Perioperative neurocognitive dysfunction and role of dexmedetomidine in radical colon cancer surgery in elderly patients

Abstract

This article explored the application of dexmedetomidine (Dex), a highly selective alpha-2 agonist, in managing postoperative cognitive dysfunction (POCD) in elderly patients undergoing radical colon cancer surgery. Aging is associated with a progressive decline in physiological functions and an increased risk of adverse surgical outcomes, including POCD, which encompasses many neurocognitive disorders that manifest during the perioperative period. The aging population is at a higher risk for POCD, which can lead to prolonged hospital stays, delayed recovery, and increased healthcare costs. Dex has neuroprotective, opioid-sparing, and sympatholytic properties, which reduces the incidence and severity of POCD. Dex was introduced for sedation in patients receiving mechanical ventilation but has since been adopted in anesthesia due to its multifaceted benefits. Its application extends to sedation, analgesia, maintenance of anesthesia, and controlling delirium. Its neuroprotective and anti-inflammatory effects have been explored in managing POCD. This article discussed the broad range of patient and procedure-related risk factors for POCD. Early identification and intervention are crucial to prevent the progression of POCD, which can have severe physical, psychological, and economic consequences. The article underscored the importance of a multidisciplinary approach in managing POCD, involving the optimization of comorbidities, depth of anesthesia monitoring, hemodynamic stability, and cerebral oxygenation monitoring.

Key Words: Colon cancer; Dexmedetomidine; General anesthesia; Elderly; Radical colon cancer surgery; Cognitive function

Core Tip: Dexmedetomidine (Dex) is a significant drug that improves surgical outcomes in varied surgeries. The neuroprotective, opioid-sparing, and sympatholytic properties of Dex have shown improved outcomes in the elderly population in various surgeries including radical colon surgeries. The decline in the incidence and severity of postoperative cognitive dysfunction, the decreased surge in proinflammatory markers, improved regional cerebral oxygenation, and better pain control due to Dex lead to improved outcomes, early discharge, and decreased healthcare costs in this vulnerable group of patients.

INTRODUCTION

Aging is associated with a progressive decline in the physiological function of all organ systems along with other major comorbidities and increased vulnerability to anesthesia drugs[1,2]. Frailty in the older population is associated with aging-related functional capacity decline and reduced tolerance to surgical interventions[3]. However, there is variability in the onset and severity of these physiological derangements. Major surgeries in this vulnerable population group carry a significant risk of adverse outcomes[4]. The major adverse outcomes include major adverse cardiac events[5], pulmonary complications[6], renal impairments[7], and postoperative cognitive dysfunction (POCD). Among the adverse outcomes associated with major surgeries in this population, perioperative neurocognitive disorder (PND) stands out due to its high prevalence and significant impact. POCD is associated with poor wound healing, delayed mobilization, prolonged hospital stays, hospital readmission[8], and delay in resumption of routine lifestyle[9].

The incidence of colon cancer has increased in the elderly population in the past few decades due to altered lifestyles, prolonged life expectancy, better screening, and increased awareness[10]. With the advancement in surgical and anesthesia techniques, a large number of the elderly population is subjected to surgical interventions. Radical colon surgeries are curative surgeries that include the removal of colon segments and lymph nodes. Enhanced recovery protocols after colorectal surgeries are aimed at early hospital discharge while minimizing perioperative physiological disturbances[11].

PND is a broad term that includes abnormalities in behavior, affect, and cognition in the perioperative period and is included in the Diagnostic and Statistical Manual 5^th edition terminology for neurocognitive disorder. PND is a well-recognized adverse complication in the elderly population that causes delays in the recovery of patients and prolongs hospital stays. PND includes entities like preexisting cognitive impairment, postoperative persistent or recurrent delirium, delayed neurocognitive recovery, and major or minor neurocognitive decline that persists or is diagnosed up to 12 months after the procedure[12]. The exact mechanism of PND is unclear, but risk factors are broadly classified into patient and procedure-related. The patient-related factors include age > 65 years, dementia, neurodegenerative disorder, excessive alcohol consumption, polypharmacy including psychotropic drugs, vascular disorders, sleep disorders, diabetes mellitus, and prior neuron damage like stroke or traumatic brain injury and frailty[13-15]. The procedure-related factors include major complex surgeries like open cardiac surgeries and joint arthroplasties, head and neck surgeries, and colorectal surgeries[16-19]. The incidence of postoperative delirium in colorectal surgeries ranges from 8% to 54%[20].

The exact pathophysiological mechanisms of PND are unclear, but systemic inflammatory responses to perioperative stress causing excessive neuroinflammation and exaggerated neurodegeneration have been postulated as the main cause of PND[21,22]. Patient and procedure-related factors mentioned above can change the extent and severity of these inflammatory processes. Dexmedetomidine (Dex) is a highly selective alpha-2 agonist that acts via activation of G protein-coupled receptors in the brainstem inhibiting norepinephrine release[23]. Dex was initially introduced in 1999 for sedation in patients receiving mechanical ventilation. Thereafter, the use of Dex has exploded in anesthesia as an “all-in-one drug.” The pharmacological properties of Dex have been widely explored, and it has been used in sedation, analgesia, sympatholysis, maintenance of anesthesia, delirium control, awake intubation, and procedural sedation[24]. Interestingly, the neuroprotection and anti-inflammatory properties of the drug were further explored to control PND. The systematic reviews and meta-analyses published in recent years have established the beneficial role of Dex in preventive cognitive dysfunction in cardiac[25,26] and noncardiac surgeries[27,28]. Bu et al[29] in their randomized control trial (RCT) have also concluded that Dex decreases cognitive dysfunction in radical colon cancer surgeries in the elderly. The article gives an insight into perioperative cognitive dysfunction and pharmacological intervention by Dex to prevent PND.

NEUROCOGNITIVE DYSFUNCTION

PND is a broader term used for various clinical entities involving behavior, affect, and cognition in the perioperative period[12]: (1) Preexisting cognitive impairment (diagnosed in the preoperative period); (2) Postoperative persistent or recurrent delirium (beyond the emergence period of general anesthesia); (3) Delayed neurocognitive recovery (diagnosed 30 days after surgery); and (4) Major or minor neurocognitive decline (diagnosed after 12 months after surgery). POCD is a generalized term often used to diagnose any postoperative cognitive impairment and is often used in clinical studies. POCD is a clinical diagnosis, and the Montreal Cognitive Assessment/Mini-Mental State Examination (MMSE) scales are often used to diagnose and assess the severity of impairment[30] (the same scale was used in the RCT by Bu et al[29]). A preoperative cognitive screening should be performed using MMSE or a shorter scale such as Mini-Cog as a baseline measurement[31-33]. Similarly, postoperative evaluation should be performed using the same scale to detect any decline in cognition. A patient with risk factors of PND should undergo regular screening at timely intervals for early detection, while all the preventive measures are carried out simultaneously.

PND is associated with delayed recovery, increased hospitalization period, increased mortality, and increased medical costs. There can be impairment of mood, memory, emotions, behavior, sleep, and personality. Even a short period of postoperative cognitive impairment can lead to permanent cognitive dysfunction like Alzheimer’s disease and dementia causing severe physical and psychological impact and loss of independence[34-36]. Thus, it is imperative to identify risk factors to prevent PND, and early clinical recognition is important to prevent progressive deterioration.

SYSTEMIC INFLAMMATION AND NEUROPROTECTION

The exact mechanisms responsible for neurocognitive disorder are still not clear. Inflammatory processes due to perioperative stress cause neuronal damage and neuroinflammation[20]. Microemboli causing neuronal injury due to blood clots or air have also been proposed as possible mechanisms. Inflammatory biomarkers play a critical role in the development of PND through their contributions to systemic and central inflammatory responses. Tumor necrosis factor-alpha promotes microglial activation and blood-brain barrier disruption, leading to increased permeability and neuronal injury. Interleukin (IL)-1β amplifies this process by further activating microglia and inducing neuroinflammation, which exacerbates cognitive decline. IL-6, another key cytokine, is involved in the acute-phase response and has been correlated with both the severity and duration of PND.

The calcium-binding protein S100B is a marker of blood-brain barrier disruption and direct neuronal injury. Elevated levels of S100B indicate neuroinflammation and correlate with cognitive dysfunction. Similarly, C-reactive protein, a systemic inflammatory marker, reflects the presence of nonspecific acute-phase responses and has been associated with prolonged POCD. Neuron-specific enolase (NSE), a biomarker of neuronal damage, further underscores the link between inflammation and cognitive impairment. Targeting inflammatory pathways, such as toll-like receptor signaling and nuclear factor kappa B activation, offers a therapeutic avenue[37]. Dex, through its anti-inflammatory effects, could potentially modulate these responses, attenuating neuroinflammation and preserving cognitive function in the perioperative period. Clinical studies have measured these inflammatory markers to establish an association with PND.

Elevated serum levels of systemic inflammatory markers like tumor necrosis factor-alpha, IL-1, and IL-6 are raised in cohorts who suffered from POCD compared to those who did not show cognitive impairment in the perioperative period in total hip arthroplasties[38]. Elevated levels of specific markers of neuronal damage and repair processes like NSE and S100β were measured by Bu et al[29] in their trial. Low regional brain oxygenation and increased brain cellular metabolism as measured by lactate production and glucose utilization rate can also produce neuronal damage[39]. Preventive measures are directed to mitigate these inflammatory processes. External factors are responsible for exaggerated inflammatory processes and steps for neuroprotection to prevent cognitive dysfunction are summarized in Table 1.

Table 1 The general and specific risk factors for perioperative neurocognitive disorders and the preventive measures to be taken to mitigate the incidence and severity of postoperative cognitive dysfunction.

Specific factors	Risk factors	Preventive measures for neuroprotection
Patient-related	Frailty	(1) Multidisciplinary approach; (2) Identification of high-risk patients; (3) Optimization of comorbidities; (4) Establishing baseline cognitive function/dysfunction; (5) Neuropsychiatric/pharmacist consult for alcohol/psychotropic dependence; (6) Consideration of informed consent with patient and family; and (7) Cognition preconditioning
	Age > 65 years
	Dementia, neurodegenerative disorder
	Excessive alcohol consumption
	Polypharmacy including psychotropic drugs
	Vascular disorders
	Sleep disorders
	Diabetes mellitus
	Prior neuron damage like stroke or traumatic brain injury
Surgery-related	Type of surgeries: (1) Open cardiac surgery; (2) Invasive cardiac surgery; (3) Major Orthopedic surgery; (4) Head and neck surgery; and (5) Colorectal surgeries	Measures to decrease the duration of surgery
	Increased duration of surgery is associated with increased risk of POCD	Identifying the type and expected duration of surgery
	Postoperative medical and surgical complications	Minimization and early treatment of any postoperative complications
Anesthesia-related	General factors: (1) Excessive depth of anesthesia under GA; (2) Excessive sedation in regional anesthesia; (3) Extremes of blood pressures; (4) Hemodynamic fluctuations; and (5) Cerebral desaturation	(1) Depth of anesthesia monitoring using BIS, entropy; (2) Minimizing excessive sedation; (3) Hemodynamic monitoring and preventing extreme fluctuations from baseline; (4) Cerebral oximetry monitoring in high-risk cases; and (5) Opioid minimizing/sparing techniques
	Specific agents: Benzodiazepines, gabapentinoids, ketamine, opioids, diphenhydramine, metoclopramide, anticholinergics (particularly scopolamine), and diphenhydramine

BIS: Bispectral index; GA: General anesthesia; POCD: Postoperative cognitive dysfunction.

GENERAL AND SPECIFIC RISK FACTORS FOR PND AND THE PREVENTIVE MEASURES TO MITIGATE THE INCIDENCE AND SEVERITY OF POCD

There is no strong evidence to support one anesthesia technique over another to prevent POCD. A recent meta-analysis suggested that the addition of regional anesthesia/neuraxial anesthesia to general anesthesia in major noncardiac surgery has decreased the incidence of PND in the first postoperative month compared to those who did not receive any supplemental regional anesthesia[40]. The addition of regional anesthesia techniques decreases pain and perioperative opioid requirements. However, the results have not been consistent in other RCTs[41-43]. Similarly, there is no consistent evidence suggesting total intravenous anesthesia is associated with a lower incidence of delirium than inhalational anesthesia in preventing postoperative delirium in adults after general anesthesia[14,44].

DEX CLINICAL USE IN THE MANAGEMENT OF COGNITIVE DYSFUNCTION

The search for an ideal neuroprotective agent has been very difficult in performing clinical trials due to the heterogeneous patient population, wide range of surgeries, and lack of objective measurement of neuroinflammation and clinical outcome measures. In the last decade, the efficacy of Dex in preventing POCD has been tried in various clinical trials with mixed results. Dex has emerged as an “all-in-one” drug with wide application in the perioperative period. Possible mechanisms by which Dex provides neuroprotection and prevents POCD are: (1) Anti-inflammatory (decrease neuroinflammation); (2) Sympatholytic (decrease circulating catecholamine); (3) Opioid minimizing effect; (4) Analgesia; and (5) Decreased intraoperative volatile anesthetics requirements.

Bu et al[29] measured some important parameters between the two groups (Dex vs placebo) to assess the neuroprotective and anti-inflammatory properties of Dex in elderly patients undergoing radical colon cancer surgeries. The use of Dex resulted in decreased levels of NSE and S100β. There were better cerebral regional brain oxygenation measurements at important time points (intubation, extubation, and 30 min after surgical commencement) in the Dex group. The findings of Bu et al[29] underscore the potential benefits of using Dex as an adjunct to general anesthesia in elderly patients undergoing major surgeries.

Although current evidence is insufficient to support the routine use of Dex to prevent delirium or other types of postoperative neurocognitive disorders, it aligns with the 2024 Professional Society recommendations that suggest it is reasonable to administer an intraoperative infusion or to continue this infusion into the postoperative period to reduce the incidence of postoperative delirium in high-risk patients[45]. Several studies have indicated that perioperative administration of Dex may mitigate or reduce the incidence of delirium. A 2023 network meta-analysis of randomized trials, which included 18 studies with a total of 2636 patients undergoing cardiac surgery, demonstrated that the administration of Dex in the postoperative period significantly reduced the risk of postoperative delirium when compared with normal saline placebo [odds ratio (OR) = 0.13, 95% confidence interval (CI): 0.03-0.35] or propofol (OR = 0.19, 95%CI: 0.04-0.66)[25]. Similar findings were reported in a 2018 meta-analysis involving patients treated with cardiac surgery[26].

Additionally, a 2018 meta-analysis of randomized trials, which included both cardiac and non-cardiac surgeries, noted a lower incidence of delirium when Dex was administered either intraoperatively or postoperatively compared to no Dex exposure (OR = 0.35, 95%CI: 0.24-0.51; 18 trials, 3309 patients)[27]. Moreover, a 2023 randomized trial involving 732 older adults (aged 65 years or above) undergoing orthopedic lower limb surgery under spinal anesthesia reported a lower incidence of delirium in patients who received Dex sedation during the procedure[28]. It is noteworthy that data are most robust in studies investigating postoperative Dex infusions in intensive care unit settings[14,26-28,46].

Results from the studies on intraoperative administration of Dex are inconsistent, with some data indicating no significant benefit for delirium reduction[47-49]. A multicenter prospective study demonstrated that a continuous infusion of Dex at 0.5 μg/kg/h for 2 h during the intraoperative period did not impact cognitive outcomes at 3 months or 6 months post-surgery, as assessed by multiple neuropsychological tests[48]. In an RCT trial conducted in elderly patients aged ≥ 65 years, Dex was found to have no significant effect on reducing the incidence of POCD at 1 week post-surgery when compared to propofol. Additionally, no notable difference in the incidence of POCD was observed between the groups at the 1-year follow-up, as evaluated by five neuropsychological test scales other than the MMSE[50].

Additionally, all these trials have various limitations. These studies on Dex include participants with varying baseline characteristics, such as age, comorbidities, and cognitive function. This heterogeneity introduces confounding factors that may obscure the true effect of Dex on PND outcomes. For instance, patients with preexisting cognitive impairment or frailty may respond differently to the drug compared to healthier individuals, making it challenging to generalize findings across diverse populations. The studies reviewed encompass a wide range of surgical procedures, including cardiac, orthopedic, and oncological surgeries. Each type of surgery involves distinct perioperative stressors and inflammatory responses, which could influence the development of PND and the effectiveness of Dex. For example, the inflammatory cascade triggered during cardiac surgery with cardiopulmonary bypass may differ significantly from that in non-cardiac surgeries, potentially altering the efficacy of the drug. The studies employ different dosages and administration protocols for Dex, ranging from intraoperative boluses to continuous perioperative infusions. This variability complicates comparisons and raises questions about the optimal dose and timing to achieve neuroprotective effects while minimizing adverse events. For instance, high doses might increase the risk of bradycardia and hypotension, especially in elderly patients with compromised cardiovascular reserves.

The assessment of PND outcomes varies significantly among studies, with methods including the MMSE, Montreal Cognitive Assessment, and other neuropsychological tools. Additionally, the timing of assessments (e.g., immediate postoperative period vs weeks or months later) influences the reported incidence and severity of PND. This inconsistency in outcome measurement limits the comparability of results and the ability to draw definitive conclusions. The lack of standardized protocols across studies contributes to variations in findings. Differences in study design, including sample size, randomization, and control for confounders, further challenge the reliability of the evidence. Methodological rigor, such as multicenter trials with standardized interventions and outcome assessments, is essential to generate more robust and generalizable data. The evidence supporting the use of Dex to prevent other types of PND is also limited[51-53].

While Dex offers significant neuroprotective and anti-inflammatory benefits, its use is not without risks, particularly in elderly patients who often have limited physiological reserves. Common adverse effects include bradycardia and hypotension, which result from its potent sympatholytic and vasodilatory properties. Excessive sedation is another concern, especially when higher doses are used or when combined with other sedatives, potentially delaying postoperative recovery. Furthermore, prolonged use of Dex can lead to rebound hypertension upon discontinuation, and its effects on renal and hepatic function require consideration in patients with organ dysfunction. These risks underscore the need for individualized dosing regimens and vigilant perioperative monitoring to maximize its benefits while minimizing harm.

Dex appears to provide neuroprotective effects, possibly due to its ability to maintain cerebral oxygenation and reduce metabolic stress on the brain. These results align with previous studies that have highlighted the sedative and analgesic properties of Dex, which can help stabilize hemodynamics and reduce the overall need for other anesthetic agents. The reduced incidence of POCD observed in the study by Bu et al[29] is particularly noteworthy in mitigating the risk of POCD. Dex not only enhances patient outcomes but also reduces the burden on healthcare systems.

A more thorough grasp of the function of Dex in neuroprotection will also be possible by examining its relative effectiveness in comparison to other pharmaceutical agents or non-pharmacological therapies. The pathophysiology of PND may be better understood and patient selection for the use of Dex may be improved with research examining the discovery and validation of biomarkers for the condition. Finally, to optimize perioperative care strategies, it will be crucial to investigate its long-term effects on cognitive outcomes, particularly in high-risk populations. Standardized dosage schedules and administration procedures catered to various surgical populations ought to be assessed in these studies.

CONCLUSION

This article advocated for the inclusion of Dex in anesthesia protocols for elderly patients undergoing major surgeries like radical colon cancer surgery. Its use not only enhances patient outcomes by mitigating the risk of POCD but also contributes to reducing healthcare costs by facilitating early discharge and minimizing the need for prolonged postoperative care. As such, Dex presents a valuable adjunct in the perioperative management of elderly patients, offering a neuroprotective strategy that aligns with modern enhanced recovery protocols.