Mechanism Research On The Increased Sensitivity To Intravenous Anesthetic Propofol In Patients With Obstructive Jaundice

BackgroundObstructive jaundice,a common clinical sign of pancreatic cancer and hilar cholangiocarcinoma in the department of hepatobiliary surgery,mainly results from mechanical obstruction of intrahepatic or extrahepatic bile duct.To reach the same level of sedation,the quantity of anesthetics in cholestatic patients is lower than patients without it,which suggests these patients get a increased sensitivity to the anesthetics.Our study had shown that the MAC-awake of desflurane was significantly reduced in patients with obstructive jaundice and MAC-Awake correlated inversely with the concentratibn of serum total bilirubin in this population.Subsequently,patients with obstructive jaundice also have increased sensitivity to etomidate.Similarly,a significant negative correlatibn between serum total bilirubin and etomidate requirement was found.Patients with obstructive jaundice suffer from hyperbilirubinemia.Unbound bilirubin can enter into the central nervous system(CNS)freely through the btood-brain barrier(BBB).Unconjugated bilirubin(UCB),at slightly elevated unbound concentrations,is toxic to astrocytes and neurons,damaging mitochondria(causing impaired energy metabolism and apoptosis)and plasma membranes(causing oxidative damage and disrupting transport of neurotransmitters),and induce a variety of cellular and molecular events that result in neurotoxicity.Propofol is the most important intravenous general anesthetic in current clinical use.It acts by potentiating GABAA(γ-aminobutyric acid type A)receptors,while GABAA receptors are widely distributed in the central nervous system.Therefore,we hypothesized that it is the bilirubin which elevated abnormally in obstructive jaundice alter the sensitivity to propofolIn present study,we investigate the influence and mechanism of obstructive jaundice on the sensitivity to propofol from clinical trials,animal and electrophysiological experiments three leveLMethods1.Clinical trials:Thirty-five patients were randomly divided into the obstructive jaundice group and control group based on serum bilirubin values.All patients were ASA physical status Ⅰ to Ⅱ.The study was designed to determine propofol requirement with loss of eyelash reflect as the end point.Propofol was delivered at a rate of 0.3mg/kg/min by a Graseby 3500 syringe pump until loss ofeyelash reflect.Every 20 s,we determine whether patients’ eyelash reflect is tost or not.We test the hypothesis that patients with obstructive jaundice have an altered sensitivity to propofol by comparing the propofol requirement of two groups.Multivariable linear regression analysis was used to determine whether serum total bilirubin,total bile acid,serum albumin,AST and ALT correlated significantly with propofol requirement.2.Animal experiment:Sprague-Dawley rats were randomly assigned to five groups:Control group,Sham group,BDL-7 group,BDL-14 group and BDL-21 group.Obstructive jaundice rat model was established by common bile duct ligation.A constant infusion rate of propofol was administered and the time required to induce toss of righting reflex was measured.Biochemical changes in blood and cerebrospinal fluid(CSF)were measured.Next,intralateroventricular micro injection was used to study the effect of bilirubin in cerebrospinal fluid on the sensitivity to propofoL3.Electrophysiological experiment:Acute brain slices of rats were used in our study.A whole-cell voltage clamp was used to study the effect of bilirubin on GABA-evoked currents in cortex pyramidal neurons.Results1.The propofol requirement in the obstructive jaundice group was lower than that in the control group(p=0.001).In addition,a significant negative correlation between serum total bilirubin and propofol requirement was found(R2=0.550,p<0.001).2.In this study,we found that common bile duct ligation rats significantly enhanced the ability of propofol induced responsiveness to external stimuli.In addition,intralateroventricular bilirubin microinjection significantly enhances the ability of propofol to induce a loss of righting reflex,showing that bilirubin in cerebrospinal fluid is an important factor in the increased sensitivity to propofol anesthesia.3.By the third part of electrophysiology experiment,we found 3μM bilirubin reduced the attenuation of channel currents and increase the extent of channel currents in 10μM.Proportion of neurons with enhanced currents after bilirubin infusion is increased.ConclusionPatients with obstructive jaundice have an increased sensitivity to intravenous anesthetic propofol and bilirubin play an inportant role in the increase of anesthetic sensitivity.Bilirubin may enhance sensitivity of propofol anesthesia by reducing the attenuation of channel currents of GABAA receptors and increase the extent of channel currents.