1Department of Anaesthesia, Musgrave Park Hospital, Belfast BT9 7JB, UK. 2Department of Clinical Chemistry, Belfast City Hospital, Belfast BT9 7AB, UK*Corresponding author
Accepted for publication: February 28, 2000
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Abstract |
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Br J Anaesth 2000; 85: 1958
Keywords: anaesthetics, volatile, halothane; anaesthetics, volatile, isoflurane; liver, function
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Introduction |
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We compared the effect of halothane and isoflurane anaesthesia on serum mAST to determine if serum mAST is a more sensitive marker for anaesthetic-induced liver damage than AST, alanine transaminase (ALT), alkaline phosphate (ALP), -glutamyl transferase (
GT) and serum bilirubin.
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Patients and methods |
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Anaesthesia and analgesia
Patients were randomly allocated to receive either halothane or isoflurane by opening sealed envelopes after enrolment into the study. Premedication consisted of temazepam (20 mg) in all cases. Anaesthesia was induced with thiopentone (5 mg kg1) and intubation of the trachea was facilitated with atracurium (0.5 mg kg1). Analgesia was provided by morphine (10 mg) at induction and droperidol (2.5 mg) was administered intravenously as an anti-emetic. Patients were ventilated to maintain their end-tidal carbon dioxide concentration at 4.65.9 kPa, and placed in a modified tuck position for surgery.5 Patients in the halothane and isoflurane groups received halothane and isoflurane, respectively, in nitrous oxide and oxygen (FIO2=0.4). Initial expired concentrations of anaesthetic agent were 1.0 MAC that was reduced if systolic arterial pressure decreased by more than 30% of baseline values. Fluid therapy was Dextran 70 in 0.9% saline (500 ml) followed by Hartmanns solution as required during surgery, and 0.18% saline in 4% dextrose (100 ml h1) after anaesthesia. Heart rate and rhythm, non-invasive arterial pressure and peripheral oxygen saturation by pulse oximeter were monitored throughout anaesthesia. End-tidal carbon dioxide and anaesthetic concentrations were also recorded during anaesthesia. Bupivacaine 0.25% (20 ml) was applied to the wound before it was sutured and neuromuscular blockade reversed with neostigmine 2.5 mg and glycopyrrolate 0.5 mg. Postoperative analgesia consisted of patient-controlled analgesia (morphine sulphate: 1 mg bolus and 5 min lock-out).
Laboratory analysis
Venous blood samples were drawn immediately before induction of anaesthesia, at the end of surgery (time 0), and 3, 6, 24 and 48 h later. The samples were centrifuged and the serum assayed for bilirubin concentration and activities of creatine kinase (CK), ALT, ALP, GT and AST using a multi-channel analyser (Prisma, Clinicon-AB). The remaining serum was stored at 20°C and assayed for mAST at a later date by an immunochemical method.4 Rabbit antibodies against human soluble AST were added to the serum in the presence of polyethylene glycol and the sample was centrifuged to precipitate the soluble AST. Residual mAST in the supernatant was then assayed in the presence of exogenous pyridoxal phosphate by coupling oxaloacetate production with NADH in reaction with malate dehydrogenase (absorbance change monitored at 340 nm (Prisma, Clinicon-AB)). The detection limit of the assay was less than 0.5 u litre1 and the coefficient of variation was less than 3% of the residual mAST.
Data were analysed using Wilcoxon ranked pairs within groups and MannWhitney U-test between groups. Ratios of enzyme activities compared to baseline values were calculated and analysed between groups using the MannWhitney U-test.
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Results |
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Discussion |
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Serum AST activity increased significantly from baseline for all samples drawn more than 6 h after surgery in the halothane group and 24 h after surgery in the isoflurane group. Serum AST activity was non-significantly greater in the halothane group prior to anaesthesia or surgery (P=0.09). Although the difference between the groups was significant (P<0.05) in all of the postoperative samples, we aimed to reduce the influence of the baseline difference by expressing the activities of AST after surgery and anaesthesia as a ratio of baseline activity (Fig. 3). This ratio did not show a statistical difference between the groups at any time after surgery, and therefore these data do not support the use of serum AST activity as an indicator of subclinical hepatic injury found after halothane anaesthesia. Other studies have provided conflicting data on the value of serum AST as an indicator of hepatic injury following halothane anaesthesia. The surgical procedure performed may be important as it has been found that serum AST activity decreases significantly after body surface or minimally invasive surgery,8 but is significantly increased after gastric or biliary surgery.9
There was no difference between the groups before surgery in terms of serum mAST activity. However, after anaesthesia and surgery, serum mAST was significantly greater in the halothane group of patients (Fig. 2). A similar pattern was found when mAST activities after anaesthesia were expressed as ratios of baseline activity (Fig. 4).
Many of the patients in this study were receiving medication, including TylexTM (paracetamol 500 mg and codeine phosphate 30 mg), diazepam and diclofenac that may cause some hepatic injury. The position of the patient during surgery may also be important because posture alters total hepatic blood flow and blood flow through the portal vein in particular.10 The tuck position may reduce blood flow through the portal vein. The hepatic arterial response to reduced portal venous blood flow is abolished in rats anaesthetized with halothane, but maintained in the presence of isoflurane.11 Therefore, a reduction in blood flow through the portal vein may be compensated in the isoflurane group but not in the halothane group. Patients undergoing more minor superficial surgery in the supine position may therefore allow a clearer examination of differences in liver function related to choice of anaesthetic agent.
The source of AST and mAST is not clear as both are found in liver, heart, kidney, brain and skeletal muscle.12 It may therefore be possible that the leakage of enzyme into the serum came from muscle damage at the time of surgery.9 13 However, the changes in serum bilirubin concentration and CK activity were similar in both groups of patients indicating similar severity of surgical tissue damage. As both groups of patients were similar in all other ways, it is most likely that the increased serum activities of mAST are due to the anaesthetic agents used and are hepatic in origin. Therefore, this study provides further evidence that a short exposure to halothane results in a greater loss of liver cell integrity than similar exposure to isoflurane.
In summary, mAST indicates hepatic dysfunction after anaesthesia with halothane. Limitations of the assay for mAST include a lack of organ specificity and the labour-intensive nature of the assay. However, the assay may become much easier in the future as automated techniques utilizing proteinases which inactivate cytosolic AST but have no effect on mAST become available.14 Although the use of halothane is diminishing in the western world, this assay may be useful in evaluating the effects of newer anaesthetic agents on hepatic function.
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Acknowledgement |
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References |
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