The Myocardial And Cerebral Protection And Mechanism Of Dexmedetomidine During Cardiac Surgery

Bankground and objectiveHeart valve replacement is the common method to crue rheumatic valvular heartdisease at present. Heart valve replacement skill is mature because of the continuousimprovement of cardiothoracic surgery, but the achievement ratio of operation isclosely related to measures of myocardial preservation during the operation. So studyon measures of myocardial preservation during perioperative period is veryimportant to increase the achievement ratio of the operation. Myocardial injury duringopen-heart surgery using cardiopulmonary bypass was influenced by the followingtwo aspects: one was the strong stress reaction caused by operation technique, whichinduced central catecholamine release, haemodynamics unsteadiness, the heartoxygen delivery and consumption unbalance. Two was physiologic derangement andpathological change occurring in the body using cardiopulmonary bypass.Myocardial cells were under oxygen deficit condition after the occlusion of the aorta.And anaerobic metabolism of myocardial cells increasing, lactic acid gathering,acidosis in myocardial cells impaired myocardium directly. After the aorta opened,myocardial cells reperfusion, oxygen radical increasing rapidly caused myocardialischemia reperfusion injury. Complement activation and monocyte activation becauseof blood contact with silica gel pipeline, heparin and protamine infusion, andstimulation of anesthesia and operation may cause the release of inflammatorymedium such as tumor necrosis factor and interleukin, and thus caused systemic inflammatory response syndrome. So myocardial preservation and restraining ofstress reaction furthest during open-heart surgery using cardiopulmonary bypassplayed an important role in operation and recovery of the patients.During the open-heart surgery using cardiopulmonary bypass the brain was underthe oxygen deficit condition. Brain arterial embolism and brain blood hypoperfusionwere the main reason of cerebral injury duing CPB. Inflammatory response caused byCPB and organ ischemia reperfusion injury may aggravate cerebral injury. Centrallesion cuased by CPB was the main reason inducing fatal complication in open-heartsurgery.Ligation of the anterior descending branch of coronary artery was commonly usedto establish myocardial ischemia reperfusion injury animal model, imitating coronaryartery bypass surgery or percutaneous coronary surgery. Study on animal model onprevention of myocardial ischemia were mainly about ischemic preconditioning,ischemic postconditioning, pharmacological preconditioning or combined application.These methods were applied to clinical study to prevent myocardial damage by CPB.Dexmedetomidine is a high selectivity α2adrenergic receptor agonist, and itseffects in clinical application were sympathetic nerve blocked, sedation and analgesia.It acted on α2adrenergic receptor in presynaptic membrane, restraining the release ofnoradrenaline., and then controlled the stress reaction caused by the operation. Usingdexmedetomidine in coronary artery bypass surgery may heighten the stability ofhaemodynamics and maintain the balance between oxygen delivery and oxygenconsumption of cardiac muscles. Retrospective study shew that usingdexmedetomidine during the operation could reduce perioperative periodcomplication such as myocardial infarction, cardiac conduction block, cardiac arrest,apoplexy and so on. Study shew that dexmedetomidine using in cerebral ischemicinjury animal model may reduce the content of S100β protein which was the mostimportant landmark of cerebral ischemic. Now more and more use ofdexmedetomidine were developed in clinical application, but the dose ofdexmedetomidine using in heart valve replacement and it was unknown whether itcould stable haemodynamics and whether it had myocardial preservation and cerebralprotection.The first part and the second part of this study took the patients undergoing heart valve replacement as study objective, discussing the moderateusing dose of dexmedetomidine in clinical, the effects on landmark of myocardialdamage and cerebral injury and its effects on cognitive function and then referencedthe clinical.Clinical study on dexmedetomidine mainly concentrated on patients undergoingcoronary artery bypass surgery, but there were no report about whether usingdexmedetomidine in heart valve replacement by CPB may stable haemodynamics,whether it had myocardial preservation and aslo no report about its moderate dose inheart valve replacement by CPB. The first part of this study mainly discusseddifferent doses of dexmedetomidine using in heart valve replacement by CPB andobserved its effects on haemodynamics and myocardial damage. The second part ofthis study mainly discussed its effects on inflammatory factor and cerebral injury.Haemodynamics in patients who suffering rheumatic heart disease troubled highpulmonary artery pressure changed seriously during operation. And those patientswere more sensitive on anesthesia and surgery. There were no report about whetherusing dexmedetomidine in these patients could stable haemodynamics and reducemyocardial damage. The third part of this study mainly observed the effects onhaemodynamics and myocardial damage of the patients troubled with high pulmonaryartery pressure undergoing mitral valve replacement, and anesthesia was continuouslyinfusion dexmedetomidine combined with inhalation sevoflurane. The third part ofthis study took patients combined high pulmonary artery pressure undergoing heartvalve replacement as study objective, observing the effects of dexmedetomidine onhaemodynamics of pulmonary circulation and systemic circulation and its myocardialpreservation. The fourth part of this study took pigs as study objective, establishingthe ischemia reperfusion model, evaluating the effects of dexmedetomidine onmyocardial infarction area, landmark of myocardial damage, NE and Big ET-1, anddiscussing the mechanism of myocardial preservation.Materals and methodsPart Ⅰ The effects of dexmedetomidine on hemodynamics and myocardialinjury in patients undergoing cardiac valve replacement surgeryNinety patients with valvulopathy, aged18~65years, weighing50~75kg, ASAⅡor Ⅲ, were randomly assigned to one of three equal groups. Anesthesia was inducedwith midazolam0.05mg/kg, sufentanil1μg/kg,etomidate0.3mg/kg. Rocuroniumbromide0.6mg/kg was administered to facilitate endotracheal intubation andCisatracurium besylate was repeated during surgery as required to maintain musclerelaxation. Anesthesia was maintained using sevoflurane1%–2%in an oxygen-airmixture and sufentanil0.4~0.7μg/kg Continuous pumping.The BIS was monitoredbetween40and50during surgery.The control group received saline (group C),whereas the treatment group received an initial bolus dose of dexmedetomidine0.5μg/kg(group D1) or1μg/kg(group D2) over10min, followed immediately by acontinuous infusion of0.5μg/kg/h. Hemodynamic variables (HR, systolic bloodpressure, diastolic blood pressure and mean arterial pressure) were recorded atbaseline (after the anesthetic induction and before the administration of the studydrug)(T0), after the administration of the bolus dose of study drug(T1), after skinincisions（T2）, after sternotomy（T3）, before CPB(T4),after10min termination ofCPB(T5) and Completing the surgry(T6).The dosage of vasoactive agent wasrecorded during surgry.In all groups, blood samples were obtained from the centralvenous catheter for assessment of heart-type fatty acid binding protein (H-FABP),creatine kinase-MB(CK-MB), cTnI which were tested by enzyme-linkedimmunoabsorbent assay (ELISA) methods. Samples were obtained at baseline, after10min termination of CPB,the end of operation,6hour after operation and24hourafter operation.Part Ⅱ Effects of dexmedetomidine on inflammatory response and cerebralneurologic injuries in patients undergoing valve transplantation surgeryperformed with cardiopulmonary bypass.Fourty ASA Ⅱor Ⅲ patients of both sexes, aged45-65yr, weighing45-80kg,undergoing elective valve transplantation surgery with CPB, were randomly dividedinto2groups(n=20each): control group(group C) and dexmedetomidine group(group D). Anesthesia was induced with iv injection ofmidazolam,sufentanyl,etomidate and rocuronium. Dexmedetomidine0.5μg/kg wasinfused intravenously over10min after induction followed by continuous infusion at0.5μg·kg-1·h-1until the end of operation in group D.While equal volume of normal saline was given in group C. Anesthesia was maintained with inhalation ofsevoflurane and continous infusion of sufentanyl. Before operation and7d afteroperation, all the patients wre required to take a battery of2neuropsychological tests,including mini-mental state examination(MMSE) and montreal cognitiveassessment(MoCA). And delirium rating scale(DRS) was estimated postoperationdelirium. Right central venous blood samples were taken before induction(T0),10min after CPB(T1), at the end of operation(T2),6h after operation(T3) and24hafter opertion(T4) for determinnation of TNF-α、IL-6、S100β、NSE.Part Ⅲ Effect of Dexmedetomidine on myocardial ischemia-reperfusion injuryin pigs and the mechanismTwenty healthy pigs of both sexes,weighing35~45kg，were randomly divided intotwo groups(n=10each):control group(group C),dexmedetomidine group(groupDex).Ketamine10~20mg/kg combined with midazolam0.1mg/kg and atropine0.2mgwere injected intramuscular, the intubation were successfully after the incision oftracheal followed by mechanical ventilation.Sufentanil and rocuronium with a loadingdose0.5μg/kg and0.6mg/kg were separately intravenously injected followed by themaintenance at the rate of0.5μg/kg/h.The right carotid arteries jugular veins wereexposed. Trocar wre insertede into the right carotid arteries for the mornitoring ofarterial pressure.Swan-Ganz catheter which were bonded with the VigilanceⅡwereput into the jugular veins.The maintenance of anesthesia:sevoflurane with1.5~2%were continuously inhaled;in Group DEX, dexmedetomidine with a loading dose0.5μg/kg followed by the maintenance at the rate of0.5μg/kg/h.After anaestheticed,catheter were inserted into the femoral artery for coronary arteriongraphy.The heartwere exposed after the open of chest, coronary artery were separated and werestricted30min with silk suture in Group P、Group S and Group DEX.coronaryarteriongraphy were administered10min after stricted.Hemostatic clamp wereunclamped30min after stricted, the reperfusion begins and will last for60min。MAP、HR、CVP、MPAP、CO、SV、CI、SVRI、PCWP、PVR were recorded at the timepoint of pre-ischemic、10and30min after the begin of pre-ischemic and10、30、60min after the reperfusion.The blood samples from the internal jugular vein werecollected, the serum were got after centrifugal separation and were stroraged at -80℃.Noradrenalin、ET-1、 cTnI and CK-MB determined by ELISA. After areperfusion period of60minutes, the tissue pieces of the left (ischemic region)and right (non-ischemic region) ventricles were excised for later measurements ofNE and ET-1levels in the myocardial tissues. Arterial blood0.5ml were collectedfor the determination for pH、HCO—3Glu and Lac through blood gas analysis.Thearrhythmia were scored20min after the reperfusion.Anterior descending coronarywere re-blocked after the end of re-perfusion, the left ventricle which were notblocked were stained with Evans blue0.25%20ml.The left ventricles were got afterthe execution, aboral axis of ordinates with the thickness of10mm were analyzed byimage analysis software.The calculation of myocardial infarction area were thenbegined.ResultsPart Ⅰ The effects of dexmedetomidine on hemodynamics and myocardialinjury in patients undergoing cardiac valve replacement surgery1. Administration initial bolus dose of dexmedetomidine resulted in a significantinrease in SBP、DBP、MAP relative to control group and baseline. In the controlgroup SBP、DBP、MAP decreased significantly relative to baseline, group D1andgroup D2,at T2、T4、T5and T6. Patients in the control group had significantlymore increased systolic blood pressure levels relative to group D1or group D2,during skin incisions and sternotomy (P <0.05).2. The dosage of vasoactive agent was used significantly lower in group D1orgroup D2than control group (P <0.05).3. H-FABP, CK-MB and cTnI levels increased significantly relative to baseline inboth groups after the use of drugs.the level of H-FABP was significantly higherin the control group compared with the group D1or group D2,after10mintermination of CPB,the end of operation,6hour after operation and24hour afteroperation (P <0.05). the CK-MB及cTnI levels were significantly higher in thecontrol group compared with the group D1or group D2at6hour after operationand24hour after operation.Part Ⅱ Effects of dexmedetomidine on inflammatory response and cerebralneurologic injuries in patients undergoing valve transplantation surgery performed with cardiopulmonary bypass.1. A total of40patients completed the tests. No significant difference was found inage, gender, height, weight and education level between the2groups (P>0.05).The scores of MMSE, MoCA and DRS were significant difference between the2groups (P>0.05).The incidence of postoperative cognitive dysfunction in Dexgroup and control group was35％and20％7d after operation respectively.Statistical analysis showed no significant difference between the2groups(P>0.05). The incidence of delirium in Dex group and control group was20％and10％after operation respectively. Statistical analysis showed no significantdifference between the2groups (P>0.05).2. Blood serum TNF-αand IL-6concertration was significantly increased after CPBin both group as compared with the baseline at T0. Compared with group C,theTNF-α concertration singnificantly higher at T1,T2,T3,T4and the IL-6concerntration significantly higher at T2,T3,T4in group D.3. Plasma S100βprotein concertration was significantly increased at T1,T2,T3,T4compared with T0in both group, and was higher at T3in group D than group C.NSE concertration was significantly increased at T1,T2,T3,T4(in group C)and atT2,T3,T4(in group D) compared with the baseline. Compared with group C, NSEconcertration was significantly higher at T1and T2in group D.Part Ⅲ Effect of Dexmedetomidine on myocardial ischemia-reperfusion injuryin pigs and the mechanism1. Hemodynamics comparison MAP in Group C were declined at the time pointof postischemia10min、30min and reperfusion30min(P<0.05),lower thanGroup D(P<0.05).HR upgraded at postischemia10min、30min (P<0.05),higherthan Group D(P<0.05).MAP in Group C upgraded at postischemia30min(P<0.05),higher than Group D(P<0.05).CVP upgraded in Group C after theischemia.PCWP in Group C upgraded (P<0.05),it also upgrade atpostischemia10min in Group D(P<0.05),lower in Group D than Group C atpostischemia30min.CO were declined significantly in Group C after ischemia(P<0.05),lower than Group D (P<0.05).SVR were declined60min afterreperfusion,which were lower than Group D (P<0.05).PVR were declined in both two groups after ischemia than pre-ischemia,while there was no differencebetween the two groups(P>0.05).2. NE and Big ET-1Compared with pre-ischemia, NE and Big ET-1weresignificantly higher in Group C at ischemia30min、re-perfusion30min and60min (P<0.05) while in Group D they were only higer at re-perfusion30min and60min and lower than Group C(P<0.05).NSE and cTnI were higher in Group Cthan Group D at re-perfusion30min and60min(P<0.05).3. Myocardial NE and ET-1levels in the ischemic and non-ischemic regionMyocardial levels of NE and ET-1were significantly increased in the groupC(P<0.05).Myocardial level of NE and ET-1signifcantly higher in thegroup C than in the group D(P<0.05).4. Myocardial infarction area and the arrhythmia The score of the arrhythmiawere(3.30±0.675) in Group C higer than Group D（2.00±0.677）(P<0.05). IS%in Group C was42.4%which was higher than Group D23.5%（P<0.05）.Conclusion1. We concluded that intraoperative dexmedetomidine infusion(0.5μg/kg bolusfollowed by a0.5μg/kg/h infusion) can be a useful adjuvant in anesthesia of heartvalve disease.Because it attenuates the hemodynamic response and decreases thedosage of vasoactive agent and the myocardial injury after CPB during surgry.2. Dexmedetomidine can decrease MMSE, MoCA and DRS scores,and reduceinflammatory response, cerebral neurologic injuries in patients undergoing valvetransplantation surgery performed with CPB. But did not effect on the incidenceof cognitive dysfunction．3. Effect of Dexmedetomidine can stabilize hamodynamics, reduce ardial infractsize and myocardial injury in myocardial ischemia-reperfusion injury pigs.4. Dexmedetomidine can decrease NE and ET-1Level in pigs serium andmyocardial.