Comment on “Effect of remimazolam on postoperative delirium in elderly patients undergoing major abdominal surgery: a randomized controlled trial”

Dear Editor, We were particularly intrigued by the findings of Zhang et al, who reported that remimazolam does not elevate the risk of postoperative delirium (POD) in elderly patients when compared to propofol[1]. We extend our congratulations to Zhang et al for conducting a high-quality, adequately powered randomized trial that significantly contributes to the evidence base regarding the use of remimazolam for delirium prevention in older adults undergoing major abdominal surgery. However, we have identified several areas where further clarification could enhance the interpretation of the study and guide future research efforts. This article was written in accordance with the TITAN guidelines[2]. First, the study’s primary endpoint was POD, a condition that is influenced by a variety of perioperative factors[3,4]. Well-documented independent risk factors for POD include preoperative anxiety, poor sleep quality, and a history of prior delirium. Notably, the study did not examine whether these baseline characteristics or other documented preoperative risk factors were evenly distributed across the two groups. This omission could potentially introduce confounding effects on the incidence of POD. We recommend that future research should actively identify and collect data on these preoperative factors. Researchers could either exclude these factors or adjust for them statistically during the study design or analysis phase to enhance the reliability of the results. Second, focusing on elderly patients undergoing major abdominal surgery with general anesthesia for POD assessment may have certain limitations. Major abdominal surgery often requires the use of multiple indwelling tubes (e.g., nasogastric, drain, urinary catheter), which can independently contribute to delirium and potentially confound the results[5]. The pain or discomfort associated with these tubes can trigger a stress response, leading to the activation of the sympathetic nervous system and the release of inflammatory cytokines, both of which are known to induce delirium. Any differences in catheterization between the two groups could have had a significant impact on the study outcomes. Third, the trial did not specify whether commonly used anticholinergic drugs in clinical anesthesia, such as glycopyrrolate or atropine, were administered intraoperatively[6]. Glycopyrrolate is typically used to reduce secretions, while atropine is employed to manage intraoperative bradycardia. These anticholinergic agents, by blocking central and peripheral cholinergic receptors, can lead to decreased acetylcholine levels. Impaired cholinergic neurotransmission is a key pathophysiological mechanism underlying POD and can directly increase its risk. In elderly patients with impaired hepatic and renal function, the duration of action of these drugs may be prolonged, exacerbating their cumulative effects on the central nervous system. Differences in the frequency or dosage of anticholinergic drug use between the two groups could represent an uncontrolled confounding factor. Lastly, the study did not compare postoperative pain levels between the two groups or report the use of opioid analgesics and other analgesic drugs during the perioperative period. Postoperative pain is an independent risk factor for delirium, and effective acute postoperative pain management can reduce its incidence[7]. Although the transverse abdominis plane block was performed before surgery to optimize postoperative analgesia, the absence of detailed pain data limits the comprehensive interpretation of the results.