Year : 2020  |  Volume : 23  |  Issue : 4  |  Page : 391--400

Neurological dysfunction after cardiac surgery and cardiac intensive care admission: A narrative review part 2: Cognitive dysfunction after critical illness; potential contributors in surgery and intensive care; pathogenesis; and therapies to prevent/treat perioperative neurological dysfunction

Mukul C Kapoor 
 Department of Anaesthesia, Max Smart Super Specialty Hospital, Saket, Delhi, India

Correspondence Address:
Mukul C Kapoor
6 Dayanand Vihar, Saket, Delhi - 110 092


Severe cognitive decline and cognitive dysfunction has been attributed to patient's stay in the cardiovascular intensive care unit. Prolonged mechanical ventilation, long duration of stay, sedation protocols, and sleep deprivation contribute to patients developing neurocognitive disorder after intensive care admission and it is associated with poor clinical outcomes. Trauma of surgery, stress of critical care, and administration of anaesthesia evoke a systemic inflammatory response and trigger neuroinflammation and oxidative stress. Anaesthetic agents modulate the function of the GABA receptors. The persistence of these effects in the postoperative period promotes development of cognitive dysfunction. A number of drugs are under investigation to restrict or prevent this cognitive decline.

How to cite this article:
Kapoor MC. Neurological dysfunction after cardiac surgery and cardiac intensive care admission: A narrative review part 2: Cognitive dysfunction after critical illness; potential contributors in surgery and intensive care; pathogenesis; and therapies to prevent/treat perioperative neurological dysfunction.Ann Card Anaesth 2020;23:391-400

How to cite this URL:
Kapoor MC. Neurological dysfunction after cardiac surgery and cardiac intensive care admission: A narrative review part 2: Cognitive dysfunction after critical illness; potential contributors in surgery and intensive care; pathogenesis; and therapies to prevent/treat perioperative neurological dysfunction. Ann Card Anaesth [serial online] 2020 [cited 2020 Nov 24 ];23:391-400
Available from:

Full Text

 Cognitive Decline After Critical Illness

Severe cognitive decline and cognitive dysfunction has been attributed to delirium in the cardiovascular intensive care unit (ICU) in several studies.[1],[2],[3] The prevalence rate of long-term cognitive impairment reported after critical illness varies widely in studies, with prevalence rates ranging from 4 to 62%.[4] Long-term adverse functional disability, after discharge from an ICU, was first reported in ARDS survivors.[5] Hospitalization for noncritical illness increases the risk of incident dementia by 50% while critical illness may double this risk.[6] In-hospital delirium is associated with adverse global cognitive function 3 and 12 months after discharge, independent of known risk factors,[7] especially if the duration of in-hospital delirium is longer.[8] A retrospective data analysis of more than 10,000 ICU survivors found a nearly 50% higher risk of subsequent dementia, than in matched controls, within 3 years.[9]

Cognitive decline is an independent marker of adverse outcomes in patients with heart failure. A nearly 80% prevalence of neurocognitive disorder (NCD) was reported in patients with acute decompensation. Factors thought to contribute to NCD are hypertension, atrial fibrillation, stroke, and impaired hemodynamics. Cerebral hypoperfusion, disruption of the blood–brain barrier (BBB), and oxidative stress are considered to be responsible. Neuroimaging in such patients reveal hyperintense white matter, lacunar infarcts, and brain volume loss.[10] Global cognitive decline has been reported to occur significantly faster after newly diagnosed heart failure than their peers, in the absence of a documented neurological event or concomitant atrial fibrillation. Though this decline is more pronounced at older ages, it is evident in all patients between 70 and 90 years. The rate of cognitive decline is not related to a reduction in ejection fraction.[11]

Several patients admitted to cardiac ICU have a prolonged ICU stay and/or have severe multiorgan involvement, making them prone to NCD. Advances in critical care have improved patient survival, but the quality of life after that has not improved significantly. After recovery from the illness, many patients have impaired cognition and functional status, which results in the necessity for institutional/supported care, regular medical support, rehabilitation support, and loss/sheltered employment. Patients commonly have memory, attention, mental processing, visual-spatial, and motor execution deficits.

The risk factors pre-ICU-admission and post-ICU-admission,[4] which make the patient susceptible to develop NCD after the ICU stay are listed in [Table 1].{Table 1}

Hospital data of patients aged >65 years, without baseline dementia, revealed a 50% higher risk of dementia in patients admitted for noncritical illness and a 100% higher risk in those admitted for critical illness.[6] The “Bringing to Light the Risk Factors and Incidence of Neuropsychological Dysfunction in Intensive Care Unit (BRAIN-ICU)” Survivors study reported that 32% of survivors had impaired activities of daily living (ADL) at 3 months which persisted even at 1 year. 26% of the BRAIN-ICU survivors had restrictions in instrumental ADL at 3 months which remained so at 1 year in 23% of them.[12] Long-term data evaluation of 743 patients, who required mechanical ventilation during critical illness, revealed that only 53% of survivors returned to functional baseline at 5 years.[13]

Apart from being associated with poor clinical outcomes, prolonged mechanical ventilation, more ICU days, and more radiological investigations for mental status assessment, deep ICU sedation is associated with an increased likelihood of patients developing delirium.[14],[15] A recent randomized control trial (RCT) reported that early goal-directed mobilization reduces the incidence of ICU delirium and increased ICU delirium-free days.[16] The MENDs RCT indicated ICU outcome benefits with the use of dexmedetomidine for ICU sedation.[17] On the other hand, several studies have demonstrated increased incidence/duration of delirium and sleep deprivation in ICU patients with the use of benzodiazepines.[17],[18] [Figure 1] displays a flow chart summarizing important aspects of long-term cognitive decline after ICU admission.{Figure 1}

Inadequate sleep and its disruption during hospitalization adversely impact patient outcomes. Polysomnographic studies have revealed extreme sleep deprivation, sleep fragmentation, and altered sleep patterns in ICU.[19] Acute withdrawal from long-term benzodiazepines/opioid sedation may result in severe sleep disruption.[20] Poor sleep hygiene results in delirium and cognitive dysfunction.[21] Perioperative sleep deprivation has been shown to induce microglia activation in the hippocampus and increase the expression of proinflammatory cytokines in the brain to induce neuroinflammatory changes.[22] [Table 2] lists the strategies recommended to prevent delirium in ICUs.{Table 2}

The pathogenesis of long-term cognitive and functional impairment is complex and multifactorial. Neuroimaging studies of patients have identified morphological changes like cerebral atrophy and white matter disruption. In case delirium persists at 3-month follow-up, it is associated with NCD for up to 12 months after discharge.[4],[23] Prolonged ICU delirium is associated with early white matter changes of the corpus callosum and anterior limb of the internal capsule. In later stages, integrity decreases, and there is increased diffusion in periventricular, frontal, and temporal white matter.[24],[25] The above indicates that the acute brain dysfunction possibly leads to structural neurological changes causing long-term cognition deficit.[4]

 Potential Contributors to Perioperative Neurological Dysfunction

Role of intraoperative hypotension

Cerebral insults may result from cerebral tissue hypoxia. Intraoperative systemic hypoxemia and hypotension result in brain tissue hypoxia. A study in the early 1990s, however, reported no association between intra- and postoperative hypotension and postoperative cognitive dysfunction (POCD).[26] Intraoperative hypoxemia is a relatively rare today, but intraoperative hypotension/relative hypotension is frequent in elderly and hypertensive patients. Incidence of hypotension during anesthesia has been reported to be higher in the group that developed dementia, but adjusted for other variables, it was not associated with increased dementia risk.[27]

A systemic review, assessing risk factors associated with cognitive decline after surgery, found several studies relating intraoperative hypotension with cognitive decline.[28] The range of cerebral autoregulation varies substantially amongst patients, especially during cardiopulmonary bypass (CPB).[29] A significant anomaly seen in most of these studies was that they did not consider cerebral autoregulation limits of individual patients. Chronic hypertensive patients have a right-ward shift in their autoregulation curve. Relative hypotension may thus lead to cerebral hypoperfusion.

A recent RCT, on patients ≥75 years of age, the protocol required prevention of relative hypotension in the study group. The anesthesiologist maintained a target blood pressure at 90% of baseline mean arterial pressure (MAP), rather than an arbitrary MAP value. With the MAP maintained in the patient's cerebral autoregulation range, the regional cerebral oxygen saturation in the target group was similar to the no-intervention group. The target group also spent lesser time with low/high depths of anaesthesia as inhaled agent concentrations were not changed to manipulate blood pressure. Z-score evaluation, by a number of neuropsychological tests, found no correlation between intraoperative hypotension and cognitive function, indicating that intraoperative hypotension plays no significant role in the development of POCD and postoperative delirium.[30]

Role of altered homeostasis

Altered homeostasis is known to cause POCD. A meta-analysis of 14 studies found a 1.26-times higher risk of POCD in diabetic patients as compared with diabetes-free patients.[31] Poor glycemic control, with intraoperative blood sugar levels >200 mg/100 mL, has been reported to impair cognitive function in nondiabetic patients 6 weeks after surgery in patients.[32] Hyperglycemia downregulates the glucose transporter on capillaries to retard glucose influx into brain tissue while hypoglycemia up-regulates it to promote glucose influx.

Data suggest that it may be equally important to avoid both hypo- and hyperglycemia to avoid PND. There is ample evidence implicating diabetes to cause oxidative and proinflammatory stress on the brain vasculature and the BBB with activation of the receptor for advanced glycation end-products (RAGE). RAGE activation impairs endothelial nitric oxide bioavailability, increases adhesion molecules expression, and promotes the release of inflammatory factors.[33]

Both hyper- and hyponatremia may lead to PND. Chronic hyponatremia in humans may cause cognitive impairment, but impairments are reversible with correction of the condition.[34] Hypotonocity in hyponatremia may cause astrocyte swelling and induce the release of osmolytes, such as glutamate, in order to regulate brain volume and thereby cause neuronal abnormalities or injury.[35] Lower extracellular sodium levels are also thought to increase markers of oxidative stress.[36] Hypernatremia (143–153 mmol/L) is also associated with cognitive decline indicating a U- or J-shape association between serum sodium level and cognitive function.[37]

Temperature management plays a major role in POCD. Hypothermic CPB decreases cerebral blood flow and cerebral metabolic rate of oxygen (CMRO2), which disrupts the BBB. Hypothermia is neuroprotective as it weakens the neuroinflammatory response, impedes free radical formation, and reduces apoptosis. However, rapid rewarming after hypothermic CPB can cause cerebral hyperthermia by disrupting autoregulation mechanisms and lead to cerebral edema.[38] The resulting rise in intracranial pressure impairs perfusion/oxygenation and can lead to POCD. Administration of inhaled anesthetics in a setting of hypothermia has been shown to enhance tau phosphorylation in animal studies leading to memory deficits.[39] Hyperthermia increases CMRO2, which results in worse neurocognitive outcomes and is associated with increased mortality risk.[40],[41]

 Pain-Related Cognitive Dysfunction

Many clinical studies strongly indicate impairment of multiple cognitive functions in patients with chronic pain. On the other hand, there are also studies disagreeing to an association between chronic pain and impaired cognitive function.[42],[43] A recent study, comparing patients with chronic pain with controls, concluded that pain negatively impacts cognition, mainly in the domains of memory and attention, and this relationship is age-dependent.[44] Moriarty et al. have suggested a model based on vying for limited resources, neuroplasticity, and dysregulated neurochemistry to explain the genesis of PND due to pain.[45]


Based on Alzheimer pathology

Mechanisms involved in the development of PND may include anaesthetic-induced acceleration of Alzheimer pathology in the gamma-amino-butyric acid (GABA) receptors; anaesthetic-induced disruption of gamma-oscillation patterns responsible for amyloid-β clearance; and direct neuronal or glial cell damage. Several histopathological features seen in patients with PND are similar to those seen in patients of Alzheimer's disease. Alzheimer's disease pathology classically presents as extracellular deposition of Aβ-amyloid protein plaques, intracellular tau proteins tangles, and inflammation of neuronal cells which is followed by neuronal death.

Biomarkers of neuronal injury, neurofilament light and tau, have been shown to increase after general anaesthesia and surgery.[46] Increased cerebrospinal fluid (CSF) β-amyloid protein and tau proteins levels have been demonstrated in patients developing PND.[47],[48],[49] Changes in these markers, glial cell integrity, and integrity of BBB were also noticed in the CSF of patients after spinal blockade with propofol sedation.[50] Positron emission tomography has also revealed an association of β-amyloid protein deposits with cognitive deficits 6 weeks after cardiac surgery.[51]

Based on neuroinflammation and oxidative stress

Data from multiple studies suggest inflammation as the pathogenic mechanism for POCD.[52],[53],[54] Sepsis and surgery are both proinflammatory conditions, which promote the production of cytokines such as tumor necrosis factor-α (TNF-α) and interleukins (IL) like IL-1, IL-6, and IL-10.[55],[56] These cytokines play a significant role in the genesis of POCD, and their high levels can also produce diminished cognitive function.[57] Impaired memory has been demonstrated in patients with high IL-6 and this cognitive impairment persisted 1 month after surgery in patients with high IL-6 levels.[58] Patients with elevated levels of IL 6 and IL-10 have poor 48-month cognitive performance.[59] Peng et al. in a meta-analysis have shown that elevated inflammatory markers, particularly IL-6, were associated with PND.[60]

Endothelial cells, pericytes, and astrocytic end-feet together ensure proper BBB formation, which protects against potentially harmful peripheral molecules.[61] The existence of the BBB and limited lymphatic drainage protects the brain from inflammatory factors, but significant inflammatory states may breach the BBB. Elevated levels of peripheral inflammatory cytokines may disrupt the BBB, and this breach may initiate neuroinflammation.[62] The high-mobility group box-1 chromatin protein (HMGB1) plays a vital role in inflammatory pathways. Elevated cytokines and oxidative stress promote the release and activation of HMGB1 after surgery.[63]

The hippocampus plays a significant role in the brain to assimilate new memories, learning, and emotions. The hippocampus contains a large number of proinflammatory cytokine receptors with a high density of IL receptors. Increased expression of IL in the hippocampus, associated with cognitive decline, has been demonstrated after minor surgery in mice indicating a role of surgery-induced neuroinflammation in cognitive impairment.[64],[65]

The microglia are innate immune cells of the central nervous system (CNS), which are functionally similar to macrophages. Microglia are motile cells that continuously monitor the brain microenvironment and facilitate the synaptic activity, pruning, and remodeling.[66] Microglia regulate cell–cell and cell–matrix interactions and also release multiple proinflammatory, immunoregulatory and oxidative factors. In Alzheimer's disease, activated microglia have been shown to produce large amounts of cytokines, leading to neuronal dysfunction and death.[67] After surgery adenosine triphosphate (ATP), alarmins, and cytokines, leak from an injury site or their levels may rise in response to systemic inflammation. These mediators enter the brain and activate the microglia to produce cytokines.[68]

Astrocytes are the principal glial cells in the CNS. The astrocyte protein S100β (S100 calcium binding protein β) plays a crucial role in most homeostatic and damage/infection-associated processes. Elevated peripheral cytokines cause neuronal apoptosis and cerebral edema by inducing an inflammatory cascade which induces the centrally located microglia to produce proinflammatory cytokines, oxygen-derived free radicals, and by recruiting monocytes to the brain.[69] S100β released from injured astrocytes spills into the extracellular space, and their elevated serum levels indicate BBB injury. Cytokines bind to the BBB promoting adhesion of cells, permeability and cytokine transfer across the barrier.[70] Acute BBB interruption has been observed, after cardiac surgery, in gadolinium-enhanced magnetic resonance imaging which correlated with subsequent neurological impairments.[71],[72]

Surgery induces elevations of both CSF and serum S100β levels, and this has been shown to correlate with neuropathological processes.[73] An association between serum S100β and impaired cognitive function after various surgery types has been demonstrated, and studies with narrower definitions of POCD have replicated these findings.[74] Elevated E-selectin is a biomarker of endothelial injury. Elevated levels of S100B and E-selectin is associated with worse cognitive function at 3 and 12 months after critical illness.[75] Inflammatory changes associated with critical illness and surgery may induce a cycle of neuroinflammation, leading to apoptosis and atrophy.[76]

POCD is associated with neuronal apoptosis.[77] Microglia induce production and release of reactive oxygen species, which has deleterious effects on brain architecture and neuronal function. Oxidative stress leads to an increase in pro-apoptotic proteins with a concomitant decrease in anti-apoptotic proteins levels in the hippocampus and frontal cortex.[78] Brain tissue has low amounts of antioxidants and is vulnerable to oxidative stress. Microglia express antioxidant brain glutathione and its circulating level have been proposed to be a predictive biomarkers of cognitive decline in patients with neurodegenerative disease.[79] Surgical stress induces a rise in brain nicotinamide adenine dinucleotide phosphate (NADPH) oxidase levels, a key oxidative stress regulator, and this rise correlates with behavioral changes in mice.[80] Superoxide dismutase and malondialdehyde are classical indices reflecting systemic redox homeostasis.[81] The impairment of superoxide dismutase and malondialdehyde, enzymes that catalyze the conversion of the superoxide radicals into hydrogen peroxide or oxygen, has been linked to oxidative stress and neurocognitive deficits.[82]

A flow chart summarizing the major steps in the pathogenesis of cognitive decline after surgery and anaesthesia, based on the neuroinflammation and oxidative stress, is displayed in [Figure 2].{Figure 2}

Based on breakdown in CNS synaptic network

Multiple “functionally connected” brain networks play essential roles in specific cognitive processes. Delirium is a failure to integrate and process information, and it has been hypothesized to represent an acute breakdown in brain network connectivity.[83] We have observed (unpublished) that, in delirious patients, delirium settles after regional blockade in patients with hip fractures indicating that the brain possibly misinterprets pain sensation due to faulty connectivity. In cardiac surgery patients, postoperative global cognitive dysfunction was found to correlate with decreased functional connectivity in critical regions of the brain's default mode network. Changes in hippocampal neurogenesis and BDNF, seen after cardiac surgery and persisting for weeks after that, are signs of impaired neuronal plasticity.[84]

Cognitive reserve relates to the resilience of the brain to an insult or pathology. Individual differences in cognitive processes or neural networks allow some people to deal with stress better than others. The available synapses and anatomical variability of the neural networks both play an essential role. Default mode network functional connectivity disruptions may underlie PND. Education helps form more neuron synapses and thus fortifies the defense against brain injury. A higher level of education thus possibly offers some protection against POCD as more significant neuronal damage, of a larger number of neurons, is needed to reach the threshold of cognitive decline.[85]

Functional MRI can measure correlated activity patterns between brain regions (functional connectivity). In cardiac surgical patients, the degree of global cognitive dysfunction was found to correlate with the expanse of decreased functional connectivity in the posterior cingulate cortex and the right superior frontal gyrus, critical regions of the brain's default mode network.[86] Decreased default mode network functional connectivity has also been reported after orthopedic surgery.[87]

Electroencephalogram (EEG) recordings have been used to identify brain connectivity patterns that may be associated with postoperative delirium and/or POCD. Elderly cardiac surgery patients with PND display decreased postoperative EEG alpha band (8–13 Hz) power and connectivity in EEG under general anaesthesia.[88] Patients have significant decreases in alpha band power. Low intraoperative alpha band power has also been correlated with lower preoperative baseline cognitive function.[89]

Based on GABA receptor theory

The anxiolytic effects of GABAA receptor agonists are thought to result from their facilitation of neuronal uptake of chloride ion.[90] Intravenous and inhaled general anaesthetics are positive modulators of synaptic and extra-synaptic GABAA receptors enabling them to enhance GABA-mediated opening of integral ion channels. Hypnosis for surgery by neuronal inhibition and neurodepression is induced by this increased influx of chloride ion into neurons. Anaesthetic exposure also activates extra-synaptic GABAA receptors on the neuronal surface in the postexposure. The low concentrations of the noneliminated endogenous GABA activate these over-expressed GABAA receptors causing a persistent chloride influx into the neurons. The resultant cognitive deficits persist even after the drugs have been eliminated. Over-expression of these extra-synaptic receptors is also actuated by cytokines released during surgery. This results in subtle neurocognitive disorders, such as postoperative delirium, in patients after surgery. Activation of α2 adrenergic receptors in astrocytes and stimulation of brain-derived neurotrophic factor (BDNF) release by dexmedetomidine prevents over-expression of these receptors and mitigates cognitive disorders.[91] A flow chart summarizing the major steps in the pathogenesis of cognitive decline after anaesthesia exposure, based on the GABA receptor theory, is displayed as [Figure 3].{Figure 3}

 Best Practices to Prevent PND

Cardiac surgery protocols should ensure proper postoperative cognitive function with the early return of the patient to presurgical functional status and independent living. The potential benefit of the surgery on an elderly, against its potential harm, including PND, must critically be evaluated before any significant intervention. The cognitive function must be evaluated preoperatively. As POCD is more frequent and severe after extensive surgery, perioperative complications must be avoided. Minimally invasive surgery may offer benefits as the procedure is less extensive, and the inflammatory response limited.[92],[93]

Several drugs used to facilitate anaesthesia and prevent perioperative adverse effects and pain of surgery/anaesthesia have been implicated for promoting PND. These drugs should be used with caution in the elderly. The medications with this stigma are listed as [Table 3].{Table 3}

Perioperative anaesthetic protocols to reduce PND need to be employed which include strategies such as avoidance of benzodiazepines, anticholinergics, meperidine; improving sleep hygiene; early mobilization; preventing sensory deprivation; encouraging interaction with family; cognitive stimulation therapies; and aerobic exercise. Use of short-acting anaesthetic drugs is recommended as the duration of cognitive impairment is shorter with them.[94] A large number of investigations have shown that benzodiazepine administration is associated with a risk of neurological dysfunction and a need for prolonged mechanical ventilation.[14],[95],[96]

The MENDS randomized trial found that dexmedetomidine use for targeted sedation was associated with a 60% lower risk of delirium/coma and more days alive as compared to lorazepam.[18] A similar benefit of recused incidence of delirium has been demonstrated with dexmedetomidine sedation vis-a-vis midazolam in the SEDCOM study. With evidence that GABA suppression protects against neurological dysfunction, propofol and dexmedetomidine are increasingly used for procedural and ICU sedation.[97]

 Therapies Evaluated for Prevention and Treatment of PND

Many non-pharmacologic, interdisciplinary and multicomponent programs, targeting different mechanisms, have been tried for delirium prevention. Therapies targeting cytokine secretion by immune cells may be useful in POCD. The therapies tried are:

COX-II inhibitors: Cyclo-oxygenase (COX) inhibitors, such as parecoxib and celecoxib, reduce activation of microglia and the neuroinflammation following that. They were, therefore, tried for Alzheimer's disease but a Cochrane review and meta-analysis found no evidence to suggest any significant benefit.[98]

Statins: A systematic review and meta-analysis reported a 29% reduction in the incidence of long-term dementia, compared to controls, with the use of statins for both short and long-term cognitive function.[99] However, their use for cognitive change is controversial, with a recent Cochrane review negating this benefit.[100]

Pregabalin: Pregabalin was hypothesized to alter the release of neurotransmitters in the hippocampus by moderating microglia activation and restricting cytokine release.[101] Evidence for cognitive preservation is, however, not well established with acute confusional state and disturbance of attention reported as a risk of pregabalin use.[102]

Dexmedetomidine: Current evidence suggests that dexmedetomidine protects against cognitive decline in the early postoperative period. Two meta-analyses have shown that it was superior to controls for reducing the risk of postoperative delirium in ICU.[103],[104]

Lidocaine: There is evidence of a significant reduction in inflammatory markers IL-1β, IL-6, IL-8; TNF-α, and c-reactive proteins along with cognitive protection, after intraoperative lidocaine administration.[105] A recent RCT, however, has demonstrated that intravenous lidocaine administered perioperatively in cardiac surgery did not reduce cognitive decline at 6 weeks.[106]

Ketamine: There is evidence that ketamine moderates inflammatory macrophage activation and production of cytokines like IL-1β, IL-6 and TNF-α.[107] However, studies have demonstrated conflicting results regards its protective cognitive effect.[108],[109]

Minocycline: Minocycline is a tetracycline antibiotic with anti-inflammatory and microglial inhibitory properties. It reduces the excitotoxicity resultant from increased glutamate production and subsequent production of mitochondrial reactive oxygen species and resulting neurodegeneration.[110]

N-acetyl cysteine: It is a precursor for glutathione which acts to reduce markers of inflammation, suppresses mitochondrial dysfunction, reduces oxidative stress and reverses the behavioral deficits resultant from glutathione depletion.[111],[112] It targets many of the cellular processes implicated in cognitive dysfunction. Several recent studies provide evidence for the its procognitive effects and highlight the potential of N-acetyl cysteine in overcoming inflammation and oxidative stress.[113]

Deferoxamine: Deferoxamine treatment was found to reduce cytokine production in microglia cultures by preventing the release of TNF-α, IL-1β, and IL6. Deferoxamine reduces oxidative stress by downregulation of NADPH oxidase subunits and p38-mitogen-activated protein kinase responsible for oxidative stress signaling after surgical trauma as a target to treat POCD.[114]


With the age scale of the patient population tilting to the geriatric end of the spectrum, PND has become a significant cause of morbidity and mortality in older adults. PND is today perhaps the most investigated health problem internationally. A random search on Pubmed displayed more than 5500 publications on the subject in the last 5 years. A large number of pharmacologic strategies are under investigation to prevent/treat PND, but they need long-term efficacy evaluations.

Inconsistencies and shortcomings, in the screening methodology, currently hinder the diagnosis/recognition of patients with PND. The Network for Investigation of Delirium: Unifying Scientists (NIDUS) was created to support a collaborative network for delirium research to determine the cause, mechanisms, outcomes, diagnosis, prevention, and treat delirium in older adults.[115] The evaluation of anaesthetics on cognitive outcome also seems to be difficult as they have been demonstrated to be potentially neurotoxic and also to be neuroprotective for ischemia-reperfusion injury.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.


1Saczynski JS, Marcantonio ER, Quach L, Fong TG, Gross A, Inouye SK, et al. Cognitive trajectories after postoperative delirium. N Engl J Med 2012;367:30-9.
2Lingehall HC, Smulter NS, Lindahl E, Lindkvist M, Engström KG, Gustafson YG, et al. Preoperative cognitive performance and postoperative delirium are independently associated with future dementia in older people who have undergone cardiac surgery: A longitudinal cohort study. Crit Care Med 2017;45:1295-303.
3Brown CH IV, Probert J, Healy R, Parish M, Nomura Y, Yamaguchi A, et al. Cognitive decline after delirium in patients undergoing cardiac surgery. Anesthesiology 2018;129:406-16.
4Rengel KF, Hayhurst CJ, Pandharipande PP, Hughes CG. Long-term cognitive and functional impairments after critical illness. Anesth Analg 2019;128:772-80.
5Herridge MS, Cheung AM, Tansey CM, Matte-Martyn A, Diaz-Granados N, Al-Saidi F, et al. Canadian Critical Care Trials Group. One-year outcomes in survivors of the acute respiratory distress syndrome. N Engl J Med 2003;348:683-93.
6Ehlenbach WJ, Hough CL, Crane PK, Haneuse SJ, Carson SS, Curtis JR, et al. Association between acute care and critical illness hospitalization and cognitive function in older adults. JAMA 2010;303:763-70.
7Pandharipande PP, Girard TD, Ely EW. Long-term cognitive impairment after critical illness. N Engl J Med 2014;370:185-6.
8Hughes CG, Patel MB, Jackson JC, Girard TD, Geevarghese SK, Norman BC, et al. Surgery and anesthesia exposure is not a risk factor for cognitive impairment after major noncardiac surgery and critical illness. Ann Surg 2016;265:1126-33.
9Guerra C, Hua M, Wunsch H. Risk of a diagnosis of dementia for elderly Medicare beneficiaries after intensive care. Anesthesiology 2015;123:1105-12.
10Celutkiene J, Vaitkevicius A, Jakštiene S, Dalius Jatužis D. Expert opinion-cognitive decline in heart failure: More attention is needed. Card Fail Rev 2016;2:106-9.
11Hammond CA, Blades NJ, Chaudhry SI, Dodson JA, Longstreth Jr WT, Heckbert SR, et al. Long-term cognitive decline after newly diagnosed heart failure longitudinal analysis in the CHS (Cardiovascular Health Study). Circ Heart Fail 2018;11:e004476.
12Jackson JC, Pandharipande PP, Girard TD, Brummel NE, Thompson JL, Hughes CG, et al. Bringing to light the risk factors and incidence of neuropsychological dysfunction in ICU survivors (BRAIN-ICU) study investigators. Depression, post-traumatic stress disorder, and functional disability in survivors of critical illness in the BRAIN-ICU study: A longitudinal cohort study. Lancet Respir Med 2014;2:369-79.
13Wilson ME, Barwise A, Heise KJ, Loftsgard TO, Dziadzko M, Cheville A, et al. Long-term return to functional baseline after mechanical ventilation in the ICU. Crit Care Med 2018;46:562-9.
14Pandharipande P, Shintani A, Peterson J, Pun BT, Wilkinson GR, Dittus RS, et al. Lorazepam is an independent risk factor for transitioning to delirium in intensive care unit patients. Anesthesiology 2006;104:21-6.
15Agarwal V, O'Neill PJ, Cotton BA, Pun BT, Haney S, Thompson J, et al. Prevalence and risk factors for development of delirium in burn intensive care unit patients. J Burn Care Res 2010;31:706-15.
16Morandi A, Hughes CG, Girard TD, McAuley DF, Ely EW, Pandharipande PP. Statins and brain dysfunction: A hypothesis to reduce the burden of cognitive impairment in patients who are critically ill. Chest 2011;140:580-5.
17Pandharipande PP, Pun BT, Herr DL, Maze M, Girard TD, Miller RR, et al. Effect of sedation with dexmedetomidine vs lorazepam on acute brain dysfunction in mechanically ventilated patients: The MENDS randomized controlled trial. JAMA 2007;298:2644-53.
18Pisani MA, Murphy TE, Araujo KL, Slattum P, Van Ness PH, Inouye SK. Benzodiazepine and opioid use and the duration of intensive care unit delirium in an older population. Crit Care Med 2009;37:177-83.
19Aurell J, Elmqvist D. Sleep in the surgical intensive care unit: Continuous polygraphic recording of sleep in nine patients receiving postoperative care. Br Med J (Clin Res Ed) 1985;290:1029-32.
20Cammarano WB, Pittet JF, Weitz S, Schlobohm RM, Marks JD. Acute withdrawal syndrome related to the administration of analgesic and sedative medications in adult intensive care unit patients. Crit Care Med 1998;26:676-84.
21Walker MP. Cognitive consequences of sleep and sleep loss. Sleep Med 2008;9(Suppl 1):S29-34.
22Zhu B, Dong Y, Xu Z, Gompf HS, Ward SA, Xue Z, et al. Sleep disturbance induces neuroinflammation and impairment of learning and memory. Neurobiol Dis 2012;48:348-55.
23Gunther ML, Morandi A, Krauskopf E, Pandharipande P, Girard TD, Jackson JC, et al.; VISIONS Investigation, VISualizing ICU SurvivOrs Neuroradiological Sequelae. The association between brain volumes, delirium duration, and cognitive outcomes in intensive care unit survivors: The VISIONS cohort magnetic resonance imaging study. Crit Care Med 2012;40:2022-32.
24Morandi A, Rogers BP, Gunther ML, Merkle K, Pandharipande P, Girard TD, et al. VISIONS Investigation, VISualizing ICU SurvivOrs Neuroradiological Sequelae. The relationship between delirium duration, white matter integrity, and cognitive impairment in intensive care unit survivors as determined by diffusion tensor imaging: The VISIONS prospective cohort magnetic resonance imaging study. Crit Care Med 2012;40:2182-9.
25Cavallari M, Dai W, Guttmann CRG, Meier DS, Ngo LH, Hshieh TT, et al. SAGES Study Group. Longitudinal diffusion changes following postoperative delirium in older people without dementia. Neurology 2017;89:1020-7.
26Moller JT, Cluitmans P, Rasmussen LS, Houx P, Rasmussen H, Canet J, et al. Longterm postoperative cognitive dysfunction in the elderly ISPOCD1 study. ISPOCD investigators. International study of post-operative cognitive dysfunction. Lancet 1998;351:857-61.
27Bijker JB, van Klei WA, Kappen TH, van Wolfswinkel L, Moons KGM, Kalkman CJ. Incidence of intraoperative hypotension as a function of the chosen definition: Literature definitions applied to a retrospective cohort using automated data collection. Anesthesiology 2007;107:213-20.
28Patel N, Minhas JS, Chung EML. Risk factors associated with cognitive decline after cardiac surgery: A systematic review. Cardiovasc Psychiatry Neurol 2015;2015:370612.
29Joshi B, Ono M, Brown C, Brady K, Easley RB, Yenokyan G, et al. Predicting the limits of cerebral autoregulation during cardiopulmonary bypass. Anesth Analg 2012;114:503-10.
30Langer T, Santini A, Zadek F, Chiodi M, Pugni P, Cordolcini V, et al. Intraoperative hypotension is not associated with postoperative cognitive dysfunction in elderly patients undergoing general anesthesia for surgery: Results of a randomized controlled pilot trial. J Clin Anesth 2019;52:111-8.
31Feinkohl I, Winterer G, Pischon T. Diabetes is associated with risk of postoperative cognitive dysfunction: A meta-analysis. Diabetes Metab Res Rev 2017;33:e2884.
32Puskas F, Grocott HP, White WD, Mathew JP, Newman MF, Bar-Yosef S. Intraoperative hyperglycemia and cognitive decline after CABG. Ann Thorac Surg 2007;84:1467-73.
33Prasad S, Sajja RK, Naik P, Cucullo L. Diabetes mellitus and blood-brain barrier dysfunction: An overview. J Pharmacovigil 2014;2:125.
34Fujisawa H, Sugimura Y, Takagi H, Mizoguchi H, Takeuchi H, Izumida H, et al. Chronic hyponatremia causes neurologic and psychologic impairments. J Am Soc Nephrol 2016;27:766-80.
35Verbalis JG. Brain volume regulation in response to changes in osmolality. Neuroscience 2010;168:862-70.
36Barsony J, Sugimura Y, Verbalis JG. Osteoclast response to low extracellular sodium and the mechanism of hyponatremia-induced bone loss. J Biol Chem 2011;286:10864-75.
37Nowak KL, Yaffe K, Orwoll ES, Ix JH, You Z, Barrett-Connor E, et al. Serum sodium and cognition in older community-dwelling men. Clin J Am Soc Nephrol 2018;13:366-74.
38van Harten AE, Scheeren TW, Absalom AR. A review of postoperative cognitive dysfunction and neuroinflammation associated with cardiac surgery and anaesthesia. Anaesthesia 2012;67:280-93.
39Khalil S, Roussel J, Schubert A, Emory L. Postoperative cognitive dysfunction: An updated review. J Neurol Neurophysiol 2015;6:290.
40Grossestreuer AV, Gaieski DF, Donnino MW, Wiebe DJ, Abella BS. Magnitude of temperature elevation is associated with neurologic and survival outcomes in resuscitated cardiac arrest patients with postrewarming pyrexia. J Crit Care 2017;38:78-83.
41Kasdorf E, Perlman JM. Hyperthermia, inflammation, and perinatal brain injury. Pediatr Neurol 2013;49:8-14.
42Soderfjell S, Molander B, Johansson H, Barnekow-Bergkvist M, Nilsson LG. Musculoskeletal pain complaints and performance on cognitive tasks over the adult life span. Scand J Psychol 2006;47:349-59.
43Scherder EJ, Eggermont L, Plooij B, Oudshoorn J, Vuijk PJ, Pickering G, et al. Relationship between chronic pain and cognition in cognitively intact older persons and in patients with Alzheimer's disease. The need to control for mood. Gerontology 2008;54:50-8.
44Moriarty O, Ruane N, O'Gorman D, Maharaj CH, Mitchell C, Sarma KM, et al. Cognitive impairment in patients with chronic neuropathic or radicular pain: An interaction of pain and age. Front Behav Neurosci 2017;11:100.
45Moriarty O, Brian E. McGuire BE, Finn DP. The effect of pain on cognitive function: A review of clinical and preclinical research. Prog Neurobiol 2011;93:385-404.
46Evered L, Silbert B, Scott DA, Zetterberg H, Blennow K. Association of changes in plasma neurofilament light and tau levels with anesthesia and surgery: Results from the CAPACITY and ARCADIAN studies. JAMA Neurol 2018;75:542-7.
47Xie Z, Swain CA, Ward SA, Zheng H, Dong Y, Sunder N, et al. Preoperative cerebrospinal fluid β-amyloid/tau ratio and postoperative delirium. Ann Clin Transl Neurol 2014;1:319-28.
48Evered L, Silbert B, Scott DA, Ames D, Maruff P, Blennow K. Cerebrospinal fluid biomarker for Alzheimer disease predicts postoperative cognitive dysfunction. Anesthesiology 2016;124:353-61.
49Cunningham EL, McGuinness B, McAuley DF, McAuley DF, Toombs J, Mawhinney T, et al. CSF betaamyloid 1-42 concentration predicts delirium following elective arthroplasty surgery in an observational cohort study. Ann Surg 2019;269:1200-5.
50Anckarsäter R, Anckarsäter H, Bromander S, Blennow K, Wass C, Zetterberg H. Non-neurological surgery and cerebrospinal fluid biomarkers for neuronal and astroglial integrity. J Neural Transm (Vienna) 2014;121:649-53.
51Klinger RY, James OG, Borges-Neto S, Bisanar T, Li YJ, Qi W, et al.; Alzheimer's Disease Neuroimaging Initiative (ADNI) Study Group; Neurologic Outcomes Research Group (NORG). 18F-florbetapir positron emission tomography-determined cerebral β-amyloid deposition and neurocognitive performance after cardiac surgery. Anesthesiology 2018;128:728-44.
52Cibelli M, Fidalgo AR, Terrando N, Ma D, Monaco C, Feldmann M, et al. Role of interleukin-1beta in postoperative cognitive dysfunction. Ann Neurol 2010;68:360-8.
53Terrando N, Monaco C, Ma D, Foxwell BM, Feldmann M, Maze M. Tumor necrosis factor-alpha triggers a cytokine cascade yielding postoperative cognitive decline. Proc Natl Acad Sci U S A 2010;107:20518-22.
54Fidalgo AR, Cibelli M, White JP, Nagy I, Maze M, Ma D. Systemic inflammation enhances surgery-induced cognitive dysfunction in mice. Neurosci Lett 2011;498:63-6.
55Kapoor MC, Ramachandran TR. Inflammatory response to cardiac surgery and strategies to overcome it. Ann Cardiac Anaesth 2004;7:113-8.
56Hotchkiss RS, Karl IE. The pathophysiology and treatment of sepsis. N Engl J Med 2003;348:138-50.
57Chen J, Buchanan JB, Sparkman NL, Godbout JP, Freund GG, Johnson RW. Neuroinflammation and disruption in working memory in aged mice after acute stimulation of the peripheral innate immune system. Brain Behav Immun 2008;22:301-11.
58Hudetz JA, Gandhi SD, Iqbal Z, Patterson KM, Pagel PS. Elevated postoperative inflammatory biomarkers are associated with short- and medium-term cognitive dysfunction after coronary artery surgery. J. Anesth 2010;25:1-9.
59Maciel M, Benedet SR, Lunardelli EB, Delziovo H, Domingues RL, Vuolo F, et al. Predicting longterm cognitive dysfunction in survivors of critical illness with plasma inflammatory markers: A retrospective cohort study. Mol Neurobiol 2019;56:763-7.
60Peng L, Xu L, Ouyang W, Role of peripheral inflammatory markers in postoperative cognitive dysfunction (POCD): A meta-analysis. PLoS One 2013;8:e79624.
61Abbott NJ, Patabendige AA, Dolman DE, Yusof SR, Begley DJ. Structure and function of the blood-brain barrier. Neurobiol Dis 2010;37:13-25.
62Zheng X, Liang Y, Kang A, Ma SJ, Xing L, Zhou YY, et al. Peripheral immunomodulation with ginsenoside Rg1 ameliorates neuroinflammaion-induced behavioral deficits in rats. Neuroscience 2014;256, 210-22.
63Manganelli V, Signore M, Pacin I, Misasi R, Tellan G, Garofalo T, et al. Increased HMGB1 expression and release by mononuclear cells following surgical/anesthesia trauma. Crit Care 2010;14:R197.
64Beloosesky Y, Hendel D, Weiss A, Hershkovitz A, Grinblat J, Pirotsky A, et al. Cytokines and C-reactive protein production in hip-fracture-operated elderly patients. J Gerontol A Biol Sci Med Sci 2007;62:420-6.
65Buvanendran A, Kroin JS, Berger RA, Hallab NJ, Saha C, Negrescu C, et al. Upregulation of prostaglandin E2 and interleukins in the central nervous system and peripheral tissue during and after surgery in humans. Anesthesiology 2006;104:403-10.
66Colonna M, Butovsky O. Microglia function in the central nervous system during health and neurodegeneration. Annu Rev Immunol 2017;35:441-68.
67Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole GM, et al. Inflammation and Alzheimer's disease. Neurobiol Aging 2000;21:383-421.
68Kim ID, Lee JK. HMGB1-binding heptamer confers anti-inflammatory effects in primary microglia culture. Exp. Neurobiol 2013;22:301-7.
69Cerejeira J, Firmino H, Vaz-Serra A, Mukaetova-Ladinska EB. The neuroinflammatory hypothesis of delirium. Acta Neuropathol 2010;119:737-54.
70Hughes CG, Pandharipande PP, Thompson JL, Chandrasekhar R, Ware LB, Ely EW, et al. Endothelial activation and blood-brain barrier injury as risk factors for delirium in critically ill patients. Crit Care Med 2016;44:e809-17.
71Merino JG, Latour LL, Tso A, Lee KY, Kang DW, Davis LA, et al. Blood-brain barrier disruption after cardiac surgery. AJNR Am J Neuroradiol 2013;34:518-23.
72Abrahamov D, Levran O, Naparstek S, Refaeli Y, Kaptson S, Abu Salah M, et al. Blood-brain barrier disruption after cardiopulmonary bypass: Diagnosis and correlation to cognition. Ann Thorac Surg 2017;104:161-9.
73Reinsfelt B, Ricksten SE, Zetterberg H, Blennow K, Fredén-Lindqvist J, Westerlind A. Cerebrospinal fluid markers of brain injury, inflammation, and blood-brain barrier dysfunction in cardiac surgery. Ann Thoracic Surg 2012;94:549-55.
74Bayram H, Hidiroglu M, Cetin L, Kucuker A, Iriz E, Uguz E, et al. Comparing S-100 beta protein levels and neurocognitive functions between patients undergoing on-pump and off-pump coronary artery bypass grafting. J Surg Res 2013;182:198-202.
75Hughes CG, Patel MB, Brummel NE, Thompson JL, McNeil JB, Pandharipande PP, et al. Relationships between markers of neurologic and endothelial injury during critical illness and long-term cognitive impairment and disability. Intensive Care Med 2018;44:345-55.
76Sankowski R, Mader S, Valdés-Ferrer SI. Systemic inflammation and the brain: Novel roles of genetic, molecular, and environmental cues as drivers of neurodegeneration. Front Cell Neurosci 2015;9:28.
77Zhang X, Dong H, Li N, Zhang S, Sun J, Zhang S, et al. Activated brain mast cells contribute to postoperative cognitive dysfunction by evoking microglia activation and neuronal apoptosis. J Neuroinflammation 2016;13:127.
78Chandravanshi LP, Yadav RS, Shukla RK, Singh A, Sultana S, Pant AB, et al. Reversibility of changes in brain cholinergic receptors and acetylcholinesterase activity in rats following early life arsenic exposure. Int J Dev Neurosci 2014;34:60-75.
79Revel F, Gilbert T, Roche S, Drai J, Blond E, Ecochard R, et al. Influence of oxidative stress biomarkers on cognitive decline. J Alzheimer's Dis 2015;45:553-60.
80Zhang T, Tian X, Wang Q, Tong Y, Wang H, Li Z, et al. Surgical stress induced depressive and anxiety like behavior are improved by dapsone via modulating NADPH oxidase level. Neurosci Lett 2015;585:103-8.
81Wu C, Gao B, Gui Y. Malondialdehyde on postoperative day 1 predicts postoperative cognitive dysfunction in elderly patients after hip fracture surgery. Biosci Rep 2019;39:BSR20190166.
82Keshavarz S, Kermanshahi S, Karami L, Motaghinejad M, Motevalian M, Sadr S. Protective role of metformin against methamphetamine induced anxiety, depression, cognition impairment and neurodegeneration in rat: The role of CREB/BDNF and Akt/GSK3 signaling pathways. Neurotoxicology 2019;72:74-84.
83Sanders RD. Hypothesis for the pathophysiology of delirium: Role of baseline brain network connectivity and changes in inhibitory tone. Med Hypotheses 2011;77:140-3.
84Hovens IB, van Leeuwen BL, Mariani MA, Kraneveld AD, Schoemaker RG. Postoperative cognitive dysfunction and neuroinflammation; cardiac surgery and abdominal surgery are not the same. Brain Behav Immun 2016;54:178-93.
85Amaoko D, Tan AMY. Postoperative cognitive dysfunction after cardiac surgery. Continuing Educ Anesthesia Crit. Care Pain 2013;13:218-23.
86Raichle ME. The brain's default mode network. Annu Rev Neurosci 2015;38:433-47.
87Huang H, Tanner J, Parvataneni H, Rice M, Horgas A, Ding M, et al. Impact of total knee arthroplasty with general anesthesia on brain networks: Cognitive efficiency and ventricular volume predict functional connectivity decline in older adults. J Alzheimers Dis 2018;62:319-33.
88van Dellen E, van der Kooi AW, Numan T, Koek HL, Klijn FA, Buijsrogge MP, et al. Decreased functional connectivity and disturbed directionality of information flow in the electroencephalography of intensive care unit patients with delirium after cardiac surgery. Anesthesiology 2014;121:328-35.
89Giattino CM, Gardner JE, Sbahi FM, Roberts KC, Cooter M, Moretti E, et al. MADCO-PC Investigators. Intraoperative frontal alpha-band power correlates with preoperative neurocognitive function in older adults. Front Syst Neurosci 2017;11:24.
90Imamura M, Prasad C. Modulation of GABA-gated chloride ion influx in the brain by dehydroepiandrosterone and its metabolites. Biochem Biophys Res Commun 1998;243:771-5.
91Orser BA, Wang DS. GABAA receptor theory of perioperative neurocognitive disorders. Anesthesiology 2019;130:618-9.
92Monk TG, Weldon BC, Garvan CW, Dede DE, van der Aa MT, Heilman KM, et al. Predictors of cognitive dysfunction after major noncardiac surgery. Anesthesiology 2008;108:18-30.
93Gameiro M, Eichler W, Schwandner O, Bouchard R, Schön J, Schmucker P, et al. Patient mood and neuropsychological outcome after laparoscopic and conventional colectomy. Surgical Innovation 2008;15;171-8.
94Rundshagen I. Postoperative cognitive dysfunction. Dtsch Arztebl Int 2014;111:119-25.
95Pandharipande P, Cotton BA, Shintani A, Thompson J, Pun BT, Morris JA Jr, et al. Prevalence and risk factors for development of delirium in surgical and trauma intensive care unit patients. J Trauma 2008;65:34-41.
96Pandharipande PP, Sanders RD, Girard TD, McGrane S, Thompson JL, Shintani AK, et al. MENDS Investigators. Effect of dexmedetomidine versus lorazepam on outcome in patients with sepsis: An a priori-designed analysis of the MENDS randomized controlled trial. Crit Care 2010;14:R38.
97Riker RR, Shehabi Y, Bokesch PM, Ceraso D, Wisemandle W, Koura F, et al. SEDCOM (Safety and Efficacy of Dexmedetomidine Compared With Midazolam) Study Group. Dexmedetomidine vs midazolam for sedation of critically ill patients: A randomized trial. JAMA 2009;301:489-99.
98Jaturapatporn D, Isaac MGEKN, McCleery J, Tabet N. Aspirin, steroidal and non-steroidal anti-inflammatory drugs for the treatment of Alzheimer's disease. Cochrane Database Syst Rev 2012;CD006378. doi: 10.1002/14651858.CD006378.pub2.
99Swiger KJ, Manalac RJ, Blumenthal RS, Blaha MJ, Martin SS. Statins and cognition: A systematic review and meta-analysis of short- and long-term cognitive effects. Mayo Clin Proc 2013;88:1213-21.
100McGuinness B, Craig D, Bullock R, Passmore P. Statins for the prevention of dementia. Cochrane Database Syst Rev 2016;4:CD003160.
101Kawano T, Eguchi S, Iwata H, Yamanaka D, Tateiwa H, Locatelli FM, et al. Pregabalin can prevent, but not treat, cognitive dysfunction following abdominal surgery in aged rats. Life Sci 2016;148:211-9.
102Zaccara G, Gangemi P, Perucca P, Specchio L. The adverse event profile of pregabalin: A systematic review and meta-analysis of randomized controlled trials. Epilepsia 2011;52:826-36.
103Li Z, Wei H, Piirainen S, Chen Z, Kalso E, Pertovaara A, et al. Spinal versus brain microglial and macrophage activation traits determine the differential neuroinflammatory responses and analgesic effect of minocycline in chronic neuropathic pain. Brain Behav Immun 2016;58:107-17.
104Man Y, Guo Z, Cao J, Mi W. Efficacy of perioperative dexmedetomidine in postoperative neurocognitive function: A meta-analysis. Clin Exp Pharmacol Physiol 2015;42:837-42.
105van der Wal SEI, van den Heuvel SAS, Radema SA, van Berkum BFM, Vaneker M, Steegers MAH, et al. The in vitro mechanisms and in vivo efficacy of intravenous lidocaine on the neuroinflammatory response in acute and chronic pain. Eur J Pain 2015;20:655-74.
106Klinger RY, Cooter M, Bisanar T, Terrando N, Berger M, Podgoreanu MV, et al.; for the Neurologic Outcomes Research Group of the Duke Heart Center. Intravenous lidocaine does not improve neurologic outcomes after cardiac surgery. A randomized controlled trial. Anesthesiology 2019;130:958-70.
107De Kock M, Loix S, Lavand'homme P. Ketamine and peripheral inflammation. CNS Neurosci Therap 2013;19:403-10.
108Hudetz JA, Iqbal Z, Gandhi SD, Patterson KM, Byrne AJ, Hudetz AG, et al. Ketamine attenuates post-operative cognitive dysfunction after cardiac surgery. Acta Anaesthesiol Scand 2009;53:864-72.
109Nagels W, Demeyere R, Van Hemelrijck J, Vandenbussche E, Gijbels K, Vandermeersch E. Evaluation of the neuroprotective effects of S(+)-Ketamine during open-Heart surgery. Anesth Analg 2004;1595-603.
110Karachitos A, Solis Garcia del Pozo J, de Groot WJ, Kmita P, Jordan J. Minocycline mediated mitochondrial cytoprotection: Premises for therapy of cerebrovascular and neurodegenerative diseases. Curr Drug Targets 2012;14:47-55.
111Dean OM, van den Buuse M, Berk M, Copolov DL, Mavros C, Bush AI. Nacetyl cysteine restores brain glutathione loss in combined 2-cyclohexene-1-one and d-amphetamine-treated rats: Relevance to schizophrenia and bipolar disorder. Neurosci Lett 2011;499:149-53.
112Otte DM, Sommersberg B, Kudin A, Guerrero C, Albayram Ö, Filiou MD, et al. N-acetyl cysteine treatment rescues cognitive deficits induced by mitochondrial dysfunction in G72/G30 transgenic mice. Neuropsychopharmacology 2011;36:2233-43.
113Skvarc DR, Berk M, Byrne LK, Dean OM, Dodd S, Lewis M, et al. Post-operative cognitive dysfunction: An exploration of the inflammatory hypothesis and novel therapies. Neurosci Biobehav Rev 2018;84:116-33.
114Li Y, Pan K, Chen L, Ning J, Li X, Yang T, et al. Deferoxamine regulates neuroinflammation and iron homeostasis in a mouse model of postoperative cognitive dysfunction. J Neuroinflammation 2016;13:268.
115Nidus-Network for Investigation of Delirium: Unifying Scientists. Available from: [Last accessed on 2019 Sep 06].