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EXPERIENTIA 33/10

E l e v a t i o n of s e r u m x a n t h i n e o x i d a s e a c t i v i t y f o l l o w i n g h a l o t h a n e a n e s t h e s i a i n m a n Sh. Giler, Y. Eshel, J. P i n k h a s , E. V e n t u r a , E. L e v y , I. Urca, O. Sperling a n d A. de Vries

Department of Surgery B, Department o/ Medicine D, Department o/ Anesthesiology and the Rogo]f-Wellcome Medical Research Institute, Tel-Aviv University Medical School, Beilinson Medical Center, Petah-Tikva (Israel), 21 February 1977 Summary. H a l o t h a n e , b u t n o t m e t h o x y f l u r a n e , w a s f o u n d to cause specific h e p a t o c e l l u l a r d a m a g e , t h e h e p a t o t o x i c i t y b e i n g p r o m p t b u t t r a n s i e n t . T h e h e p a t o t o x i c i t y was d e m o n s t r a t e d b y t h e e l e v a t i o n in t h e s e r u m a c t i v i t y of x a n t h i n e oxidase, a h i g h l y s e n s i t i v e m a r k e r for a c u t e liver d a m a g e . H a l o t h a n e a n d m e t h o x y f l u r a n e are c o m m o n l y e m p l o y e d a n e s t h e t i c agents. Since t h e i r i n t r o d u c t i o n , c o n t r a d i c t o r y reports have been published concerning their hepatotoxic i t y 1-3. Massive h e p a t i c necrosis r a r e l y occurs following h a l o t h a n e 2-~, a n d m e t h o x y f l u r a n e anesthesia1, 5, b u t w h e t h e r t h e s e c o m p o u n d s h a v e a m o r e c o m m o n specific, a l t h o u g h mild, h e p a t o t o x i c effect is a m a t t e r of d i s p u t e . To solve t h i s q u e s t i o n , v a r i o u s m a r k e r s for t h e d e t e c t i o n of liver d a m a g e h a v e b e e n used. M o s t i n v e s t i g a t o r s s t u d i e d t h e a c t i v i t y in s e r u m of h e p a t o c e l l u l a r e n z y m e s , such as t h e t r a n s a m i n a s e s , S G O T a n d S G P T , or o t h e r p a r a m e t e r s of liver f u n c t i o n , s u c h as s e r u m b i l i r u b i n a n d p l a s m a p r o t h r o m b i n t i m e e-12. W h e r e a s in s o m e of t h e s t u d i e s n o hep a t o t o x i c i t y could b e d e m o n s t r a t e d following h a l o t h a n e a n d m e t h o x y f l u r a n e a n e s t h e s i a 1.-1., in o t h e r s e v i d e n c e of h e p a t o t o x i c i t y w a s i n d e e d f o u n d a n d was s h o w n t o b e of similar s, zs, 16 or e v e n g r e a t e r m a g n i t u d e t h a n t h a t c a u s e d b y o t h e r a n e s t h e t i c agents*, ?, 8-1% X a n t h i n e o x i d a s e act i v i t y in m a n is c o n f i n e d m a i n l y t o t h e liver tissue iv. S i g n i f i c a n t e n z y m e a c t i v i t y h a s also b e e n d e m o n s t r a t e d i n j e j u n a l m u c o s a a n d in c o l o s t r u m ls-2~ H o w e v e r , exp e r i m e n t a l s t u d i e s in t h e c a t h a v e d e m o n s t r a t e d t h a t i s c h e m i a of t h e s m a l l i n t e s t i n e did n o t i n c r e a s e s e r u m x a n t h i n e o x i d a s e (SXO) a c t i v i t y , w h e r e a s liver i n j u r y r e s u l t e d in r a p i d a n d r e m a r k a b l e rise in S X O a c t i v i t y sl. Several s t u d i e s h a v e e s t a b l i s h e d t h a t S X O a c t i v i t y o r i g i n a t e s a l m o s t e x c l u s i v e l y f r o m t h e liverZZ, 22, its release t o t h e s e r u m b e i n g h i g h l y sensitive t o h e p a t o c e l l u l a r d a m a g e 2 , , 24. E m p l o y i n g S X O as a m a r k e r for h e p a t o cellular d a m a g e , we could d e m o n s t r a t e in t h e r a t t h a t h a l o t h a n e h a s a h e p a t o t o x i c effect s6 w h i c h was n o t det e c t a b l e b y t h e m o r e c o m m o n l y used e n z y m a t i c m a r k e r SGOT. I n t h e p r e s e n t s t u d y , we utilized t h e specific a n d

0x

1

S.G. Elkington, J. A. Goffinet and H. O. Conn, Ann. intern. Med. 69, 1229 (1968). S. Sherlock, Gut 12, 324 (1971). F.M.T. Colaley and R. A. Van Dyke, Anesth. Analg. curr. Res. 57, 135 (1972). J . B . Bunker, W. H. Forrest, F. Mosteller and L. D. Wandam, National Ha!othane study. U.S. Government Printing Office, Washington 1969. F . P . Becker, Lancet 2, 719 (1970). F . J . Tornetta and W. P. Bog9 Archs Surg. 90, 253 (1965). S.A. Akdiknen, T. V. Flanagen and C. M. Landmesser, Anesth. Analg. curt. Res. 45, 819 (1966). J. Brohult, Acta anaesth, scand. 11,201 (1967). H . D . Stein, H. R. Keiser and A. Sjoerdsma, Lancet 1, 106 (1970). D.S. Thompson and F. E. Greifenstein, S. Med. J. 67, 69 (1974). R . E . Johnstone, E. M. Kennell, W. Brummund, L. M. Shaw and R. C. Ebersole, Clin. Chem. 22, 217 (1976). B. Kalow, E. Ragoman and F. H. Sims, Can. Anaesth. Soc. J. 23, 71 (1976). M.J. Kirwan, .1. W. Dundee and D. W. Neill, Anaesthesia 20, 66 (1965). M.S. Christensen, V. F. Askrog, T. S. Olsen, E. Kemp and N. Trygstrup, Acta med. scand. 180, 29 (1966). B. Dawson, M. A. Adson, W. F. McGucken, M. N. Dockerty, G. A. Fleisher, R. R. Jones, V. B. Hartridge, N. Chnelle and W. H. J. Summerskill, Mayo Clin. Proc. 41,599 (1966). A.A. Smith, P. P. Volpitto, Z. W. Grambing, M. B. De Vore and A. B. Glassman, Anesth. Analg. curr. Res. 52, 1 (1973). E, J. Morgan, Biochem. J. 20, 1282 (1926). R . W . E . Watts, J. E. M. Watts and J. E. Seegmiller, J. Lab. clin. Med. 66, 688 (1965). R . W . E . Watts, K. Engelman and J. R. Klinenherg, Nature 207, 395 (1964). R . W . E . Watts, K. Engelman, J. R. Klinenberg, J. E. Seegmiller and A. Sjoerdsma, Biochem. J. 90, 4P (1963).

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Changes in SXO level following anesthesia (the actual values are given) : A Control. B Halothane. C Methoxyflurane. Dotted line represents upper norma! limit Ira9 + 2 SD):

15. 10. 1977

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Specialia

highly sensitive m a r k e r S X O to clarify w h e t h e r h a l o t h a n e or m e t h o x y f l u r a n e a r e h e p a t o t o x i c i n m a n . T h e s e r u m levels of t h e i n t r a c e l l u l a r e n z y m e s S G O T a n d L D H were s t u d i e d for c o m p a r i s o n . Materials and methods. 60 p a t i e n t s , s c h e d u l e d for e l e c t i v e s u r g i c a l p r o c e d u r e s s u c h a s r e p a i r of i n g u i n a l h e r n i a , h e m o r r h o i d e c t o m y , p l a s t i c or m i n o r o r t h o p e d i c s u r g e r y , w e r e c h o s e n for t h e s t u d y . N o n e of t h e m h a d a h i s t o r y of liver d i s e a s e . V e n o u s b l o o d s a m p l e s w e r e t a k e n b e f o r e i n d u c t i o n of a n e s t h e s i a , i m m e d i a t e l y f o l l o w i n g c o m p l e t i o n of s u r g e r y , a n d o n e a c h of t h e m o r n i n g s of t h e 1st, 3rd, 5 t h a n d 7 t h p o s t o p e r a t i v e d a y s . B l o o d s a m p l e s w e r e allowed t o clot, c e n t r i f u g e d a n d t h e s e p a r a t e d s e r a w e r e a s s a y e d for S X O b y m e a s u r i n g r a d i o c h e m i c a l l y t h e c o n v e r s i o n of C x*l a b e l l e d h y p o x a n t h i n e t o uric a c i d ~4. S G O T a n d L D H w e r e a n a l y z e d b y T e c h n i c o n A u t o a n a l y z e r S M A 12/60. All p a t i e n t s w e r e p r e m e d i c a t e d w i t h 2 m l of T h a l a m o n a l ( d e h y d r o b e n z p e r i d o l 5 m g a n d F e n t a n y l 0.1 mg) a n d a t r o p i n 0.5 m g i.m. 1 h p r i o r to o p e r a t i o n . A n e s t h e s i a w a s i n d u c e d w i t h s o d i u m t h i o p e n t a l 0.4 m g J k g b . w t , followed b y succinylcholine chloride 1 m g / k g b.wt, to facilitate e n d o t r a c h e a l i n t u b a t i o n . All 60 p a t i e n t s w e r e g i v e n a m i x t u r e of n i t r o u s - o x i d e (60%) a n d o x y g e n (40%) a t a t o t a l flow r a t e of 8 l/rain, u s i n g a s e m i c l o s e d circle s y s t e m with carbon dioxide absorption. T h e p a t i e n t s w e r e r a n d o m l y d i v i d e d i n t o 3 g r o u p s : 31 p a t i e n t s r e c e i v e d h a l o t h a n e , 12 p a t i e n t s r e c e i v e d m e t h o x y f l u r a n e a n d 17 p a t i e n t s s e r v e d a s c o n t r o l s . I n t h e g r o u p anesthetized with methoxyflurane, anesthesia was maintained through a Pentec II vaporizer. Methoxyflurane c o n c e n t r a t i o n of 1 . 0 % w a s u s e d for 5 rain, t h e n 0 . 5 % f o r t h e r e m a i n d e r of t h e o p e r a t i o n . I n t h e h a l o t h a n e g r o u p a c o n c e n t r a t i o n of 1 . 0 % w a s d e l i v e r e d t h r o u g h a F t u o t e k

Mark II Vaporizer. The control group received F e n t a n y l 0.002 m g / k g b . w t a n d Alloferine 0.2 m g / k g b . w t i.v., a n d ventilation was controlled with a volume-limited ventilator. Results. T h e m e a n v a l u e s of S X O , L D H a n d S G O T i n t h e 3 g r o u p s of p a t i e n t s , p r i o r a n d f o l l o w i n g a n e s t h e s i a , a r e p r e s e n t e d in t h e t a b l e . T h e s c a t t e r i n g of S X O a c t i v i t i e s p r i o r a n d f o l l o w i n g a n e s t h e s i a is d e p i c t e d in a h i s t o g r a m (figure). I n t h e c o n t r o l g r o u p of p a t i e n t s , t h e m e a n S X O , L D H and SGOT values following anesthesia were not s i g n i f i c a n t l y e l e v a t e d , in c o m p a r i s o n w i t h t h e p r e o p e r a t i v e v a l u e s . I n t h e h a l o t h a n e g r o u p , in c o m p a r i s o n w i t h t h e p r e o p e r a t i v e level, t h e r e w a s s i g n i f i c a n t e l e v a t i o n i n S X O a c t i v i t y i m m e d i a t e l y f o l l o w i n g c o m p l e t i o n of a n e s thesia, the activity increasing to m a x i m u m value on t h e 3rd p o s t o p e r a t i v e d a y ( m o r e t h a n 6fold t h e p r e o p e r a t i v e v a l u e ) , t h e n d e c r e a s i n g g r a d u a l l y . T h e S X O level w a s still significantly elevated on the 7th postoperative day, the l a s t d a y it w a s m e a s u r e d . W h e n , h o w e v e r , t h e S X O levels on t h e different d a y s following h a l o t h a n e a n e s t h e s i a were c o m p a r e d w i t h the respective values obtained in the control group, a significant elevation was found i m m e d i a t e l y f o l l o w i n g a n e s t h e s i a a n d o n t h e 1st a n d 3rd p o s t o p e r a t i v e d a y s only. On the other h a n d , the p o s t - b a l o t h a n e L D H

F . J . Dagher, A. Panoissian and S. B. Saab, Surgery 62, 1044 (1967). 22 Sh. Giler, O. Sperling, S. Brosh, I. Urca and A. de Vries, Int. Surgery 61, 153 (1976). 23 U.S.A. Al-Khalidi and R. Geha, Clin. chim. Acta 74, 833 (1966). 24 Sh. Giler, O. Sperling, S. Brosh, I. Urca and A. de Vries, Clin. chim. Acta. 63, 37 (1975). 25 Sh. Giler, E. Ventura, E. Levy, I. Urca, O. Sperling and A. de Vries, Experientia 32, 620 (1976). 21

Effects of anesthetic agents on serum levels of intracellular enzymes Anesthetic group

Control (17) Preoperative Postoperative Immediately Day 1 Day 3 Day 5 Day 7 Halothane (31) Preoperative Postoperative Immediately Day 1 Day 3 Day 5 Day 7 Methoxyflurane (12) Preoperative Postoperative Immediately Day 1 Day 3 Day 5 Day 7

Enzyme activity (U/l) SXO Mean SD Px

78.5

43.9

90.7 121.3 147.8 127.5 76.9

93.2 84.4 113.3 127.8 85.1

63.6

62.3

313.1 309.8 392.4 206.0 132.1

412.8 272.5 387.3 227.3 127.0

71.2

44.4

99.0 267.7 156.0 115.5 95.3

78.3 279.1 206.8 105.1 108.3

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n.s. n.s. n.s. n.s. n.s.

Elevation of serum xanthine oxidase activity following halothane anesthesia in man.

1356 Specialia EXPERIENTIA 33/10 E l e v a t i o n of s e r u m x a n t h i n e o x i d a s e a c t i v i t y f o l l o w i n g h a l o t h a n e a...
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