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.*

EPENDING on their chemical configura­ thetized with 30 mg./kg. of pentobarbital D tion, local anesthetic agents are in­ sodium injected intravenously. The femoral activated chiefly either in the plasma or in vein and artery were cannulated. After a the liver. Lidocaine hydrochloride, an anes­ 5 m!. control arterial blood sample was ob­ thetic with an amide structure, has been tained, a 2 percent solution of lidocaine Hel, thought to be primarily metabolized in the 2.5 mg./kg. intravenously, was administered liver with little or no extrahepatic degrada­ during a 30-second period. Arterial blood tion.1-3 This contention was tested in he­ patectomized dogs with nearly normal car­ samples were drawn 2, 5, 10, 15, 30, 60, 90, diodynamics and, during the anhepatic pe­ and 120 minutes later. One hour after pro­ riod, in 2 patients undergoing liver trans­ curement of the last sample, portacaval plantation. shunt and total hepatectomy were per­ formed, leaving the inferior vena cava in­ MATERIALS AND METHODS tact.4 This was followed by control sam­ Anhepatic Dogs - Five mongrel dogs, pling, lidocaine injection, and the procure­ weighing between 14 and 17 kg., were anes- 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 Blood and solutions of glucose and sodium panied by hypoglycemia and metabolic aci­ bicarbonate were infused during these oper­ dosis, Ii arterial blood gases and pH and ations to replace blood loss, prevent hypo­ blood glucose were measured every 15 min­ glycemia, and correct metabolic acidosis utes. A solution of 50 percent glucose was during the anhepatic phase. The lidocaine used to maintain the glucose level between level in the blood was determined according 130 and 175 mg./l00 ml. Arterial blood to the technic described by Keenaghan,7 pressure and heart rate were continuously using a dual-column Aerograph Model 1520 monitored. After hepatectomy two animals gas chromatograph, which is sensitive to (dogs 11 and 12) also received an infusion concentrations as low as 0.5 mcg./ml. of of 5 percent glucose in 0.9 percent saline the local anesthetic in blood. solution at a rate of 20 ml./kg./hr., whereas dogs 13, 14, and 15 were not given the extra RESULTS infusion. Animal Studies - Blood levels of lido­ caine observed in intact anesthetized dogs Anhepatic Patients - Two adult patients declined similarly in every instance, being undergoing orthotopic liver transplantation, 0.7 mcg./ml. or less at 60 minutes and 0.5 as described by Starzl,6 were studied while mcg./ml. or less at 2 hours after injection. under anesthesia. Thiopental sodium and succinylcholine were administered to induce After hepatectomy, the 2 dogs that re­ sleep and facilitate orotracheal intubation. ceived dilute glucose in the intravenous Thereafter, fluroxene-nitrous oxide-oxygen saline solution had lidocaine values between was given by inhalation in a semiclosed­ 3.3 and 4.2 mcg. in the immediate postin­ circle system. After obtaining a control ar­ jection period. At 2 hours, these remained terial sample, lidocaine HCl, 2.5 mg./kg., above 1.2 mcg./ml. (fig. 1). In contrast, was given intravenously, and other arterial aliquots were obtained at the same intervals ~20 as described in the dog experiments. During Anhepatlc do 18 this time, the diseased host liver was being <.> dissected preparatory to removal but the ~ 16 ;:;l14 blood supply was intact. 0--0 Dog If e ~ 12 -.!: --.-. Dog 12. At least 3 hours after lidocaine injection, 8 10 iJ 0 ~:::i total host hepatectomy was performed, at ...J III 8 H which time a second injection of lidocaine .... 6 was given and subsequent samples obtained 0~ 4 0 at the same time intervals as earlier. The 0 2 homograft was revascularized 50 minutes ::; 0 after the local anesthetic agent had been 0 60 120 0 60 120 ISO 240 injected. However, the schedule of sampling TIME IN MINUTES was continued as in the preanhepatic stud­ FIG. 1. Blood levels observed after intravenous ies, except in patient A, from whom an extra injection of lidocaine (2.5 mg.jkg.) into 2 dogs under control conditions and after hepatectomy. A sample was obtained 240 minutes after lido­ solution of 5 percent glucose in 0.9 percent saline caine injection. 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

Anhepatl~ tion of a previously transplanted liver and ~20 recipient B as a result of long-standing cir­ 0.18 rhosis with repeated hematemesis. Two ~ 16 0--0 Do; 13 minutes after intravenous injection of lido­ ct 14 ..... 00.14 caine, the blood levels were 6.6 and 5 meg./ ...... Dog 1$ ~ 12 mi., respectively, and fell to 1.5 and 1.7 8 10 mcg./mi. at 1 hour, and to 1.1 and 1.4 ~ 8 mcg./mi. at 2 hours (fig. 3). After revascu­ zIII 6 larization, a downward trend of the arterial ~ 4 • blood levels was apparent, to a degree that e 2 4 hours after injection, the concentration of ~ oLl~~~~~1-~-=~=-~~~ lidocaine was only 0.4 mcg./mi. o 60 120 0 60 120 180 240 TIME IN MINUTES Neither dogs nor patients showed toxic FIG. 2. Changes of blood levels observed after manifestations from the lidocaine injections. 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 DISCUSSION solution of dextrose (50 percent). 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 the 3 animals that received concentrated docholinesterase.8 ,9 Disappearance of lido­ glucose alone and were not, therefore, he­ caine Hel is less dependent upon metabolic modiluted, had initial lidocaine levels rang­ degradation and more upon its high lipid ing from 7.9 to 18.4 mcg./ml. rapidly declin­ solubility permitting rapid distribution in ing to levels between 3 and 5 mcg./ml. (fig. tissue. l However, the ultimate metabolism 2). However, the lidocaine concentrations of lidocaine has been said to take place in remained above 1 mcg./mi. at 120 minutes the liver by microsomal enzymes with re­ after injection and even at 180 minutes in duced Nicotinamide-adenine dinucleotide the one sample (figs. 1 and 2). phosphate and oxygen,l,:J,lO undergoing ei­ ther oxidation first, or hydrolysis followed Hepatectomized Patients-Preoperatively, by oxidation prior to sulfate conjugation.l1 both patients had severe hepatic insuffi­ ciency, recipient A owing to chronic rejec- 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 ~ go 18 were not ordinarily required during hepa­ ..5 16 tectomy and because an excellent cardiody­ . namic state could be maintained at all times. ~ 14 il ...... Patient A ~ 12 u .... With these conditions, most of the lidocaine - H 0--0 Patient B 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 O~~~~~~~~~~~~~ then depend upon other routes (kidney or o 60 120 0 60 120 180 240 TIME IN MINUTES gastrointestinal tract). If extrahepatic de­ gradation occurred at all, it must have been FIG. 3. Comparison of the rate of lidocaine dis­ a t an imperceptible pace. appearance from blood after intravenous admin­ istration of 2.5 mg.jkg. in 2 patients with terminal cirrhosis undergoing orthotopic transplantation. Despite the seriously diseased livers in Blood samples in the second series were obtained the 2 human subjects, early disappearance during the anhepatic stage, which lasted 50 minutes of lidocaine was rapid, presumably because in both cases. Thereafter, decline of lidocaine levels is presumably due to restoration of normal function of prompt tissue distribution. In the ensuing by the homograft. 40 minutes, blood concentrations decreased 690 ANESTHESIA AND ANALGESIA ... Current Researches VOL. 49, No.5, SEPT.-OCT., 1970 slowly but steadily. During the anhepatic Generic and Trade Names of Drugs state, the tissue distribution phase was also Lidocaine (HCI) -Xylocaine noted but the subsequent decline of lidocaine Procaine CHCI)-Novocain concentration was not so rapid, the levels Pentobarbital sodium-Nembutal remaining above 2.5 mcg./ml. even 45 min­ Sodium thiopental-Pentothal Sodium utes after the new liver had been revascu­ Succinylcholine-Anectine, Quelicine larized. Ultimately, the homograft appar­ Fluoroxene-Fluoromar ently assumed the burden of lidocaine degra­ Sodium bicarbonate dation, since by 4 hours after revasculariza­ tion, the concentration was only 0.4 mcg./ REFERENCES ml. Although not of practical significance, 1. Sung, C. and Truant, P.: The Physiological lidocaine clearance from blood could be Disposition of Lidocaine and Its Comparison m interpreted as a sign of acceptable liver Some Respects with Procame. J. Pharmacol. Exp. homograft function. Ther. 112:432-443 (August) 1954. 2. Geddes, I. C.: La methode de detoxication de In this investigation, it was necessary to la Xylocame au moyen de l'isotope C'". Anesth. give two doses of the drug tested. A criticism Analg. (Paris) 15:908-915 (May) 1958. 3. Hollunger, G.: On the Metabolism of Lido­ of the protocol might be that the adminis­ caine: II. The Biotransformation of Lidocaine. tered agent could accumulate in the tissues Acta Pharmacol. 17:365-373 (September) 1960. and contribute to an artificially high value 4. Starzl, T. E., Bernhard, V. M., Cortes, N. after the second injection.12 Such an ex­ and Benvenuto, R.: A Technique for one-Stage planation would not seem to account for the Hepatectomy m Dogs. Surgery 46:880-886 (Novem­ results in the present study, first because the ber) 1959. 5. Aldrete, J. A.: Anesthesia and Intraoperative doses were small; second, because lidocaine Care. In: Starzl, T. E.: Experience m Hepatic disappeared almost completely before the Transplantation. Philadelphia, W. B. Saunders second injection in the presence of the liver; Company, 1969, pp. 81-111. and finally, because, in the human experi­ 6. Starzl, T. E.: Donor Hepatectomy. In: Starzl, ence, the restoration of liver function with T. E.: Experience m Hepatic Transplantation. Phila­ the homograft was attended by a secondary delphia, W. B. Saunders Company, 1969, pp. 48-58. 7. Keenaghan, J. B.: The Determination of late acceleration of lidocaine disappearance. Lidocame and Prilocaine in Whole Blood by Gas Chromatography. Anesthesiology 29:110-112 (Janu­ SUMMARY ary-February) 1968. The disappearance from blood of intra­ 8. Kalow, W.: Hydrolysis of Local Anesthetics venously injected lidocaine HCI was studied by Human Serum Cholmesterase. J. Pharmacol. in 5 dogs before and after total hepatectomy. Exp. Ther. 104:122-123 (September) 1952. In the intact state, the lidocaine concentra­ 9. Foldes, F. F., Davis, D. L., Shanor, S. and Van Hees, G.: Hydrolysis of Ester-Type Local tions in the blood fell rapidly at first and Anesthetics and Their Halogenated Analogs by more slowly in the late phase. After hepa­ Purified Plasma Cholmesterase. J. Amer. Chem. tectomy, the disappearance rates were re­ Soc. 77:5149-5151 (October 5) 1955. duced both early and late after injection. 10. Hollunger, G.: On the Metabolism of Lido­ came: I. The Properties of the Enzyme System The findings were consistent with the hy­ Responsible for the Oxidative Metabolism of Lido­ pothesis that the liver is responsible for came. Acta Pharmacol. 17:356-364 (August) 1960. the ultimate disposition of lidocaine. 11. McMahon, F. G. and Woods, L. A.: Further Studies on the Metabolism of Lidocaine (Xylo­ Analogous experiments were performed caine) in the Dog. J. Pharmacol. Exp. Ther. in 2 patients with terminal cirrhosis under­ 103:354 (December) 1951. going orthotopic liver transplantation. The 12. Bromage, P. R. and Robson, J. G.: Concen­ results indicated that the conclusions from trations of Lignocaine in the Blood After Intra­ the animal experiments pertained as well venous, Intramuscular, Epidural and Endotracheal Administration. Anaesthesia 16:461-478 (October) in humans. 1961.