesthesia induction. Data are displayed as means (SD) (A–C) or medians (D). Data were compared using repeated-measures two-way analysis of variance (ANOVA) with Geisser-Greenhouse correction, followed by Bonferroni`s multiple comparisons test. (A) Drug: F (1, 112) = 0.8040, p=0.3718; Time: F (11, 1232) = 127.5, p<0.0001; Drug Ⅹ Time: F (11, 1232) = 1.597, p=0.0936; Subject: F (112.1232) = 8.416, p<0.0001. (B) Drug: F (1, 112) = 0.0362, p=0.8494; Time: F (11, 1232) = 11.92, p<0.0001; Drug Ⅹ Time: F (11, 1232) = 7.392, p<0.0001; Subject: F (112.1232) = 14.33, p<0.0001. (C) Drug: F (1, 112) = 1.045, p=0.3088; Time: F (11, 1232) = 11.43, p<0.0001; Drug Ⅹ Time: F (11, 1232) = 0.5367, p=0.8793; Subject: F (112.1232) = 4.385, p<0.0001. (D) Drug: F (1, 112) = 0.7292, p=0.3950; Time: F (8, 896) = 639.0, p<0.0001; Drug Ⅹ Time: F (8, 896) = 1.627, p=0.1131; Subject: F (112.896) = 3.800, p<0.0001. Abbreviations: RMZ, remimazolam; AF, alfentanil; MBP, mean arterial blood pressure; HR, heart rate; SpO2, pulse oximetry; LOC, loss of consciousness; BIS, bispectral index; PACU, post-anaesthesia care unit.

Discussion

This is the first reported randomised controlled trial investigating the interaction between remimazolam and alfentanil. The main finding of our results showed that the time to LOC and the doses of remimazolam required to reach LOC and BIS ≤ 60 during anaesthesia induction were shorter and lower, respectively, in the AF-RMZ group than in the RMZ-AF group. These results confirm our hypothesis that alfentanil enhances the sedative effects of remimazolam during anaesthesia induction in patients undergoing urological day surgery.

Drug interactions can be classified as synergism, additivity, or antagonism, regardless of whether one drug exerts an effect on its own.^14–17 During anaesthesia induction and maintenance, it is a common practice to use two or more drugs either successively or simultaneously. Combining sedatives and opioids has a synergistic effect, enhancing anaesthesia, reducing the dosage of both drugs, and minimising adverse events.¹⁸ For instance, the combination of propofol and alfentanil changed alfentanil’s pharmacokinetics by decreasing elimination clearance by 15%, rapid distribution clearance by 68%, slow distribution clearance by 51%, and lag time by 62%.⁶ Although we did not conduct pharmacokinetic assessments in this study, we speculate that pretreatment with alfentanil can also affect the pharmacokinetics of remimazolam by decreasing elimination clearance and slowing distribution clearance, thereby enhancing the sedative effect of remimazolam.

Drug interactions may occur through the modulation of the action site.¹⁹ Therefore, understanding the mechanisms underlying these interactions is critical. The combination of propofol and alfentanil produced synergistic antinociceptive effects²⁰ through the inhibition of phosphorylated extracellular signal-regulated kinase 1/2, c-Fos protein²¹ and the adenylyl cyclase pathway.²² Propofol exerts sedative effects by potentiating GABA responses and activating GABA type A receptors (GABAARs).²³ Similarly, remimazolam exerts sedative effects by also acting on GABAARs.⁷ Alfentanil exerts its analgesic effect by acting on mu-opioid receptors (MOR). Since both GABAARs and MOR are co-expressed in some primary afferent neurons, it is plausible that propofol–alfentanil and remimazolam-alfentanil administration may activate the same neural pathways, thereby enhancing their sedative effects.

Alfentanil has been used as a sedative regimen in intensive care without causing prolonged respiratory depression.²⁴ Given that the time to LOC or BIS ≤ 60 and the doses of remimazolam required were significantly shorter or lower, respectively, in the AF-RMZ group compared with the RMZ-AF group, we concluded that alfentanil enhances the sedative effect of remimazolam. The peak effect of a bolus injection of alfentanil occurs at approximately 3–4 min,²⁵ while remimazolam reaches a peak effect at 2–3 min. By administering alfentanil immediately before remimazolam, the peak effect of both drugs overlaps, maximising remimazolam’s sedative efficacy. As the exact nature of their interaction – whether synergistic or additive – remains unclear, further investigation is required to elucidate the underlying mechanisms.

Combining alfentanil and midazolam is recommended in different clinical practices. The combination of remimazolam with alfentanil for anaesthesia during endoscopic retrograde cholangiopancreatography (ERCP), colonoscopy, and gastroscopy procedures showed fewer respiratory depression events and haemodynamic advantages than the propofol-alfentanil combination.^26–28 Hypertension, hypotension, and tachycardia were the major adverse events among the two groups; however, no differences were found between the groups in our trial. The awakening time was slightly longer, and the incidence of adverse events (nausea, abdominal pain, fatigue, dizziness, and abdominal distension) were lower in remimazolam-alfentanil group than that in the propofol-alfentanil group during gastroscopy.²⁷ The postoperative 15-item quality of recovery questionnaire score was higher, and the abdominal pain was lower in the remimazolam-alfentanil group than in the propofol-alfentanil group during ERCP procedure.²⁶ Thus, combining remimazolam and alfentanil may be a safe option for anaesthesia.

Sedative-hypnotic drugs and opioids are risk factors for post-operative nausea and vomiting (PONV), which can prolong recovery. None of the patients developed PONV during our trial. Consistent with a previous report, alfentanil reduced the incidence of PONV than fentanyl.²⁹ The use of rapidly metabolic sedative-hypnotic drugs and opioids for anaesthesia is effective in reducing the risk of PONV.³⁰

None of the patients developed emergence delirium (ED) during our trial. Intranasal alfentanil, in addition to oral midazolam, did not decrease sevoflurane-induced ED.³¹ Intravenous alfentanil decreased the incidence of ED in the PACU.³² Compared with intravenous injection, the bioavailability of intranasal alfentanil was reduced to 64.7%.³³ We infer that the different bio-availabilities of alfentanil result in this discrepancy in preventing ED.

Hiccups are a troublesome adverse event associated with remimazolam. Although remimazolam-induced hiccups are generally self-limiting, they are associated with the risk of regurgitation and aspiration, particularly in patients with a full stomach. No patients developed hiccups during this trial. The incidence of hiccups depends on the bolus rate of remimazolam administered during sedation induction.³⁴ We believe that remimazolam administration at a rate of 6 mg kg⁻¹ h⁻¹ during anaesthesia induction would be appropriate. No patients in our trial experienced injection pain, dysphoria, or increased awareness.

Although there was no significant difference in the incidence of adverse events between the two groups in this study, which differed from those of other studies,^26,27 the reasons may be differences in the study population, differences in drug dosage and administration methods, and the study sample size.

This study had several limitations. First, the trial focused exclusively on patients undergoing urological day surgery, limiting the generalisability of the findings to other populations. Further studies are needed to validate these conclusions in other contexts. Second, this was a single-blinded trial. Although the patients, surgeons, and data collectors were blinded to the group assignment throughout the process, the possibility of bias cannot be entirely excluded. Third, all patients were drawn from a single centre, and genetic and racial factors may limit the applicability of our findings to other populations. Further multi-centre clinical trials are required to confirm this conclusion.

Conclusion

In conclusion, alfentanil enhances the sedative effects of remimazolam during anaesthesia induction in patients undergoing urological day surgery. The combination of remimazolam and alfentanil for general anaesthesia would improve efficacy, reducing the adverse effects and dosage of drug. But the potential mechanisms need further study.

Abbreviations

MBP, mean arterial blood pressure; CI, confidence interval; GABA_A, gamma-aminobutyric acid receptor subunit A; ASA, American Society of Anaesthesiologist; PACU, post-anaesthesia care unit; SpO₂, pulse oximetry; BIS, bispectral index; LOC, loss of consciousness; IQR, interquartile range; ASD, absolute standardized difference; ANOVA, analysis of variance; RMZ, remimazolam; AF, alfentanil.

Data Sharing Statement

The data generated during the current study are available from the corresponding author on reasonable request.

Ethic Approval

This study was approved by the Medical Ethics Committee of the First Affiliated Hospital of Guangxi Medical University (identifier: 2022-KY-E-302; Chairperson: Prof. Songqing He) on 13 September 2022 and was registered with the Chinese Clinical Trial Registry (https://www.chictr.org.cn; registration number: ChiCTR2200064130, principal investigator: Xuehai Guan; date of registration: 27 September 2022). Written informed consent was obtained from all patients before enrolment. This trial was performed at the First Affiliated Hospital of Guangxi Medical University in accordance with the Declaration of Helsinki and CONSORT guidelines.

Acknowledgments

This study was supported by the Natural Science Foundation of Guangxi Zhuang Autonomous Region (2022GXNSFAA035628, 2024GXNSFAA010222), the Clinical Research “Climbing” Program of the First Affiliated Hospital of Guangxi Medical University (YYZS2022005), the Guangxi Zhuang Autonomous Region Health Commission’s Self-Fund Research Project on Western Medicine (Z-A20230492), and the Guangxi Zhuang Autonomous Region Traditional Chinese Medicine Appropriate Technology Development and Promotion Project (GZSY22-59). The funder had no role in the concept, patient recruitment, data collection, analysis, interpretation, trial design, or making the decision to submit for publication.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

The authors report no conflicts of interest in this work.

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