The Cerebral Protection Of Penehyclidine Hydrochloride And Ulinastatin In Patients Undergoing Heart Valve Replacement Surgery With CPB

Objective Brain tissue has low tolerance to hypoxia for the features of hyper-metabolism, high oxygen consumption and low reserve of oxygen and glucose. Cardiopulmonary bypass (CPB) makes auto-regulation of cerebral blood flow in the presence of varying degrees of loss. Inadequate blood flow to the brain perfusion, embolus and micro-thrombus, systemic inflammatory response and other factors during CPB may cause or aggravate hypoxic-ischemic brain injury, and even bring brain tissue into the imbalance between supply and demand of oxygen and the metabolic disorder of energy. So it is very important for maintaining the normal function of brain to monitor the oxygen balance and the energy metabolism and to improve them during perioperative period of cardiac surgery under CPB.Active brain protection measures during the peri-operative period of cardiac surgery under CPB have been the focus and emphasis of clinical research. The measures currently used include mainly:strengthening the preoperative management and intraoperative monitoring, proper surgical procedures, application of cerebral hypothermia protection technology and management of steady blood-gas, application of cerebral protection drugs, ischemic preconditioning, and so on. Preoperative screenings for high-risk populations and ultrasonography have become clinical routines. Diagnostic measures of noninvasive monitoring and imaging which are applied to judge the early brain injury are limited. At the present stage, the surgical procedures, application of hypothermia brain protection technology and management of steady blood-gas during CPB are relatively fixed. Limb ischemic preconditioning can reduce ischemic brain injury, but its application is only limited to animal experiment. Drug treatment is most simple among cerebral protection measures during the perioperative period of cardiac surgery under CPB, and the evaluation index is also much more mature.The commonly used clinical cerebral protective drugs include inhaled anesthetics, propofol, lidocaine, calcium antagonists and traditional Chinese medicines, etc.The protection mechanisms involve:removal of oxygen free radicals, inhibition of lipid peroxidation and intracellular calcium overload, reduction of the accumulation of excitatory amino acids, etc.The method of combined application of drugs and the specific dose-effect relation ship of it are still the difficulties in present study. It deserves deep study on how to apply drugs in combination to eliminate adverse reactions, reduce adverse factors, and play the best features of nerve cells in brain tissue.Penehyclidine hydrochloride (PHC) is a new type of anti-cholinergic drug with selective central and peripheral anti-muscarinic effects on M1 and M3 receptors but few on M2-associated with cardiac function. The unique tertiary amine groups of the molecular structure enable it pass the blood brain barrier into the central nervous system and take effect. It has been found that PHC can protect the brain through lightening cerebral ischemia reperfusion injury and reducing the nerve cell apoptosis in animal studies. The mechanism is related with lightening CPB-induced inflammatory response and ultrastructural changes in blood-brain barrier.Ulinastatin (UTI) separated and purified from the human urine is one of the trypsin inhibitor. It can inhibit kinds of hydrolases such as trypsin, chymotrypsin, elastase, hyaluronidase, cathepsin G etc. It can protect visceral organs (including heart) by stabilizing lysosomal membrane, inhibiting the release of lysosomal enzymes, scavenging oxygen free radicals, inhibiting the release of inflammatory mediators and regulating immunologic function. It has been proved that, for patients undergoing brain surgery and heart surgery under CPB, UTI has protective effects on brain with alleviating cerebral ischemia reperfusion injury, systemic and cerebral inflammatory reactions by inhibiting activity of enzyme and apoptosis, eliminating inflammation, scavenging oxygen free radicals. UTI can also reduce the cerebral anaerobic metabolism caused by CPB, improve cerebral oxygen uptake and utilization, alleviate capillary permeability, and improve cerebral microcirculation perfusion during CPB.PHC and UTI are commonly used as auxiliary drugs for anesthesia of cardiac surgery under CPB. They have different pharmacological properties.This research would focus on whether they can play a protective role in brain through other pathway s and whether the combined application of these two drugs can balance the cerebral oxygen metabolism and energy metabolism and reduce cerebral ischemia reperfusion injury better.The applications of PHC and UTI are taken more and more seriously in cardiac surgery under CPB, but few reports about whether they affect the cerebral oxygen supply-consumption balance and energy metabolism or not if used alone or in combination. In this study, the concentrations of S-100β protein and neuron specific enolase (NSE), jugular bulb venous oxygen saturation (SjvO2), arteriovenous oxygen content difference (Ca-jvO2), cerebral oxygen extraction rate (CERO2), brain glucose uptake rate (GluER), lactic acid generation rate (LacPR) and lactic acid oxygen index (LOI) in the blood of jugular bulb were detected in order to find out the effect of the single or combined use of these two drugs on balance of cerebral oxygen and energy metabolism, and to discuss the cerebral protective effect on patients undergoing cardiac surgery under CPB. Then, we try to analysis the relationship between the cerebral protective effect and S-100β protein, NSE content, the balance of cerebral oxygen supply-consumption, and the metabolic of energy.Method1 General Information48 patients undergoing selective cardiac valve replacement surgery with CPB, aged from 20 to 65 years old, ASA graded Ⅱ, NYHA graded Ⅱ, were randomly divided into 4 groups (n=12):The PHC group (group P), the UTI group (group U), PHC and UTI group (group PU) and the control group (group C). Patients with diseases of the endocrine system and nervous system, mental illness, severe anemia, hypertension or with the history of liver and kidney dysfunction, coagulopathy or thrombus were excluded. No Patients had hyperlipidemia, hyperbilirubinemia and received drug therapy which affects oxygen and glucose metabolism.2 AnesthesiasAnesthesia was induced with intravenous midazolam 0.05mg/kg, etomidate 0.3mg/kg, fentanyl 5～10μg/kg, acid cisatracurium 0.3mg/kg.5 minutes later endotracheal intubation was implemented and mechanically controlled ventilation began. Respiratory parameters:respiratory rate 10～12 times/min, tidal volume 8-10 ml/kg, inspiratory to expiratory ratio 1:2, oxygen concentration 100, after a successful endotracheal intubation via the right internal jugular vein plsma propofol target controlled infusion of 1%, target concentration of 2.0μg/ml. Anesthesia was maintained with fentanyl (total 20μg/kg), intermittent injection of cisatracurium, during CPB. The type of CPB machine was Germany STOCKERT-C. The U.S. Medtronic membrane oxygenator was installed on the circulation line filled with priming solution. The artery end was equipped with micro switch filter. Roller pump adopted nonpulsatile perfusion.400u/kg of heparin was injected before CPB and activated clotting time (ACT) was maintained above 480s. The ascending aorta, superior and inferior vena cava was intubated and connected to CPB machine. Flow rate was 60～70ml/kg-min, mean arterial pressure (MAP) 50-80mmHg, hematocrit (Hct) 20%～30%. Cold cardioplegic solution was perfused into the aortic root. The stabilization of blood-gas was managed with astat. Nasal temperature dropped to 30～32℃. Re warming speed was controlled in 1℃ in each of 4-5min. CPB wasn’t stopped until the circulation was stable. Then, protamine was given to neutralize heparin. Fentanyl was used for patient-controlled analgesia (PCA), dilute with saline to 100ml, background dose 2ml/h, PCA 0.5ml, Lockout duration 15min.Apart from the priming solution should not be used in liquids containing lactic acid, intraoperative and postoperative without entering a sugary liquid, in order to avoid an impact on results.PHC (0.02mg/kg) was injected 15 minutes before anesthesia induction in group P. 30% of the total UTI (2×104u/kg) was given before the surgery after induction,40% was added into the priming solution, and the remaining 30% was injected while the aorta was opened in group U. The application method of these two drugs in group PU was the same with group P and group U. Equivalent 0.9% saline solution was given at the same time in group C.3 Specimen collectionsBlood were taken from jugular bulb and radial artery for blood-gas analysis at the time before the surgery began after induction (T1),30 minutes after the start of CPB (T2),30min after the stop of CPB (T3),6 hours and 24 hours after CPB (T4,T5).3ml of jugular bulb venous blood were taken into a test tube for centrifuging. 4 Testing IndexesTesting indexes contained jugular bulb venous oxygen saturation (SjvO2), arterial oxygen content (CaO2), internal jugular venous oxygen content (CjVO2), arteriovenous oxygen content difference (Ca-jvO2), cerebral oxygen extraction rate (CERO2), rates of glucose uptake (GluER), lactic acid generation rate (LacPR) and lactic acid oxygen index (LOI), S-100β protein and neuron specific enolase (NSE) in internal jugular bulb venous.MMSE score was also measured.Results1 General condition of four groupsThere were no significant differences in the gender, age, weight, aortic clamping time, time of CPB, operation time and the lowest nasopharyngeal temperature and total amount of propofol used between the 4 groups. Preoperative Hb、HCT、ALT、 AST、CRE、TBIL and GLU were not significantly different. There were no significant differences in the surgical operation, intraoperative bleeding and blood transfusion between the 4 groups.2 Index of cerebral oxygen balance2.1 CaO2There was significant difference between different times in the same group (F=9.680, P<0.001). It decreased significantly at T2-T5 than at T1 for each group (P<0.05).There was no significant difference between different groups at the same time point (F=2.635, P=0.067).2.2 CjvO2There was significant difference between different times in the same group (F=25.732, P<0.001). The levels of CjvO2 at T2-T5 were lower than at T1 significantly (P<0.05).There was no significant difference between different groups at the same time point (F=2.023, P=0.127).2.3 SjvO2There was significant difference between different times in the same group (F=44.968, P<0.001).The level of SjvO2 at T2 was significantly higher than at T1 for each group (P<0.01). It was significantly lower at T3 than at T2 (P<0.01).There was significant difference between different groups at the same time point (F=7.757, P<0.001). It increased significantly in group P and U than in group C at T2 . T3. It increased significantly in group PU than in group C at T2、T3、T4 (P<0.01).2.4 Ca-jvO2There was significant difference between different times in the same group (F=4.856, P<0.01).The level of Ca-jvO2 at T2 was significantly lower than at T1 in each group. It significantly increased at T3 than at T2 in each group. It decreased significantly in group P、U and PU at T2、T3 than at T1 (P<0.01).There was significant difference between different groups at the same time point (F=6.145, P<0.001). It decreased significantly in group P、U、PU than in group C at T2 and T3 (P<0.05).2.5 CERO2There was significant difference between different times in the same group (F=27.446, P<0.001). The level of CERO2 at T2 was significantly lower than at Tl (P<0.01), while it was significantly higher at T3 than at T2 (P<0.01).There was significant difference between different groups at the same time point (F=5.006, P=0.005).Compared with group C, it decreased significantly in group P and U at T2、T3 (P<0.01), and decreased significantly in group PU at T2、T3、T4 (P<0.01).3 Brain energy metabolisms3.1 GluERThere was significant difference between different times in the same group(F=29.527, P<0.001). The level of GluER at T2 was significantly lower than at T1 (P<0.01), while it was significantly higher at T3 than at T2 (P<0.01).There was significant difference between different groups at the same time point (F=28.582, P<0.001). Compared with group C at T2, T3, it decreased significantly in group P、U and PU (P<0.01).3.2jv-aLacThere was significant difference between different times in the same group (F=9.87, P<0.001). The level of jv-aLac at T2 was significantly lower than at T1 (P<0.01), and it increased significantly at T3、T4 than at T2 (P<0.01).There was no significant difference between different groups (F=2.259, P=0.059).3.3 LacPRThere was significant difference between different times in the same group (F=23.302, P<0.001). Compared with T1, the level of LacPR was significantly lower at T2 (P<0.01), and it was significantly higher at T3、T4 (P<0.01).There was no significant difference between different groups (F=2.492, P=0.073).3.4 LOIThere was significant difference between different times in the same group (F=10.938, P<0.001). Compared with T1, the level of LacPR was significantly lower at T2 (P<0.01)and it was significantly higher at T3、T4 (P<0.01).There was no significant difference between different groups (F=1.758, P=0.185).4 Concentration of serum S-100β protein in internal jugular bulbThere was significant difference between different times in the same group (F=63.028, P<0.001).The concentration of serum S-100β protein at T2、T3 increased significantly than at T1 (P<0.01)There was significant difference between different groups at the same time point. (F=7.735, P<0.001). Compared with group C, it decreased significantly in group P and U at T2、T3 and also decreased significantly in group PU at T2～T4 (P<0.01). It was significantly lower in group PU than in group P and U at T2、T3 (P<0.01).5 Concentration of serum NSE in internal jugular vein bulbThere was significant difference between different times in the same group (F=13.326, P<0.001).The concentration of serum S-100β protein at T2-T4 increased significantly than at T1 in each group (P<0.01).There was significant difference between different groups at the same time point. (F=15.654, P<0.001). Compared with group C, it decreased significantly in group P and U at T2、T3 and also decreased significantly in group PU at T2～T4 (P<0.01). It was significantly lower in group PU than in group P and U at T2、T3 (P<0.01).6 The incidence of POCDThe incidence of POCD 3 days after surgery was significantly different with that of before surgery (Χ2=15.036, P=0.000).Compared with 3 days after surgery, it significantly decreased 7 days after surgery (Χ2=9.943, P=0.467).Compared with before surgery, there was significant difference at 7 days after surgery (Χ2=9.931, P=0.003).The incidences of POCD 3 days after surgery were 33.33% in group C and P, 25.00% in group U,16.67% in group PU. The overall incidence was 27.08%.The statistical method was chi-square test (Χ2=1.271, P=0.891).There was no significant different between group P and C. There was no significant different between group PU and U. Compared with group U and PU, they were significantly different in group P and C (Χ2=25.152,.P=0.000; Χ2=25.750, P=0.000).The incidences of POCD 7 days after surgery were 25.00% in group C and P, 16.67% in group U,8.33% in group PU. The overall incidence was 18,75%.The statistical method was chi-square test (Χ2=1.620, P=0.849).As the same with between group PU and U, there was no significant difference between group P and C. Compared with group P, they were significantly different in group U and PU (Χ2=25.152, P=0.000;Χ2=25.750, P=0.000).Conclusions1. Patients undergoing cardiac valve replacement surgery with CPB existe in a normal range of changes of cerebral oxygen metabolism and energy metabolism; the concentrations of S-100β and NSE significantly increased during surgical operation, to 24 hours after surgery they dropped to preoperative levels.2. Infusion of penehyclidine hydrochloride before surgery can correct the imbalance of cerebral oxygen supply and consumption in patients undergoing cardiac valve replacement surgery with CPB, it can reduced cerebral glucose metabolism, no significant effect on lactate metabolism, it can reduced the concentrations of S-100β and NSE in serum. It had no effect on the incidence of POCD, and plays a role of cerebral protection.3. Infusion of ulinastatin can correct the imbalance of cerebral oxygen supply and consumption in patients before undergoing cardiac valve replacement surgery with CPB, it can reduced cerebral glucose metabolism, no significant effect on lactate metabolism, it can reduced the concentrations of S-100β and NSE in serum and the incidence of POCD, which play a protective effect.4. Composite application of penehyclidine hydrochloride and ulinastatin in patients undergoing cardiac valve replacement surgery with CPB, which can correcte the imbalance of cerebral oxygen supply and consumption and reduced cerebral glucose metabolism in patients, han no significant effect on lactate metabolism, it can reduced the concentrations of S-100β and NSE in serum, produced a better effect than two drugs separate application. It also can reduce the incidence of POCD. Two drugs combined application of peri-operative, brain protective effect is more significant.