To date, studies of sedation management in non-intubated agitated patients are scarce. Although haloperidol and some atypical antipsychotics (olanzapine, risperidone, etc.) are recommended by the guidelines, relevant studies have shown conflicting results.5–7 A study in non-intubated patients with agitated delirium showed that the failure rate for haloperidol was 43%, whereas dexmedetomidine could be used as a rescue agent for haloperidol-resistant hyperactive delirium.6 However, dexmedetomidine may not be applicable in elderly patients with uncooperative or even dangerous agitation. Lower doses of dexmedetomidine are usually ineffective for rapid sedation, and adverse cardiovascular effects caused by a higher initial dose are unavoidable, especially in fragile patients. Meta-analysis showed that the incidence of bradycardia, hypotension, and hypoxemia in elderly patients treated with dexmedetomidine was 23.1%, 36.3%, and 10.4%, respectively. 8 Among benzodiazepines, midazolam and lorazepam are considered the drugs of choice for transcycling. in patients with acute agitation or induced delirium due to its rapid onset of action and short half-life.4,9 As a new ultra-short-acting benzodiazepine, remimazolam tosylate has been approved for procedural sedation in China.10 Remimazolam has a faster onset of action and a higher safety profile, does not rely on a specific organ to be metabolized and can be rapidly removed even after prolonged infusion. 23.7% and 1.1% to 3.1%, respectively, which were significantly lower than those in the propofol sedation group.13,14 In addition, flumazenil reverses the effects of remimazolam in adverse events, an advantage that it is not available to non-benzodiazepines.10 Based on these unique pharmacologic effects, we hypothesized that remimazolam should be a reasonable choice for the relief of agitated delirium in non-intubated elderly patients. The objective of this randomized clinical trial was to evaluate the efficacy and safety of remimazolam besylate compared with dexmedetomidine for the relief of agitated delirium in non-intubated elderly patients after orthopedic surgery.

Methods

Study Design

This single-center, prospective, randomized, single-blind, controlled clinical trial was conducted in the Geriatric Orthopedic Center of Sichuan Provincial Orthopedic Hospital from September 2020 to November 2021. In our institution, the perioperative management process for elderly patients follows established standards .15

All procedures performed in this study complied with the ethical guidelines of the Declaration of Helsinki and were approved by the Ethics Committee of Sichuan Provincial Orthopedic Hospital (KY-2020-031-01). For research purposes, participants recruited for the study were experiencing agitation and had lost their normal cognitive, behavioral abilities. Therefore, we obtained informed consent for participation from the patient’s legal representative. Given the risk of sedation in non-intubated elderly patients, the study should be conducted in an intensive care unit (ICU) setting. In emergency situations (in the presence of risk of adverse effects of acute stimulation, such as unexpected tube removal, dislocation of prosthetic hip and other self-inflicted physical injuries), patients could be transferred to the ICU with the verbal consent of their representatives. However, written informed consent must be obtained before study drug administration. Patients or their representatives can withdraw consent at any stage. The clinical trial was pre-registered in the Chinese Clinical Trial Registry on August 21, 2020, with the unique identifier: ChiCTR2000036101.

Registration Criteria

Elderly patients (aged ≥70 years) after orthopedic surgery were eligible for the study if they presented with agitated delirium. The following criteria must be met to determine agitated delirium: 1) Confusion Assessment Method for ICU (CAM-ICU) results indicated the presence of delirium with a Richmond Agitation-Sedation Scale (RASS) score ≥216 and 2) Assessment of motor activity Scale score (MAAS) ≥5.17 Patients were excluded if 1) they developed acute agitation before or within 4 hours of resuscitation with anesthesia (successful removal of an artificial airway was considered an indication of recovery from anesthesia); 2) were already receiving dexmedetomidine or other sedatives; 3) had grade C or higher from Heart Failure Stages and second degree or higher AV block. 4) had severe disorders of the central nervous system (craniocerebral trauma, acute stroke, progressive dementia). 5) had a history of mental disorders or alcohol dependence. 6) were unable to complete the relevant assessment due to language, hearing and vision problems. and 7) were allergic to the drugs used in the study.

Randomization and Blinding

To ensure a balance of the number of participants between the two groups, a blocked randomization was used. Block sizes were randomly assigned to 2, 4, and 6. Participants in each block were identified according to their inclusion sequence number and randomly assigned 1:1 to receive sedation with remimazolam besylate or dexmedetomidine based on a randomization code generated by SPSS version 20.0. This clinical trial was a single blind study because the sedation protocols were completely different between the two groups. The attending physician and bedside nurse performing the sedation protocols could not be blinded to study group allocation. However, the study outcome assessors were independent.

Drug Study

Predetermination of study drug dose

Subjects randomized to the dexmedetomidine group received a loading infusion of 0.5 μg/kg dexmedetomidine {Yangtze River Pharmaceutical (Group) Co., Ltd. Jiangsu, China} over 10 min, followed by a maintenance dose of 0.2 to 0.7 μg/h .6 A loading dose of 0.075 mg/kg for remimazolam besylate (Hengrui Pharmaceuticals Co., Ltd. Jiangsu, China) was predetermined considering the subjects’ poor sedation tolerance.10,18,19 Due to the limited use of remimazolam in non-anesthesia settings, it was difficult to predetermine the appropriate dose for maintenance of sedation. A study in healthy Chinese volunteers recommended 1.0 mg/kg/h remimazolam besylate as a maintenance dose for general anesthesia. During continuous infusion at this dose, the venous plasma concentration was maintained at approximately 800 ng/mL with a bispectral index value of 40 to 60 (no response to noxious stimuli) and a bispectral index value approaching 80 (response to vocal orders) when the plasma concentration decreased to approximately 200 ng/mL.20,21 Based on the above findings, the maintenance dose of remimazolam besylate was tentatively preset at 0.1 to 0.3 mg/kg/h (almost one quarter of the maintenance dose for general anaesthesia) the present study. To minimize the risk of oversedation, a dose titration guided by the RASS score was performed at the next treatment.

Dose titration of study drug

Study drugs were titrated by the bedside nurse to achieve the targeted range of sedation (RASS score from -2 to 0) according to the following protocol: 1) If 1 ≤ RASS score ≤2 after continuous infusion of sedatives for more than 15 min, h The doses of remimazolam besylate and dexmedetomidine were increased in steps of 0.05 mg/kg/h and 0.1 μg/kg/h, respectively. The interval between each dose adjustment should be at least 15 minutes. 2) If the infusion doses of the study drugs reached the predetermined upper limit for more than 15 minutes and the RASS score remained at 3 or above, 0.5 to 1 mg/kg propofol was given temporarily as rescue with supervised sedation doctor to prevent serious side effects related to stimulation. 3) If RASS score ≤−3 during continuous infusion, sedation was reduced or stopped until patients returned to acceptable range of sedation.

Intermittent wake-up protocol

To avoid as much as possible the use of nonessential sedatives and to reduce the risk of bias from the assessment of delirium in moderately sedated patients,22 we designed an intermittent awakening protocol with a reference to “daily awakening”. After the goal of sedation was initially achieved, the continuous infusion of sedatives was discontinued every 8 hours unless the patient was agitated at this stage. If agitation recurred within 1 h after cessation of sedation, sedatives were re-administered as previously described in the protocol. If the MAAS score remained at 2 to 4 after 1 hour, agitation was considered to have resolved and sedation therapy was discontinued completely. Therefore, 8 h of continuous sedation and one interruption of sedation was considered a complete “observation period” in this study.

Security measures

Excessive sedation in the absence of a secure airway can have catastrophic…