| Background:The improvement of surgical treatment on children with congenital heart diseases (CHD) depend on identifying the patients who are prone to organ failure, regulating the risk factors in the preoperative and intraoperative period and effectively interfering about the organ protection during the pediatric open-heart surgery. Whether the children have respiratory and circulatory dysfunction after pediatric cardiopulmonary bypass (CPB) is the key factor leading to a successful pediatric open-heart surgery. How to prevent or mitigate the damages on the lung tissue and myocardium is a very important issue, which also is one of the greatest important problems that cardiac surgery, anesthesiology department, cardiopulmonary bypass department and even postoperative intensive care unit (ICU) care most. The drugs or other intervention perioperatively is significant for prevention and mitigation of respiratory and circulatory complications after CPB.CPB is non-physiology situation. On the one hand it can cause permeability changes in the intestines, blood vessel and other tissues and organs, resulting in endotoxemia; on the other hand, blood, tubes and other CPB installations stimulate the body's inflammatory responses. Respiratory and circulatory systems are the most vulnerable to the impact.It had been confirmed by a large number of in vitro an in vivo animal experiments and clinical studies that the belladonna drugs can improve microcirculation, protect cells and inhabit ischemia-reperfusion injuries. The cell protective effect of belladonna drugs may be related to blocking calcium influx and inhibiting membrane lipid peroxidation. It had been proved that anisodamine have a kind of protective effect on organs, but its side effects limit their clinical application. Penehyclidine hydrochloride (PHC) is a novel prolonged action cholinergic receptor blocker studied by China. The main mechanism is the selective interruption to the central and peripheral M1, M3 and N1, N2 receptors which have cell protective effects and can improve cell tolerance to hypoxia and ischemia, stabilize lysosomes and mitochondria and other sub-membrane structure inhibit the formation of arachidonic acid metabolites and shock factors, reduce the release of lysosomal enzymes and the permeability of capillary walls and the exudation of inflammatory factors, make central nervous system sedate lastingly and ameliorate the microcirculation. So it has been widely used in clinic. There are a few articles about protective effects of PHC on respiration and circulation and its mechanism. This study investigates the respiratory and circulatory protective effects and mechanism of PHC to the children after CPB. It can supply proper drugs, dosage and the theory to the protective effects of important organs on the children during the CPB. First, through the pretreatment of PHC in a large number of pediatric abdominal surgeries, present study observes the effect of different doses of PHC during anesthesia in abdominal surgery compared with the atropine group and lay the foundation for the PHC pretreatment to the rat model with the endotoxin-induced acute lung injury (ALI) and the pediatric open heart surgeries. Second, real-time-PCR (RT-PCR) technique was applied. The protective effects of PHC on rats with ALI provide the experimental and theoretical basis for respiratory protective effect of the pretreatment in the pediatric open heart surgeries. At last, present study takes PHC of 0.04mg/kg and the double dose as the premedication, observes the changes about cell factors, pulmonary respiratory function parameters, hemodynamics, stress response and myocardial injury and investigates the protective effects of different doses of PHC on infants after CPB.Objective:Investigation of respiratory and circulatory protective effects of PHC on infants after CPB.Materials and methods:Part 1 Investigation of PHC as premedication in pediatric surgeryThere are 1535 cases of pediatric abdominal surgeries (coming from pediatric surgery of the First Affiliated Hospital of Zhengzhou University from Jan,2008 to Dec,2009) which were divided in three groups randomly:P1 group:there were 608 cases of intravenous injection of PHC 0.02mg/kg; P2 group:729 cases of intravenous injection of PHC 0.04mg/kg; A group:198 cases of intravenous injection of atropine O.Olmg/kg; All the 1535 patients were injected in the peripheral vein by the experimental drugs and ketamine 2mg/kg 30 minutes after that in the induction room, then the children will be transferred into the operating room receiving the intravenous general anesthesia after lossing their consciousness. Present study observes the changes of the saliva secretion, temperature and blood flow dynamics in three groups.Part 2 Investigation of effects of PHC on repair of acute 1 ung injury (ALI)There are 48 cases healthy adult male SD rats which are divided into four groups randomly and there are 12 rats in each group:C group:tail vein injection of saline 1 ml/kg; M group:tail vein injection of E.coli Lipopolysacharide (LPS) 5mg/kg; P1: tail vein injection of E.coli LPS 5mg/kg and PHC 0.25mg/kg; P2:tail vein injection of E.coli LPS 5mg/kg and PHC 0.75mg/kg. In this part of experiment, animal study combined with RT-PCR technique was applied. Through establishment of endotoxin-induced rat model and comparison of controlled and model groups, present study investigate the plasma TNF-alpha and IL-6, PaO2 and PaCO2, water in lung tissue (WLT), water/dry (W/D) of lung tissue, gray scale rate of CD14 mRNA, pathology slides and electron microscope.Part 3 This part is composed of the following two sections.Section 1 Investigation of the respiratory protective effect of penehyclidine hydrochloride of infants after cardiopulmonary bypassSection 2 Investigation of the circulatory protective effect of penehyclidine hydrochloride of infants after cardiopulmonary bypass65 cases CHD surgeries (Department of Cardiac Surgery in the First Affiliated Hospital of Zhengzhou University) are divided into three groups randomly:P1 group: 25 cases are injected by PHC 0.04 mg·kg-1; P2 group:29 cases are injected by PHC 0.08 mg·kg-1; C group:11 cases are injected by the same volume saline at the same time which is slowly injected from the right internal jugular vein after the success of internal jugular vein puncture. Age range:8 months to 35 months. The male cases is 37 and female is 28 whose weight range is 6-16kg. There is no server pulmonary hypertension and disorder of hepatic function, renal function and coagulation in all children whose cardiac function is inⅡ～Ⅲgrade and ejection fraction (EF) is more than 60%. Collect the left radial artery blood 4 ml at each time point with heparin anticoagulation. One milliliter is used to monitor blood gas and the other three milliliters immediately centrifugate for 10 minutes at 4℃at 3000r/min. Then take the upper plasma to the -80℃refrigerator under test and record the peak airway pressure. Compared with the control group, this study investigate the effect of hemodynamics, Cd. RI,OI, Pmax, TNF-a,IL-6, cortisol, lactic acid, blood glucose, cTn-I,CK-MB in different doses of PHC groups.The SPSS 17.0 statistical package is applied for statistical analysis to all data. The measurement data is showed in mean±standard deviation (x+s). The analysis of variance is used between groups. If the results are different, LSD will be used for pairwise comparison. Paired t test was applied to compare before and after CPB with count data usingχ2 test and ranked data using non-parametric test. The significant difference is a=0.05.Conclusions:Part 11. there is no significant difference among the groups of gender, age, weight, anesthesia time (from the time entering to the induction room to out of the recovery room),operative time and recovery time(from the end of surgery to the time out of the recovery room, p> 0.05).2. The comparison of the saliva secretion:non-parametric test is used for comparison between groups and Mann-Whitney test is used for prirwise comparisons. It needed to calibrate because there are two comparisons between groups, a'=0.05/3=0.0167. There is significant difference of secretion during the endotracheal intubation (χ2=3342.76, P<0.01). There is significant difference between A group and P1 group(Z=46.26, P<0.01), and between the two PHC groups (Z=47.98,P<0.01) while there is no significant difference between A group and P2 group (Z=2.25, P=0.025>0.0167). while during the tracheal extubation, there is significant difference between groups(χ2=3607.57, P<0.01): A group and P1 group (Z=37.64, P<0.01), A group and P1 group (Z=52.12, P<0.01), P1 group and P2 group (Z= 47.07, P<0.01)3. Temperature comparison:There is significant difference of body temperature among the three groups (x 2=3407.82, P<0.05). While there is no significant difference of basal body temperature (P>0.05). The temperature in atropine group increased 30 minutes after treatment (P<0.05). compared with A group, the temperature in the two PHC group decrease at T1 (P<0.05)4. The comparison of heart rate (HR) and mean arterial blood pressure (MAP):HR:there is significant difference of heart rate among the three groups (χ2=3278.17,P<0.05) and there is no significant difference of basal heart rate (P >0.05). As comparing with the basal heart rate, the HR increased at 5 minute,30 minute and 60 minute after treatment in the atropine group (P<0.01) and there is no difference in the PHC low-dose group and high-dose group (P>0.05).The HR in the two PHC groups decreased significantly compared with the atropine group (P>0.01). There is no significant difference between the two PHC groups (P>0.05).MAP:there is no significant difference of mean arterial bood pressure (χ2=263.19, P>0.05).Part 21. Plasma TNF-alpha:Compared with controlled group, plasma TNF-alpha among model group, low-dose PHC group and high-dose PHC increased significantly (P<0.01). TNF-alpha in both low-dose and high-dose PHC group were higher than that in model group (P<0.01). Compared with low-dose group, TNF-alpha in high-dose group reduced significantly (P<0.01).2. Plasma IL-6:Compared with controlled group, plasma IL-6 among model group, low-dose PHC group and high-dose PHC increased significantly (P<0.01). IL-6 in both low-dose and high-dose PHC group were higher than that in model group (P<0.01). Compared with low-dose group, IL-6 in high-dose group reduced significantly (P<0.01).3. PaO2 and PaCO2In comparison with PaO2 in controlled group, it was declined significantly in model, low-dose PHC and high-dose PHC group (P<0.01). Level of PaO2 in low-dose and high-dose was raised significantly than that in model group (P<0.01) while there was no significant difference between the two PHC groups (P>0.05).Compared with controlled group, PaCO2 in model group augmented significantly (P<0.01). PaCO2 in model group was higher than that in both PHC groups (P<0.05).4. Water in Lung Tissue (WLT)Compared with controlled group, WLT in model and both PHC groups was higher. In comparison with model group, WLT in both PHC groups was trimmed down (P<0.05). There was no significant difference of WLT between the two PHC groups (P>0.05).5. Water/Dry (W/D) of Lung TissueIn comparison with controlled group, rate of W/D in model and both PHC groups elevated significantly (P<0.05). Compared with model group, rate of W/D in both PHC groups was down significantly (P<0.05).6. Gray Scale Rate (A value) of CD14 mRNAIn comparison with controlled group, A value in model and both PHC groups elevated significantly (P<0.05). Compared with model group, A value in both PHC groups was down significantly (P<0.05).7. Pathology Slides(200×)Pathology slides from controlled group demonstrated normal rat lung tissue with clear structure, thin alveolar wall and no infiltration of inflammatory cells between alveolar wall and interstitial substance. These from model group showed severe edema of lung tissue, hemorrhage, increased interstitial space, and significant collapse of alveoli, spreading of a great amount of red cells in interstitial and alveolar space, filtration of inflammatory cells and destroy of integrity of part of pulmonary alveoli. These from low-dose PHC group displayed mild edema of lung tissue, less amount of infiltrated inflammatory cells, reduced thickening of interstitial and collapse of alveoli with relative intact of structure of alveoli. Compared with pathology slides from low-dose PHC group, these form high-dose PHC group exhibited mild pulmonary edema, less infiltration of inflammatory cells and decreased injury of lung tissue with intact alveolar structure.8. Morphology of pulmonary capillary endothelium and basement membrane under electron microscope (6000 X)Structure of pulmonary capillary endothelium and basement membrane under electron microscope in controlled group was normal. In model group, pulmonary capillary endothelia had severe swollen; basement membrane revealed defect, loose and vague; and electronic density of capillary wall exhibited reduction. In both low-dose and high-dose PHC group, pulmonary capillary endothelia had mild edema with relatively normal morphology, less loosen basement membrane, and nearly normal electronic density of capillary wall.9. Morphology of alveolar typeⅡepithelial cells (ATⅡ) under electron microscope(6000 X)Morphology of ATⅡunder electron microscope in controlled group showed that microvilli lined up in good order with slim finger-like projections. There were a lot of lamellar bodies with clear structure and mitochondria in cytoplasm. Basement membrane was intact. In model group, microvilli shed severely with vacuolization of lamellar bodies, blurred, ruptured and shortened microfilament, vacuolar degeneration of mitochondria and damage of basement membrane. In low-dose group, microvilli lined up in good order with mild swollen mitochondria. Microfilament was clearly visible and basement membrane was relatively intact. In high-dose group, the order of microvilli was neat with normal morphologic lamellar bodies and mitochondria, clear microfilament and relatively intact basement membrane.Part 31. There is no significant difference of gender, age, weight, operative time, bypass time, aortic cross-clamp time, cardiac resuscitation situation, mechanical ventilation of postoperative children followed up and the resistance time in ICU (P>0.05).2. Dynamic Lung Compliance (Cd):compared with the basal point, the Cd in the control group is higher at any point (P<0.05), and that in PHC low-dose group and high-dose group increased before bypass, after aortic opening and the outage time (P<0.05).3. Respiratory index (RI):the RI in the control group increased comparing with the basal point (P<0.05); and that increased in the two PHC groups after intubation, before bypass, aortic opening up and the outage time (P<0.05).4. oxygenation index(OI):in comparison with the basal point the 01 in the control group increased (P<0.05); and it increased after intubation, before bypass, aortic opening up and the outage point in the PHC low-dose group and high-dose group (P<0.05).5. Peak airway (Pmax):compared with the basal point, the Pmax in the control group decreased (P<0.05); and it decreased before bypass, aortic opening up and outage point in the PHC low-dose group and high-dose group (P<0.05).6. TNF-a:in comparison with the basal value, the plasma TNF-alpha the control group increased (P<0.05); and it decreased before bypass, aortic opening up and the outage point in the PHC low-dose group and high-dose group (P<0.05).7. IL-6:compared with the basal value, IL-6 in the control group increased (P<0.05); and it decreased at the time of before bypass, aortic opening up and stopping point in the two PHC groups (P<0.05).8. Hemodynamics:HR:As compared with the basal point, the HR in three groups increased at 1 minute after intubation (P<0.05), and that in control group increased at 1 minute after skin incision and 1 minute after sternotomy (P<0.05).while HR decreased in the PHC low-dose group and high-dose group at 1 minute after skin incision and 1 minute after sternotomy (P<0.05).MAP:In comparison with the basal value, the MAP decreased before intubation in three groups(P<0.05), while that in control group increased at 1 minute after skin incision and 1 minute after sternotomy (P<0.05).The MAP in the two PHC groups decreased at 1 minute after skin incision and 1 minute after sternotomy (P<0.05).9. Stress reaction:9.1 Cortisol:Compared with the basal point, the cortisol in the three groups increased at the time of bypass beginning,2 hours after aortic opening and 24 hours after the opening (P<0.05).In companion with the control group, that in the PHC low-dose group and high-dose group decreased at the time of bypass beginning,2 hours after aortic opening (P<0.05) and 24 hours after the opening (P<0.01).9.2 lactic acid:Compared with the basal point, the lactic acid increased at the time of bypass beginning,2 hours after aortic opening and 24 hours after the opening in the three groups (P<0.05). As comparing with the control group, the lactic acid in the PHC low-dose group and high-dose group decreased at the time of bypass beginning,2 hours after aortic opening and 24 hours after the opening (P<0.05).9.3 blood glucose:Compared with the base line, the blood glucose in the three groups increased at the time of aortic opening,2 hours after aortic opening and 24 hours after the opening (P<0.05). In comparison with the control group, the blood glucose in the two PHC grous decreased at the time of aortic opening,2 hours after aortic opening and 24 hours after the opening (P<0.05).10. cardiac troponin (cTn-I):Compared with the base line, the cTn-I increased at the time of bypass beginning,2 hours after aortic opening and 24 hours after the opening in the three groups (P<0.01). As comparing with the control group, that in the PHC low-dose group and high-dose group decreased at the time of bypass beginning,2 hours after aortic opening and 24 hours after the opening (P<0.01).11. MB isoenzyme of creatine kinase (CK-MB):Compared to the base line, the CK-MB increased at the time of bypass beginning,2 hours after aortic opening and 24 hours after the opening in the three groups (P<0.01). While compared with the control group, the CK-MB in the two PHC groups decreased at the time of bypass beginning,2 hours after aortic opening and 24 hours after the opening (P<0.01).Conclusions:1. PHC 0.04mg/kg is used in the pediatric abdominal surgeries as premedication. It can effectively inhibit the salivary gland secretion, maintain a stable temperature and hemodynamics, which lay the foundation for its widely use in pediatric open heart surgery and provide the experimental and theoretical basis for respiratory protective effect of the PHC to the rat model with the endotoxin-induced acute lung injury (ALI) and the pediatric open heart surgeries.2. The endotoxin-induced rat model had been established. The intravenous injection of PHC 0.25mg/kg and 0.75mg/kg can effectively reduce the inflammatory response in septic rats with ALI and showed a definite dose-effect relationship.3. The application of PHC 0.04mg/kg before CPB can effectively inhibit the release of TNF-α,IL-6, increase the dynamic pulmonary compliance and oxygenation index, reduce the respiratory index and the peak airway pressure, stable hemodynamic changes, inhibit stress response, improve microcirculation and reduce cTn-I and CK-MB of the damaged heart cells. So it has a certain kind of respiratory and circulatory protection.4. It is an important mechanism of PHC as pretreatment that reduces the respiratory and circulatory disorder after CPB. There is no dose-effect relationship between the PHC 0.04mg/kg and PHC 0.08mg/kg in the pediatric open heart surgery.
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