Pharmacodynamics Of In Travenously Injected Propofol In Rats With Hepatic Cirrhosis At Different Phases

References reported that the tolerant anesthetic dosage for patients of hepatic cirrhosis was greatly reduced than other patients,and the recovery time for consciousness after surgery was also elongated,but our observation discovered that the postoperative recovery time of consciousness was related to the functioning status of cirrhotic liver. Liver fibrosis is a mandated stage in the process of liver cirrhosis,and the hepatic cirrhosis is separated into the compensation stage and the decompensation stage.During the progression of cirrhosis,at different stage,the appropriate anesthetic dosage could vary greatly,and this relationship between the degree of cirrhosis and the anesthetic dosage is poorly understood.Also,there are still no reports on the postoperative recovery time of consciousness for the decompensation & compensation stages and the stage of liver fibrosis with chronic hepatitis,as well as for the patients with normal liver function.Propofol,as a commonly used anesthetic,primarily was metabolized by liver.It has fairly ideal characteristic in anesthetic pharmacology,and quickly anesthetic action, shortly maintain time,quickly and completely palinesthesia,few postoperative adverse effect,no sequela as well.To establish animal model whish is similar to mankind is indispensable component element to study liver cirrhosis.We,through the use of hepatic cirrhotic models, measured the ED₅₀ at different stages induced by intravenous injection of propofol and the recovery time for the body-righting reflex of rats after 30,60,and 90 minutes of continuous transfusion of propofol,in order to reveal the pharmacodynamic effect of propofol on different stages of liver cirrhosis.It would also provide theoretical and experimental evidences for anesthetization of patients with liver cirrhosis.ObjectiveThe objective was to measure the ED₅₀ at different stages induced by intravenous injection of propofol and the recovery time for the body-righting reflex of rats after 30,60,and 90 minutes of continuous transfusion of propofol by pump,in order to reveal the pharmacodynamic effect of propofol on different stages of liver cirrhosis.It would also provide theoretical and experimental evidences for anesthetization of patients with liver cirrhosis.Method1.Establishment of a rat model of liver cirrhosis120 SD laboratory rats were grouped into the control group(n = 40) and the model group(n = 80).The control group was subdivided into two subgroups,where each group contained 20 rats.Onesubgroup was called C1 group,and was fed with normal clean water for 9 weeks.The other subgroup was called C2 group,fed with Phenobarbital sodium solution(0.35 g/1000 mL) for a week before the addition of 10%ethanol(prepared by drinking white wine) and sweetener(aspartame) for another 9 weeks.The hypodermic injection for the control group was all saline solution(0.5 ml/100 g),and was performed twice per week.The model group was subdivided into three subgroups:M1 group was prepared for 6 weeks,which was equivalent to hepatic fibrotic stage;M2 group was prepared for 9 weeks,equivalent to compensation stage;and M3 group was prepared for 12 weeks,equivalent to decompensation stage.The hypodermic injection for the model group was CCI4(0.5 ml/100 g).The cell number,blood biochemical & hepatopathological examinations,body weight,and the weights of liver and spleen,were used as condition assessments.2.To measure the ED₅₀ at different stages induced by intravenous injection of propofol.Measurment of ED₅₀ in the rats induced by intravenous transfusion of propofol using sequential method.The indication for ending anesthetization was the loss of righting reflex of front paws (LFRR),and the indication of recovering from anesthetization was the regain of righting reflex of front paws(RFRR).After the injection, rats were immediately turned to supine position,where animals which could not automatically overturn were considered as having lost the reflex ability,while(+) sign was assigned,and vice versa with(-) sign.3.The measurement of the recovery time from continuous transfusion of propofol at different stage of the progression of hepatic cirrhosis in rats Before transfusion for each group,1.5 times of ED₅₀ amount was given to corresponding group.After administration,it was washed with 0.2 ml saline solution.The dosage for continuous intravenous transfusion of propofol was 60 mg/kg/h.The time points of transfusion for each group were 30,60,and 90 minutes.The RFRR was measured.Results1.Animals of the liver cirrhosis model group had reduced activities,as well as decreases in food and water intake.They became slim,with apparent weight drop when compared to other normal rats of same age. They were also slow in response to external stimuli.Animals' fur was dried and withered,while the control group showed lustrous hairs and was active,with high spirit and more intakes of water and foods.2.The TSP,SAB,WBC,RBC,PT,and HG of M2 and M3 groups were significantly lower than the ones of M1 group and control group(p＜0.01),while the ratio of liver wet weight and body weight,the ratio of spleen and body weight,and the ALT & AST,were dramatically higher than that of M1 and control groups(p＜0.01).The TSP,SAB, WBC,RBC,PT,and HG of the M3 group were significantly lower than those of M2 group(p＜0.01).The ratio of spleen and body weight of the M3 group was much higher than that of the M2 group(p＜0.01).The indices of blood routine examination and liver function test,except the values of ALB,showed without statistical differences in C1,C2,and M1 groups(p＞0.05).3.After intravenous injection of propofol,the body-righting reflex of all positive rats disappeared within 5 seconds.The comparison of ED₅₀ of the C1,C2,M1,M2,and M3 groups,after the intravenous induction by propofol,showed:when comparing the M3 group to the M2,M1, C2,and C1 groups,it was decreased by 16.4%,32.9%,26.2%,and 20.3%,respectively(p＜0.01);ED50 of M2 was reduced by 19.8% when compared to M1 group(p＜0.01);ED50 of M1 was increased by 18.8%when compared to C1 group(p＜0.01).For the RFRR,it was shown:M3 group,when comparing to M2,M1,C2,and C1 groups, was delayed by 37.0%,62.1%,78%,and 126.0%,respectively(p＜0.01);RFRR of M2 group was delayed by 18.3%when compared to M1 group(p＜0.01).the time of RFRRs in the M1,C2,and C1 groups had no statistical significance(p＞0.05).For the LFRR,the comparison of C1,C2,M1,M2,and M3 groups showed no statistical significance(p＞0.05).4.The RFRRs of normal rats(C1),alcohol-drinking rats(C2),various stages of hepatic cirrhosis(M1,M2,and M3) infused by intravenous propofol were cpmpared.In the comparison of the five groups,the time of RFRR in M3 and M2 groups after 30,60,and 90 minutes of transfusion were delayed longer than the M1,C2,and C1 groups(p＜0.01),while the average delaying factors were(3.0,2.5),(4.2,2.8), and(5.0,3.4),respectively;the RFRR in M3 group after 60 and 90 minutes of transfusion by pump showed longer delay than that of the M2(p＜0.01),with the average delaying factors as(1.5,1.5).When comparing the five groups,the RFRR of the M3 group showed delay after 60 minutes,while the delay became longer in the following order: 90 min＞60 min＞30 min(p＜0.01),and the average delaying factors were(1.4,1.8,1.3).The RFRR of the M2 group showed delay after 90 minutes,and it became longer in the following order:90 min＞30 min (p＜0.01),with an average delay by 1.4 times.The RFRRs at 60 and 30 minutes had no statistical significance(p＞0.05).The RFRRs of the M1,C2,and C1 groups after 30,60,and 90 minutes of transfusion by pump showed no statistical significance(p＞0.05).5.The RFRRs of the compensation group and the decompensation group after 30,60,and 90 minutes of transfusion showed significant delays than that of the control group and the fibrosis group.The compensation group showed delay after 90 minutes of transfusion, while the decompensation group showed this delay as early as after 60 minutes of transfusion.Also,the decompensation group's RFRRs at 60 and 90 minutes were delayed by 1.5 times of the one in the compensation period.The decompensation group's RFRRs at 30,60, and 90 minutes of transfusion of propofol were delayed by 3 to 5 folds than that of normal group.Conclusion1.Preparation of rat hepatic cirrhosis model by synthetic analysis of four factors,including phenobarbital sodium induction,hypodermic injection of CCl₄ to induce hepatic injury,edible distillate spirit as the only drinking water,addition of edulcorator in drinking water,can significantly increase the animal survival rate and save experimental animals,as well as lower the experimental cost.The hepatic cirrhotic models provided convenience for studying the pathology,physiology, and anesthetic pharmacology of liver cirrhosis.2.As the hepatic fibrosis progressed to hepatic cirrhotic stage and the increased severity of fibrosis and cirrhosis was seen,the ED₅₀ of single-dose injection of propofol was gradually reduced by 16.4 to 32.9%and the time for recovering consciousness was also elongated by 37 to 126%.It suggested that the dosage of propofol for clinical anesthetization on patients of cirrhosis,especially for patients in decompensation period with ascites,should be reduce by 1/3,while their time for regaining consciousness would probably be delayed by more than twice of that in non-cirrhotic patients.3.As the hepatic fibrosis progressed to hepatic cirrhotic stage and the increased severity of fibrosis and cirrhosis was seen,the time for regaining consciousness within 30 minutes of continuous transfusion was not affected.However,when the transfusion was more than 30 minutes,the recovery time was elongated by 3 to 5 folds.It suggested that during the clinical anesthetization of cirrhotic patients,the transfusion time for propofol increased as the liver became more decompensated,while the recovery time was delayed by folds.