Analyzing the Neuroprotective Effect of Dexmedetomidine in Terms of Preserving Brain Functional Connectivity in Elderly Patients After Major Surgery

Cognitive impairment after anesthesia in older patients The average age of the world population is rapidly increasing as is the number of elderly patients who undergo surgery. According to projections of the last census, the Chilean population is also undergoing a process of demographic ageing. Elder patients are more prone to adverse cognitive outcomes such as post-operative delirium (POD) and postoperative cognitive dysfunction (POCD). The observed overall incidence of POD and POCD is 40% and 10% respectively and both can represent transient or permanent brain damage. Both conditions are associated with an increased risk of death, functional decline, and health care costs. POD is an acute and transient condition that occurs during the first few days after surgery. In contrast, POCD manifests with more subtle deficits in memory, attention, and cognition over a much longer period of time (months to years). Even though the increase in age and the degree of frailty are well known risk factors for adverse postoperative cognitive outcomes, the etiology of these conditions remains poorly understood and most likely involves a combination of patient, surgical, and anesthetic factors.

Surgical trauma and inflammatory response Several studies in animals and humans have shown that surgical trauma triggers immune and inflammatory responses that can potentially generate neuroinflammation and degeneration. Neuroinflammation is a localized inflammation occurring in both the peripheral and central nervous system in response to trauma, neurodegeneration, bacterial or viral infection, autoimmunity and toxins. The pathogenesis of surgery-induced neuroinflammation involve the release of biomolecules known as damage-associated molecular patterns (DAMPs) such as the high molecular group box 1 protein (HMGB1). The various DAMPs molecules released activate nuclear factor-kappa B (NF-κB) signaling pathways in bone marrow derived monocytes20. The activated monocytes increase the activity and expression of cyclooxygenase 2 isozyme (COX-2), expression of pro-inflammatory cytokines interleukin-1 beta (IL-1β), interleukin 6 (IL-6), and tumor necrosis factor alpha (TNFα). These pro-inflammatory cytokines promote further release of HMGB1 from injured cells, further activation of monocytes, and finally disruption of the blood brain barrier allowing pro-inflammatory mediators to enter the central nervous system.

Several studies have shown that the magnitude of postoperative cognitive impairment is strongly associated with the levels of pain and inflammation. Major surgeries, like cardiac surgery and major orthopedic surgery, have been associated with POCD in up to 50% of patients. Regarding memory formation and brain cognitive processes, the presence of pro-inflammatory cytokines in the central nervous system have detrimental effects on the regulation of neurotransmitter signaling in different brain areas, especially the hippocampus, ultimately resulting in neuronal dysfunction and cognitive impairment. For example, the hippocampus is readily affected by pro-inflammatory factors, which break the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-to- N-Methyl-d-aspartic acid or N-Methyl-d-aspartate (NMDA) balance in glutamatergic synapsis, disrupting the process of long-term potentiation, and thus the ability to form memories. Additionally, HMGB1 produced in the brain increases the influx of glutamate in hippocampal neurons, which ultimately results in glutamate toxicity, neuronal death and cognitive impairment.

Anesthetic neurotoxicity Anesthetics induced neurotoxicity has become an area of great concern in recent decades due to numerous studies showing anaesthetics may promote neuroapoptosis in immature brains of animals. Although, general anesthetics are normally considered safe in adults, several studies suggest that anesthetic exposure is associated with postoperative cognitive dysfunction in adult patients. Most used inhaled general anesthetics (isoflurane, sevoflurane and desflurane) are highly lipid-soluble and can rapidly access the brain in high concentrations. Since they act on many receptors, such as γ-aminobutyric acid (GABA) and NMDA receptors, second messenger systems, enzymes, and even cytoskeletal components, it is not surprising that they might be involved in neurodegenerative changes in vulnerable populations, especially after high concentrations and long exposure times. There is strong evidence in animals to support that exposure to anesthetics can induce dose-dependent neurotoxicity. Cellular degeneration from isoflurane exposure have shown to result in altered white matter integrity indicating damage in fiber tracts, leading to the development of neurological and cognitive deficits. In addition, volatile anesthetics have been shown to increase concentrations of the β-amyloid protein and can lead to hyperphosphorylation of the tau protein, changes that are paramount in the cytotoxicity of Alzheimer's disease. Studies using in vitro models have provided consistent evidence that volatile general anesthetics suppress transmission in different types of synapses, altering neuronal network excitability.

Dexmedetomidine neuroprotection Dexmedetomidine is a highly selective alfa-2 adrenergic agonist with sedative and analgesic properties but minimal respiratory effects. Dexmedetomidine produces its sedative effects by acting at the locus coeruleus, analogous to the natural induction of sleep, and independent of NMDA or GABAA receptors. In intensive care units, dexmedetomidine's anti-inflammatory, organ-protective, and sympatholytic effects have been associated to better outcomes when compared to benzodiazepine sedative regimes. A recent study in septic patients showed that individuals receiving dexmedetomidine had more days free of brain dysfunction and were less likely to die than those that received lorazepam sedation. There is also growing evidence of dexmedetomidine organ protective properties in ischemia reperfusion, inflammation, and traumatic brain injury models. A randomized control trial reported a 60% reduction of POD after an infusion of dexmedetomidine. Another randomized controlled trial showed improved cognitive function and quality of life in 3-year survivors, as well as increasing survival up to 2-years after a low-dose dexmedetomidine infusion in non-cardiac surgery. In a recent meta-analysis, dexmedetomidine administration showed an overall 40% reduction in the risk of POCD.