Unlocking cognitive clarity: the neuroprotective potential of low-dose S-ketamine in elderly thoracic surgery patients

Postoperative delirium (POD) and postoperative cognitive dysfunction (POCD) represent significant challenges in the management of elderly patients undergoing thoracic surgery[1]. The acute and sporadic disruptions in attention, awareness, and cognition that characterize these conditions can have a detrimental effect on a patient’s ability to recover, lengthen hospital stays, and raise the expense of healthcare[2]. Traditional approaches to mitigating these complications have had mixed results, However, the powerful N-methyl-d-aspartate (NMDA) receptor antagonist S-ketamine, when taken at low doses, may be a viable new treatment option, according to ongoing studies. Compared to racemic ketamine, S-ketamine, the S(+) enantiomer of ketamine, has a stronger anesthetic potency and a higher affinity for NMDA receptors[3]. This unique pharmacological profile suggests that S-ketamine could provide substantial neuroprotection, potentially reducing the incidence and severity of POD and POCD as seen in mice models[4]. Recent studies have highlighted S-ketamine’s role in modulating neuroinflammation, a critical factor in the pathophysiology of these postoperative neurocognitive disorders[5,6]. Following surgery, S-ketamine preserves neuronal integrity and function by preventing the activation of inflammatory cytokines and lowering neuronal apoptosis[7]. In a recent retrospective cohort study by Wang et al. involving patients aged 65 years and older who underwent elective thoracic surgery, it was found that those who received low-dose S-ketamine intraoperatively had a significantly lower incidence of POD at seven days postsurgery than those who did not receive S-ketamine (12.0% vs. 26.7%, P < 0.001)[8]. Moreover, these patients exhibited reduced POCD at one month (18.7% vs. 36.0%, P < 0.05) and 6 months (10.7% vs. 21.3%, P < 0.05) postoperatively. The S-ketamine group also had significantly higher median Montreal Cognitive Assessment scores at one month (P = 0.021) and 6 months (P = 0.007) than the control group, indicating better cognitive function recovery. The mechanism by which S-ketamine exerts its protective effects involves the modulation of glutamatergic neurotransmission[4,5]. By preferentially blocking N-methyl-D-aspartate (NMDA) receptors on inhibitory gamma-aminobutyric acid (GABAergic) interneurons, S-ketamine reduces the inhibitory control over excitatory neurons, thus enhancing neuroplasticity and synaptogenesis[9]. This process is crucial for cognitive recovery postsurgery. S-ketamine may also be useful in reducing the neuroinflammatory reaction that is frequently observed following major surgeries, as evidenced by its capacity to lower levels of pro-inflammatory cytokines like Interleutin (IL-6), Tumor necrosis factor (TNF-α), and IL-1β[10]. Despite these promising findings, the clinical application of S-ketamine remains challenging. Concerns regarding its dissociative side effects and potential for abuse have limited its widespread adoption. Moreover, evidence from randomized controlled trials (RCTs) is mixed. Ketamine does not generally significantly lower the incidence of POD, according to several studies, and may even increase the likelihood of negative side effects such as hallucinations and nightmares[7,11,12]. However, these studies often did not differentiate between racemic ketamine and S-ketamine, which may have differing efficacy and safety profiles. The variability in outcomes across studies may also be attributed to differences in dosing regimens, patient populations, and surgical procedures. For instance, a study focusing on cardiac surgery patients found no significant benefit of low-dose ketamine in preventing POD, while another study involving noncardiac thoracic surgery patients highlighted its efficacy[13,14]. This underscores the need for further research to refine dosing strategies and identify patient populations that would benefit most from S-ketamine administration. Given the aging global population and increasing number of elderly patients undergoing complex surgeries, the potential of S-ketamine to improve postoperative outcomes is of great clinical significance. Future research should aim to conduct larger multicenter RCTs to confirm these findings and establish standardized protocols for S-ketamine use. Investigations of the long-term effects of S-ketamine on cognitive function and its interactions with other anesthetics and perioperative medicines should be part of these investigations. In conclusion, although the available data indicate that older patients undergoing thoracic surgery may experience a considerable decrease in the frequency of POD and POCD when administered at low doses, caution should be exercised when using this medication. When adding S-ketamine to anesthetic procedures, clinicians should evaluate the advantages against any hazards and consider the unique circumstances of each patient. As research continues to evolve, S-ketamine holds promise as a valuable tool in enhancing postoperative recovery and quality of life for elderly surgical patients.

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