Introduction
Postoperative delirium is a common and serious problem in older patients after orthopedic surgery, with an incidence of 24.0% to 55.9% in patients with femur fracture and 12.5% to 24.3% in geriatric patients. undergoing spinal surgery.1–3 Hyperactive delirium is the most common subtype and is often characterized by agitation.3,4 Uncooperative agitation is dangerous in orthopedic procedures that require temporary postoperative immobilization because of the risk of self-inflicted physical injury, such as dislocation of a prosthesis. It can also cause great distress to caregivers, healthcare professionals, and patients themselves.4 In addition to mechanically ventilated patients with endotracheal intubation, agitation is not uncommon in non-intubated patients. Sedation management in such populations is more difficult due to the lack of a secure airway.5
To date, studies on the management of sedation in non-intubated agitated patients are rare. Although haloperidol and some atypical antipsychotics (olanzapine, risperidone, etc.) are recommended by guidelines, relevant studies show conflicting results.5-7 A study in non-intubated patients with agitated delirium showed that the failure rate with haloperidol was 43%, while dexmedetomidine it can be used as a rescue agent for haloperidol-refractory hyperactive delirium.6 Nevertheless, dexmedetomidine may not be applicable in older patients with uncooperative or even dangerous agitation. Lower doses of dexmedetomidine are generally ineffective for rapid sedation, while adverse cardiovascular effects induced by a higher starting dose are inevitable, especially in frail patients. A 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 the benzodiazepines, midazolam and lorazepam are considered the preferred quick sedation drugs. in patients with acute agitation or agitated delirium due to their rapid onset of action and short half-life.4,9 As a new ultra-short-acting benzodiazepine, remimazolam tosylate is approved for procedural sedation in China.10 Remimazolam has a faster onset of action and a more high safety profile, does not depend on a specific organ to be metabolized, and can be rapidly removed even after prolonged infusion.11,12 During procedural sedation, the incidence of hypotension and respiratory depression in patients sedated with remimazolam, was 13.0% to 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 reversed the effects of remimazolam in case of adverse events, an advantage not available with non-benzodiazepines.10 Based on these unique pharmacologic effects, we hypothesized that remimazolam should be a reasonable option for the relief of agitated delirium in non-intubated older 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 excited delirium in non-intubated adult patients after orthopedic surgery.
Methods
I 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 of elderly patients follows established standards .15
Ethical approval and consent to participate
All procedures performed in this study conformed to 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, subjects recruited for the study experience agitation and have lost their normal cognitive and behavioral abilities. We therefore obtained informed consent to participate from the patient’s legal representative. Given the risk of sedation in non-intubated older patients, the study should be performed in an intensive care unit (ICU). In emergency situations (the presence of risks of adverse events related to acute agitation, such as unexpected removal of the tube, dislocation of the hip prosthesis and other self-inflicted physical injuries), patients can be transferred to an intensive care unit with the verbal consent of their representatives. However, written informed consent must be obtained before study drug administration. Patients or their representatives can withdraw their consent at any stage. The clinical trial was pre-registered in the Chinese Clinical Trial Registry on August 21, 2020 with a unique identifier: ChiCTR2000036101.
Enrollment criteria
Older patients (aged ≥70 years) following orthopedic surgery were eligible for the study if they developed excited delirium. The following criteria must be met to define agitated delirium: 1) Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) results indicate the presence of delirium with a Richmond Agitation-Sedation Scale (RASS) score ≥216 and 2) Assessment Motor Activity Scale Score (MAAS) ≥5.17. Patients were excluded if 1) they developed acute agitation before or within 4 h of resuscitation with anesthesia (successful removal of an artificial airway was considered a sign of recovery from anesthesia); 2) were already receiving dexmedetomidine or other sedatives; 3) had grade C or higher heart failure and second degree or higher atrioventricular block; 4) there are serious disorders of the central nervous system (craniocerebral trauma, acute stroke, progressive dementia); 5) has a history of mental disorders or alcohol dependence; 6) were unable to complete the relevant assessment due to language, hearing and visual impairment; 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, blocked randomization was used. Block sizes were randomly set to 2, 4, and 6; participants in each block were identified by their inclusion sequence number and were randomly assigned 1:1 to receive remimazolam besylate or dexmedetomidine sedation 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 Research Administration
Preliminary determination of the dose of the study drug
Subjects randomized to the dexmedetomidine group received a loading infusion of 0.5 μg/kg dexmedetomidine {Yangtze River Pharmaceutical (Group) Co., Ltd. Jiangsu, China} for 10 minutes, followed by a maintenance dose of 0.2 to 0.7 μg/kg/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 sedative tolerance.10,18,19 Due to the limited use of remimazolam in non-anesthetic settings , it was difficult to predetermine an appropriate dose to maintain 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 of this dose, the venous plasma concentration is maintained around 800 ng/mL with a bispectral index value of 40 to 60 (unresponsive to noxious stimuli) and a bispectral index value approaching 80 (responsive to voice commands ), when the plasma concentration decreases to about 200 ng/mL.20,21 Based on the above findings, the maintenance dose of remimazolam besylate is tentatively predetermined at 0.1 to 0.3 mg/kg/h (almost one-fourth of the maintenance dose for general anesthesia) in the present study. To minimize the risk of oversedation, subsequent treatment was dose titrated guided by the RASS score.
Dose titration of the study drug
Study drugs were titrated by the bedside nurse to achieve the target range of sedation (RASS score of -2 to 0) according to the following protocol: 1) If 1 ≤ RASS score ≤2 after continuous infusion of sedatives for more than 15 minutes , doses of remimazolam besylate and dexmedetomidine were titrated 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 study drugs reach the predetermined upper limit for more than 15 minutes and the RASS score remains 3 or more, 0.5 to 1 mg/kg propofol is administered temporarily as rescue sedation under the supervision of the attending physician to prevent serious adverse events related to agitation. 3) If RASS score ≤-3 during continuous infusion, sedation was reduced or discontinued until patients returned to an acceptable range of sedation.
Intermittent wakeup protocol
To avoid as much as possible the use of non-essential sedation and to reduce the risk of bias in the assessment of delirium in patients receiving moderate sedation,22 we created an intermittent awakening protocol in conjunction with the “daily awakening”. After reaching the sedation goal for the first time, the continuous infusion of sedatives was interrupted every 8 hours unless the patient was in an agitated state at that stage. If agitation recurred within 1 h of sedation interruption, sedatives were re-administered as described earlier in the protocol. If the MAAS score remains 2 to 4 after 1 hour, agitation is considered resolved and sedation is completely discontinued. Therefore, 8 hours of continuous sedation and one interruption of sedation was considered a complete “observation period” in this study.
Precautions
Excessive sedation in the absence of a safe airway can have catastrophic…
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