Sedation with remimazolam besylate versus midazolam in acute respiratory distress syndrome patients supported by venovenous extracorporeal membrane oxygenation: a study protocol for a multicenter prospective randomized trial

Introduction

Acute respiratory distress syndrome (ARDS) remains a life-threatening condition with mortality rates exceeding 50% despite advancements in critical care (1). In cases where conventional treatment is ineffective, extracorporeal membrane oxygenation (ECMO) serves as a critical means of ensuring lung-protective ventilation by providing adequate oxygenation support while correcting hypercapnia and respiratory acidosis caused by low tidal volume ventilation (2). Venovenous extracorporeal membrane oxygenation (VV-ECMO) serves as salvage therapy for severe ARDS, demonstrating a 60-day survival rate of 65% compared to 54% in conventional management groups based on the EOLIA trial (3). During VV-ECMO treatment, an appropriate sedation method not only may help with alleviating pain and anxiety for patients, but also reduces oxygen consumption, decreases metabolic load, and thereby facilitates the recovery of impaired organ function (4). Studies have shown that compared with patients receiving veno-arterial ECMO (VA-ECMO), those receiving VV-ECMO have higher median doses of opioid medications (5,6). In accordance with Extracorporeal Life Support Organization (ELSO) recommendations, sedation is recommended within 12 to 24 hours after ECMO cannulation, assisting in reducing systemic oxygen consumption, optimizing circulatory blood flow, and achieving synchronized ventilation (7). Therefore, proper sedation is essential to reduce oxygen consumption and facilitate lung recovery for VV-ECMO supported patients (4). Deep sedation is normally achieved during the early duration of ECMO in the real-world practice (8-10). Currently, midazolam is the most widely used sedative during VV-ECMO (11,12). However, it is limited by high delirium risk, long half-life and pharmacokinetic variability in ECMO-supported patients due to drug sequestration in the circuit (13). Remimazolam besylate acts on the γ-aminobutyric acid type A receptors, opening chloride channels to promote chloride ion influx, leading to hyperpolarization of the neuronal membrane. This inhibits neuronal activity, resulting in reduced motor function, sedation, and amnesia (14). Remimazolam besylate is rapidly metabolized by tissue esterases into inactive metabolites, leading to a quick decline in sedative effects and a short recovery time. The metabolites are primarily excreted renally (15). Consequently, it offers faster induction and recovery, superior sedative efficacy, and enhanced controllability (16,17). Additionally, its effects can be rapidly reversed by specific antagonists (16). When remimazolam is administered via prolonged infusion or at high doses, accumulation of the drug or its metabolites does not occur. Thus, compared to midazolam, remimazolam is a more suitable agent for anesthesia maintenance (18,19). These properties make it a potential alternative sedative in the intensive care unit (ICU) setting. Currently, remimazolam is widely used in clinical practice. It is not only applied for gastrointestinal endoscopy but also demonstrates advantages over propofol by reducing the incidence of post-induction hypotension. Additionally, it effectively lowers the occurrence of pediatric delirium (20-22). Studies have shown that compared with propofol, remimazolam is both effective and safe, whether in ICU patients requiring long-term mechanical ventilation or those undergoing deep sedation, including ARDS patients (23,24). Meanwhile, a recent randomized controlled trial demonstrated that remimazolam besylate provides equivalent sedative efficacy to dexmedetomidine in mechanically ventilated ARDS patients (25). However, evidence in ECMO-supported ARDS patients is limited. Of note, a recent in-vitro study suggested that remimazolam showed less sequestration than midazolam in blood-primed ECMO circuits (26). This pharmacokinetic profile may allow for more predictable sedation control, potentially lower cumulative dosing, and faster recovery in ECMO supported patients. The objective of this pilot trial is to explore the comparative safety and efficacy of remimazolam besylate versus midazolam for sedation in ARDS patients undergoing VV-ECMO treatment. We present this article in accordance with the SPIRIT reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-aw-2179/rc).

Methods

Study setting and design

This investigator-initiated, multicenter, single-blind, randomized controlled trial will be conducted across the following hospitals: The First Affiliated Hospital of Guangzhou Medical University, The Second Affiliated Hospital of Guangzhou Medical University, The Third Affiliated Hospital of Guangzhou Medical University, Panyu Central Hospital Affiliated to Guangzhou Medical University, Fangcun Branch of Guangdong Provincial Hospital of Traditional Chinese Medicine, Jiangmen Wuyi Hospital of Traditional Chinese Medicine, Maoming People’s Hospital, The First Hospital of Quanzhou City in Fujian Province, and The Second Affiliated Hospital of Shantou University. The study protocol version is version 3.0, approved on May 11, 2025. The study is set to commence in Oct 2025, and it is expected to take 2 years from initiation to completion. With a 1:1 randomization ratio, enrolled patients will be assigned to either the experimental group (receiving remimazolam besylate) or the control group (receiving midazolam). This study adheres to the standard protocol item guidelines for randomized trials. Table 1 presents the overall timeline, while Figure 1 illustrates the study flowchart. The detailed study protocol including statistical analysis plan is accessible in the additional files.

Figure 1 Flowchart of study design. ARDS, acute respiratory distress syndrome; ICU, intensive care unit; RASS, Richmond Agitation-Sedation Scale; TTR, time within the target sedation range; VV-ECMO, venovenous extracorporeal membrane oxygenation.

Participant recruitment

This multicenter prospective randomized trial will recruit participants from nine medical centers in China, with The First Affiliated Hospital of Guangzhou Medical University as the lead site. Potential candidates will be screened daily from ICU admissions requiring VV-ECMO support for ARDS. Patients will be recruited within 24 hours of ECMO initiation. Eligibility will be assessed by trained research coordinators through medical record review and clinical evaluation, strictly adhering to the predefined inclusion and exclusion criteria. This trial was approved by the Ethics Committee of The First Affiliated Hospital of Guangzhou Medical University (approval No. ES-2025-097-01), and registered at the Chinese Clinical Trials Registry (identifier: ChiCTR2500108567). Written informed consent will be obtained from patients or their legally authorized representatives after detailed explanation of the study protocol, including randomization, blinding, and potential risks. The study will be conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The other medical centers were also informed of and agreed on the study. The recruitment phase is planned over 24 months to ensure enrollment of a representative sample. Regular inter-center coordination meetings will maintain consistency in recruitment procedures and ethical compliance. This multicenter approach enhances the generalizability of findings to real-world critical care settings.

Inclusion criteria

• Age ≥18 years and ≤80 years, both sexes.
• Severe ARDS patients or patients with severe hypercapnic respiratory failure [pH <7.25 with a partial pressure of arterial carbon dioxide (PaCO₂) ≥60 mmHg] requiring ECMO support.
• Diagnostic criteria for severe ARDS: new or worsening respiratory failure within 7 days, not fully explained by heart failure. Bilateral infiltrates on chest X-ray/computed tomography or bilateral B-lines/consolidation on lung ultrasound. Intubated patients, partial pressure of arterial oxygen (PaO₂)/fraction of inspired oxygen (FiO₂) ≤100 mmHg or peripheral oxygen saturation (SpO₂)/FiO₂ ≤148 mmHg (if SpO₂ ≤97%).
• Written informed consent is obtained from the patient or a legal representative.

Exclusion criteria

• Pregnant or lactating women.
• Known allergy to benzodiazepines.
• Participation in another clinical trial within 30 days prior to enrollment.
• Acute severe neurological disorder and any other condition that interfere with the assessment of Richmond Agitation-Sedation Scale (RASS).
• Any other condition that treating physicians or researchers determine to be unsuitable for participation in this trial.

Sample size calculation

This study employs a pilot design to evaluate the feasibility and preliminary efficacy of remimazolam compared to midazolam in critically ill patients undergoing ECMO. Due to the lack of preliminary data for this specific population, the sample size is referenced from similar pilot studies on efficacy of remimazolam in critically ill mechanically ventilated cohorts, which utilized a total sample size of 60 patients (30 per group) (25,27). To account for potential attrition due to ECMO circuit drug sequestration and the exploratory nature of this study, we inflated the sample size by 30%, resulting in a final enrollment target of 78 patients (39 per group) randomized in a 1:1 ratio.

Randomisation and blinding

Eligible patients will be randomly assigned in a 1:1 ratio to either the midazolam or remimazolam group using a computer-generated random sequence. To implement blinding, two dedicated teams will be established. An unblinded team with access to group allocation, are responsible for calculating drug doses, preparing medications, and administering them using identical syringes and tubing to eliminate visual cues, while documenting actions with neutral terms without disclosing dose or group information. A blinded team consisting of independent medical staffs who perform all outcome assessments including RASS scores, with no access to group allocation or drug details, and no communication with the unblinded team regarding medication matters. The principal investigator (PI) may authorize unblinding exclusively for clinically urgent scenarios involving acute clinical deterioration during ECMO support or confirmed serious adverse events (SAEs). Until the final analysis is completed, patients, blinded outcome assessors, and statistical analysts will remain unaware of group allocation.

Data management and monitoring

Demographics, clinical data (vital signs, key laboratory tests, arterial blood gas analysis), illness severity metrics (Acute Physiology and Chronic Health Evaluation II score, Sequential Organ Failure Assessment score), and comorbidities will be recorded when patients are enrolled. During sedation, all vital parameters—including blood pressure, heart rate, SpO₂, and respiratory rate—are tracked continuously. RASS score, vital signs, and vasopressor administration are documented at 4-hour intervals. RASS score assessment is carried out by a dedicated blinded team of trained healthcare providers who are independent of drug preparation and administration. Daily records include the cumulative doses of sedatives and analgesics, as well as the use of rescue medications. Daily responsibilities of a trained investigator at each center include screening patients, enrolling eligible participants, ensuring protocol adherence, and completing the electronic case report form (e-CRF). All information collected throughout the study will undergo anonymization. Data management, along with the checking of data accuracy, will be the responsibility of the PI. The research will also be tasked to a specific steering committee for management and monitoring. The data monitoring board comprising members M.L., L.Z. and R.Z. will perform periodic audits to verify the precision and uniformity of data acquisition and coding procedures. Data integrity will be managed through weekly security assessments under M.G.’s supervision. Monthly assemblies of the steering committee will be convened to monitor study progress and validate dataset quality. Detailed records tracking subject enrollment, eligibility verification, consent procedures, and information input will be systematically preserved. The monitoring board will additionally perform recurrent quality assurance verifications and dataset evaluations to maintain data reliability and comprehensiveness.

Intervention

Following successful ECMO cannulation and establishment of stable extracorporeal blood flow (≥3 L/min), a washout period is implemented. All the sedatives are discontinued while continuous infusion of remifentanil (0.01–0.05 µg/kg/min) is maintained to control baseline pain, with the dose titrated based on the Critical Care Pain Observation Tool (CPOT) score to maintain a target CPOT score of ≤2. Sedation depth is monitored by assessing the RASS score every 15 minutes throughout the washout period until the patient achieves a RASS score of −1. Subsequently, study drug infusion begins when RASS −1 is achieved. For patients in the remimazolam group, remimazolam besylate (Yichang Humanwell Pharmaceutical Co., Ltd., China) is administered intravenously at an initial rate of 0.3 mg/kg/h (23), titrated between 0.3–3 mg/kg/h at 5-minute intervals until the target RASS score of −4 is achieved. Once stabilized, adjustments are made every 4 hours based on RASS assessments performed by a dedicated blinded medical staff team. Similarly, the midazolam group receives midazolam (Nhwa Pharmaceutical Co., Ltd., Jiangsu, China) intravenously at an initial rate of 0.05 mg/kg/h, titrated between 0.02–0.2 mg/kg/h at 5-minute intervals to reach RASS −4, followed by dose adjustments every 4 hours. When adequate sedation cannot be achieved even with the maximum dose of the study drug, dexmedetomidine (0.1–0.7 µg/kg/h) may be administered intravenously as rescue sedation. All RASS assessments adhere to standardized protocols with inter-rater reliability ensured through centralized training across multiple centers. The shortest expected treatment time will be 24 hours and the longest will be no more than 72 hours. All the medical staff who deliver the interventions are licensed nurses or doctors. In the event that the patient’s blood pressure goes down by over 20% from its baseline value during ECMO treatment, vasopressors should be administered and their dosage is recorded. Treatment with the study drug will be terminated under the following circumstances: patient death, planned surgery requiring alternative sedation, discontinuation of the study drug by the attending physician for ≥12 hours, discharge from the ICU and voluntary withdrawal from the trial. Patients are followed up to 28 days for monitoring outcomes.

Primary and secondary outcomes

Primary outcome

The percentage of time within the target sedation range (TTR) without rescue sedation.

Secondary outcomes

• Compare the difference in time to awakening between the two groups.
• Compare the differences between the two groups in 28-day ECMO free time, ECMO weaning rate, 28-day mortality rate, 28-day mechanical ventilation-free time, ICU length of stay, and hospital length of stay.
• Compare hemodynamic parameters, blood routine tests, hepatic/renal functions, and coagulation routine tests between the two groups to evaluate which medication has less impact on patients.
• Record adverse events (AEs) (e.g., nausea, vomiting, delirium, self-extubation) during medication in both groups to observe which drug regimen is associated with fewer AEs.
• Compare sedative drug usage and total hospitalization costs between the two groups during the trial period, aiming to provide personalized options for patients.

Statistical analysis

SPSS version 21.0 will be used for statistical analysis. All endpoints will be analyzed according to the intention-to-treat principle. All statistical inferences will be performed with two-tailed tests, and a significance level of α=0.05 will be set for these statistical analyses. Parameter estimates will be reported with 95% confidence intervals (CIs). Total dropout rates and dropouts due to AEs will be compared between groups using the Chi-squared (χ²) test. Continuous variables will be reported as mean ± standard deviation (SD) with 95% CIs. If necessary, additional descriptors (minimum, maximum, P25, median, P75) will be provided. For nonparametric analyses, median and mean ranks will be reported. Categorical variables will be presented as frequency distributions and percentages. Baseline characteristics will be analyzed using appropriate statistical descriptions and inferences to ensure comparability between groups. Statistical significance will be defined as a P value of <0.05. Regarding missing data, we have no plans to perform imputation.

AEs and SAEs

During the study period, AEs are defined as any unpredictable or unfavorable clinical results caused by medical interventions. In this study, potential AEs may include, but are not limited to, bradycardia and hypotension decreased oxygen saturation, delirium, self-extubation, liver and kidney deterioration. Effort should be made to determine if the study drug is responsible for the AEs (including SAEs). Whether it is assessed as definitely related or probably related, the event will be classified as a drug-related adverse reaction.

Upon detection of an SAE, the supervising physician must immediately terminate investigational sedative delivery and initiate emergent therapeutic interventions. The PI is obligated to systematically conduct causality assessments, document therapeutic interventions, and track clinical outcomes for all AEs, with expedited SAE reporting to the institutional review board within protocol-defined timelines.

Discussion

This is a randomized, multicenter clinical trial providing the first prospective evidence on remimazolam besylate in sedating ARDS patients supported by VV-ECMO. Designed as an exploratory study, it offers critical insights into remimazolam’s feasibility, safety, and preliminary efficacy in this high-risk population. While the sample size may limit definitive conclusions, the study lays a foundational basis for future research by identifying key parameters specific to ECMO patients, including optimal dosing ranges and safety thresholds. If results demonstrate comparable performance to midazolam, remimazolam will emerge as a viable alternative sedative for critically ill patients undergoing ECMO support. The findings may advance sedation strategies for complex ICU settings.

An ideal sedative for critical care offers rapid recovery, enabling timely neurological assessments and faster weaning from mechanical ventilation. Evidence suggests that patients sedated with remimazolam experience significantly shorter time to awakening compared to those receiving midazolam (28-30). This rapid offset can potentially facilitate quicker extubation, reduce ICU length of stay, and minimize complications associated with prolonged sedation. Furthermore, the clinical application of remimazolam is already extending into the ICU. Research demonstrates its effectiveness for sedation in mechanically ventilated ICU patients (23,24), showing a superior safety profile with lower incidences of hypotension compared to propofol (31), and less variability in heart rate compared to midazolam (32). Remimazolam was also demonstrated to have a more stable hemodynamics effects than propofol for patients undergoing endoscopic submucosal dissection surgery (33). Its favorable hemodynamic stability makes it a particularly valuable option for ECMO patients, who often exhibit precarious cardiovascular function. Moreover, its unique metabolism via non-specific tissue esterases reduces dependence on hepatic and renal function, which is a significant advantage for patients with multi-organ dysfunction or those on ECMO support where drug pharmacokinetics are altered. Another important consideration for sedative efficacy in ECMO patients is drug sequestration within the circuit. A recent in-vitro study comparing remimazolam and midazolam in blood-primed circuit (26). At 24 hours, the percentage of the initial drug dose remaining was lower for remimazolam (15%) than for midazolam (52%). This suggests that midazolam undergoes greater sequestration which can lead to unpredictable plasma concentrations. In contrast, the lower sequestration of remimazolam, coupled with its rapid esterase metabolism may contribute to more stable sedation and a more predictable pharmacokinetic profile in ECMO patients. This characteristic could potentially translate into a reduced need for dose adjustments over time, although further confirmation is required in clinical trials. Therefore, remimazolam besylate represents a significant advancement in sedation for ECMO patients.

This study has several limitations. First, even though RASS and SAS are the most valid and common sedation assessment tools for evaluating the depth of sedation in adult ICU patients, the RASS score is evaluated subjectively (34). Therefore, a standardized multi-center training program is implemented prior to trial initiation to ensure consistency in RASS assessments across all sites and minimize inter-rater variability. Second, as participants are screened and enrolled under sedation, a pre-trial sedation period may introduce bias. To resolve this, a washout procedure will be conducted prior to the study drugs administration. All sedatives will be discontinued until a RASS score of −1 is achieved. Subsequently, protocol-directed sedation with either remimazolam or midazolam will be administered as per the randomization protocol. Third, this study is a single-blind design. Although all outcome assessments, including the primary endpoint of RASS scores, will be performed by a dedicated, blinded team independent of the intervention group, the inability to blind the treating clinicians at the bedside represents a potential source of bias. Fourth, the inclusion age range is set from 18 to 80 years, this may lead to a potential bias in favor of the elderly population. To address this, pre-specified subgroup analyses based on age (18–65 and 65–80 years) will be performed to validate the consistency of the treatment effects across different age groups.

The strength of our study lies in its multicenter design, which enhances both population heterogeneity and participant diversity, thereby improving the generalizability of the findings. As the first prospective, single-blind, multicenter, randomized controlled trial assessing the safety and efficacy of remimazolam besylate in ARDS patients receiving VV-ECMO support, this study aims to systematically assess its sedative effects and clinical outcomes in comparison with the commonly used midazolam. We seek to provide high-quality scientific evidence to inform sedation management in ECMO-supported patients.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the SPIRIT reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-aw-2179/rc

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-aw-2179/prf

Funding: This study was supported by Noncommunicable Chronic Diseases-National Science and Technology Major Project (No. 2024ZD0530002), Guangzhou Clinical Specialty Program (No. 2023C-TS01) and Guangzhou Science and Technology Plan Project (No. 202102010369).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-aw-2179/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This trial was approved by the Ethics Committee of the First Affiliated Hospital of Guangzhou Medical University (Approval No. ES-2025-097-01), and registered at the Chinese Clinical Trials Registry (Identifier: ChiCTR2500108567). Written informed consent will be obtained from patients or their legally authorized representatives after detailed explanation of the study protocol, including randomization, blinding, and potential risks. The study will be conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The other medical centers were also informed of and agreed on the study.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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