Chinese expert consensus on the diagnosis and treatment of postoperative brain injury in adult cardiac surgery

doi:10.3969/j.issn.2095-4344.2808

Abstract

Abstract:

BACKGROUND: Brain injury, as a serious complication of adult cardiac surgery, has an increasing incidence, which is one of the most important factors leading to poor prognosis in cardiac surgery patients except for heart failure.

OBJECTIVE: To establish the relevant standards for the diagnosis and treatment of postoperative complications so as to reduce the neurological complications, such as stroke, after cardiac surgery in adults.

METHODS: To decrease the incidence of brain injury and reduce the neurological complications after cardiac surgery in adults, experts from cardiology and cardiosurgery, neurology and neurosurgery, intensive care unit, cardiopulmonary bypass, anesthesia and emergency have been organized to write the consensus by Cardiac Intensive Brain Care Group and Neurocritical Care and Rehabilitation Group which is belonging to the Neural Regeneration and Repair Committee of Chinese Association of Research Hospitals. Relevant domestic

and foreign guidelines have been referred to, and also combined with the actual situation in China. The consensus was written based on manifestation, risk factors, non-drug protection strategies, intraoperative neuromonitoring, and drug protection strategies. The writing purpose of this consensus is to promote the rehabilitation of patients' cerebral nerve function. During this period, the draft has been discussed many times by the writing team before the final edition. We hope that it will be helpful to guide the clinical practice.

RESULTS AND CONCLUSION: To reduce the incidence of brain injuries and neurological complications after cardiac surgery in adults, several personalized, patient-centric approaches are needed to manage those risk factors for alterable brain injury, including the prevention of intraoperative embolism, management of blood pressure, blood sugar and body temperature, and drug treatment for postoperative neuro-inflammatory reactions, with the aim of improving surgical effect and patients’ quality of life. However, high-quality, results-oriented, randomized controlled trials to further provide evidence for management strategies of brain injury are needed.

Key words: heart, surgery, cardiopulmonary bypass, brain injury, brain protection, neurologic complications, postoperative stroke, consensus

CLC Number:

Cerebral Protection in Cardiac Intensive Care Group, Neural Regeneration and Repair Committee, Chinese Research Hospital Association, Neural Intensive Nursing and Rehabilitation Group, Neural Regeneration and Repair Committee, Chinese Research Hospital Association. Chinese expert consensus on the diagnosis and treatment of postoperative brain injury in adult cardiac surgery[J]. Chinese Journal of Tissue Engineering Research, 2020, 24(32): 5203-5212.

Figures/Tables 1

References

[1] BERGER M, TERRANDO N, SMITH SK, et al. Neurocognitive Function after Cardiac Surgery: From Phenotypes to Mechanisms. Anesthesiology. 2018;129(4): 829-851.

[2] VLISIDES PE, MASHOUR GA, DIDIER TJ, et al. Recognition and Management of Perioperative Stroke in Hospitalized Patients. A A Case Rep. 2016;7(3): 55-56.

[3] GAUDINO M, RAHOUMA M, DI MAURO M, et al. Early Versus Delayed Stroke After Cardiac Surgery: A Systematic Review and Meta-Analysis. J Am Heart Assoc. 2019;8(13): e012447.

[4] SANTARPINO G, MOSCARELLI M. Postoperative Cognitive Dysfunction: A Forgotten Part of the Quality of Life. Ann Thorac Surg. 2019;108(5): 1583.

[5] LIU Y, CHEN K, MEI W. Neurological complications after cardiac surgery: anesthetic considerations based on outcome evidence. Curr Opin Anaesthesiol. 2019;32(5):563-567.

[6] RAFFA GM, AGNELLO F, OCCHIPINTI G, et al. Neurological complications after cardiac surgery: a retrospective case-control study of risk factors and outcome. J Cardiothorac Surg. 2019;14(1):23.

[7] VEDEL AG, HOLMGAARD F, RASMUSSEN LS, et al. High-Target Versus Low-Target Blood Pressure Management During Cardiopulmonary Bypass to Prevent Cerebral Injury in Cardiac Surgery Patients: A Randomized Controlled Trial. Circulation. 2018;137(17):1770-1780.

[8] SUN LY, CHUNG AM, FARKOUH ME, et al. Defining an Intraoperative Hypotension Threshold in Association with Stroke in Cardiac Surgery. Anesthesiology. 2018;129(3):440-447.

[9] KNIPP SC, MATATKO N, WILHELM H, et al. Cognitive outcomes three years after coronary artery bypass surgery: relation to diffusion-weighted magnetic resonance imaging. Ann Thorac Surg. 2008;85(3):872-879.

[10] LOBERMAN D, CONSALVI C, HEALEY A, et al. Adverse Cerebral Outcomes after Coronary Artery Bypass Surgery-More Than a Decade of Experience in a Single Center. Thorac Cardiovasc Surg. 2018;66(6): 452-456.

[11] KEELING B, HALKOS ME. The modern Hydra: Perioperative stroke and cardiac surgery. J Thorac Cardiovasc Surg. 2018;155(2): 507.

[12] HOGUE CW JR, PALIN CA, ARROWSMITH JE. Cardiopulmonary bypass management and neurologic outcomes: an evidence-based appraisal of current practices. Anesth Analg.2006;103(1):21-37.

[13] PATEL N, MINHAS JS, CHUNG EM. The Presence of New MRI Lesions and Cognitive Decline After Cardiac Surgery: A Systematic Review. J Card Surg. 2015;30(11):808-812.

[14] NEWMAN MF, MATHEW JP, GROCOTT HP, et al. Central nervous system injury associated with cardiac surgery. Lancet. 2006;368(9536): 694-703.

[15] HUSEBRÅTEN IM, FIANE AE, RINGDAL M, et al. Measurement of gaseous microemboli in the prime before the initiation of cardiopulmonary bypass. Perfusion. 2018;33(1):30-35.

[16] MITZ MA. CO2 biodynamics: a new concept of cellular control.J Theor Biol.1979;80(4):537-551.

[17] WEBB WR, HARRISON LH JR, HELMCKE FR, et al. Carbon dioxide field flooding minimizes residual intracardiac air after open heart operations. Ann Thorac Surg. 1997;64(5):1489-1491.

[18] MARTENS S, THEISEN A, BALZER JO, et al. Improved cerebral protection through replacement of residual intracavital air by carbon dioxide: a porcine model using diffusion-weighted magnetic resonance imaging. J Thorac Cardiovasc Surg. 2004;127(1):51-56.

[19] MARTENS S, DIETRICH M, WALS S, et al. Conventional carbon dioxide application does not reduce cerebral or myocardial damage in open heart surgery. Ann Thorac Surg. 2001;72(6):1940-1944.

[20] SVENARUD P, PERSSON M, VAN DER LINDEN J. Effect of CO2 insufflation on the number and behavior of air microemboli in open-heart surgery: a randomized clinical trial. Circulation. 2004; 109(9):1127-1132.

[21] PERSSON M, VAN DER LINDEN J. De-airing of a cardiothoracic wound cavity model with carbon dioxide: theory and comparison of a gas diffuser with conventional tubes. J Cardiothorac Vasc Anesth. 2003;17(3): 329-335.

[22] VAN DER ZEE MP, KOENE BM, MARIANI MA. Fatal air embolism during cardiopulmonary bypass: analysis of an incident and prevention measures. Interact Cardiovasc Thorac Surg. 2014;19(5):875-877.

[23] NEEMA PK, PATHAK S, VARMA PK, et al. Case 2--2007: Systemic air embolization after termination of cardiopulmonary bypass. J Cardiothorac Vasc Anesth. 2007;21(2):288-297.

[24] NEWMAN MF, GROCOTT HP, MATHEW JP, et al. Report of the substudy assessing the impact of neurocognitive function on quality of life 5 years after cardiac surgery. Stroke. 2001;32(12): 2874-2881.

[25] DÁVILA-ROMÁN VG, MURPHY SF, NICKERSON NJ, et al. Atherosclerosis of the ascending aorta is an independent predictor of long-term neurologic events and mortality. J Am Coll Cardiol. 1999; 33(5):1308-1316.

[26] TUNICK PA, PEREZ JL, KRONZON I. Protruding atheromas in the thoracic aorta and systemic embolization. Ann Intern Med. 1991;115(6): 423-427.

[27] WAREING TH, DAVILA-ROMAN VG, BARZILAI B, et al. Management of the severely atherosclerotic ascending aorta during cardiac operations[J]. A strategy for detection and treatment. J Thorac Cardiovasc Surg. 1992;103(3): 453-462.

[28] KATZ ES, TUNICK PA, RUSINEK H, et al. Protruding aortic atheromas predict stroke in elderly patients undergoing cardiopulmonary bypass: experience with intraoperative transesophageal echocardiography. J Am Coll Cardiol. 1992;20(1): 70-77.

[29] RIBAKOVE GH, KATZ ES, GALLOWAY AC, et al. Surgical implications of transesophageal echocardiography to grade the atheromatous aortic arch. Ann Thorac Surg. 1992;53(5):758-61; discussion762-763.

[30] URBANSKI PP, SABIK JF, BACHET JE. Cannulation of an arch artery for hostile aorta. Eur J Cardiothorac Surg. 2017;51(1):2-9.

[31] HEDAYATI N, SHERWOOD JT, SCHOMISCH SJ, et al. Axillary artery cannulation for cardiopulmonary bypass reduces cerebral microemboli. J Thorac Cardiovasc Surg. 2004;128(3): 386-390.

[32] PAPPA M, THEODOSIADIS N, TSOUNIS A, et al. Pathogenesis and treatment of post-operative cognitive dysfunction. Electron Physician. 2017;9(2):3768-3775.

[33] CARRIER M, DENAULT A, LAVOIE J, et al. Randomized controlled trial of pericardial blood processing with a cell-saving device on neurologic markers in elderly patients undergoing coronary artery bypass graft surgery. Ann Thorac Surg. 2006;82(1):51-55.

[34] JEWELL AE, AKOWUAH EF, SUVARNA SK, et al. A prospective randomised comparison of cardiotomy suction and cell saver for recycling shed blood during cardiac surgery. Eur J Cardiothorac Surg. 2003;23(4):633-636.

[35] RUBENS FD, BOODHWANI M, MESANA T, et al. The cardiotomy trial: a randomized, double-blind study to assess the effect of processing of shed blood during cardiopulmonary bypass on transfusion and neurocognitive function. Circulation. 2007;116(11 Suppl):I89-197.

[36] YASUKAWA T, MANABE S, HIRAOKA D, et al. Safety and efficacy of a simple cardiotomy suction system as a blood salvage procedure during off-pump coronary artery bypass surgery. J Artif Organs. 2019; 22(3):194-199.

[37] SELNES OA, GOTTESMAN RF, GREGA MA, et al. Cognitive and neurologic outcomes after coronary-artery bypass surgery. N Engl J Med. 2012;366(3):250-257.

[38] LO COCO D, LOPEZ G, CORRAO S. Cognitive impairment and stroke in elderly patients. Vasc Health Risk Manag. 2016;12:105-116.

[39] 李双磊,吴远斌,龚志云,等.心脏骤停患者心肺复苏后神经系统的维护[J].中国体外循环杂志,2019,17(4):249-251,256.

[40] BLÁHA J, MRÁZ M, KOPECKÝ P, et al. Perioperative Tight Glucose Control Reduces Postoperative Adverse Events in Nondiabetic Cardiac Surgery Patients. J Clin Endocrinol Metab. 2015;100(8): 3081-3089.

[41] KNAAK C, WOLLERSHEIM T, MÖRGELI R, et al. Risk Factors of Intraoperative Dysglycemia in Elderly Surgical Patients. Int J Med Sci. 2019;16(5):665-674.

[42] NAVARATNARAJAH M, REA R, EVANS R, et al. Effect of glycaemic control on complications following cardiac surgery: literature review. J Cardiothorac Surg. 2018;13(1):10.

[43] MOGHISSI ES, KORYTKOWSKI MT, DINARDO M, et al. American Association of Clinical Endocrinologists and American Diabetes Association consensus statement on inpatient glycemic control. Diabetes Care. 2009;32(6):1119-1131.

[44] GOLD JP, CHARLSON ME, WILLIAMS-RUSSO P, et al. Improvement of outcomes after coronary artery bypass. A randomized trial comparing intraoperative high versus low mean arterial pressure. J Thorac Cardiovasc Surg.1995;110(5):1302-1311; discussion 1311-1314.

[45] SIEPE M, PFEIFFER T, GIERINGER A, et al. Increased systemic perfusion pressure during cardiopulmonary bypass is associated with less early postoperative cognitive dysfunction and delirium. Eur J Cardiothorac Surg.2011;40(1):200-207.

[46] WESSELINK EM, KAPPEN TH, VAN KLEI WA, et al. Intraoperative hypotension and delirium after on-pump cardiac surgery. Br J Anaesth. 2015;115(3):427-433.

[47] HORI D, BROWN C, ONO M, et al. Arterial pressure above the upper cerebral autoregulation limit during cardiopulmonary bypass is associated with postoperative delirium. Br J Anaesth. 2014;113(6):1009-1017..

[48] HORI D, NOMURA Y, ONO M, et al. Optimal blood pressure during cardiopulmonary bypass defined by cerebral autoregulation monitoring. J Thorac Cardiovasc Surg. 2017;154(5):1590-1598.e2.

[49] MURKIN JM, FARRAR JK, TWEED WA, et al. Cerebral autoregulation and flow/metabolism coupling during cardiopulmonary bypass: the influence of PaCO2. Anesth Analg. 1987;66(9):825-832.

[50] JOSHI B, ONO M, BROWN C, et al. Predicting the limits of cerebral autoregulation during cardiopulmonary bypass. Anesth Analg.2012; 114(3):503-510.

[51] GOTTESMAN RF. Asymptomatic Carotid Stenosis in Cardiac Surgery Patients: Is Less More? Stroke.2017;48(10):2650-2651.

[52] GROGAN K, STEARNS J, HOGUE CW. Brain protection in cardiac surgery. Anesthesiol Clin. 2008;26(3):521-538.

[53] NAYLOR AR, BOWN MJ. Stroke after cardiac surgery and its association with asymptomatic carotid disease: an updated systematic review and meta-analysis. Eur J Vasc Endovasc Surg. 2011;41(5):607-624.

[54] MORESOLI P, HABIB B, REYNIER P, et al. Carotid Stenting Versus Endarterectomy for Asymptomatic Carotid Artery Stenosis: A Systematic Review and Meta-Analysis.Stroke. 2017;48(8): 2150-2157.

[55] MCDONAGH DL, BERGER M, MATHEW JP, et al. Neurological complications of cardiac surgery. Lancet Neurol.2014;13(5):490-502.

[56] NEJIM B, DAKOUR ARIDI H, LOCHAM S, et al. Carotid artery revascularization in patients with contralateral carotid artery occlusion: Stent or endarterectomy? J Vasc Surg. 2017;66(6):1735-1748.e1.

[57] MASABNI K, RAZA S, BLACKSTONE EH, et al. Does preoperative carotid stenosis screening reduce perioperative stroke in patients undergoing coronary artery bypass grafting?. J Thorac Cardiovasc Surg.2015;149(5):1253-1260.

[58] TOMAI F, PICCOLI A, CASTRIOTA F, et al. Long-Term Outcomes of Coronary and Carotid Artery Disease Revascularization in the FRIENDS Study. J Interv Cardiol.2019;2019:8586927.

[59] IRQSUSI M, VANNUCCHI A, BECKERS J, et al. Early Results of Surgical Simultaneous Therapy for Significant Carotid Artery Stenosis and Heart Disease. Thorac Cardiovasc Surg. 2018;66(3):261-265..

[60] STARKE RM. Optimal management of patients with asymptomatic carotid stenosis. Neurology. 2017,88(21):1988-1989.

[61] ABBOTT AL, BRUNSER AM, GIANNOUKAS A, et al. Misconceptions regarding the adequacy of best medical intervention alone for asymptomatic carotid stenosis. J Vasc Surg.2019;71(1):257-269.

[62] Authors/Task Force members, WINDECKER S, KOLH P, et al. 2014 ESC/EACTS Guidelines on myocardial revascularization: The Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS)Developed with the special contribution of the European Association of Percutaneous Cardiovascular Interventions (EAPCI). Eur Heart J. 2014;35(37): 2541-2619.

[63] DHIR A, TEMPE DK. Anemia and Patient Blood Management in Cardiac Surgery-Literature Review and Current Evidence. J Cardiothorac Vasc Anesth.2018;32(6):2726-2742.

[64] RANUCCI M, DI DEDDA U, CASTELVECCHIO S, et al. Impact of preoperative anemia on outcome in adult cardiac surgery: a propensity-matched analysis. Ann Thorac Surg. 2012;94(4): 1134-1141.

[65] KARKOUTI K, DJAIANI G, BORGER MA, et al. Low hematocrit during cardiopulmonary bypass is associated with increased risk of perioperative stroke in cardiac surgery. Ann Thorac Surg. 2005;80(4): 1381-1387.

[66] PAONE G, LIKOSKY DS, BREWER R, et al. Transfusion of 1 and 2 units of red blood cells is associated with increased morbidity and mortality. Ann Thorac Surg.2014;97(1):87-93; discussion 93-94.

[67] BAHRAINWALA ZS, GREGA MA, HOGUE CW, et al. Intraoperative hemoglobin levels and transfusion independently predict stroke after cardiac operations. Ann Thorac Surg, 2011;91(4):1113-1118.

[68] MARISCALCO G, BIANCARI F, JUVONEN T, et al. Red blood cell transfusion is a determinant of neurological complications after cardiac surgery. Interact Cardiovasc Thorac Surg. 2015;20(2):166-171.

[69] KIM J, WEIGAND M, PALMER AF, et al. Single cell analysis of aged RBCs: quantitative analysis of the aged cells and byproducts. Analyst. 2019;144(3):935-942.

[70] Society of Thoracic Surgeons Blood Conservation Guideline Task Force, FERRARIS VA, BROWN JR, et al. 2011 update to the Society of Thoracic Surgeons and the Society of Cardiovascular Anesthesiologists blood conservation clinical practice guidelines. Ann Thorac Surg.2011;91(3):944-982.

[71] HORI D, EVERETT AD, LEE JK, et al. Rewarming Rate During Cardiopulmonary Bypass Is Associated With Release of Glial Fibrillary Acidic Protein. Ann Thorac Surg. 2015;100(4):1353-1358.

[72] GEOCADIN RG, WIJDICKS E, ARMSTRONG MJ, et al. Practice guideline summary: Reducing brain injury following cardiopulmonary resuscitation: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology.2017;88(22):2141-2149.

[73] CARIOU A, PAYEN JF, ASEHNOUNE K, et al. Targeted temperature management in the ICU: Guidelines from a French expert panel. Anaesth Crit Care Pain Med.2018;37(5):481-491.

[74] MENG L, WANG Y, ZHANG L, et al. Heterogeneity and Variability in Pressure Autoregulation of Organ Blood Flow: Lessons Learned Over 100+ Years. Crit Care Med.2019;47(3):436-448.

[75] LEWIS C, PARULKAR SD, BEBAWY J, et al. Cerebral Neuromonitoring During Cardiac Surgery: A Critical Appraisal With an Emphasis on Near-Infrared Spectroscopy. J Cardiothorac Vasc Anesth. 2018;32(5):2313-2322.

[76] ENGELMAN R, BAKER RA, LIKOSKY DS, et al. The Society of Thoracic Surgeons, The Society of Cardiovascular Anesthesiologists, and The American Society of ExtraCorporeal Technology: Clinical Practice Guidelines for Cardiopulmonary Bypass-Temperature Management During Cardiopulmonary Bypass. J Cardiothorac Vasc Anesth. 2015;29(4):1104-1113.

[77] GROCOTT HP, MACKENSEN GB, GRIGORE AM, et al. Postoperative hyperthermia is associated with cognitive dysfunction after coronary artery bypass graft surgery. Stroke. 2002;33(2):537-541.

[78] KIVINIEMI T, MALMBERG M, BIANCARI F, et al. Thromboembolisms related to post-operative electrical cardioversions for atrial fibrillation in patients with surgical aortic valve replacement. Eur Heart J Qual Care Clin Outcomes.2018;4(2):120-125.

[79] GAUDINO M, ANGIOLILLO DJ, DI FRANCO A, et al. Stroke After Coronary Artery Bypass Grafting and Percutaneous Coronary Intervention: Incidence, Pathogenesis, and Outcomes. J Am Heart Assoc. 2019;8(13):e013032.

[80] JACKSON JC, MOZAFFARIAN D, GRAVES AJ, et al. Fish Oil Supplementation Does Not Affect Cognitive Outcomes in Cardiac Surgery Patients in the Omega-3 Fatty Acids for Prevention of Post-Operative Atrial Fibrillation (OPERA) Trial. J Nutr.2018;148(3): 472-479.

[81] MARIANI J, DOVAL HC, NUL D, et al. N-3 polyunsaturated fatty acids to prevent atrial fibrillation: updated systematic review and meta-analysis of randomized controlled trials. J Am Heart Assoc. 2013;2(1):e005033.

[82] KUHN EW, SLOTTOSCH I, WAHLERS T, et al. WITHDRAWN: Preoperative statin therapy for patients undergoing cardiac surgery. Cochrane Database Syst Rev.2016;(5):CD008493.

[83] WANG X, YAO L, GE L, et al. Pharmacological interventions for preventing post-operative atrial fibrillation in patients undergoing cardiac surgery: a network meta-analysis protocol. BMJ Open.2017; 7(12):e018544..

[84] BUDERA P, STRAKA Z, OSMANČÍK P, et al. Comparison of cardiac surgery with left atrial surgical ablation vs. cardiac surgery without atrial ablation in patients with coronary and/or valvular heart disease plus atrial fibrillation: final results of the PRAGUE-12 randomized multicentre study. Eur Heart J.2012;33(21):2644-2652.

[85] REDDY VY, DOSHI SK, SIEVERT H, et al. Percutaneous left atrial appendage closure for stroke prophylaxis in patients with atrial fibrillation: 2.3-Year Follow-up of the PROTECT AF (Watchman Left Atrial Appendage System for Embolic Protection in Patients with Atrial Fibrillation) Trial. Circulation.2013;127(6):720-729.

[86] FEDOROW C, GROCOTT HP. Cerebral monitoring to optimize outcomes after cardiac surgery. Curr Opin Anaesthesiol.2010; 23(1): 89-94.

[87] Guarracino F. Cerebral monitoring during cardiovascular surgery. Curr Opin Anaesthesiol. 2008;21(1):50-54.

[88] SAIDI N, MURKIN JM. Applied neuromonitoring in cardiac surgery: patient specific management. Semin Cardiothorac Vasc Anesth.2005; 9(1):17-23.

[89] POLITO A, RICCI Z, DI CHIARA L, et al. Cerebral blood flow during cardiopulmonary bypass in pediatric cardiac surgery: the role of transcranial Doppler--a systematic review of the literature. Cardiovasc Ultrasound.2006;4:47.

[90] GROCOTT HP, AMORY DW, LOWRY E, et al. Transcranial Doppler blood flow velocity versus 133Xe clearance cerebral blood flow during mild hypothermic cardiopulmonary bypass. J Clin Monit Comput.1998; 14(1):35-39.

[91] WANG X, JI B, YANG B, et al. Real-time continuous neuromonitoring combines transcranial cerebral Doppler with near-infrared spectroscopy cerebral oxygen saturation during total aortic arch replacement procedure: a pilot study. ASAIO J.2012; 58(2):122-126.

[92] SELIM M. Perioperative stroke. N Engl J Med. 2007;356(7):706-713.

[93] SALAZAR JD, WITYK RJ, GREGA MA, et al. Stroke after cardiac surgery: short- and long-term outcomes. Ann Thorac Surg.2001; 72(4):1195-1201; discussion 1201-1202.

[94] MURKIN JM. Applied neuromonitoring and improving CNS outcomes. Semin Cardiothorac Vasc Anesth.2005;9(2):139-142.

[95] SLOAN MA. Prevention of ischemic neurologic injury with intraoperative monitoring of selected cardiovascular and cerebrovascular procedures: roles of electroencephalography, somatosensory evoked potentials, transcranial Doppler, and near-infrared spectroscopy. Neurol Clin.2006;24(4):631-645.

[96] SHAABAN ALI M, HARMER M, LATTO I. Jugular bulb oximetry during cardiac surgery. Anaesthesia.2001;56(1):24-37.

[97] MACMILLAN CS, ANDREWS PJ. Cerebrovenous oxygen saturation monitoring: practical considerations and clinical relevance. Intensive Care Med.2000;26(8):1028-1036.

[98] SCHELL RM, COLE DJ. Cerebral monitoring: jugular venous oximetry. Anesth Analg. 2000;90(3):559-566.

[99] NAKAJIMA T, OHSUMI H, KURO M. Accuracy of continuous jugular bulb venous oximetry during cardiopulmonary bypass. Anesth Analg. 1993;77(6):1111-1115.

[100] CROUGHWELL ND, FRASCO P, BLUMENTHAL JA, et al. Warming during cardiopulmonary bypass is associated with jugular bulb desaturation. Ann Thorac Surg.1992;53(5):827-832.

[101] CROUGHWELL ND, NEWMAN MF, BLUMENTHAL JA, et al. Jugular bulb saturation and cognitive dysfunction after cardiopulmonary bypass. Ann Thorac Surg.1994;58(6):1702-1708.

[102] COOK DJ, OLIVER WC JR, ORSZULAK TA, et al. A prospective, randomized comparison of cerebral venous oxygen saturation during normothermic and hypothermic cardiopulmonary bypass. J Thorac Cardiovasc Surg.1994;107(4):1020-1028; discussion 1028-1029.

[103] MARCUSE LV, BRONSTER DJ, FIELDS M, et al. Evaluating the obtunded patient after cardiac surgery: the role of continuous electroencephalography. J Crit Care.2014;29(2):316.e1-5.

[104] AVIDAN MS, ZHANG L, BURNSIDE BA, et al. Anesthesia awareness and the bispectral index. N Engl J Med.2008;358(11):1097-1108.

[105] RAMPIL IJ. A primer for EEG signal processing in anesthesia. Anesthesiology. 1998;89(4):980-1002.

[106] MYLES PS, LESLIE K, MCNEIL J, et al. Bispectral index monitoring to prevent awareness during anaesthesia: the B-Aware randomised controlled trial. Lancet.2004;363(9423):1757-1763.

[107] VASUNILASHORN SM, NGO L, INOUYE SK, et al. Cytokines and Postoperative Delirium in Older Patients Undergoing Major Elective Surgery. J Gerontol A Biol Sci Med Sci. 2015;70(10):1289-1295.

[108] HOVENS IB, VAN LEEUWEN BL, NYAKAS C, et al. Prior infection exacerbates postoperative cognitive dysfunction in aged rats. Am J Physiol Regul Integr Comp Physiol. 2015;309(2):R148-159.

[109] SALAMEH A, DHEIN S, DÄHNERT I, et al. Neuroprotective Strategies during Cardiac Surgery with Cardiopulmonary Bypass. Int J Mol Sci. 2016;17(11). pii: E1945.

[110] BHAMIDIPATI D, GOLDHAMMER JE, SPERLING MR, et al. Cognitive Outcomes After Coronary Artery Bypass Grafting. J Cardiothorac Vasc Anesth.2017;31(2):707-718.

[111] LORD JM, MIDWINTER MJ, CHEN YF, et al. The systemic immune response to trauma: an overview of pathophysiology and treatment. Lancet.2014;384(9952):1455-1465.

[112] ABRAHAMOV D, LEVRAN O, NAPARSTEK S, et al. Blood-Brain Barrier Disruption After Cardiopulmonary Bypass: Diagnosis and Correlation to Cognition. Ann Thorac Surg. 2017;104(1):161-169.

[113] MERINO JG, LATOUR LL, TSO A, et al. Blood-brain barrier disruption after cardiac surgery. AJNR Am J Neuroradiol.2013;34(3):518-523..

[114] STEINBERG BE, SUNDMAN E, TERRANDO N, et al. Neural Control of Inflammation: Implications for Perioperative and Critical Care. Anesthesiology.2016;124(5):1174-1189.

[115] NTALOUKA MP, ARNAOUTOGLOU E, TZIMAS P. Postoperative cognitive disorders: an update. Hippokratia.2018;22(4):147-154.

[116] GLUMAC S, KARDUM G, SODIC L, et al. Effects of dexamethasone on early cognitive decline after cardiac surgery: A randomised controlled trial. Eur J Anaesthesiol.2017;34(11):776-784.

[117] MARDANI D, BIGDELIAN H. Prophylaxis of dexamethasone protects patients from further post-operative delirium after cardiac surgery: A randomized trial. J Res Med Sci. 2013;18(2):137-143.

[118] OTTENS TH, DIELEMAN JM, SAUËR AM, et al. Effects of dexamethasone on cognitive decline after cardiac surgery: a randomized clinical trial. Anesthesiology. 2014;121(3):492-500.

[119] DIELEMAN JM, NIERICH AP, ROSSEEL PM, et al. Intraoperative high-dose dexamethasone for cardiac surgery: a randomized controlled trial. JAMA.2012;308(17):1761-1767.

[120] WANG X, XUE Q, YAN F, et al. Ulinastatin as a neuroprotective and anti-inflammatory agent in infant piglets model undergoing surgery on hypothermic low-flow cardiopulmonary bypass. Paediatr Anaesth. 2013;23(3):209-216.

[121] QIU Y, LIN J, YANG Y, et al. Lack of Efficacy of Ulinastatin Therapy During Cardiopulmonary Bypass Surgery. Chin Med J (Engl).2015; 128(23):3138-3142.

[122] SAYED S, IDRISS NK, SAYYEDF HG, et al. Effects of propofol and isoflurane on haemodynamics and the inflammatory response in cardiopulmonary bypass surgery. Br J Biomed Sci. 2015;72(3):93-101.

[123] BAKI ED, ALDEMIR M, KOKULU S, et al. Comparison of the effects of desflurane and propofol anesthesia on the inflammatory response and s100β protein during coronary artery bypass grafting. Inflammation. 2013;36(6):1327-1333.

[124] BILOTTA F, STAZI E, ZLOTNIK A, et al. Neuroprotective effects of intravenous anesthetics: a new critical perspective. Curr Pharm Des. 2014;20(34):5469-5475.

[125] KANBAK M, SARICAOGLU F, AVCI A, et al. Propofol offers no advantage over isoflurane anesthesia for cerebral protection during cardiopulmonary bypass: a preliminary study of S-100beta protein levels. Can J Anaesth.2004;51(7):712-717.

[126] SEDRAKYAN A, TREASURE T, ELEFTERIADES JA. Effect of aprotinin on clinical outcomes in coronary artery bypass graft surgery: a systematic review and meta-analysis of randomized clinical trials. J Thorac Cardiovasc Surg.2004;128(3):442-448.

[127] STAMOU SC, REAMES MK, SKIPPER E, et al. Aprotinin in cardiac surgery patients: is the risk worth the benefit?. Eur J Cardiothorac Surg.2009;36(5):869-875.

[128] HÉBERT PC, FERGUSSON DA, HUTTON B, et al. Regulatory decisions pertaining to aprotinin may be putting patients at risk. CMAJ. 2014;186(18):1379-1386.

[129] BENEDETTO U, ALTMAN DG, GERRY S, et al. Safety of Perioperative Aprotinin Administration During Isolated Coronary Artery Bypass Graft Surgery: Insights From the ART (Arterial Revascularization Trial). J Am Heart Assoc. 2018;7(5). pii: e007570.

[130] TIAN Z, DONG C, FUJITA A, et al. Expression of heat shock protein HSP-70 in the retrosplenial cortex of rat brain after administration of (R,S)-ketamine and (S)-ketamine, but not (R)-ketamine. Pharmacol Biochem Behav.2018;172:17-21.

[131] NAGELS W, DEMEYERE R, VAN HEMELRIJCK J, et al. Evaluation of the neuroprotective effects of S(+)-ketamine during open-heart surgery. Anesth Analg.2004;98(6):1595-1603.

[132] HUDETZ JA, IQBAL Z, GANDHI SD, et al. Ketamine attenuates post-operative cognitive dysfunction after cardiac surgery. Acta Anaesthesiol Scand.2009;53(7):864-872.

[133] LENG T, GAO X, DILGER JP, et al. Neuroprotective effect of lidocaine: is there clinical potential? Int J Physiol Pathophysiol Pharmacol.2016; 8(1):9-13.

[134] FUJITANI T, ADACHI N, MIYAZAKI H, et al. Lidocaine protects hippocampal neurons against ischemic damage by preventing increase of extracellular excitatory amino acids: a microdialysis study in Mongolian gerbils. Neurosci Lett.1994;179(1-2):91-94.

[135] WANG D, WU X, LI J, et al. The effect of lidocaine on early postoperative cognitive dysfunction after coronary artery bypass surgery. Anesth Analg.2002;95(5):1134-1141, table of contents.

[136] KLINGER RY, COOTER M, BISANAR T, et al. Intravenous Lidocaine Does Not Improve Neurologic Outcomes after Cardiac Surgery: A Randomized Controlled Trial. Anesthesiology. 2019;130(6):958-970.

[137] SALAMEH A, EINENKEL A, KÜHNE L, et al. Hippocampal Neuroprotection by Minocycline and Epigallo-Catechin-3-Gallate Against Cardiopulmonary Bypass-Associated Injury. Brain Pathol. 2015;25(6):733-742.

[138] DRABEK T, JANATA A, WILSON CD, et al. Minocycline attenuates brain tissue levels of TNF-α produced by neurons after prolonged hypothermic cardiac arrest in rats. Resuscitation. 2014;85(2):284-291.

[139] HAN XY, LIU H, LIU CH, et al. Synthesis of the optical isomers of a new anticholinergic drug, penehyclidine hydrochloride (8018). Bioorg Med Chem Lett.2005;15(8):1979-1982.

[140] WANG D, JIANG Q, DU X. Protective effects of scopolamine and penehyclidine hydrochloride on acute cerebral ischemia-reperfusion injury after cardiopulmonary resuscitation and effects on cytokines. Exp Ther Med.2018;15(2):2027-2031.

[141] ZADEK F, SPINA S, HU J, et al. Nitric Oxide Treatment for Lungs and Beyond. Novel Insights from Recent Literature. Am J Respir Crit Care Med.2019;200(5):628-630.

[142] MARRAZZO F, SPINA S, ZADEK F, et al. Protocol of a randomised controlled trial in cardiac surgical patients with endothelial dysfunction aimed to prevent postoperative acute kidney injury by administering nitric oxide gas. BMJ Open. 2019;9(7):e026848.

[143] DEBSKA G, MAY R, KICIŃSKA A, et al. Potassium channel openers depolarize hippocampal mitochondria. Brain Res. 2001;892(1):42-50.

[144] FOSTER MN, COETZEE WA. KATP Channels in the Cardiovascular System. Physiol Rev. 2016;96(1):177-252.

[145] HAAPANEN HJ, ARVOLA O, HERAJÄRVI J, et al. Pharmacological Preconditioning with Diazoxide in the Experimental Hypothermic Circulatory Arrest Model. Heart Surg Forum. 2017;20(2): E069-069, E076.

[146] 中国心脏重症镇静镇痛专家委员会(2017). 中国心脏重症镇静镇痛专家共识[J].中华医学杂志, 97(10):726-734.

[147] DUNCAN D, SANKAR A, BEATTIE WS, et al. Alpha-2 adrenergic agonists for the prevention of cardiac complications among adults undergoing surgery. Cochrane Database Syst Rev. 2018;3:CD004126.

[148] SULEMANJI DS, DÖNMEZ A, ALDEMIR D, et al. Dexmedetomidine during coronary artery bypass grafting surgery:is it neuroprotective?--A preliminary study.Acta Anaesthesiol Scand.2007;51(8):1093-1098.

[149] 贾龙飞,陈群清.心脏手术脑保护药物及其机制研究进展[J].广东医学, 2016,37(2):300-302.

[150] 陈倩,顾健腾,鲁开智.右美托咪定的器官保护作用研究进展[J].中国药房, 2014,25(25):2385-2388.

[151] XIONG J, QUAN J, QIN C, et al. Dexmedetomidine Exerts Brain-Protective Effects Under Cardiopulmonary Bypass Through Inhibiting the Janus Kinase 2/Signal Transducers and Activators of Transcription 3 Pathway. J Interferon Cytokine Res. 2020;40(2):116-124.

[152] 张玉辉,高亚坤,肖连波, 等.右美托咪定对老年心脏瓣膜置换术患者心肌保护和脑保护的影响[J].中国老年学杂志,2015,35(16):4606-4608.

[153] 陈贤,黎必万,檀文好,等.盐酸右美托咪定对先天性心脏病快通道麻醉患儿的脑保护作用[J].重庆医学,2016,45(23):3252-3255.