PROSPECTIVE STUDY OF LIVER FUNCTION IN CHILDREN FOLLOWING MULTIPLE HALOTHANE ANAESTHETICS AT SHORT INTERVALS

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1 Br. J. Anaesth. (86), 8, -8 PROSPECTIVE STUDY OF LIVER FUNCTION IN CHILDREN FOLLOWING MULTIPLE HALOTHANE ANAESTHETICS AT SHORT INTERVALS H. WARK, M. O'HALLORAN AND J. OVERTON Two retrospective studies have assessed the risk of a child developing postoperative jaundice caused by halothane-associated hepatitis as between in 8 and in (Wark, 8; Warner et al., 8). The incidence of minor degrees of hepatic dysfunction after halothane anaesthesia in children is unknown. A prospective study in children was designed to assess the effect, on liver function, of repeated anaesthetics at short intervals. The investigation was performed at the Royal Alexandra Hospital for Children, Sydney between January 8 and December 8. PATIENTS AND METHODS Multiple halothane anaesthetics within year Hospital lists were scrutinized for s having relatively minor surgery in whom multiple exposures to halothane were likely to occur within year. To minimize the effect of surgery on liver function, s having major abdominal and thoracic surgery were not included. Patients on drugs or treatments known to affect liver function, and s with severe systemic disease, were excluded also. Each was followed prospectively for months and no new s were entered into the study after December 8. If, after the initial -month period, it was likely that a would receive many further halothane anaesthetics, then the was readmitted to the study as a separate entry. While in hospital, s were examined daily for the presence of postoperative jaundice. At each H. WARK, F.F.A.R.CS.; M. CHALLORAN, B.SC., F.A.A.C.B.; J. OVERTON, F.F_A.R.C.S., F.P.A.R.A.C..; Royal Alexandra Hospital for Children, Pynnont Bridge Road, Camperdown, Sydney, Australia. SUMMARY In the years January 8 to December 8, 86 children received 6 halothane anaesthetics. Twenty-five s were anaesthetized with halothane at least times in a year. No developed postoperative jaundice. Sixtynine children were exposed to two halothane anaesthetics within 8 days on occasions and serial estimations of serum liver enzyme concentrations were obtained. Minor increases in the concentrations of serum AST and ALT were recorded in.6% and.% of, respectively. Postoperative GGTandSAP concentrations were increased in.% of. Patients in whom enzyme values were increased before the first anaesthetic were no more likely than other subjects to develop further changes. out attendance after discharge, the 's parents were asked about a history of jaundice and the was examined for evidence of liver disease. Effect of repeated halothane anaesthetics within 8 days on tests of liver function It was considered inappropriate to collect blood from an awake child solely for the purpose of the investigation. Thus only children having two halothane anaesthetics within 8 days and who would be anaesthetized again within 8 days were considered suitable for study. When possible, blood was taken at the initial anaesthetic and at each subsequent anaesthetic to permit biochemical assessment of liver function. After the child was anaesthetized, but before surgery commenced, - ml of blood was withdrawn from the venous cannula and placed in a

2 REPEATED HALOTHANE ANAESTHETICS TABLE I. Normal laboratory values of liver function tests used Liver function test Aspartate amino transferase (AST) (u. litre" ) < month > month Alanine amino transferase (ALT) (u. litre" ) < month > month Gamma glutamyl transpeptidase (GGT) (u. litre-') All ages Alkaline phosphatase (SAP) (u. litre"') < 6 months 6 months- yr Adult Bilirubin (TSB) (mmol litre" ) Normal range SD lithium-heparin container. A separate venepuncture was not performed if blood could not be aspirated from the venous cannula inserted by the anaesthetist. Blood taken at the third anaesthetic was used to assess the effect of the first and second anaesthetics on the concentrations of the liver enzymes. If a was anaesthetized a fourth time within 8 days of the third halothane anaesthetic, blood was taken again. This blood was used to assess the effect of the second and third anaesthetics on liver function and these results were included in the study as a separate entry. Some children already admitted to the study, presented again for further surgery after a period of months or years. If the entry criteria were again met, these s were included in the study as a separate entry. The study was approved by the Hospital Ethics Committee. Laboratory tests Tests of liver function were performed in the hospital biochemistry department by a biochemist (M.O'H.) who had no knowledge of the 's anaesthetic history. Serum bilirubin concentration was determined using the method of Jendrassick and Grof (8). Serum concentrations of aspartate aminotransferase (AST), alanine aminotransferase (ACT), gamma glutamyl transferase (GGT) and alkaline phosphatase (SAP) were determined using an IL Multistat auto analyser. The concentrations of the liver enzymes were measured. at C end the results reported in u. litre". The criterion for an "abnormal" increase in enzyme concentration was that the value after anaesthesia exceeded the preoperative value by more than three standard deviations of the method of analysis. The standard deviation of the method of analysis was calculated from the coefficient of variation of several hundred repeated estimations on " control" sera over the period of the study and is expressed at the upper limit of the "normal" range. The " normal" enzyme ranges and corresponding standard deviations are shown in table I. RESULTS Multiple halothane anaesthetics in year In the years January 8 to December 8, 86 s received 6 halothane anaesthetics (table II). There were boys and 8 girls. No developed clinical signs of liver disease. Twenty-five s were anaesthetized with halothane at least times a year. One -yr-old boy with an oesophageal stricture caused by the ingestion of a caustic material had 6 halothane anaesthetics in a -month period. Another with laryngeal papillomata had halothane anaesthetics in years. Effect of repeated halothane anaesthesia within 8 days on tests of liver function One hundred and two s were admitted to this section of the study. Forty-nine involving s were excluded from analysis because insufficient blood samples had TABLE II. Clinical details of 86 children who had multiple halothane anaesthetics in year. Tmenty-lhree s were studiedfor years ; four s were studiedfor y tars and three s were studied for years Operation Neurosurgical Airway endoscopy Oesophageal dilatation Orthopaedic Plastic Genera] Miscellaneous 6 anaesthetics in year >6 8 8

3 6 BRITISH JOURNAL OF ANAESTHESIA TABLE III. Operations performed in children having a second halothane anaesthetic vnthin 8 days Operation Neurosurgical Airway endoscopy Oesophageal dilatation Orthopaedic Plastic General Miscellaneous s been obtained. There were three reasons for this failure to obtain specimens. First, a may not have had the number of repeated halothane anaesthetics that was anticipated. Second, the interval between repeated anaesthetics may not have been sufficiently short. Third, it may not have been possible to withdraw blood from the venous cannula inserted for anaesthetic purposes. Three hundred and ninety-four blood samples were examined. The mean age and standard deviation of children studied was.±6 months with an age range from months to 6 yr. Operations performed in s having a second halothane anaesthetic within 8 days are shown in table III. The two major groups of s were those having repeat laryngoscopy/ bronchoscopy for the assessment of airway obstruction and those having peripheral limb surgery, for example bilateral club foot correction. Changes in liver function tests in s receiving two halothane anaesthetics within 8 days are shown in table IV. The average age of children in whom there was an abnormal increase in serum AST and ALT concentrations was ± months and ± months, respectively. The highest postoperative serum transaminase concentrations were an AST of u. litre" and an ALT of 8 u. litre". Both s had two neuroradiological procedures within days for the investigation of an intracranial mass. Children older than yr did not develop increases in liver enzyme concentrations more frequently than younger children. The children in the study older than years of age did not show any evidence of abnormal increases in enzyme concentrations. The responses to the halothane anaesthesia, of children in whom the preoperative enzyme concentrations were increased, are shown in table V. Five children had an increase in serum AST concentration and two an increase in serum ALT concentration on initial entry to the study. TABLE IV. Changes in liver function tests after two halothane anaesthetics within 8 days. -[Days, following second anaesthetic, that liver function tests were performed Days of testst with increased values after testing: AST ALT GGT SAP TSB (.6%) (.%) (.6%) (.6%) TABLE V. Responses to halothane in children with preoperative increases in liver enzyme concentrations. Liver function tests were measured within month of the second halothane anaesthetic Liver function tests Change in concentration Increase Decrease No change AST ALT GGT SAP

4 REPEATED HALOTHANE ANAESTHETICS DISCUSSION Adult s having multiple halothane anaesthetics at short intervals (-8 weeks) are at particular risk of developing halothane-associated hepatitis (Inman and Mushin, 8). In our prospective study in children over the -year period January 8 to December 8, 86 s had 6 halothane anaesthetics. No developed clinical evidence of liver disease, although minor hepatic dysfunction may have been missed. Likewise, Kennedy, Chinyanga and Steward (8) in a -year retrospective review of halothane anaesthetics in 8 children having laryngeal surgery at the Hospital for Sick Children, Toronto, found no evidence of postoperative jaundice. Two prospective studies in children have looked at alterations in the concentrations of the liver enzymes following a single halothane anaesthetic. Lomaz (6) reported a series of children in whom AST and ALT values were determined at the beginning and at the end of halothane anaesthesia. Resurrection and colleagues (8), using a similar method, collected data on eight children. No changes in liver enzymes were detected in either of these studies. However, the interval between exposure to halothane and onset of hepatitis can be as long as 8 days. Normal liver enzyme values in the immediate postoperative period cannot be interpreted as excluding halothane-induced liver dysfunction. Our study in children examined the effect on liver function of two halothane anaesthetics within 8 days. Sixty-nine s were studied on occasions. No became jaundiced and there were no sequelae related to anaesthesia. Postoperative AST concentrations were increased on 6 occasions (.6%). In adults, Wright and co-workers () found a % incidence of increased AST concentrations following repeat halothane at short intervals. Increases in postoperative ALT concentration were noted on seven occasions (.%) an incidence substantially less than that reported in adults by Trowell, Peto and Crampton-Smith (). These authors found that four of 8 s (%) given repeat halothane anaesthetics at short intervals developed ALT concentrations greater than u. litre". Dundee and colleagues (8) found that % of adult s having an interval of -6 weeks between halothane anaesthetics had an abnormal increase in GGT concentration. In our series only. % of children developed abnormalities of GGT after two halothane anaesthetics within 8 days. Some children in the study had minor abnormalities of liver enzyme(s) in blood taken before the halothane anaesthetic. This was usually a result of the hepatitic effects of a systemic viral illness. Many of the children in the study had either viral croup or a lower respiratory tract infection secondary to upper airway obstruction. The response of these s to a further halothane anaesthetic within 8 days was variable, but in the majority of s the concentrations of the liver enzyme(s) either remained unchanged or decreased. This finding supports the work of Dundee and colleagues (8), who found that adults with slight increases in enzyme concentration before halothane anaesthesia were not more likely than other subjects to develop further changes. Transaminase concentrations of greater than u. litre" are associated with severe hepatitis and values less than u. litre" with mild disease, but correlation with liver necrosis in the individual is poor (Rosali, 6). In our series, two s developed serum transaminase values greater than u. litre" : one had an AST of u. litre" and another an ALT of 8 u. litre". Neither had any other evidence of liver disease while in hospital, or after discharge. Minor changes in liver function are common in the period immediately after operation and may be the result of surgical trauma, hypoxia, hypotension and anaesthetic agents (Nickell and Allbritten, ; Person and Judge, 8; Clark, Doggart and Lavery, 6). Our study in children showed that the incidence of minor disturbances in serum transaminase values following repeated halothane anaesthesia within 8 days was % and %. Fatal postoperative hepatic failure following halothane in children is rare. Less than cases have been reported in the world literature since the introduction of halothane to clinical practice in. Our study supports the view of Strunin () that minor abnormalities of liver enzymes and fulminant hepatic failure following halothane are two separate, unrelated entities. Several authors (Inman and Mushin, 8; Sherlock, 8; Neuberger and Williams, 8) recommend that s who are likely to require multiple anaesthetics within a short period should

5 8 BRITISH JOURNAL OF ANAESTHESIA not be given halothane more than once. We feel that in children, this restriction on the use of halothane is unwarranted. ACKNOWLEDGEMENT This work was funded by a grant from the Children's Medical Research Foundation. REFERENCES Clarke, R. S. J., Doggart, J. R., and Lavery, T. (6). Changes in liver function after different types of surgery. Br. J. Anaesth., &,. Dundee, J. W., Mcllroy, P. D. A., Fee, J. P. H., and Black, G. W. (8). Prospective study of liver function following repeat halothane and enflurane. J. R. Soc. Med.,, 86. Inman, W. H. W., and Mushin, W. W. (8). Jaundice after repeated exposure to halothane: a further analysis of reports to the Committee on Safety of Medicine. Br. Med. J.,,. Jendrassick, L., and Grof, P. (8). Vereinfacthe photometrische Methoden zur Bestimmung des Blutbilirubins. Biochem, Z.,, 8. Kennedy, J. G., Chinyanga, H. M., and Steward, D. J. (8). Anaesthetic experience using a standard technique for laryngeal surgery in infants and children. Can. Anaesth. Soc.J., 8, 6. Lomaz, J. G. (6). Halothane and jaundice in paediatric anaesthesia. Anaesthesia,,. Neuberger, J., and Williams, R. (8). Halothane anaesthesia and liver damage. Br. Med. J., 8, 6. Nickell, W. K., and Allbritten, F. F. jr (). Serum txansaminase content related to tissue injury. Surgery,,. Person, D. A., and Judge, R. D. (8). Effect of operation on serum transaminase levels. Arch. Surg.,, 8. Resurrection, M. A., Cornell, J. E., Brown, A., Jongco, B., and Ryee, H. (8). Hepatic function after halothane in neonates and infants. Anesthesiology,, S. Rosali, S. B. (6). Enzyme tests in diseases of the liver and hepatobiliary tract; in The Principles and Practice of Diagnostic Enzymology (ed. J. H. Wilkinson), p. 8. Chicago: Year Book. Sherlock, S. (8). Halothane hepatitis. Lancet,, 6. Strunin, L. (). Liver dysfunction after repeat anaesthesia. Br.J. Anaesth.,,. Trowell, J., Peto, R., and Crampton-Smith, A. (). Controlled trial of repeated halothane anaesthetics in s with carcinoma of the uterine cervix treated with radium. Lancet,, 8. Wark, H. J. (8). Postoperative jaundice in children: The influence of halothane. Anaesthesia, 8,. Warner, L. O., Beach, T. P., Garvin, J. P., and Warner, E. J. (8). Halothane and children: The first quarter century. Anesth. Analg., 6, 88. Wright, R., Chisholm, M., Lloyd, B., Edwards, J. C, Bade, O. E., Hawksley, M., Moles, T. M., and Gardener, M. J. (). Controlled prospective study of the effect on liver function of multiple exposures to halothane. Lancet,, 8.