Plasma Inorganic Fluoride Concentrations Research Articles

Renal Safety and Extrahepatic Defluorination of Sevoflurane in Hepatic Transplantations

Background The main metabolic pathway for defluorination of sevoflurane in the liver produces inorganic fluoride (Fl). The metabolism and effect of sevoflurane on the kidney is not clear during anhepatic phase in liver transplantation. The goal of the present study was to investigate the metabolism and renal effect of sevoflurane by measuring plasma and urine inorganic fluoride, urinary N-acetyl-glucosaminidase (NAG), and plasma creatinine levels in patients undergoing liver transplantations. Methods After institutional approval and informed consent, we studied nine cases of orthotopic liver transplantation after anesthesia was induced with 5 mg · kg −1 thiopental, 1 μg · kg −1 fentanyl intravenously, the trachea was intubated after vecuronium bromide 0.1 mg · kg −1. Anesthesia was maintained with sevoflurane (2%), O 2, and N 2O at a total gas flow of 6 L · min −1 using a semiclosed circle system with a sodalime canister. Blood and urine samples were obtained to measure plasma and urine fluoride concentrations and urinary NAG excretions before induction (P0), hourly during resection (P1, P2, P3), every 15 minutes during anhepatic phase (A1, A2, A3), hourly after reperfusion (neohepatic phase) (N1, N2, N3), and postoperative first hour (Po1). Preoperative (T0) and postoperative day 1 (T1), 3 (T3), 7 (T7) plasma blood urea nitrogen (BUN) and creatinine (Cr) levels were also recorded. Results Mean duration of surgery was 9:06 ± 0:09 hours. Mean inorganic fluoride concentrations in plasma were in the range of 0.71 ± 0.30 to 28.73 ± 3.31 μmole · L −1. In P3, N1, N2, N3, increases in plasma inorganic fluoride concentrations were significant ( P < .05) and reached a peak value at Po1. The mean urine inorganic fluoride concentrations were 12.49 ± 2.04 to 256.7 ± 49.62 μmole · L −1. In A2, A3, N1, N2, and N3, mean urine inorganic fluoride concentrations were significantly increased ( P < .05) and the peak value was observed at Po1. Mean NAG concentrations in urine varied (5.6 ± 1.6 IU · L −1 to 12.5 ± 1.14 IU · L −1) and peak level was observed at 30 minutes of the anhepatic phase (A2), which did not exceed the normal values for urine NAG levels (1.5 to 6.1 U · L −1). No impairment was observed in serum BUN and creatinine levels at any time. While there was only a slight increase in NAG during anhepatic phase, there was no change in plasma F1. Conclusions Sevoflurane seemed to have minimal effect on kidney functions of BUN and Cr levels during liver transplantation. Although urine F1 and NAG levels increased during the anhepatic phase plasma F1, BUN, and Cr levels did not, suggesting that renal F1 production may occur in the absence of hepatic function. The renal effect of sevoflurane in chronic liver disease is controversial and must be investigated in further studies.

Halogenated inhalational anaesthetics

The halogenated inhalational anaesthetics halothane, enflurane, isoflurane and desflurane can produce metabolic hepatocellular injury in humans to a variable extent. During metabolism of these anaesthetics, tissue acetylation occurs due to the formation of reactive intermediates. Proteins modified by acetylation may constitute neo-antigens with a potential for triggering an antibody-mediated immune response. The likelihood of suffering post-operative immune hepatitis depends on the amount of the anaesthetic metabolized and is thereby considerably less with enflurane, isoflurane or desflurane compared with halothane. Plasma inorganic fluoride concentrations are regularly increased after sevoflurane. Elevated inorganic fluoride concentrations have been associated with nephrotoxicity following methoxyflurane anaesthesiabut not after sevoflurane. Another source of concern is the products of degradation from reactions with carbon dioxide absorbents. Most important is compound A, which has been shown to exhibit nephrotoxicity in rodents. However, no significant changes in renal function parameters have been reported in surgical patients.

Effects of sevoflurane anesthesia on plasma inorganic fluoride concentrations during and after cardiac surgery.

Sevoflurane metabolism results in the production of inorganic fluoride, which is known to be nephrotoxic. Since marked changes in body temperature and hemodynamics in cardiac surgery affect sevoflurane metabolism, plasma inorganic fluoride concentrations may differ in this situation compared with other types of surgery. We therefore measured plasma inorganic fluoride concentrations during and after sevoflurane anesthesia in patients undergoing cardiac surgery. Sixteen patients undergoing coronary artery bypass grafting or valve replacement were premedicated with 5-10 mg midazolam and 0.5 mg scopolamine injected intramuscularly. Anesthesia was induced with 5-10 mg midazolam, 0.5-1 mg fentanyl, and 0.12-0.15 mg.kg(-1) vecuronium. Following tracheal intubation, anesthesia was maintained with oxygen, sevoflurane, and fentanyl. At the onset of cardiopulmonary bypass (CPB), sevoflurane was discontinued, and additional fentanyl, midazolam, and pancuronium were administered. Plasma inorganic fluoride concentrations were measured before anesthesia, immediately before and after CPB, and at 0, 2, 6, 12, 24, and 48 h after anesthesia. The individual maximum plasma inorganic fluoride concentration was 19.2 +/- 7.2 micromol.l(-1) (mean +/- SD; range, 9.2-36.7). The mean plasma inorganic fluoride concentrations increased during anesthesia, but the rate of increase decreased after the initiation of CPB. Concentrations peaked at 2 h after anesthesia and decreased thereafter. The concentrations in three cases continued to increase 2 h after anesthesia. The plasma inorganic fluoride concentrations observed in patients undergoing cardiac surgery were below nephrotoxic levels. However, the decrease in mean fluoride concentration after anesthesia was slower than that in the previous study in general surgical patients.

Intracranial Pressure, Middle Cerebral Artery Flow Velocity, and Plasma Inorganic Fluoride Concentrations in Neurosurgical Patients Receiving Sevoflurane or Isoflurane

Intracranial Pressure, Middle Cerebral Artery Flow Velocity, and Plasma Inorganic Fluoride Concentrations in Neurosurgical Patients Receiving Sevoflurane or Isoflurane

Intracranial Pressure, Middle Cerebral Artery Flow Velocity, and Plasma Inorganic Fluoride Concentrations in Neurosurgical Patients Receiving Sevoflurane or Isoflurane

Intracranial Pressure, Middle Cerebral Artery Flow Velocity, and Plasma Inorganic Fluoride Concentrations in Neurosurgical Patients Receiving Sevoflurane or Isoflurane

A phase III, multicenter, open-label, randomized, comparative study evaluating the effect of sevoflurane versus isoflurane on the maintenance of anesthesia in adult ASA class I, II, and III inpatients

Study Objective: To compare the clinical efficacy and safety of sevoflurane and isoflurane when used for the maintenance of anesthesia in adult ASA I, II, and III inpatients undergoing surgical procedures of at least 1 hour's duration. Design: Phase III, randomized, open-label clinical trial. Setting: 12 international surgical units. Patients: 555 consenting inpatients undergoing surgeries of intermediate duration. Interventions: Subjects received either sevoflurane (n = 272) or isoflurane (n = 283) as their primary anesthetic drug, each administered in nitrous oxide (N 2O) (up to 70%) and oxygen (O 2) after an intravenous induction using thiopental and low-dose fentanyl. The concentration of volatile drug was kept relatively constant but some titration in response to clinical variables was permitted. Comparison of efficacy was based on observations made of the rapidity and ease of recovery from anesthesia and the frequency of untoward effects for the duration of anesthesia to the return of orientation. Safety was evaluated by monitoring adverse experiences, hematologic and non-laboratory testing, and physical assessments. In 25% of patients (all patients in both treatment groups at selected investigational sites), plasma inorganic fluoride concentrations were determined preoperatively, every 2 hours during maintenance, at the end of anesthesia, and at 1, 2, 4, 8, 12, 24, 48, and 72 hours postoperatively. Measurements and Main Results: Emergence, response to commands, orientation, and the first request for postoperative analgesia were all more rapid following discontinuation of sevoflurane than following discontinuation of isoflurane (sevoflurane, 11.0 ± 0.6, 12.8 ±0.7, 17.2 ± 0.9, 46.1 ± 3.0 minutes, respectively, versus isoflurane, 16.4 ± 0.6, 18.4 ± 0.7, 24.7 ± 0.9, 55.4 ± 3.2 minutes). The incidence of adverse experiences was similar for sevoflurane and isoflurane patients. Forty-eight percent of patients in the sevoflurane group had no untoward effects versus 39% in the isoflurane group. Three patients who received sevoflurane had serum inorganic fluoride levels 50 μM/L or greater though standard tests indicated no evidence of associated renal dysfunction. Conclusion: Sevoflurane anesthesia, as compared with isoflurane, may be advantageous in providing a smoother clinical course with a more rapid recovery.

The Effects of Sevoflurane and Isoflurane Anesthesia on Renal Tubular Function in Patients with Moderately Impaired Renal Function

Increasing evidence indicates that sevoflurane anesthesia does not impair renal function in healthy patients despite higher concentrations of plasma inorganic fluoride. However, whether sevoflurane further affects renal tubular function in patients with impaired renal function is not known. We compared the effect of sevoflurane anesthesia with that of isoflurane anesthesia on renal tubular function in patients with moderately impaired renal function. Fourteen patients with creatinine clearance between 10 and 55 mL/min were anesthetized with either sevoflurane or isoflurane using a semiclosed circuit system. Plasma inorganic fluoride concentrations and urine N-acetyl-beta-D-glucosaminidase (NAG), gamma-glutamyltranspeptidase (gamma-GTP), and beta 2-microglobulin (beta 2MG) excretions were measured up to post-anesthetic day 14. Although both the peak plasma inorganic fluoride concentrations and the areas under the curve of plasma inorganic fluoride concentration versus time were significantly greater in the sevoflurane group than in the isoflurane group, urine NAG, gamma-GTP, and beta 2MG excretions per day did not differ between the two groups. These results indicate that sevoflurane and isoflurane may have similar effects on the renal tubules in patients with moderately impaired renal function.

The Effects of Sevoflurane and Isoflurane Anesthesia on Renal Tubular Function in Patients with Moderately Impaired Renal Function

Increasing evidence indicates that sevoflurane anesthesia does not impair renal function in healthy patients despite higher concentrations of plasma inorganic fluoride.However, whether sevoflurane further affects renal tubular function in patients with impaired renal function is not known. We compared the effect of sevoflurane anesthesia with that of isoflurane anesthesia on renal tubular function in patients with moderately impaired renal function. Fourteen patients with creatinine clearance between 10 and 55 mL/min were anesthetized with either sevoflurane or isoflurane using a semiclosed circuit system. Plasma inorganic fluoride concentrations and urine N-acetyl-beta-D-glucosaminidase (NAG), gamma-glutamyltranspeptidase (gamma-GTP), and beta2-microglobulin (beta2 MG) excretions were measured up to postanesthetic day 14. Although both the peak plasma inorganic fluoride concentrations and the areas under the curve of plasma inorganic fluoride concentration versus time were significantly greater in the sevoflurane group than in the isoflurane group, urine NAG, gamma-GTP, and beta2 MG excretions per day did not differ between the two groups. These results indicate that sevoflurane and isoflurane may have similar effects on the renal tubules in patients with moderately impaired renal function. (Anesth Analg 1996;82:909-13)

Biotransformation of sevoflurane.

Several characteristics of sevoflurane biotransformation are apparent from the preceding investigations. Metabolism is rapid, with fluoride and HFIP appearing in plasma within minutes after the start of sevoflurane administration (38-40,51). Peak plasma fluoride concentrations generally occur within approximately 1 h after the termination of sevoflurane administration in most patients, regardless of the dose or duration of exposure (ranging from 0.35-9.5 MAC-h) (39,48). Peak plasma inorganic fluoride concentrations are proportional to sevoflurane dose, measured in MAC-h (42-44). Inorganic fluoride concentrations decline rapidly after termination of sevoflurane administration, with concentrations well below peak levels by the first postoperative day. HFIP is rapidly conjugated, with more than 85% circulating in plasma as the glucuronide. Plasma HFIP concentrations peak later than fluoride concentrations, but both metabolites are eliminated at similar rates (52). Metabolism of sevoflurane does not contribute to the termination of clinical drug effect (52), unlike more extensively metabolized drugs such as halothane (55). Sevoflurane is metabolized by P-450 2E1, so pathophysiologic factors and drug interactions altering P-450 2E1 activity will also influence sevoflurane metabolism (52). The extent of metabolism of sevoflurane, 2% to 5%, is less than that of all other volatile anesthetics except isoflurane and desflurane. It has been proposed that the ideal anesthetic should resist biotransformation because anesthetic toxicity is related to anesthetic metabolism (67,68). Experience to date suggests that biotransformation of sevoflurane has not been causally related to either hepatic or renal toxicity. Sevoflurane does not result in formation of fluoroacetylated liver neoantigens or other reactive metabolites. Although both sevoflurane and methoxyflurane may produce plasma fluoride concentrations in excess of 50 microM, they have not produced the same nephrotoxic effects. Clearly, anesthetic metabolism and anesthetic toxicity can no longer be considered synonymous. The introduction of sevoflurane into clinical practice will hopefully stimulate new investigations into biochemical mechanisms of anesthetic toxicity and continued clinical investigations regarding the relationship between anesthetic metabolism and organ toxicity.

Plasma inorganic fluoride and intracircuit degradation product concentrations in long-duration, low-flow sevoflurane anesthesia.

Plasma inorganic fluoride (F-) concentrations in long-duration, low-flow sevoflurane anesthesia were studied to assess effects on renal and hepatic function. The intracircuit concentration of degradation product generated by reaction between sevoflurane and CO2 absorbant was also determined. Ten patients undergoing prolonged surgery of 10 h or longer received sevoflurane anesthesia at 1 L/min. Plasma F- concentration was measured and clinical laboratory tests were performed. Intracircuit gas was analyzed to measure the concentration of degradation products. Plasma F- concentration increased during anesthesia, and decreased 3 h after termination. Individual maximum plasma F- concentrations were 38.8-88.6 mumol/L (56.6 +/- 4.7 mumol/L, mean +/- SE). Minimum alveolar anesthetic concentration (MAC) hours (1 MAC = 2.05%) exposure correlated with individual maximum plasma F- concentration (r2 = 0.68, P < 0.01). CF2 = C(CF3)-O-CH2F (compound A) was the only degradation product detected in the circuit. Its individual maximum concentrations were 13.6-35.1 ppm (24.3 +/- 2.4 ppm). Postanesthesia clinical laboratory tests showed no renal impairment and only mild hepatic dysfunction that was not associated with anesthesia. Hyperfluorinemia and minute quantities of compound A were detected following long-duration, low-flow sevoflurane anesthesia.

Plasma Fluoride Concentrations During and After Prolonged Anesthesia

Serum inorganic fluoride concentrations were studied in 19 adult patients undergoing prolonged head and neck surgery with either halothane or isoflurane anesthesia (mean 19.5 and 19.2 MAC-hours, respectively). In the group of nine patients anesthetized with isoflurane, plasma inorganic fluoride increased from a mean concentration of 3.5 mumols/L (baseline) to a peak of 43.2 mumols/L. Forty percent of the patients in the isoflurane group had peak plasma inorganic fluoride concentrations of more than 50 mumol/L. In the group that received halothane, plasma inorganic fluoride concentrations increased from a mean of 3.8 mumols/L to a peak of 12.6 mumols/L. Despite similar exposures to both anesthetics, the differences in serum inorganic fluoride concentrations between the two groups were significant at 10, 24, and 48 h after induction of anesthesia (P = 0.035, P = 0.003, and P = 0.003, respectively). Serum electrolyte, urea, and creatinine concentrations and urine output rates during and after surgery were similar in both groups. We conclude that, after anesthesia of up to 20 MAC-hours, metabolism of isoflurane to inorganic fluoride may be of a greater magnitude than has previously been realized. Although no clinical or biochemical evidence was found to suggest postoperative renal dysfunction, we recommend caution using isoflurane when prolonged anesthesia and surgery are planned.

Plasma Inorganic Fluoride With Sevoflurane Anesthesia

The biotransformation and plasma inorganic fluoride ion production of sevoflurane (the new volatile anesthetic) during and after surgical anesthesia was studied in 50 ASA I or II surgical patients. Twenty-five additional patients served as controls by receiving isoflurane. Sevoflurane or isoflurane was administered with a semiclosed (total gas flow, 2 L/min O2) circle absorption system for durations of 1.0 to greater than 7.0 minimal alveolar concentration (MAC) hours for surgical anesthesia (sevoflurane MAC, 2.05%; isoflurane MAC, 1.15%). Preoperative and postoperative blood urea nitrogen and creatinine concentrations were determined. Blood samples were obtained during and after anesthesia in both groups for determining anesthetic blood concentration analysis and plasma fluoride level. Plasma fluoride concentrations did not significantly increase during isoflurane anesthesia. Sevoflurane biotransformation produced a mean peak plasma inorganic fluoride concentration of 29.3 +/- 1.8 mumol/L, 2 h after anesthesia, which decreased to 18 mumol/L concentration by 8 h after anesthesia. The peak plasma inorganic fluoride ion concentration correlated with duration of sevoflurane anesthetic exposure. Five patients given sevoflurane had peak levels transiently exceeding 50 mumol/L, and one of these had a history of ingesting drugs potentially producing hepatic enzyme induction. No increases in postoperative levels of creatinine, blood urea nitrogen, direct bilirubin, or hepatic transaminase and no changes in serum electrolyte level occurred in either anesthetic group. Indirect bilirubin concentration increased significantly after sevoflurane anesthesia, but the increase was not of clinical significance (from 0.30 +/- 0.03 to 0.38 +/- 0.06 mg/dL). Indirect bilirubin concentrations did not increase after isoflurane anesthesia; the concentrations reached 0.31 +/- 0.04 mg/dL and did not differ significantly from those found with sevoflurane.(ABSTRACT TRUNCATED AT 250 WORDS)

Plasma Inorganic Fluoride Concentrations During and After Prolonged (&gt;24 h) Isoflurane Sedation

We studied the effect of prolonged sedation (greater than 24 h) with isoflurane on plasma inorganic fluoride concentrations and renal function in 60 critically ill patients allocated randomly to receive either isoflurane or midazolam for sedation. In the isoflurane group, plasma fluoride increased from a mean concentration of 3.1 mumol/L to 20.0 mumol/L at the end of sedation, continued to increase to a peak of 25.3 mumol/L 16 h later, and then decreased exponentially (t1/2 = 111 h) to reach normal levels by the fifth day. In the midazolam group, the plasma fluoride increased from a mean concentration of 4.2 mumol/L to a peak of 6.8 mumol/L 12 h after starting the sedation and then decreased toward normal. Serum and urinary electrolytes, urine osmolality, and creatinine clearance during and after sedation were similar in the two groups. Isoflurane sedation was associated with an increase in plasma fluoride concentration without any clinical deterioration of renal function.

ISOFLURANE SEDATION FOR PATIENTS UNDERGOING MECHANICAL VENTILATION: METABOLISM TO INORGANIC FLUORIDE AND RENAL EFFECTS

The metabolism and renal effects of isoflurane sedation were studied for 24 h in patients undergoing mechanical ventilation. Forty-six patients admitted to our intensive therapy unit were allocated randomly to receive either 0.1-0.6% isoflurane or midazolam 0.01-0.2 mg kg-1 h-1 for sedation. In 26 patients sedated with isoflurane, plasma inorganic fluoride increased from a mean concentration of 4.03 mumol litre-1 to 13.57 mumol litre-1 12 h after stopping sedation. Plasma inorganic fluoride concentrations in 20 patients sedated with midazolam were unchanged from baseline values (mean 5.32 mumol litre-1). Serum electrolyte, urea and creatinine concentrations, and urine output rates during and after sedation in patients who received isoflurane were similar to those who received midazolam. We conclude that, following isoflurane sedation for up to 24 h, metabolism to inorganic fluoride is insufficient to cause clinical renal dysfunction.

Isoflurane inhibits enflurane metabolism in man.

Halogenated inhalation anaesthetics interfere with each other's hepatic microsomal metabolism. The increase in plasma inorganic fluoride concentration, caused by the metabolism of a standardised dose of enflurane, was attenuated by isoflurane given either before or after the enflurane exposure. It is concluded that isoflurane inhibits the metabolism of enflurane in man, a fact that might be advantageous in certain clinical situations.

GENERAL ANAESTHESIA FOR CAESAREAN SECTION IN SEVERE PRE-ECLAMPSIA: Comparison of the renal and hepatic effects of enflurane and halothane

In a randomized study of patients undergoing Caesarean section, either enflurane (mean 0.24 MAC-h) or halothane (mean 0.23 MAC-h) and 50% nitrous oxide in oxygen were administered to women (n = 12) with severe pre-eclampsia-eclampsia and to 16 healthy pregnant patients with normal renal and hepatic function. No evidence of nephrotoxicity was found in any pre-eclamptic or normal patient. Metabolism of enflurane resulted in plasma inorganic fluoride concentrations (max 15 mumol litre -1) which were well below the toxic value. Postoperative liver function tests showed no important changes from preoperative values, although reductive metabolites of halothane were not measured. In patients with severe pre-eclampsia there appears no contraindication to enflurane or, probably, halothane as volatile supplements during general anaesthesia.