Centrilobular necrosis and a ten-fold elevation in serum alanine amino-transferase (ALT) consistently followed 2 hours of 1% halothane anaesthesia in an animal model. Conditional factors were the presence of enzyme induction and moderate hypoxia (14% oxygen), indicating an association between reductive metabolism and hepatotoxicity. Under these conditions there was at least a four-fold increase in reductive metabolites detected in the exhaled air.
In clinical studies, reductive metabolites were also detected in the exhaled air of all patients examined, even after halothane anaesthesia with 100% oxygen. The amounts of reductive metabolites were comparable in man and the model, following equivalent halothane doses. It appears that a model with a similar route and rate of halothane biotransformation to man has been identified. The lesion of halothane hepatotoxicity in this model appears to be similar to that reported in man — centrilobular hepatic necrosis.
References
1.
BarrG. A., CousinsM. J., MazzeR. T. (1974): “A comparison of the renal effects of enflurane and methoxyflurane in Fischer 344 rats”, J. Pharmacol. Exp. Ther., 188, 257–264.
2.
BrownB. R., and SipesI. G. (1977): “Commentary. Biotransformation and hepatotoxicity of halothane”, Biochem. Pharmacol, 26, 2091–2094.
3.
BunkerJ. P., and BlumenfeldC. M. (1963): “Liver necrosis after halothane anaesthesia: Cause or Coincidence?”, New Eng. J. Med., 268, 53–534.
4.
CohenE. N., TrudellJ. R. (1975): “Urinary metabolites of halothane in man”, Anesthesiology43, 392–401.
5.
CousinsM. J., and MazzeR. I. (1973): “Methoxyflurane nephrotoxicity: A study of dose-response in man”, J. Amer. Med. Ass., 225, 1611–1616.
6.
CousinsM. J., MazzeR. I., KosekJ. C., HittB. A., and LoveF. V. (1974): “The etiology of methoxyflurane nephrotoxicity”, J. Pharmacol. Exp. Ther.190, 530–541.
7.
CousinsM. J., and MazzeR. I. (1974): “Biotransformation of enflurane (Ethrane) and isoflurane (Forane)”, International Anesthesiology Clinics, 12, 111–119.
8.
CousinsM. J., GreensteinL. R. (1976): “Metabolism and renal effects of enflurane in man”, Anesthesiology, 44, 44–53.
9.
CousinsM. J., FultonA., HaynesW. D. G., and WhiteheadR. (1978): “Enflurane nephrotoxicity and pre-existing renal dysfunction”, Anaesth. Intens. Care, 6, 4.
10.
DykesM. H. M. (1977): “Is halothane hepatitis chronic active hepatitis?”, Anesthesiology, 46, 233.
11.
FrascinoJ. A. (1972): “Effect of inorganic fluoride on the renal concentrating mechanism: possible nephrotoxicity in man”, J. Lab. Clin. Med., 79, 192–203.
12.
HittB. A., MazzeR. I., CousinsM. J. (1974): “Metabolism of isoflurane in Fischer 344 rats and man”, Anesthesiology, 40, 62–67.
13.
JoshiP. H., and ConnH. O. (1974): “The syndrome of methoxyflurane associated hepatitis”, Ann. Intern. Med., 80, 395.
14.
JohnstonR. R., CromwellT. H., EgerE. I. (1973): “The toxicity of fluroxene in animals and man”, Anesthesiology, 38, 313.
15.
MazzeR. I., CousinsM. J., and KosekJ. C. (1972): “Dose-related nephrotoxicity due to methoxyflurane anaesthesia in the rat: A biochemical and pathological correlation”, Anesthesiology, 36, 571–587.
16.
MazzeR. I., CousinsM. J., and KosekJ. C. (1973): “Strain differences in metabolism and susceptibility to the nephrotoxic effects of methoxvflurane in rats”, J. Pharmacol. Exp. Ther., 184, 481–488.
17.
MukaiS., MorioM. (19771): “Volatile metabolites of halothane in the rabbit”,Anesthesiology, 47, 248–251.
18.
National Halothane Study (1969): A study of the possible association between halothane anaesthesia and post-operative necrosis. ed. BunkerJ. P., ForrestW. H., MostellerF., and VandamL. D.Washington: U.S. Government Printing Office.
19.
PoserS., PoserW., and Muller-OerlinghausenB. (1974): “Use of bromide electrodes for rapid screening of elevated bromide concentrations in biological fluids”, Z. Klin. Chem. Klin. Biochem., 12, 350–351.
20.
PriceC. D., GibbsA. K., and Jones-WilliamsW. (1977): “Evaluation of the macrophage migration inhibition test in halothane induced hepatitis (halothane MIF test)”, Journal of Clinical Pathology, 30, 96.
21.
RaventosJ. (1956): “The action of fluothane — a new volatile anaesthetic”, Brit. J. Pharmacol., 11, 394–410.
22.
ReynoldsE. S., and MoslenM. T. (1977): “Halothane Hepatotoxicity: Enhancement of polychlorinated biphenyl pretreatment”, Anesthesiology, 47, 19–27.
23.
SchollerK. L. (1970): “Modification of the effects of chloroform on the rat liver”, Brit. J. Anaesth., 42, 603.
24.
SchwartzkopffT., SchwartzkopffG., PieulO., and KewitzH. (1977): Mechanism of the enrichment of phosphatidylcholine in liver accompanying enzyme induction by phenobarbital”, Naunyn-Schmiedeberg's Arch. Pharmacol., 297, 275–281.
25.
SharpJ. H., TrudellJ. R., and CohenE. N. (1978): “Volatile metabolites and decomposition products of halothane in man”,Anesthesiology, In Press.
26.
SimpsonB. R., StruninL., and WaltonB. (1973): “Halothane hepatitis — fact or fallacy”, Proc. Roy. Soc. Med., 66, 56–63.
27.
StoykaW. W., and HavasiG. (1977): “The effects of repeated 14C halothane exposure in mice.Canad. Anaesth. Soc. J., 24, 243.
28.
TreyC., LipworthL., ChalmersT. C., DavidsonC. S., GottliebL. S., PopperH., and SaundersS. J. (1968): “Fulminant Hepatic Failure: Presumable contribution of halothane”, New Eng. J. Med., 279, 798–801.
29.
UzunalimogluB., YardleyJ. H., and BoitnottJ. K. (1970): “The Liver in mild halothane hepatitis: Light and Electron Microscopic Findings with special reference to the mononuclear cell infiltrate”.Amer. J. Path., 61, 457–478.
30.
Van DykeR. A., and GandolfiA. J. (1976): Anaerobic release of fluoride from halothane: Relationship to the binding of halothane metabolites to hepatic cellular constituents”, Drug Metab. Disp., 4, 40–44.
31.
VirtueR. W., PayneK. W., CabarraL. J., GordonG. S., and RemberR. R. (1958): “Observations during experimental and clinical use of ‘fluothane’”, Anesthesiology, 19, 478–487.
32.
WaltonB., DrumondeD. C., WilliamsC. (1973): “Lymphocyte transformation: Absence of increased response in alleged halothane jaundice”, J. Amer. Med. Ass., 225, 494.
WidgerL. A., GandolfiA. J., and Van DykeR. A. (1976): “Hypoxia and halothane metabolism in vivo: Release of inorganic fluoride and halothane metabolite binding to cellular constituents”, Anesthesiology.44, 197–201.
35.
WillsE. J., and WaltonB. (1978): “A Morphologic study of unexplained hepatitis following halothane anesthesia”, Amer. J. Pathol., 91, 11–32.
