Intranasal Insulin Administration To Prevent Delayed Neurocognitive Recovery And Postoperative Neurocognitive Disorder Part 2

Clinical Evidence

The hormone insulin was isolated from dogs for the first time in 1921 by Dr. Frederick Banting, a Canadian doctor surgeon, and Charles Best, a medical student [27] (Table 2). It was subsequently injected intravenously or subcutaneously into animal and human models. Clinical observations reported the following conclusions: reduction in the blood glucose concentration, abolishment of glycosuria, disappearance of acetone bodies from the urine, and increase in the use of carbohydrates. The use of insulin as non-glycemia management therapy dates back to the 1930s, when Manyfreed Sakel used it, with intravenous administration, to treat morphine addiction and schizophrenia [28]. Sakel’s method consisted in a four-phase approach that led to an insulin-induced coma: the preparatory phase, shock phase, rest phase, and terminal phase. Patients with schizophrenia reported a reduction in or the disappearance of all sorts of hallucinations during insulin-induced hypoglycemia and protraction of the lucid phase’, thus proving the clinical evidence of a psychotropic effect of insulin [28]. Furthermore, hypoglycemia shock induced by insulin was used in dementia praecox patients [29]. All these approaches were abandoned after the introduction of antipsychotic drugs (such as chlorpromazine) into clinical practice [30].

Plasma insulin arrives at the brain's interstitial fluid and cerebrospinal fluid (CSF) via an IR-mediated transcytosis mechanism through endothelial BBB cells [31]. In addition, some brain areas, such as the hypothalamus, hippocampus, and brain stem, are shown to independently produce insulin [32]. Intranasal insulin administration in humans has been proven to be feasible, safe, effective, and independent of BBB [33]. The administration through this route uses olfactory and trigeminal neurons that pass through the cribriform plate and induces rapid distribution to the CNS (within minutes) [33]. The peptide hormone is detectable in the CSF for at least 80 min, and less than 3% of the administered insulin reaches the systemic bloodstream without causing systemic hypoglycemia or hepatic first-pass metabolism [33].

Intranasal insulin administration was shown to have pleiotropic effects during acute, subacute, and chronic phases after acute ischemic stroke events [34]. During the acute phase, insulin suppresses the pro-inflammatory transcription response, induces vasodilatory effects by promoting activation of endothelial nitric oxide synthase, enhances the effects of thrombolysis, and reduces the final infarct volume. In addition to the acute phase, insulin’s effects extend to the subacute and chronic phases through an anti-apoptotic effect, promotion of neurite regeneration, neurotransmission, and functional connectivity [33,34]. Effects on neurocognitive and memory performance were positive according to the results obtained in 38 healthy individuals, without memory impairment, evaluated with a double-blind and between-subject comparison that showed improved word recall ability and self-confidence in cognitive tasks after 8-week treatment [35]. Another systematic review showed that only high doses of intranasal insulin (160 IU/die) compared to lower doses (≥60 IU/die) induced potential beneficial effects in healthy people, with greater improvements in females when compared to men [36].

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Recent clinical evidence supports intranasal insulin administration also in memory-impaired patients such as those with mild cognitive impairment (MCI), AD, Parkinson’s disease (PD), and multiple system atrophy diagnosis [37–43]. The therapeutic effects of intranasal insulin administration in 26 memory-impaired individuals (13 with early AD and 13 with amnestic MCI) and 35 controls were evaluated [37]. Insulin treatment facilitated recall of verbal memory, with stronger effects in memory-impaired apolipoprotein E4 (APOE)– patients compared to APOE4+ ones. Another systematic review including seven studies and a total of 293 patients showed that intranasal insulin administration in patients with MCI or AD improved verbal memory and story recall, especially for APOE4– patients [38]. It is unclear whether the difference is due to the stronger association between insulin resistance and AD in patients without as compared to those with the risk allele or whether insulin administration aggravates impairments in brain glucose metabolism in carriers of the APOE4+ genotype [39]. Furthermore, there were positive results in functional status and daily activity. Daily intranasal insulin therapy for 4 months in patients with MCI and AD improved delayed memory and preserved the brain volume by reducing the progression of brain hypometabolism [40]. The role of intranasal insulin administration was investigated in two randomized controlled trials (RCTs) enrolling, respectively, 104 and 60 MCI or AD patients [18,41]. In the first one, insulin was administered for 4 months, while in the second one, long-lasting insulin detemir administration was conducted for 21 days. Insulin administration improved verbal, visuospatial, and working memory and preserved general cognition and functional abilities, while placebo-assigned participants showed decreased fludeoxyglucose 18 uptakes in the parietotemporal, frontal, precuneus, and cuneus regions. A prospective, randomized, double-blinded, placebo-controlled, pilot study of 16 enrolled patients (15 with Parkinson’s disease and 1 with multiple system atrophy diagnosis) reported that intranasal insulin administration for 4 weeks improved cognitive and motor performance in PD patients, while there was a lack of disease progression in the multiple system atrophy case, compared to intranasal sterile saline administration [42].

Discussion

This narrative review is intended to report available preclinical and clinical evidence of the implication of intranasal insulin in preventing changes in the brain molecular pattern and/or neurobehavioral impairment, which influence anesthesia-induced DNR/NCD.

Collected preclinical evidence shows that anesthesia administration enhances the phosphorylation status of tau protein in the brain, reduces the expression of brain synaptic proteins and BDNF, and induces cognitive decline both in wild-type and AD models, including adult and aged mice; long-term neurobehavioral effects are also demonstrated when anesthesia is administered in neonatal mice. As suggested by preclinical evidence, insulin can blunt anesthetic-induced apoptosis and tau phosphorylation at various levels (Figure 1). While biochemical changes, including hyperphosphorylation of tau protein, are reported to be transient, long-lasting cognitive and neurobehavioral effects have been reported and confirmed by several studies. Intranasal administration of insulin has been found effective in preventing biochemical, cognitive, and neurobehavioral changes that are induced by anesthesia.

General anesthetics contribute to DNR/pNCD by indirectly promoting neuronal apoptosis and by interfering with synaptic protein synthesis. Neuronal apoptosis is favored by the hyperphosphorylation of tau protein mainly by the kinase GSK-3β, which is stimulated by anesthetics. Moreover, the inhibition of the mTOR-eEF2 pathway leads to a reduction in specific synaptic proteins and BDNF synthesis. Intranasal administration of insulin has been proven to reduce GSK-3β activity, through the activation of the PI3K/PDK1/AKT signaling pathway, and to stimulate the mTOR-eEF2 pathway, thus resulting in counteracting the deleterious effects of general anesthesia.

Insulin is a peptide hormone, and the blood glucose concentration is the principal regulator of its secretion [13]. IRs are found in many tissues in different concentrations and present an intracellular tyrosine phosphorylation transduction that defines two major insulin signaling pathways: (1) PI3K/PDK1/AKT, which promotes intracellular glucose transport, glycogen, protein, and lipid synthesis; stimulates axonal outgrowth; and has an anti-apoptotic pathway inhibiting proapoptotic proteins, and (2) mTOR/eEF2K/eEF2, which promotes mitosis by gene transcription, cell proliferation, survival, motility, and protein synthesis. There is some crosstalk between these two intracellular pathways. The CNS-IRs have a characteristic distribution in the brain, with the highest concentration in the thalamus, caudate-putamen, hippocampus, amygdala, and parahippocampal gyrus; intermediate concentration in the cerebellum, cerebral cortex, and caudate nucleus; and the lowest concentration in the substantia nigra, red nucleus, white matter, and cerebral peduncles. This specific distribution and the anti-apoptotic and cell proliferation action of the intracellular signaling pathway suggest that CNS-IR function may relate to cognitive performance, memory, and neuromodulation because of the effects of insulin on neuronal metabolism, neuronal function, and neurotransmission. Insulin exerts a trophic function in the CNS by regulating cell growth, differentiation, and neuronal survival. Furthermore, insulin has a neuromodulatory role as it participates in synaptic plasticity by modulating the activities of excitatory and inhibitory receptors.

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The occurrence of DNR/pNCD is among the most serious adverse complications after surgery and anesthesia that cause poor recovery, increased use of social-financial assistance, and a higher mortality rate [7,43]. It is associated with memory and language impairment and might last for months or even years [9]. The pathogenesis is still unclear, but risk factors such as advanced age, low baseline cognition, education level, history of DM, dehydration, malnutrition, major surgery (cardiac and orthopedic), intraoperative blood pressure fluctuation, and hyperglycemia, postoperative respiratory complications, type and depth of anesthesia, etc., have been shown to contribute [8]. Anesthesia was shown to evoke a systemic and neuroinflammatory response, accumulation of Aβ proteins, increase in tau protein phosphorylation, mitochondrial dysfunction, and calcium dysregulation [44].

To prevent this serious complication, several pharmacological and non-pharmacological strategies have been tested [8,43]. A systematic review tested 16 drugs to prevent DNR/pNCD, and only 3 of them were shown to be associated with benefits: lidocaine, magnesium sulfate, and ketamine [43]. In the original studies, lidocaine and magnesium sulfate were administered intra- and postoperatively, while ketamine was tested as a single dose during induction of general anesthesia [45–48]. The non-pharmacological tested approach includes environmental adaptations (such as normal circadian function and good sleep quality), behavioral interventions, intraoperative depth of anesthesia monitoring with the bispectral index (BIS) or cerebral oximetry, postoperative rehabilitation, psychological and social supports, and complementary and alternative medicine [8].

The clinical use of insulin as non-glycemia management therapy administered intravenously was first described for morphine addiction treatment, schizophrenia symptom mitigation, and dementia praecox. Hypoglycemic shock induced by insulin was shown to have a psychotropic effect in these patients. This approach consisted of four phases (preparatory phase, shock phase, rest phase, and terminal phase) and was abandoned after the introduction of antipsychotic drugs. Subsequently, the administration of intranasal insulin was found to be safe and have positive effects on neurocognitive performance, memory performance, daily activity, and brain volume during acute, subacute, and chronic phases after ischemic stroke events, both in healthy individuals and in patients with memory impairment such as MCI, AD, PD, and multiple system atrophy. Several approaches have been tested to prevent DNR/pNCD, and these include pre-rehabilitation and enhanced recovery. There are no effective pharmacological therapies that have reached an adequate level of evidence to warrant clinical use, and intranasal insulin might represent an innovative approach [13,49,50]. Of interest, when administered intranasally, insulin bypasses the BBB and reaches the brain along the perineural spaces of the olfactory and trigeminal nerves [33,49]. Subsequently, it is distributed along cerebral perivascular spaces without raising peripheral insulin levels or lowering blood glucose. This might explain the absence of associated effects on systemic glycemia, thus making this therapy suitable for perioperative use with no relevant effects on blood glucose concentration.

The main limitations of the narrative review consist of the limited clinical evidence in the current literature of the causative role of anesthesia exposure in cognitive impairment >6 months postoperatively and the role of intranasal insulin administration in preventing the onset of DNR/NCD. Another limitation is the lack of ultimate indications of the usefulness and appropriateness of nasal delivery systems for insulin administration. A recent clinical trial on patients with AD reported no differences in the use of two different tools for intranasal insulin administration [19]. This study could be used to design clinical trials in the future.

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Future Perspectives

The promising role of the potential effects of intranasal insulin administration in mitigating or possibly avoiding the onset of DNR/pNCD and behavioral impairment after general anesthesia should stimulate researchers to design clinical trials aimed at confirming or excluding these findings in human patients. Since the therapeutic effects of intranasal insulin administration have been reported in different clinical settings, including healthy individuals, patients with acute ischemic stroke, and patients with memory impairment with different etiology and severity, there is room to test its effects also in a perioperative setting. Ideally, different population subsets should be tested in specifically designed RCTs, including healthy patients and individuals with prior cognitive deficits admitted for scheduled surgery and randomized to receive either intranasal insulin or saline. Among the relevant outcomes that should be investigated, there is the cognitive status before and after surgery, possibly with long-term follow-up.

Conclusions

DNR/pNCD are major complications that can occur after surgery and anesthesia. Several pharmacological and non-pharmacological strategies have been tested to prevent their onset, but few prove to be effective. The use of intranasal insulin, considering the available preclinical trials and the limited clinical evidence, has the potential to effectively contribute to the prevention of DNR/NCD. This therapeutic effect can be explained through the action on insulin brain receptors and interference with molecular mechanisms of anesthesia-induced cognitive decline. Moreover, the possibility that intranasal administration of insulin could represent a preemptive treatment unfolds very important issues that need to be explored. Further confirmation of the molecular basis of this insulin-related cognition-sparing effect could both strengthen the evidence collected thus far and represent a solid therapeutic target. Future clinical studies should be appropriately designed—with selected patient populations, preoperative screening, and postoperative long-term follow-up—to further confirm available evidence on the use of intranasal insulin administration perioperatively to reduce or prevent the incidence of DNR/pNCD after anesthesia.

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References

1. Evered, L.; Silbert, B.; Knopman, D.S.; Scott, D.A.; DeKosky, S.T.; Rasmussen, L.S.; Oh, E.S.; Crosby, G.; Berger, M.; Eckenhoff, R.G.; et al. Recommendations for the nomenclature of cognitive change associated with anesthesia and surgery-2018. Anesthesiology 2018, 129, 872–879.

2. Evered, L.; Silbert, B.; Scott, D.A.; Eckenhoff, R.G. Recommendations for a new perioperative cognitive impairment nomenclature. Alzheimer's Dement. 2019, 15, 1115–1116.

3. Bilotta, F.; Qeva, E.; Matot, I. Anesthesia and cognitive disorders: A systematic review of the clinical evidence. Expert. Rev. Neurother. 2016, 16, 1311–1320.

4. Needham, M.J.; Webb, C.E.; Bryden, D.C. Postoperative cognitive dysfunction and dementia: What we need to know and do. Br. J. Anaesth. 2017, 119, i115–i125.

5. Evered, L.A.; Silbert, B.S. Postoperative cognitive dysfunction and noncardiac surgery. Anesth. Analg. 2018, 127, 496–505.

6. Van Harten, A.E.; Scheeren, T.W.; Absalom, A.R. A review of postoperative cognitive dysfunction and neuroinflammation associated with cardiac surgery and anesthesia. Anaesthesia 2012, 67, 280–293.

7. Steinmetz, J.; Christensen, K.B.; Lund, T.; Lohse, N.; Rasmussen, L.S. ISPOCD Group: Long-term consequences of postoperative cognitive dysfunction. Anesthesiology 2009, 110, 548–555.

8. Borozdina, A.; Qeva, E.; Cinicola, M.; Bilotta, F. Perioperative cognitive evaluation. Curr. Opin. Anaesthesiol. 2018, 31, 756–761.

9. Hermanides, J.; Qeva, E.; Preckel, B.; Bilotta, F. Perioperative hyperglycemia and neurocognitive outcome after surgery: A systematic review. Minerva Anestesiol. 2018, 84, 1178–1188.

10. Ballard, C.; Jones, E.; Gauge, N.; Aarsland, D.; Nilsen, O.B.; Saxby, B.K.; Lowery, D.; Corbett, A.; Wesnes, K.; Katsaiti, E.; et al. Optimized anesthesia to reduce post-operative cognitive decline (POCD) in older patients undergoing elective surgery, a randomized controlled trial. PLoS ONE 2012, 7, e37410.

11. Shoair, O.A.; Grasso, M.P., II; Lahaye, L.A.; Daniel, R.; Biddle, C.J.; Slattum, P.W. Incidence and risk factors for postoperative cognitive dysfunction in older adults undergoing major noncardiac surgery: A prospective study. J. Anaesthesiol. Clin. Pharmacol. 2015, 31, 30–36.

12. Mason, S.E.; Noel-Storr, A.; Ritchie, C.W. The impact of general and regional anesthesia on the incidence of postoperative cognitive dysfunction and postoperative delirium: A systematic review with meta-analysis. J. Alzheimer's Dis. 2010, 22, S67–S79.

13. Bilotta, F.; Lauretta, M.P.; Tewari, A.; Haque, M.; Hara, N.; Uchino, H.; Rosa, G. Insulin and the brain: A sweet relationship with intensive care. J. Intensive Care Med. 2017, 32, 48–58.

14. Kleinridders, A.; Ferris, H.A.; Cai, W.; Kahn, C.R. Insulin action in the brain regulates systemic metabolism and brain function. Diabetes 2014, 63, 2232–2243.

15. Erol, A. An integrated and unifying hypothesis for the metabolic basis of sporadic Alzheimer’s Disease. J. Alzheimer's Dis. 2008, 13, 241–253.

16. Stoeckel, L.E.; Arvanitakis, Z.; Gandy, S.; Small, D.; Kahn, C.R.; Pascual-Leone, A.; Pawlyk, A.; Sherwin, R.; Smith, P. Complex mechanisms linking neurocognitive dysfunction to insulin resistance and other metabolic dysfunction. F1000Research 2016, 5, 353.

17. Frölich, L.; Blum-Degen, D.; Riederer, P.; Hoyer, S. A disturbance in the neuronal insulin receptor signal transduction in sporadic Alzheimer’s disease. Ann. N. Y. Acad. Sci. 1999, 893, 290–293.

18. Craft, S.; Baker, L.D.; Montine, T.J.; Minoshima, S.; Watson, G.S.; Claxton, A.; Arbuckle, M.; Callaghan, M.; Tsai, E.; Plymate, S.R.; et al. Intranasal insulin therapy for Alzheimer disease and amnestic mild cognitive impairment: A pilot clinical trial. Arch. Neurol. 2012, 69, 29–38.

19. Craft, S.; Raman, R.; Chow, T.W.; Rafii, M.S.; Sun, C.K.; Rissman, R.A.; Donohue, M.C.; Brewer, J.B.; Jenkins, C.; Harless, K.; et al. Safety, efficacy, and feasibility of intranasal insulin for the treatment of mild cognitive impairment and Alzheimer disease dementia: A randomized clinical trial. JAMA Neurol. 2020, 77, 1099–1109.

20. Chen, Y.; Run, X.; Liang, Z.; Zhao, Y.; Dai, C.L.; Iqbal, K.; Liu, F.; Gong, C.X. Intranasal insulin prevents anesthesia-induced hyperphosphorylation of tau in 3xTg-AD mice. Front. Aging Neurosci. 2014, 6, 100.

21. Zhang, Y.; Dai, C.L.; Chen, Y.; Iqbal, K.; Liu, F.; Gong, C.X. Intranasal insulin prevents anesthesia-induced spatial learning and memory deficit in mice. Sci. Rep. 2016, 6, 21186.

22. Chen, Y.; Dai, C.L.; Wu, Z.; Iqbal, K.; Liu, F.; Zhang, B.; Gong, C.X. Intranasal insulin prevents anesthesia-induced cognitive impairment and chronic neurobehavioral changes. Front. Aging Neurosci. 2017, 9, 136.

23. Li, H.; Dai, C.L.; Gu, J.H.; Peng, S.; Li, J.; Yu, Q.; Iqbal, K.; Liu, F.; Gong, C.X. Intranasal administration of insulin reduces chronic behavioral abnormality and neuronal apoptosis induced by general anesthesia in neonatal mice. Front. Neurosci. 2019, 13, 706.

24. Dai, C.L.; Li, H.; Hu, X.; Zhang, J.; Liu, F.; Iqbal, K.; Gong, C.X. Neonatal exposure to anesthesia leads to cognitive deficits in old age: Prevention with intranasal administration of insulin in mice. Neurotox. Res. 2020, 38, 299–311.

25. Yu, Q.; Dai, C.L.; Zhang, Y.; Chen, Y.; Wu, Z.; Iqbal, K.; Liu, F.; Gong, C.X. Intranasal insulin increases synaptic protein expression and prevents anesthesia-induced cognitive deficits through mTOR-eEF2 pathway. J. Alzheimer's Dis. 2019, 70, 925–936.

26. Li, X.; Run, X.; Wei, Z.; Zeng, K.; Liang, Z.; Huang, F.; Ke, D.; Wang, Q.; Wang, J.Z.; Liu, R.; et al. Intranasal insulin prevents anesthesia-induced cognitive impairments in aged mice. Curr. Alzheimer Res. 2019, 16, 8–18.

27. Banting, F.G.; Best, C.H.; Collip, J.B.; Campbell, W.R.; Fletcher, A.A. Pancreatic extracts in the treatment of diabetes mellitus. Can. Med. Assoc. J. 1922, 12, 141–146.

28. Sakel, M. The origin and nature of the hypoglycemic therapy of the psychoses. Bull. N. Y. Acad. Med. 1937, 13, 97–109.

29. Mack, C.W.; Burch, B.O. Insulin shock therapy in dementia praecox: A report of a series of cases. Calif. West. Med. 1939, 50, 339–344.

30. Fink, M.; Shaw, R.; Gross, G.E.; Coleman, F.S. Comparative study of chlorpromazine and insulin coma in the therapy of psychosis. J. Am. Med. Assoc. 1958, 166, 1846–1850.

31. Begg, D.P. Insulin transport into the brain and cerebrospinal fluid. Vitam. Horm. 2015, 98, 229–248.

32. Dorn, A.; Bernstein, H.G.; Rinne, A.; Ziegler, M.; Hahn, H.J.; Ansorge, S. Insulin—and glucagonlike peptides in the brain. Anat. Rec. 1983, 207, 69–77.

33. Lioutas, V.A.; Alfaro-Martinez, F.; Bedoya, F.; Chung, C.C.; Pimentel, D.A.; Novak, V. Intranasal insulin and Insulin-Like Growth Factor 1 as neuroprotectants in acute ischemic stroke. Transl. Stroke Res. 2015, 6, 264–275.

34. Lioutas, V.A.; Novak, V. Intranasal insulin neuroprotection in ischemic stroke. Neural. Regen. Res. 2016, 11, 400–401.

35. Benedict, C.; Hallschmid, M.; Schultes, B.; Born, J.; Kern, W. Intranasal insulin to improve memory function in humans. Neuroendocrinology 2007, 86, 136–142.

36. Shemesh, E.; Rudich, A.; Harman-Boehm, I.; Cukierman-Yaffe, T. Effect of intranasal insulin on cognitive function: A systematic review. J. Clin. Endocrinol. Metab. 2012, 97, 366–376.

37. Reger, M.A.; Watson, G.S.; Frey, W.H., 2nd; Baker, L.D.; Cholerton, B.; Keeling, M.L.; Belongia, D.A.; Fishel, M.A.; Plymate, S.R.; Schellenberg, G.D.; et al. Effects of intranasal insulin on cognition in memory-impaired older adults: Modulation by APOE genotype. Neurobiol. Aging 2006, 27, 451–458.

38. Avgerinos, K.I.; Kalaitzidis, G.; Malli, A.; Kalaitzoglou, D.; Myserlis, P.G.; Lioutas, V.A. Intranasal insulin in Alzheimer’s dementia or mild cognitive impairment: A systematic review. J. Neurol. 2018, 265, 1497–1510.

39. Benedict, C.; Frey, W.H., 2nd; Schiöth, H.B.; Schultes, B.; Born, J.; Hallschmid, M. Intranasal insulin as a therapeutic option in the treatment of cognitive impairments. Exp. Gerontol. 2011, 46, 112–115.

40. Chapman, C.D.; Schiöth, H.B.; Grillo, C.A.; Benedict, C. Intranasal insulin in Alzheimer’s disease: Food for thought. Neuropharmacology 2018, 136, 196–201.

41. Claxton, A.; Baker, L.D.; Hanson, A.; Trittschuh, E.H.; Cholerton, B.; Morgan, A.; Callaghan, M.; Arbuckle, M.; Behl, C.; Craft, S. Long-acting intranasal insulin detemir improves cognition for adults with mild cognitive impairment or early-stage Alzheimer’s disease dementia. J. Alzheimer's Dis. 2015, 44, 897–906.

42. Novak, P.; Pimentel Maldonado, D.A.; Novak, V. Safety and preliminary efficacy of intranasal insulin for cognitive impairment in Parkinson disease and multiple system atrophy: A double-blinded placebo-controlled pilot study. PLoS ONE 2019, 14, e0214364.

43. Bilotta, F.; Gelb, A.W.; Stazi, E.; Titi, L.; Paoloni, F.P.; Rosa, G. Pharmacological perioperative brain neuroprotection: A qualitative review of randomized clinical trials. Br. J. Anaesth. 2013, 110, i113–i120.

44. Eckenhoff, R.G.; Maze, M.; Xie, Z.; Culley, D.J.; Goodlin, S.J.; Zuo, Z.; Wei, H.; Whittington, R.A.; Terrando, N.; Orser, B.A.; et al. Perioperative neurocognitive disorder: State of the preclinical science. Anesthesiology 2020, 132, 55–68.

45. Mitchell, S.J.; Pellett, O.; Gorman, D.F. Cerebral protection by lidocaine during cardiac operations. Ann. Thorac. Surg. 1999, 67, 1117–1124.

46. Mathew, J.P.; Mackensen, G.B.; Phillips-Bute, B.; Grocott, H.P.; Glower, D.D.; Laskowitz, D.T.; Blumenthal, J.A.; Newman, M.F.; Neurologic Outcome Research Group (NORG) of the Duke Heart Center. Randomized, double-blinded, placebo-controlled study of neuroprotection with lidocaine in cardiac surgery. Stroke 2009, 40, 880–887.

47. Mack, W.J.; Kellner, C.P.; Sahlein, D.H.; Ducruet, A.F.; Kim, G.H.; Mocco, J.; Zurica, J.; Komotar, R.J.; Haque, R.; Sciacca, R.; et al. Intraoperative magnesium infusion during carotid endarterectomy: A double-blind placebo-controlled trial. J. Neurosurg. 2009, 110, 961–967.

48. Hudetz, J.A.; Iqbal, Z.; Gandhi, S.D.; Patterson, K.M.; Byrne, A.J.; Hudetz, A.G.; Pagel, P.S.; Warltier, D.C. Ketamine attenuates post-operative cognitive dysfunction after cardiac surgery. Acta Anaesthesiol. Scand. 2009, 53, 864–872.

49. Thorne, R.G.; Pronk, G.J.; Padmanabhan, V.; Frey, W.H., 2nd. Delivery of insulin-like growth factor-I to the rat brain and spinal cord along olfactory and trigeminal pathways following intranasal administration. Neuroscience 2004, 127, 481–496. [CrossRef] [PubMed] 50. Brown, C., IV; Deiner, S. Perioperative cognitive protection. Br. J. Anaesth. 2016, 117, iii52–iii61.

Rafael Badenes 1, Ega Qeva 2, Giovanni Giordano 2 , Nekane Romero-García 1 and Federico Bilotta 2

1 Department of Anesthesiology and Surgical Trauma Intensive Care, Hospital Clinic Universitari Valencia, the University of Valencia, 46010 Valencia, Spain; nekaneromerog@gmail.com

2 Department of Anesthesiology, Critical Care and Pain Medicine, Sapienza University of Rome, 00161 Rome, Italy; giordano.gj@gmail.com (G.G.); bilotta@tiscali.it (F.B.)