Effects of dexmedetomidine versus remimazolam protocolized sedation during lower limb nerve block on early stress response and quality of recovery in patients undergoing diabetic foot ulcer repair: a randomized controlled trial protocol

Abstract

Background

For patients undergoing diabetic foot ulcer (DFU) repair, lower limb nerve block is the preferred anesthetic regimen. However, the block alone often fails to fully eliminate intraoperative anxiety and stress responses. Adjunctive procedural sedation and analgesia (PSA), using agents such as dexmedetomidine or remimazolam, is a key strategy to enhance surgical comfort. Nevertheless, the comparative effects of these two agents on early stress response and quality of recovery remain unclear.

Methods

This is a prospective, randomized, single-center, single-blind, superiority controlled trial. A total of 160 patients aged 18 to 75 years undergoing elective DFU repair will be enrolled and randomized into Group A (dexmedetomidine) and Group B (remimazolam). The primary outcome is the change in serum cortisol levels from preoperative baseline to 2 h postoperatively. Secondary outcomes include the following: vital signs; postoperative pain intensity scores; intraoperative stress level; postoperative quality of recovery; and patient and surgeon satisfaction scores.

Discussion

This study aims to compare the effects of dexmedetomidine and remimazolam PSA on attenuating stress hormone release and improving early postoperative quality of recovery in patients undergoing DFU repair. The future findings will provide high-quality clinical evidence for reducing perioperative stress levels, enhancing patient comfort, and accelerating postoperative recovery.

Trial registration

Chinese Clinical Trial Registry ChiCTR2500113746. Registered on 2 December 2025.

Supplementary Information

The online version contains supplementary material available at https://doi.org/10.1186/s13063-026-09937-4.

Introduction

Background and rationale {6a}

Diabetic foot ulcer (DFU) is among the most serious chronic complications of diabetes, commonly associated with lower extremity arterial disease and refractory infection, and is characterized by a prolonged disease course, poor healing, and high rates of disability and mortality [1, 2]. Lower limb surgical interventions, including debridement, skin grafting, and flap reconstruction, represent pivotal strategies for controlling infection, achieving limb salvage, and improving clinical prognosis in patients with DFU [1, 3]. Given that patients with diabetic foot ulcers are often elderly and frequently have serious comorbidities, including cardiovascular, cerebrovascular, and renal dysfunction, maintaining perioperative hemodynamic stability is of paramount importance [4]. Consequently, compared with general anesthesia, lower limb nerve block, characterized by minimal systemic physiological interference, has emerged as the preferred anesthetic regimen for patients undergoing DFU repair [5, 6]. It is particularly advantageous for high-risk patients with multisystem comorbidities or contraindications to neuraxial anesthesia [7]. However, reliance on nerve block alone cannot adequately mitigate the anxiety, fear, and associated physiological and psychological stress responses inherent to surgery in awake patients. These responses may lead to sympathetic hyperactivity, resulting in increased blood pressure, tachycardia, and glycemic fluctuations, which is particularly detrimental in diabetic patients with compromised physiological reserve.

Procedural Sedation and Analgesia (PSA) represents an analgesia-based, goal-directed management paradigm [8]. By establishing specific sedation targets and utilizing sedation depth scales, PSA involves the dynamic titration of sedative agents under rigorous monitoring to enhance procedural comfort while ensuring patient safety [8, 9]. PSA has been extensively implemented in intensive care units (ICU), pediatric critical care, and various invasive diagnostic or therapeutic procedures, and can effectively alleviate pain and anxiety, improve patient cooperation, and contribute to a reduction in adverse clinical outcomes [10, 11]. Consequently, the concomitant application of an optimized PSA regimen alongside lower limb nerve block holds promise for achieving both stable analgesia and adequate sedation, thereby further attenuating stress responses, enhancing the perioperative patient experience, and facilitating postoperative recovery. Dexmedetomidine, a highly selective α₂-adrenergic receptor agonist, is widely favored for sedation in elderly and high-risk populations due to its unique ability to induce cooperative sedation that mimics natural sleep, coupled with minimal respiratory depression and sympatholytic properties [12, 13]. However, its clinical utility is somewhat tempered by a relatively slow onset of action and the potential for hemodynamic adverse events, particularly bradycardia [14]. Remimazolam is a novel, ultra-short-acting benzodiazepine that exerts sedative and anxiolytic effects via γ-aminobutyric acid type A receptors [15]. Distinguished by its rapid onset, organ-independent metabolism via tissue esterases, predictability, and minimal cardiorespiratory depression, remimazolam has demonstrated excellent safety and efficacy in procedural sedation settings, such as gastrointestinal endoscopy [15, 16]. Although both agents are viable options for PSA, there is currently a paucity of prospective, randomized controlled evidence comparing their differential impacts on perioperative stress response and early quality of recovery, specifically within the distinct context of DFU repair.

Accordingly, this study protocol is designed to compare the efficacy of protocolized sedation using dexmedetomidine versus remimazolam, in conjunction with lower limb nerve block, on attenuating perioperative stress responses and improving the early quality of recovery in patients undergoing DFU repair. The findings are expected to help identify an optimized anesthetic sedation regimen for DFU patients, thereby reducing perioperative stress, improving early postoperative recovery, and further advancing comfort-oriented anesthetic management and enhanced recovery after surgery.

Objectives {7}

The primary objective of this study is to compare the effects of protocolized sedation using dexmedetomidine versus remimazolam, as an adjunct to lower limb nerve block, on early perioperative stress response and quality of recovery in patients undergoing DFU repair. The primary outcome is the change in serum cortisol levels from preoperative baseline to 2 h postoperatively. The secondary outcomes are the following: hemodynamic and respiratory stability; postoperative pain intensity scores; intraoperative stress level; early postoperative quality of recovery; and patient and surgeon satisfaction scores.

Trial design {8}

This study is a single-center, prospective, randomized, single-blind, parallel-group, superiority controlled trial with an allocation ratio of 1:1. Patients undergoing elective DFU repair under lower limb nerve block will be randomly assigned to receive PSA using either dexmedetomidine or remimazolam. The trial is designed and will be conducted in strict accordance with the SPIRIT 2013 checklist, ensuring a comprehensive and standardized approach to trial design, implementation, and reporting.

Methods: participants, interventions, and outcomes

Study setting {9}

All participants will be recruited from Huzhou Central Hospital, affiliated with the Fifth School of Clinical Medicine of Zhejiang Chinese Medical University in Huzhou, China. The study will be conducted through a multidisciplinary collaboration involving the Department of Burn and Plastic Surgery, the Department of Anesthesiology, and the Operating Room Nursing Department. The trial protocol has been reviewed and approved by the Ethics Committee of Huzhou Central Hospital (Approval No: 202503019-02) on April 9, 2025.

Eligibility criteria {10}

Inclusion criteria: participants must meet all of the following criteria to be eligible for the study:

1. Age between 18 and 75 years.

2. American Society of Anesthesiologists (ASA) physical status II-III.

3. Diagnosis of DFU requiring elective DFU repair under lower limb nerve block.

4. Fasting plasma glucose controlled between 4.0 and 11.0 mmol/L before surgery.

5. Body mass index between 18.5 and 30.0 kg/m².

6. Willingness to participate in the study and ability to provide written informed consent.

Exclusion criteria: participants meeting any of the following criteria will be excluded:

1. Severe respiratory or circulatory disease (unstable angina, uncontrolled arrhythmia, myocardial infarction within the last 6 months, severe heart failure (NYHA class III–IV), or severe respiratory failure).

2. Coagulation abnormalities, defined as prothrombin time, international normalized ratio, or activated partial thromboplastin time > 1.5 times the upper limit of normal, or platelet count < 80 × 10⁹/L.

3. Known allergy or hypersensitivity to local anesthetics, dexmedetomidine, benzodiazepines (including remimazolam), or any excipients of the study drugs.

4. History of substance abuse or chronic use of opioids, sedatives, or psychotropic medications.

5. Infection at the puncture site, anatomical deformities, or pre-existing severe neurological deficits in the lower limb (unrelated to diabetic neuropathy).

6. Cognitive or communication impairment, or vulnerable populations.

Who will take informed consent? {26a}

Potential participants will be identified from patients scheduled for elective DFU repair at Huzhou Central Hospital. During the routine pre-anesthesia assessment, the principal investigator from the Department of Anesthesiology will screen patients against the eligibility criteria and introduce the trial. Eligible patients will be approached in a private and quiet clinical setting to obtain written informed consent. The investigator will verify the patient’s capacity to provide consent and explain the study in plain, non-technical language. The explanation will cover the study’s purpose, procedures (specifically the use of lower limb nerve block combined with randomization to either dexmedetomidine or remimazolam sedation), potential benefits and risks, alternative anesthetic options, data collection, and follow-up procedures. A copy of the informed consent form, detailing all planned interventions, will be provided. Patients will be afforded sufficient time to read the document, ask questions, and discuss participation with family members if desired. Only after all questions have been satisfactorily addressed and the patient has voluntarily agreed to participate will the investigator obtain the signed and dated informed consent form, typically on the day prior to surgery. Patients will be explicitly informed that refusal to participate or withdrawal from the study at any time will not affect their routine clinical care or their relationship with the treating medical team.

Additional consent provisions for collection and use of participant data and biological specimens {26b}

Biological specimens for this trial are limited to venous blood collected specifically for serum cortisol analysis. To minimize invasiveness, residual blood from routine clinical monitoring will be prioritized. At study-specific time points without routine sampling (specifically 2 h postoperatively), blood will be obtained via an existing indwelling catheter. Samples will be analyzed at the Huzhou Central Hospital laboratory and will not be biobanked for long-term storage. Immediately following analysis, all remaining specimens will be disposed of in accordance with standard hospital biohazard protocols. No samples will be stored for future use, secondary research, product development, or genetic testing.

Interventions

Explanation for the choice of comparators {6b}

Dexmedetomidine is used as the control (standard-of-care) comparator in this trial. Due to its well-established efficacy, sleep-like sedation profile, and safety in high-risk populations, it is currently the routine regimen for patients undergoing DFU repair under nerve block at our center. Remimazolam is a novel, ultra-short-acting benzodiazepine sedative characterized by rapid onset and offset, fine titratability of sedation depth, and relatively mild cardiovascular and respiratory depression. Although proven effective in various procedural sedation settings, evidence regarding its use in DFU patients under nerve block is limited. This study compares remimazolam PSA against the dexmedetomidine PSA to determine the superior regimen for controlling perioperative stress and improving early recovery outcomes.

Intervention description {11a}

Preoperative preparation and monitoring

Confirmed eligible participants will fast from solid food or non-clear liquids for at least 6 h before procedural sedation, and clear fluids will be allowed until 2 h before procedural sedation, unless clinically contraindicated. Upon arrival in the operating room, a standardized checking procedure will be performed by the anesthesiologist, surgeon, and circulating nurse to verify patient identity, surgical site and planned anesthetic technique. Standard monitoring will be established, including 5-lead electrocardiography, noninvasive blood pressure (or invasive arterial blood pressure if clinically indicated), pulse oximetry, and bispectral index (BIS) monitoring. Prior to the nerve block, allergies (specifically to local anesthetics), coagulation status, and platelet count will be reconfirmed.

Ultrasound-guided lower limb nerve block

All eligible patients will receive combined popliteal sciatic nerve block and femoral nerve block under ultrasound guidance, performed by the same experienced anesthesiologist proficient in ultrasound-guided regional anesthesia techniques.

Popliteal sciatic nerve block: with the patient in the prone or lateral decubitus position, a linear or convex ultrasound probe will be placed 5–7 cm proximal to the popliteal crease to identify the posterior thigh muscles. The sciatic nerve (or its bifurcation into the tibial and common peroneal nerves) will be visualized as a hyperechoic structure within the fascial plane between the biceps femoris and semitendinosus-semimembranosus muscle group. Using an out-of-plane technique, the needle will be advanced until the tip is adjacent to the nerve. Following negative aspiration for blood, up to 20 mL of 0.375% ropivacaine will be injected in divided doses, observing circumferential spread of local anesthetic around the nerve.

Femoral nerve block: with the patient in the supine position and the leg slightly abducted, a high-frequency linear probe will be placed parallel to the inguinal crease. The femoral nerve will be identified lateral to the femoral artery (1–2 cm) as a hyperechoic, oval, or flattened structure. Using the out-of-plane technique, the needle will be advanced beneath the fascia iliaca close to the femoral nerve. Following negative aspiration, up to 20 mL of 0.375% ropivacaine will be injected, ensuring spread beneath the fascia iliaca. Adequacy of the block will be confirmed by loss of pinprick sensation in the surgical field before proceeding.

The total dose of ropivacaine will not exceed 2.5 mg/kg or 150 mg, whichever is lower. In older patients, patients with low body weight, frailty or sarcopenia, and patients with significant cardiovascular disease, hepatic impairment, or other risk factors for local anesthetic systemic toxicity, the total dose will be further reduced and will not exceed 2.0 mg/kg. The final dose and volume will be determined by the attending anesthesiologist according to body weight, clinical condition, and block requirements. All injections will be performed under ultrasound guidance with repeated aspiration and fractionated administration. Patients will be continuously monitored for relevant neurological and cardiovascular signs during and after injection. A predefined management protocol will be available in the operating room, and 20% lipid emulsion will be immediately accessible for rescue treatment if systemic toxicity is suspected.

PSA regimen

Group A (dexmedetomidine-based PSA): patients will receive a loading dose of 1 μg/kg infused intravenously over 10 min; followed by a continuous maintenance infusion at 0.2 to 0.7 μg/kg/h, titrated dynamically to achieve the target sedation depth. Group B (remimazolam-based PSA): patients will receive an initial intravenous bolus loading dose of 0.1 mg/kg administered over 30 s (± 10 s); followed by a continuous maintenance infusion starting at 0.5 mg/kg/h; the infusion rate will be adjusted within the range of 0 to 3.0 mg/kg/h to maintain the target sedation depth. In both groups, PSA will be provided on top of effective lower limb nerve block-mediated analgesia, aiming to maintain BIS values between 65 and 85 during surgery. Throughout the surgery, the same anesthesia team will continuously adjust drug dosing based on vital signs and sedation levels to ensure patient safety and comfort.

Criteria for discontinuing or modifying allocated interventions {11b}

During the trial, allocated sedation interventions may be discontinued or modified if any of the following conditions occur. In such cases, the attending anesthesiologist will adjust the anesthetic management at their discretion (including the use of alternative sedatives or conversion to general anesthesia), while all data collected up to the time of discontinuation will be retained whenever possible:

1. Sedation failure: if the participant’s BIS value remains > 90 for more than 5 min despite the continuous infusion of the study drug at the maximum allowable rate (dexmedetomidine > 0.7 μg/kg/h or remimazolam > 3.0 mg/kg/h). In such cases, the study intervention will be declared a failure, the infusion will be stopped, and rescue sedation will be administered to ensure patient comfort and surgical safety.

2. Safety concerns and adverse events: occurrence of severe perioperative complications (massive hemorrhage, cardiac arrest, or anaphylactic shock) requiring immediate resuscitation or deviation from the standard surgical or anesthetic protocol; development of severe adverse events related to the study drug (severe bradycardia or hypotension refractory to vasoactive agents) where the investigator determines that continuing the infusion poses a significant risk to the participant.

3. Unplanned ICU admission: Any participant requiring unplanned admission to ICU due to intraoperative surgical mishaps or severe physiological instability.

4. Participant withdrawal: the participant requests to withdraw their consent and discontinue participation in the study at any time, for any reason.

Participants who discontinue or have their allocated intervention modified will no longer receive the study sedation regimen but will continue to receive standard clinical care. Their data up to the point of discontinuation will be included in the safety and/or efficacy analyses according to the intention-to-treat (ITT) principle and will be appropriately documented in the final statistical analysis.

Strategies to improve adherence to interventions {11c}

Prior to trial initiation, all participating anesthesiologists will undergo unified training on the standard operating procedures, covering the ultrasound-guided nerve block and the specific dosing algorithms for both the dexmedetomidine and remimazolam groups. Adherence will be monitored by documenting actual dosages, infusion rates, BIS values, and any protocol deviations or rescue medication use in the Case Report Form (CRF). These records will be subject to regular audits by the research team to identify and rectify any deviations promptly. At the participant level, the purpose and methods of pain assessment using the Numerical Rating Scale (NRS) and the Quality of Recovery-15 (QoR-15) questionnaire will be explained in simple language before enrollment, ensuring that patients understand the 0–10 pain scores and how to respond to each QoR-15 item. Given the high prevalence of diabetic retinopathy and potential postoperative fatigue in DFU patients, postoperative assessments at predefined time points will be conducted via bedside interviews. These interviews will be performed by a designated independent investigator who is blinded to group allocation. The investigator will use standardized, neutral phrasing to efficiently assist participants in completing the questionnaires, strictly avoiding any leading questions to minimize bias.

Relevant concomitant care permitted or prohibited during the trial {11d}

All participants will receive standard perioperative care in the operating room, postanesthesia care unit (PACU), and ward in accordance with institutional guidelines. The concomitant use of nonprotocol sedatives is prohibited during surgery. If the use is deemed clinically necessary, the dosage and rationale must be documented as a protocol deviation.

Rescue analgesia: intraoperative pain will be continuously monitored. If the investigator observes clinical signs of pain or assesses a behavioral pain scale score ≥ 6 [17], a bolus of sufentanil (5 μg) will be administered. This may be repeated if necessary, but no more than two doses are permitted within any 30-min period. Rescue sedation: if the BIS value remains > 90 for more than 5 min despite continuous infusion of the study drug at the maximum maintenance rate, the study sedation regimen will be considered to have failed. The study drug infusion will be immediately terminated. Propofol 0.5–1.0 mg/kg will be administered intravenously to maintain the BIS value between 65 and 85 and facilitate surgical completion. The specific timing, dosage, and indication for any rescue medications mentioned above will be meticulously recorded in the CRF.

Provisions for post-trial care {30}

Given the short-acting nature of dexmedetomidine and remimazolam, no specific ancillary or post-trial care is required for the intervention itself. Upon completion of the intraoperative and immediate postoperative periods, all participants will return to standard-of-care management for their diabetic foot ulcers and comorbidities under the supervision of their treating physicians. Any adverse events or complications potentially related to the study interventions will be managed promptly by the treating clinical team without additional cost to the participant. In the event that trial-related injury is confirmed, medical treatment and financial compensation will be provided in accordance with applicable laws, regulations, and the policies of Huzhou Central Hospital.

Outcomes {12}

Primary outcome

The primary outcome is the change in serum cortisol levels from preoperative baseline (T0) to 2 h after surgery (T7).

Secondary outcomes

1. Hemodynamic and respiratory stability. Vital signs, including mean arterial pressure (MAP), heart rate (HR), peripheral oxygen saturation (SpO₂), and respiratory rate (RR), will be recorded at the following predefined time points. T0: baseline; T1: completion of lower limb nerve block; T2: achieving target PSA sedation; T3: skin incision; T4: end of surgery; T5: arrival at PACU; T6: arrival at the ward.

2. Postoperative pain intensity. Assessed using the NRS [18] (0 = no pain, 10 = worst imaginable pain) at T0, T1, T4, T7, 6 h after surgery (T8), and 24 h after surgery (T9).

3. Intraoperative stress level: evaluated using the PRST (Evans) score [19] at T2, T3, and T4. The PRST score is a composite index based on changes in systolic blood pressure (P), heart rate (R), sweating (S), and tearing (T). Each component is scored from 0 to 2, yielding a total score ranging from 0 to 8, with higher scores indicating greater stress or inadequate analgesia.

4. Postoperative quality of recovery. Assessed using the QoR-15 scale [20] at T9 and 48 h after surgery (T10). The QoR-15 is a validated, patient-reported outcome measure covering five dimensions: pain, physical comfort, physical independence, psychological support, and emotional state. The total score ranges from 0 to 150, with higher scores indicating better quality of recovery.

5. Patient and surgeon satisfaction scores. Patient satisfaction will be assessed before discharge from the PACU using three 0–10 scales for: sedation comfort (absence of anxiety or fear); pain management; and overall satisfaction with the anesthesia experience. Surgeon satisfaction will be assessed after surgery using three 0–10 scales for: surgical conditions and patient immobility; intraoperative hemodynamic stability; and overall cooperation with anesthesia.

Participant timeline {13}

The participant timeline is shown in Fig. 1.

Fig. 1.

Time schedule of enrollment, interventions, assessments and visits for participants. T0: baseline; T1: completion of lower limb nerve block; T2: achieving target PSA sedation; T3: skin incision; T4: end of surgery; T5: arrival at PACU; T6: arrival at the ward; T7: 2 h after surgery; T8: 6 h after surgery; T9: 24 h after surgery; T10: 48 h after surgery. Other collected data*: Baseline demographic and clinical data will include age; sex; body mass index; ASA physical status; duration of diabetes; HbA1c; Wagner grade; hypertension; coronary artery disease; chronic kidney disease; STOP-Bang score; history of smoking and alcohol consumption; long-term medication history; duration of surgery; duration of PSA; length of hospital stay; total hospitalization costs. PSA, procedural sedation and analgesia; NRS, Numerical Rating Scale; PRST, systolic blood pressure (P), heart rate (R), sweating (S), and tearing (T); QoR-15, Quality of Recovery-15

Sample size {14}

The sample size calculation was performed using PASS 16.0 software, and based on the primary outcome measure: the change in serum cortisol levels. Based on published data regarding the typical range and variability of perioperative cortisol levels [21, 22], we assumed a preoperative serum cortisol level of approximately 15 ng/mL in both groups, a mean postoperative value of about 34 ng/mL in the dexmedetomidine group and 30 ng/mL in the remimazolam group, with a common standard deviation of approximately 8.6 ng/mL. Using PASS for two-sample comparison of means, a sample size of 72 participants per group was required to detect a significant difference with a two-sided significance level (α) of 0.05 and a statistical power (1-β) of 80%. To account for a potential 10% dropout, the sample size was adjusted to 80 participants per group, resulting in a total enrollment target of 160 participants.

Recruitment {15}

Participants will be recruited exclusively from the Department of Burn and Plastic Surgery at Huzhou Central Hospital. Potential candidates scheduled for elective DFU repair will be screened during the preoperative outpatient visit and subsequent ward admission by the surgical and anesthesia teams according to the predefined eligibility criteria. Recruitment is planned to start on January 1, 2026. Given the stable case volume of DFU repair at this center, we anticipate that enrollment of the required 160 patients can be completed within approximately 6 months.

Assignment of interventions: allocation

Sequence generation {16a}

A computer-generated randomization sequence will be created using a 1:1 allocation ratio. To ensure a balanced distribution, simple randomization will be employed based on the parity of generated random numbers (odd numbers represent group A with dexmedetomidine PSA; even numbers represent group B with remimazolam PSA). The master randomization list documents all random sequences along with their corresponding sequential participant numbers.

Concealment mechanism {16b}

The allocation sequence will be concealed in sequentially numbered, opaque, sealed envelopes. To prevent selection bias, the envelopes are impermeable to light and tampering, ensuring that the group assignment remains unknown until the moment of allocation.

Implementation {16c}

The random allocation sequence and sequentially numbered, opaque, sealed envelopes will be prepared before enrollment by an independent operating room nurse who will not otherwise participate in patient recruitment, anesthetic management, postoperative follow-up, outcome assessment, data collection, or statistical analysis. Participants will be enrolled by the principal investigator. Following the successful completion of the lower limb nerve block, the investigator responsible for PSA who is independent of the recruitment process will retrieve the next sequential envelope corresponding to the participant’s order of entry. The envelope will be opened to reveal the group assignment, and the assigned study drug will be prepared immediately.

Assignment of interventions: Blinding

Who will be blinded {17a}

This is a single-blind trial. Participants will be blinded to group allocation. The anesthesia investigator administering PSA cannot be blinded due to the distinct physical properties, dosing algorithms, and safety titration requirements of dexmedetomidine and remimazolam. To maintain scientific rigor and objectivity, all investigators responsible for follow-up (NRS, QoR-15, and satisfaction questionnaires), data collection, and statistical analysis will be strictly blinded to group allocation and will not have access to anesthesia records containing specific drug details.

Procedure for unblinding if needed {17b}

Given that the investigator for PSA is unblinded for safety reasons, traditional emergency unblinding procedures for the interventionist are not applicable. In the event of a medical emergency or Serious Adverse Event (SAE) where knowledge of the specific study drug is critical for clinical management by other providers (unplanned ICU transfer or severe allergic reaction), the investigator for PSA is authorized to immediately disclose the allocated intervention to the treating medical team, with the reason and timing of such disclosure meticulously documented in the CRF.

Data collection and management

Plans for assessment and collection of outcomes {18a}

All study data will be recorded on standardized paper CRFs by designated investigators who have received protocol-specific training and have prior experience in clinical research [23–25]. Baseline demographic, clinical and laboratory variables will be obtained from the medical record, the pre-anesthesia assessment form and the hospital electronic medical record system, and will be verified at enrollment. Venous blood samples at T0 and T7 for serum cortisol measurement will be collected and analyzed at the Department of Clinical Laboratory of Huzhou Central Hospital using the same validated immunoassay and quality-control procedures throughout the trial, with laboratory personnel remaining blinded to group allocation. Vital signs (MAP, HR, SpO₂, RR) will be continuously monitored by standard operating room monitors, and values at each predefined time point (T0–T6) will be abstracted from the anesthesia record and monitor printouts into the CRF. The PRST score and details of any rescue sedation or analgesia will be documented intraoperatively by investigators for PSA. To minimize measurement bias, postoperative assessments (NRS pain scores, QoR-15 questionnaires and satisfaction scores) will be conducted via face-to-face bedside interviews by independent follow-up investigators who are blinded to group assignment.

All completed CRFs will be reviewed by the principal investigator for completeness, internal consistency and plausibility. Data from paper CRFs will be double-entered independently into a password-protected electronic database and cross-checked, with programmed range and logic checks used to identify outliers and missing values.

Plans to promote participant retention and complete follow-up {18b}

All primary and key secondary outcomes will be assessed during the index hospitalization, within 48 h after surgery; the risk of loss to follow-up is expected to be low. To maximize participant retention and ensure complete outcome collection, several strategies will be implemented. During the informed consent process, patients will be clearly informed about the timing and content of postoperative assessments and reassured that these assessments are brief and will not impose substantial additional burden. The assessment time points will be aligned as far as possible with routine postoperative ward rounds by the anesthesia and surgical teams, so that outcome measurements can be performed at the bedside without additional transfers. In accordance with the ITT principle, participants who experience sedation failure or adverse events leading to discontinuation of the study drug will not be withdrawn from the trial; they will continue to be followed and will undergo all scheduled safety and efficacy assessments. For patients discharged before the 48-h endpoint, the remaining outcome assessments will be completed by structured telephone follow-up to minimize missing data.

Data management {19}

All trial data will be managed in accordance with Good Clinical Practice and the data protection policy of Huzhou Central Hospital. Original study data will be first recorded on standardized paper CRFs. Completed CRFs will be retained by the principal investigator and stored in locked filing cabinets within the Department of Anesthesiology. Data from CRFs will be independently double-entered into a password-protected electronic database by two designated investigators. The two datasets will be compared, and any discrepancies will be resolved against the original CRFs. The electronic database will incorporate built-in range checks and logic consistency checks to automatically identify outliers, irrational values, or missing data, and will be hosted on a secure hospital server, with regular backups performed by the Information Technology Department. Access to the raw database containing potentially identifiable information is strictly restricted to the principal investigator and authorized data managers via individual password-protected accounts. Datasets used for statistical analysis will be de-identified using unique study codes. The master key linking study codes to participant identity will be stored separately as an encrypted file. All study data will be retained for a minimum of 5 years following the publication of the primary results.

Confidentiality {27}

All patient information will be handled in strict confidence. Each participant will be assigned a unique study identification code (not the patient’s name or medical record number), and will be used on all CRFs and in the electronic database. The correspondence between study codes and personal identifiers will be stored separately in an encrypted file accessible only to the principal investigator. Paper CRFs will be kept in locked cabinets, and electronic data will be stored on secure, password-protected hospital servers. No individual patient will be identifiable in any reports, presentations or publications arising from this trial; only aggregated, de-identified data will be presented. The informed consent form will clearly explain how personal data are collected, stored, protected and used for research purposes.

Plans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use {33}

The biological specimens collected in this trial are strictly limited to venous blood samples for the biochemical quantification of serum cortisol levels (the primary outcome). No genetic or molecular analysis will be performed on these samples. There is no plan for biobanking or long-term storage of specimens for future unspecified research. Upon completion of the required biochemical assays, all residual samples will be immediately disposed of in accordance with the standard biohazard waste protocols of Huzhou Central Hospital.

Statistical methods

Statistical methods for primary and secondary outcomes {20a}

All statistical analyses will be performed using SPSS 29.0 (IBM Corp., Armonk, NY, USA) and R 4.3.0 (R Foundation for Statistical Computing). Analyses will be conducted primarily on an ITT principle, including all randomized participants in the groups to which they were assigned. A per-protocol sensitivity analysis will be performed for participants without major protocol deviations. Continuous variables will be tested for normality using the Kolmogorov–Smirnov test and visual inspection of histograms. Normally distributed data will be presented as mean ± standard deviation (SD) and compared using the independent samples t-test. Non-normally distributed data will be presented as median (interquartile range, IQR) and compared using the Mann–Whitney U test. Categorical variables will be expressed as counts and percentages (n, %) and compared using the Chi-square test or Fisher’s exact test. Baseline characteristics will be summarized descriptively to assess balance between groups, and no formal statistical hypothesis testing will be performed for baseline comparisons. The between-group difference in the primary outcome (change in serum cortisol) will be reported as the mean difference with 95% confidence intervals (CI) and P-values. An analysis of covariance (ANCOVA) model will be employed, with postoperative cortisol levels as the dependent variable, the study group as a fixed effect, and baseline cortisol levels as a covariate. For repeated measures secondary outcomes (MAP, HR, SpO₂, RR, PRST scores, NRS scores), a linear mixed-effects model will be used to evaluate the effects of group, time and the group × time interaction, with a random intercept for each participant. Estimated marginal means with 95% CIs will be reported for each time point, with pairwise comparisons corrected using the Bonferroni method. All statistical tests will be two-sided, and a P-value < 0.05 will be considered statistically significant.

Interim analyses {21b}

No formal interim efficacy analysis or sample size reestimation is planned, given the modest total sample size (160 participants) and the relatively short recruitment and follow-up period.

Methods for additional analyses (e.g., subgroup analyses) {20b}

Pre-specified subgroup analyses will be conducted to explore potential heterogeneity of the treatment effect on the outcome. Subgroups will be defined according to clinically relevant baseline characteristics, specifically age (≥ 65 years (elderly) vs < 65 years (non-elderly)) and glycemic control (HbA1c ≥ 7.5% vs < 7.5%). For each subgroup, an interaction term between treatment group and subgroup category (group × subgroup) will be included in the ANCOVA model, and a P-value for interaction < 0.10 will be considered indicative of potential effect modification. These subgroup analyses will be exploratory in nature, and the trial is not specifically powered to detect differences within subgroups.

Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c}

Nonadherence to the protocol will be documented in detail in the case report form. The primary analysis will follow the ITT principle, including all randomized participants according to their originally assigned groups. A per-protocol analysis restricted to participants without major protocol violations (sedation failure) will be performed as a sensitivity analysis to assess the robustness of the findings. Reasons for missing outcome data will be recorded. If the proportion of missing data for the primary outcome is ≤ 5%, a complete-case analysis will be performed. If > 5% of primary outcome data are missing, multiple imputation under a missing-at-random assumption will be used to impute serum cortisol values, incorporating relevant baseline and perioperative variables into the imputation model, and results from the imputed and complete-case analyses will be compared as a sensitivity analysis. For repeated-measures secondary outcomes analyzed with linear mixed-effects models, all available data will be used under the assumption that data are missing at random, which is handled naturally by the modeling approach. No imputation will be performed for safety endpoints; these will be analyzed based on observed data.

Plans to give access to the full protocol, participant-level data and statistical code {31c}

The full trial protocol will be available from the corresponding author on reasonable request and will be uploaded as a supplementary file at the time of main results publication where journal policy permits. After publication of the primary results, a de-identified participant-level dataset and the main statistical analysis code will be made available from the corresponding author upon reasonable written request for non-commercial academic purposes, subject to approval by the principal investigator and the Ethics Committee of Huzhou Central Hospital.

Oversight and monitoring

Composition of the coordinating centre and trial steering committee {5d}

The coordinating center for this single-center trial is the Department of Anesthesiology at Huzhou Central Hospital, which will be responsible for day-to-day trial management, staff training, patient recruitment, data collection and monitoring, and communication with the Ethics Committee. A trial steering committee (TSC) will consist of a chief anesthesiologist, a senior surgeon from the Department of Burn and Plastic Surgery, a nurse supervisor from the operating room, and a patient representative. The TSC provides overall supervision and independent scientific oversight to ensure the trial is conducted in strict accordance with the protocol, and will convene every two weeks to review recruitment progress, protocol adherence, and safety data, offering objective recommendations to the principal investigator.

Composition of the data monitoring committee, its role and reporting structure {21a}

Given the single-center design, modest sample size and short follow-up period, a formal independent data monitoring committee will not be established. Safety oversight will be undertaken by the principal investigator in conjunction with the TSC. The TSC will periodically review recruitment progress, protocol adherence, completeness of outcome data, and the incidence and nature of adverse events (AEs) and SAEs. Any safety concerns, unexpected patterns of SAEs, or protocol-related risks identified during these reviews will be reported to the Ethics Committee of Huzhou Central Hospital, together with recommendations on whether the trial should continue as planned, be modified, or be terminated early.

Adverse event reporting and harms {22}

All AEs spanning from the time of consent signing to 48 h postoperatively will be monitored, regardless of suspected causality. AEs of special interest will include clinically significant hypotension or bradycardia, hypoxemia, oversedation, agitation, postoperative nausea and vomiting, respiratory depression, and any unexpected reactions potentially related to dexmedetomidine or remimazolam. Each AE will be assessed by the attending anesthesiologist for severity (mild, moderate, severe) and its relationship to the study drug (unrelated, unlikely, possible, probable, definite). SAEs will be defined according to standard criteria (events that result in death, are life-threatening, require unplanned ICU admission or prolongation of hospitalization, or cause persistent or significant disability). All SAEs potentially related to the study intervention will be reported to the principal investigator within 24 h of recognition, and subsequently notified to the hospital Ethics Committee. Appropriate medical treatment will be provided immediately, and may result in temporary suspension or early termination of trial for that patient.

Frequency and plans for auditing trial conduct {23}

Independent auditing of trial conduct will be performed by the quality management office of Huzhou Central Hospital, which is operationally independent from the principal investigator and TSC. On-site audits are planned approximately once every 3 months, and will focus on key aspects of informed consent procedures, eligibility assessment, completeness and accuracy of CRFs, source data verification, reporting and management of AEs. Audit findings and any corrective or preventive actions will be documented in writing and communicated to the principal investigator and the Ethics Committee.

Plans for communicating important protocol amendments to relevant parties (e.g., trial participants, ethical committees) {25}

Any substantial amendments to the protocol will be formally documented and submitted to the Ethics Committee of Huzhou Central Hospital for approval. Revisions will be updated on the Chinese Clinical Trial Registry, and all investigators will be notified and trained on the revised protocol. If the amendment affects patient safety or the validity of consent, current participants will be informed, and re-consenting will be conducted if required.

Dissemination plans {31a}

The results of this trial will be disseminated through publication in peer-reviewed scientific journals in the fields of Anesthesiology, perioperative medicine or diabetic foot care. The investigators commit to publishing the results regardless of the magnitude or direction of the effect, and will strictly adhere to the CONSORT statement. Additionally, a summary of the key findings will be updated on the Chinese Clinical Trial Registry.

Discussion

Patients with DFU are typically elderly, have a long duration of diabetes, and frequently present with multiple comorbidities such as cardiovascular disease and renal impairment. Consequently, maintaining perioperative hemodynamic stability and minimizing physiological stress are of paramount importance. Although peripheral nerve blocks can provide excellent site-specific analgesia, they often fail to completely abolish surgical anxiety, fear and stress responses in awake patients, as well as the generalized sympathetic activation induced by prolonged positioning. In this trial, we compare two distinct PSA regimens using dexmedetomidine and remimazolam as adjuncts to lower limb nerve block, with the aim of generating clinically relevant evidence to guide sedative selection for truly comfort-oriented anesthesia in patients with DFU repair.

As an α₂-adrenoceptor agonist with sympatholytic effects, dexmedetomidine is widely regarded as a reference sedative in surgery because of its sympatholytic profile and minimal respiratory depression [13, 26], and it has been shown in multiple clinical studies to attenuate perioperative surges in stress hormones and improve hemodynamic stability [21]. Remimazolam, a newer ultra-short-acting benzodiazepine, has been demonstrated in recent studies to provide effective and controllable procedural sedation, with faster recovery and lower incidences of hypotension and respiratory depression than propofol or midazolam, particularly in elderly or high-risk patients undergoing endoscopic procedures and other interventions [27, 28]. Cortisol is a key biomarker of hypothalamic–pituitary–adrenal axis activation [29]. In patients with diabetes, surgery-induced cortisol surges can trigger pronounced hyperglycemia and insulin resistance, directly impair wound healing and increase the risk of infection [29, 30]. Thus, blunting cortisol peaks is not merely a proxy for sedation depth but a critical physiological target for improving surgical outcomes, providing the rationale for selecting the change in serum cortisol from baseline to 2 h postoperatively as the primary biological endpoint. In parallel, this trial incorporates hemodynamic variables and the PRST score to characterize intraoperative stress, NRS pain scores to reflect the adequacy of analgesia, and the validated QoR-15 questionnaire to comprehensively assess early postoperative recovery. In addition, patient and surgeon satisfaction ratings provide an integrated evaluation of comfort and acceptability from both the patient and clinician perspectives.

To our knowledge, this will be the first randomized controlled trial to investigate, on the background of lower limb nerve block, the comparative effects of dexmedetomidine versus remimazolam PSA on early stress responses and postoperative quality of recovery in patients undergoing DFU repair. The study is closely aligned with contemporary concepts of comfort-focused care and enhanced recovery after surgery (ERAS), which emphasize optimizing sedation, analgesia, and stress modulation to reduce physiological burden, improve glycemic control, minimize opioid requirements and facilitate early rehabilitation. The findings of this trial are expected to provide a robust physiological and clinical basis for optimizing PSA strategies in DFU repair and to inform future multicenter investigations, larger-scale trials, and guideline development aimed at improving perioperative outcomes and patient experience in this population.

Trial status

The trial has been registered in the Chinese Clinical Trial Registry (http://www.chictr.org.cn) under the identifier ChiCTR2500113746 on December 2, 2025. The current protocol is version 3.0, dated April 7, 2025. Participant recruitment is planned to begin on January 1, 2026, and is expected to be completed by June 30, 2026. At the time of manuscript submission, no participants had yet been enrolled.

Abbreviations

AE

Adverse event

ANCOVA

Analysis of covariance

ASA

American Society of Anesthesiologists

BIS

Bispectral index

CRF

Case report form

DFU

Diabetic foot ulcer

ERAS

Enhanced recovery after surgery

HbA1c

Glycated hemoglobin A1c

HR

Heart rate

ICU

Intensive care unit

IQR

Interquartile range

ITT

Intention-to-treat

MAP

Mean arterial pressure

NRS

Numerical Rating Scale

PACU

Postanesthesia care unit

PRST

Pressure–Rate–Sweating–Tears

PSA

Procedural sedation and analgesia

QoR-15

Quality of Recovery-15

RR

Respiratory rate

SAE

Serious adverse event

SD

Standard deviation

SpO₂

Peripheral oxygen saturation

TSC

Trial steering committee

Authors’ contributions {31b}

YWT, HJG: Study conception and protocol development. JMH, SGW, HL, LT: Patient recruitment, perioperative management and data collection. QZ, YHH: Outcome assessment and postoperative follow-up. HL: Statistical analysis plan and data interpretation. YWT, HJG: Manuscript drafting and critical revision. All authors read and approved the final manuscript.

Funding {4}

None.

Data availability {29}

No datasets are currently available, as this is a study protocol.

Declarations

Ethics approval and consent to participate {24}

This study received ethical approval from the Ethics Committee of Huzhou Central Hospital on April 9, 2025 (Approval No: 202503019-02). Before enrollment, written informed consent will be obtained from each participant by the principal investigator.

Consent for publication {32}

A template informed consent form for trial participation is provided in Additional file 2. No individually identifiable personal data will be published.

Competing interests {28}

The authors declare that they have no competing interests.