Starzl, Thomas E

PubMed

Starzl, TE

Name not available

Transplantation of whole human organs

D-Scholarship@Pitt

687 Effects of Hepatectomy on the Disappearance Rate of Lidocaine from Blood in Man and Dog J. ANTONIO ALDRETE, M.D., M.Sc.*t JOHN HOMATAS, M.D.* R. NICHOL BOYES, Ph.D.:!: THOMAS E. STARZl, Ph.D., M.D.* D EPENDING on their chemical configura-tion, local anesthetic agents are in-activated chiefly either in the plasma or in the liver. Lidocaine hydrochloride, an anes-thetic with an amide structure, has been thought to be primarily metabolized in the liver with little or no extrahepatic degrada-tion. 1-3 This contention was tested in he-patectomized dogs with nearly normal car-diodynamics and, during the anhepatic pe-riod, in 2 patients undergoing liver trans-plantation. MATERIALS AND METHODS Anhepatic Dogs - Five mongrel dogs, weighing between 14 and 17 kg., were anes-thetized with 30 mg./kg. of pentobarbital sodium injected intravenously. The femoral vein and artery were cannulated. After a 5 m!. control arterial blood sample was ob-tained, a 2 percent solution of lidocaine Hel, 2.5 mg./kg. intravenously, was administered during a 30-second period. Arterial blood samples were drawn 2, 5, 10, 15, 30, 60, 90, and 120 minutes later. One hour after pro-curement of the last sample, portacaval shunt and total hepatectomy were per-formed, leaving the inferior vena cava in-tact. 4 This was followed by control sam-pling, lidocaine injection, and the procure-ment of blood samples as before. *Departments of Anesthesiology and Surgery, University of Colorado Medical Center and Veterans Ad-ministration Hospital, Denver, Colorado 80220. :J;Astra Pharmaceutical Products, Inc., Worcester, Massachusetts. ,Current address: Department of Anesthesiology, University of Miami Medical School, Miami, Florida 33152 Reprinted from Anesthesia and Analgesia - Current Researches, Sept.-Oct., 1970 688 ANESTHESIA AND ANALGESIA ••• Current Researches VOL. 49, No.5, SEPT.-OCT., 1970 Since hepatectomy is known to be accom-panied by hypoglycemia and metabolic aci-dosis, Ii arterial blood gases and pH and blood glucose were measured every 15 min-utes. A solution of 50 percent glucose was used to maintain the glucose level between 130 and 175 mg./l00 ml. Arterial blood pressure and heart rate were continuously monitored. After hepatectomy two animals (dogs 11 and 12) also received an infusion of 5 percent glucose in 0.9 percent saline solution at a rate of 20 ml./kg./hr., whereas dogs 13, 14, and 15 were not given the extra infusion. Anhepatic Patients - Two adult patients undergoing orthotopic liver transplantation, as described by Starzl, 6 were studied while under anesthesia. Thiopental sodium and succinylcholine were administered to induce sleep and facilitate orotracheal intubation. Thereafter, fluroxene-nitrous oxide-oxygen was given by inhalation in a semiclosed-circle system. After obtaining a control ar-terial sample, lidocaine HCl, 2.5 mg./kg., was given intravenously, and other arterial aliquots were obtained at the same intervals as described in the dog experiments. During this time, the diseased host liver was being dissected preparatory to removal but the blood supply was intact. At least 3 hours after lidocaine injection, total host hepatectomy was performed, at which time a second injection of lidocaine was given and subsequent samples obtained at the same time intervals as earlier. The homograft was revascularized 50 minutes after the local anesthetic agent had been injected. However, the schedule of sampling was continued as in the preanhepatic stud-ies, except in patient A, from whom an extra sample was obtained 240 minutes after lido-caine injection. Blood and solutions of glucose and sodium bicarbonate were infused during these oper-ations to replace blood loss, prevent hypo-glycemia, and correct metabolic acidosis during the anhepatic phase. The lidocaine level in the blood was determined according to the technic described by Keenaghan,7 using a dual-column Aerograph Model 1520 gas chromatograph, which is sensitive to concentrations as low as 0.5 mcg./ml. of the local anesthetic in blood. RESULTS Animal Studies - Blood levels of lido-caine observed in intact anesthetized dogs declined similarly in every instance, being 0.7 mcg./ml. or less at 60 minutes and 0.5 mcg./ml. or less at 2 hours after injection. After hepatectomy, the 2 dogs that re-ceived dilute glucose in the intravenous saline solution had lidocaine values between 3.3 and 4.2 mcg. in the immediate postin-jection period. At 2 hours, these remained above 1.2 mcg./ml. (fig. 1). In contrast, ~20 do 18 <.> ~ 16 ;:;l14 ~ 12 8 10 0 ...J 8 III .... 6 ~ 4 0 0 0 2 ::; 0 e -.!: iJ ~:::i H 0 Anhepatlc 0--0 Dog If --.-. Dog 12. 60 120 0 60 120 ISO 240 TIME IN MINUTES FIG. 1. Blood levels observed after intravenous injection of lidocaine (2.5 mg.jkg.) into 2 dogs under control conditions and after hepatectomy. A solution of 5 percent glucose in 0.9 percent saline was infused at a rate of 20 ml.jkg.jhr. * J. ANTONIO ALDRETE, M.D. is a 1960 graduate of the National University of Mexico, College of Medicine, in his native Mexico City. A residency in anesthesiology at University Hospitals, Cleveland, Ohio, followed an intern-ship and two years of surgical training in the United States. Prior to his current position as Associate Professor, University of Miami School of Medicine, Department of Anesthesiology and a member of the Staff of the Jackson Memorial Hospital, Miami, he was Associate Professor of Anesthesiology at the University of Colorado Medical Center and Chief Anesthesiologist, Veter-ans Administration Hospital in Denver, Colorado. Hepatectomy and Lidocaine Metabolism ... Aldrete, et a1 689 ~20 0.18 ~ 16 ct 14 ~ 12 8 10 ~ 8 III 6 z ~ 4 e 2 Anhepatl~ • 0--0 Do; 13 ..... 00.14 ....... Dog 1$ ~ oLl~~~~~1-~-=~=-~~~ o 60 120 0 60 120 180 240 TIME IN MINUTES FIG. 2. Changes of blood levels observed after intravenous injection of 2.5 mg.jkg. into 3 dogs before and after hepatectomy. The glucose demand in these animals was supplied with a concentrated solution of dextrose (50 percent). the 3 animals that received concentrated glucose alone and were not, therefore, he-modiluted, had initial lidocaine levels rang-ing from 7.9 to 18.4 mcg./ml. rapidly declin-ing to levels between 3 and 5 mcg./ml. (fig. 2). However, the lidocaine concentrations remained above 1 mcg./mi. at 120 minutes after injection and even at 180 minutes in the one sample (figs. 1 and 2). Hepatectomized Patients-Preoperatively, both patients had severe hepatic insuffi-ciency, recipient A owing to chronic rejec-~ go 18 ..5 16 . ~ 14 il ~ 12 u .... - H ....... Patient A 0--0 Patient B O~~~~~~~~~~~~~ o 60 120 0 60 120 180 240 TIME IN MINUTES FIG. 3. Comparison of the rate of lidocaine dis-appearance from blood after intravenous admin-istration of 2.5 mg.jkg. in 2 patients with terminal cirrhosis undergoing orthotopic transplantation. Blood samples in the second series were obtained during the anhepatic stage, which lasted 50 minutes in both cases. Thereafter, decline of lidocaine levels is presumably due to restoration of normal function by the homograft. tion of a previously transplanted liver and recipient B as a result of long-standing cir-rhosis with repeated hematemesis. Two minutes after intravenous injection of lido-caine, the blood levels were 6.6 and 5 meg./ mi., respectively, and fell to 1.5 and 1.7 mcg./mi. at 1 hour, and to 1.1 and 1.4 mcg./mi. at 2 hours (fig. 3). After revascu-larization, a downward trend of the arterial blood levels was apparent, to a degree that 4 hours after injection, the concentration of lidocaine was only 0.4 mcg./mi. Neither dogs nor patients showed toxic manifestations from the lidocaine injections. DISCUSSION After entry into the blood stream, the disposition of a number of local anesthetic agents such as procaine occurs by prompt degradation subserved by the enzyme pseu-docholinesterase. 8 ,9 Disappearance of lido-caine Hel is less dependent upon metabolic degradation and more upon its high lipid solubility permitting rapid distribution in tissue. l However, the ultimate metabolism of lidocaine has been said to take place in the liver by microsomal enzymes with re-duced Nicotinamide-adenine dinucleotide phosphate and oxygen,l,:J,lO undergoing ei-ther oxidation first, or hydrolysis followed by oxidation prior to sulfate conjugation. l1 A prediction, based on the foregoing facts, that the early phase of lidocaine disappear-ance would be less affected by the liverless state than the late phase, proved valid both in dogs and in man. The canine experiments were the most decisive, since transfusions were not ordinarily required during hepa-tectomy and because an excellent cardiody-namic state could be maintained at all times. With these conditions, most of the lidocaine disappeared from the blood in the first hour, although at a somewhat slower rate than normal. Thereafter, the fall in blood levels either declined very slowly or not at all, suggesting that equilibration had occur-red. Presumably, further elimination would then depend upon other routes (kidney or gastrointestinal tract). If extrahepatic de-gradation occurred at all, it must have been a t an imperceptible pace. Despite the seriously diseased livers in the 2 human subjects, early disappearance of lidocaine was rapid, presumably because of prompt tissue distribution. In the ensuing 40 minutes, blood concentrations decreased 690 ANESTHESIA AND ANALGESIA ... Current Researches VOL. 49, No.5, SEPT.-OCT., 1970 slowly but steadily. During the anhepatic state, the tissue distribution phase was also noted but the subsequent decline of lidocaine concentration was not so rapid, the levels remaining above 2.5 mcg./ml. even 45 min-utes after the new liver had been revascu-larized. Ultimately, the homograft appar-ently assumed the burden of lidocaine degra-dation, since by 4 hours after revasculariza-tion, the concentration was only 0.4 mcg./ ml. Although not of practical significance, lidocaine clearance from blood could be interpreted as a sign of acceptable liver homograft function. In this investigation, it was necessary to give two doses of the drug tested. A criticism of the protocol might be that the adminis-tered agent could accumulate in the tissues and contribute to an artificially high value after the second injection.12 Such an ex-planation would not seem to account for the results in the present study, first because the doses were small; second, because lidocaine disappeared almost completely before the second injection in the presence of the liver; and finally, because, in the human experi-ence, the restoration of liver function with the homograft was attended by a secondary late acceleration of lidocaine disappearance. SUMMARY The disappearance from blood of intra-venously injected lidocaine HCI was studied in 5 dogs before and after total hepatectomy. In the intact state, the lidocaine concentra-tions in the blood fell rapidly at first and more slowly in the late phase. After hepa-tectomy, the disappearance rates were re-duced both early and late after injection. The findings were consistent with the hy-pothesis that the liver is responsible for the ultimate disposition of lidocaine. Analogous experiments were performed in 2 patients with terminal cirrhosis under-going orthotopic liver transplantation. The results indicated that the conclusions from the animal experiments pertained as well in humans. Generic and Trade Names of Drugs Lidocaine (HCI) -Xylocaine Procaine CHCI)-Novocain Pentobarbital sodium-Nembutal Sodium thiopental-Pentothal Sodium Succinylcholine-Anectine, Quelicine Fluoroxene-Fluoromar Sodium bicarbonate REFERENCES 1. Sung, C. and Truant, P.: The Physiological Disposition of Lidocaine and Its Comparison m Some Respects with Procame. J. Pharmacol. Exp. Ther. 112:432-443 (August) 1954. 2. Geddes, I. C.: La methode de detoxication de la Xylocame au moyen de l'isotope C'". Anesth. Analg. (Paris) 15:908-915 (May) 1958. 3. Hollunger, G.: On the Metabolism of Lido-caine: II. The Biotransformation of Lidocaine. Acta Pharmacol. 17:365-373 (September) 1960. 4. Starzl, T. E., Bernhard, V. M., Cortes, N. and Benvenuto, R.: A Technique for one-Stage Hepatectomy m Dogs. Surgery 46:880-886 (Novem-ber) 1959. 5. Aldrete, J. A.: Anesthesia and Intraoperative Care. In: Starzl, T. E.: Experience m Hepatic Transplantation. Philadelphia, W. B. Saunders Company, 1969, pp. 81-111. 6. Starzl, T. E.: Donor Hepatectomy. In: Starzl, T. E.: Experience m Hepatic Transplantation. Phila-delphia, W. B. Saunders Company, 1969, pp. 48-58. 7. Keenaghan, J. B.: The Determination of Lidocame and Prilocaine in Whole Blood by Gas Chromatography. Anesthesiology 29:110-112 (Janu-ary-February) 1968. 8. Kalow, W.: Hydrolysis of Local Anesthetics by Human Serum Cholmesterase. J. Pharmacol. Exp. Ther. 104:122-123 (September) 1952. 9. Foldes, F. F., Davis, D. L., Shanor, S. and Van Hees, G.: Hydrolysis of Ester-Type Local Anesthetics and Their Halogenated Analogs by Purified Plasma Cholmesterase. J. Amer. Chem. Soc. 77:5149-5151 (October 5) 1955. 10. Hollunger, G.: On the Metabolism of Lido-came: I. The Properties of the Enzyme System Responsible for the Oxidative Metabolism of Lido-came. Acta Pharmacol. 17:356-364 (August) 1960. 11. McMahon, F. G. and Woods, L. A.: Further Studies on the Metabolism of Lidocaine (Xylo-caine) in the Dog. J. Pharmacol. Exp. Ther. 103:354 (December) 1951. 12. Bromage, P. R. and Robson, J. G.: Concen-trations of Lignocaine in the Blood After Intra-venous, Intramuscular, Epidural and Endotracheal Administration. Anaesthesia 16:461-478 (October) 1961. 