Effect of 3 g of intravenous paracetamol on post-operative analgesia, platelet function and liver enzymes in patients undergoing tonsillectomy under local anaesthesia.

BACKGROUND: Paracetamol is often given as an adjunctive analgesic to reduce opioid-related adverse effects but its optimal dose is unknown. We studied the analgesic effect and safety of a single 3-g intravenous (i.v.) dose of paracetamol in adults. METHODS: One hundred and seven patients undergoing tonsillectomy under local anaesthesia were randomly allocated to receive i.v. 3 g of paracetamol, 75 mg of diclofenac or placebo prior to surgery. The consumption of post-operative morphine using a patient-controlled analgesia-device was quantified for 6 h. Platelet aggregation and the concentrations of paracetamol, liver aminotransferases, glutathione transferase alpha 1-1 (GSTA1-1) and thromboxane B(2) were measured. RESULTS: During the first hours after surgery, both paracetamol and diclofenac reduced (P < 0.05) the consumption of morphine but had no effect thereafter. The values for the 6-h cumulative consumption of morphine in patients given paracetamol (18.7 +/- 13.8 mg), diclofenac (16.1 +/- 9.9 mg) and placebo (22.0 +/- 12.1 mg) did not differ. Paracetamol had no effect on platelet aggregation, which was impaired only by diclofenac in response to arachidonic acid (P < 0.005). Both paracetamol (P < 0.01) and diclofenac (P < 0.005) inhibited the release of thromboxane B(2) at 1 h but they did not affect serum aminotransferase and GSTA1-1 levels. One patient given paracetamol displayed a transient increase in GSTA1-1 and liver aminotransferases. CONCLUSION: During the initial hours after tonsillectomy, the administration of 3 g of i.v. paracetamol and 75 mg of diclofenac reduced the consumption of morphine. Both drugs also reduced the release of thromboxane B(2) from activated platelets but only diclofenac had a negative effect on platelet aggregation. In sensitive individuals, large doses of paracetamol may disturb the hepatocellular integrity. We do not recommend the use of i.v. doses of paracetamol higher than 1 g.

Changes in hepatocellular integrity during and after desflurane or isoflurane anaesthesia in patients undergoing breast surgery.

We have assessed hepatocellular integrity in patients anaesthetized with desflurane or isoflurane using glutathione transferase Alpha (GSTA) as a sensitive indicator. Volatile anaesthetic was administered to 72 women at 0.7 MAC for 25 min and thereafter at 1.0 MAC. GSTA was measured with a time-resolved immunofluorometric assay in serum samples. Mild or moderate increases in GSTA were found in approximately 40% of patients immediately after anaesthesia. In the desflurane group (n = 30) the increase in GSTA concentration was from a baseline value of the geometric mean of 1.3 microgram litre-1 (95% confidence interval 0.9-1.9 microgram litre-1) to a peak of 2.6 (1.8-3.8) micrograms litre-1. The corresponding increase in the isoflurane group (n = 31) was from 1.3 (0.9-1.9) microgram litre-1 to 3.0 (2.2-4.2) micrograms litre-1. The change in GSTA concentration was significant in both groups but not between groups. No predictive factors for the increase in GSTA concentrations were found. Increased GSTA concentrations were not accompanied by increases in amino-transferases. We conclude that desflurane and isoflurane anaesthesia were associated with a mild subclinical disturbance of hepatocellular integrity.

Hepatocellular integrity during and after isoflurane and halothane anaesthesia in surgical patients.

Subclinical disturbance in hepatocellular integrity, indicated by glutathione transferase Alpha (GSTA), has been associated with halothane, sevoflurane and propofol, but not with isoflurane anaesthesia. We anaesthetized 82 patients with isoflurane or halothane at 1 MAC for superficial surgery. GSTA concentration were measured with a sensitive time-resolved immunofluorometric assay in serum samples. GSTA concentrations increased from a baseline value of geometric mean 1.8 micrograms litre-1 (95% confidence intervals 1.4-2.2 micrograms litre-1) to a peak of 4.3 (3.3-5.7) micrograms litre-1 in the isoflurane group and from 2.1 (1.6-2.9) micrograms litre-1 to 6.2 (4.1-9.5) micrograms litre-1 in the halothane group. The change in GSTA was significant within groups but the difference between groups was not significant. Two patients exhibited an unexpectedly large increase in GSTA (peaks 370 and 620 micrograms litre-1) and a mild increase in alanine aminotransferase after halothane anaesthesia. We conclude that hepatocellular integrity was mildly disturbed after isoflurane and halothane anaesthesia but there was no difference between anaesthetics. Halothane anaesthesia may be associated with more advanced hepatocellular disturbance in some cases.

Hepatocellular integrity in liver donors and recipients indicated by glutathione transferase alpha.

Glutathione transferase Alpha (GSTA) is a sensitive indicator of hepatocellular integrity. Its reference range is low (0.7-14 microgram/L) and its half-life is short (1 hr) in serum. We evaluated the changes in GSTA concentration in 18 recipients during and after liver transplantation. The respective liver donors were also included in 13 cases. The baseline GSTA concentrations were normal or slightly elevated in all donors, 1.2-79 micrograms/L (median 5.1 micrograms/L) and recipients, 1.1-34 micrograms/L (median 6.4 micrograms/L). Surgical dissection of donor liver caused a moderate or even large increase in GSTA concentration, peak 80-6500 microgram/L (median 800 micrograms/L). In the recipients the peak of GSTA concentrations varied from 1400 to 47000 micrograms/L (median 5000 micrograms/L), and it was always observed within 45 min after reperfusion of the graft. The highest GSTA values were observed after long cold ischemia and in patients transplanted for acute liver failure. However, they were not associated with early graft dysfunction. There was a correlation between the AUC of GSTA and cold ischemia time in the recipients with chronic nonalcoholic liver failure (r=0.94). There was no correlation between GSTA values in the donors and recipients (r=0.14). The apparent half-life of GSTA in serum was 56 min (median). Perioperative GSTA concentrations in the donors had no obvious predictive value. In the recipients an exceptionally long apparent half-life of GSTA immediately after transplantation or a large second increase in GSTA were predictors of postoperative complications.

Disturbance of hepatocellular integrity associated with propofol anaesthesia in surgical patients.

Propofol anaesthesia has not been associated with any hepatic consequences. We used glutathione transferase Alpha (GSTA), a very sensitive indicator of hepatocellular integrity, to evaluate the effect of propofol on the liver. Total intravenous anaesthesia was induced and maintained with propofol without any supplements in 30 female patients undergoing breast surgery. Ten healthy female volunteers given the lipid vehicle of propofol served as controls. Serum GSTA concentration was measured with a sensitive time-resolved immunofluorometric assay. Total intravenous propofol anaesthesia was stable and postoperative nausea negligible. A significant increase in GSTA from 3.1 micrograms.l-1 (mean baseline) to 10.0 micrograms.l-1 (mean peak) was noted after propofol infusion, indicating subclinical disturbance in hepatocellular integrity. No change in aminotransferases and no clinical signs of hepatotoxicity were observed. A small increase in GSTA from 2.4 micrograms.l-1 (mean baseline) to 4.1 micrograms.l-1 (mean peak) was observed during lipid infusion. We detected a subclinical disturbance in hepatocellular integrity after propofol anaesthesia for breast surgery. The mechanisms of hepatocellular impairment are not clear but the lipid vehicle of propofol alone does not explain it.

Comparison of the effects of sevoflurane and halothane on the quality of anaesthesia and serum glutathione transferase alpha and fluoride in paediatric patients.

We have compared sevoflurane and halothane anaesthesia in paediatric patients with reference to induction and recovery. We also assessed hepatocellular integrity by measurement of serum glutathione transferase alpha (GSTA) concentration and sevoflurane metabolism by serum fluoride concentration. Fifty unpremedicated 5-12-yr-old children were allocated randomly to induction of anaesthesia via a face mask with 66% nitrous oxide in oxygen and sevoflurane (up to 7%) or halothane (up to 3.5%). Anaesthesia was maintained for 1.8 h at 1-1.2 MAC of the volatile agent. Children receiving sevoflurane had significantly faster induction and recovery variables than those receiving halothane. There was a small postanaesthetic increase in GSTA in both groups, suggesting that halothane and sevoflurane may disturb hepatocellular integrity. Serum concentrations of fluoride were significantly greater after sevoflurane than after halothane anaesthesia. There were no clinical signs or symptoms of hepatic or renal disturbance. Children tolerated sevoflurane better than halothane, which may have been because of the nonpungency of sevoflurane and the rapid psychomotor recovery after anaesthesia.

Ultrasensitive time-resolved immunofluorometric assay of glutathione transferase alpha in serum.

Glutathione transferase Alpha (GSTA) is a very sensitive marker of acute centrilobular liver damage. We purified glutathione transferases from human liver and separated the isoenzymes. Polyclonal rabbit antibodies specific for Alpha-class isoenzymes were produced and labeled with Eu(3+)-chelate. We set up a sandwich-type time-resolved immunofluorometric assay (TR-IFMA) to measure GSTA in serum. The detection limit was 0.03 microgram/L, and measuring range was from 0.03 to 100 micrograms/L. The reference range for serum GSTA in this assay was 0.7-6.0 micrograms/L for women and 0.7-14 micrograms/L for men. This TR-IFMA is practical, and the modified rapid assay can be completed in 3 h. Therefore it is applicable for diagnostic purposes in acute liver damage, e.g., associated with drug toxicity or hypoperfusion of the liver.