Portal de Periódicos da CAPES

The Hepatic Effects of Sevoflurane

1995; Lippincott Williams & Wilkins; Volume: 81; Issue: Supplement Linguagem: Inglês

10.1097/00000539-199512001-00007

1526-7598

Edward J. Frink,

Intensive Care Unit Cognitive Disorders

When evaluating the usefulness and safety of a new volatile anesthetic, the effects on hepatocellular function and integrity are paramount. As experienced in the past with the anesthetic halothane, biotransformation can produce undesirable results, including fulminant hepatocellular necrosis. However, we have learned much from halothane, and armed with the knowledge obtained from this anesthetic, we are better able to evaluate new anesthetics. This review will evaluate the effects of sevoflurane on liver function. Sevoflurane has many desirable clinical attributes, including a low blood-gas solubility coefficient, which provides rapid induction and emergence, and a nonpungent smell. With respect to the evaluation of sevoflurane's effects on liver function, three areas of concern require attention: 1) Does the anesthetic produce hepatotoxicity either directly or via metabolites? 2) How does the inhaled anesthetic alter hepatic perfusion and oxygenation? 3) How does the anesthetic influence hepatocellular metabolic function? Hepatotoxic Potential Much has been learned from halothane about the hepatotoxicity of inhalation anesthetics. After the introduction of halothane into clinical practice, there were several anecdotal reports of hepatocellular injury [1,2]. Although the phenomenon of rare toxicity appeared real, the mechanisms of hepatic injury have taken years to elucidate because of the paucity of cases. The mechanism currently favored is hepatic biotransformation of the anesthetic with the production of reactive metabolites and the binding of these products to liver macromolecules, which then elicits an immune response [3,4] in a small number of individuals. Based on our knowledge of halothane hepatotoxicity, what can we say about sevoflurane's potential for producing an immune-mediated liver injury? There is now an extremely large patient base of anesthetic exposure to sevoflurane, including approximately 2 million anesthetic procedures in Japan; however, this is a relatively isolated genetic population that may not reflect results in more diverse populations. More than 3000 administrations have been done during clinical trials in the United States and Europe. Sevoflurane has been utilized in several patient populations without evidence of hepatotoxicity. Current concepts regarding the initiation of halothane hepatotoxicity include the following sequence: 1) biotransformation forming a metabolite that has at least a moderate degree of reactivity to proteins (trifluoroacetyl chloride in the case of halothane); 2) covalent binding of the metabolite(s) to contiguous hepatic proteins forming a hapten; 3) production of an immune response to this hapten in certain susceptible individuals leading to hepatocellular necrosis Figure 1.Figure 1: Biotransformation of halothane, isoflurane, and desflurane producing metabolites capable of liver protein binding. The product of halothane is then capable of functioning as a hapten to elicit an immune response. The products of isoflurane and desflurane are theoretically capable of initiating a similar immune response; however, the quantity of metabolite is much less than with halothane.This sequence has been implicated in the production of halothane-induced hepatic necrosis. Antibodies to the trifluoroacetic acid (TFA) metabolite protein complex are present in patients with halothane hepatitis [5,6]. Other inhaled anesthetics have TFA as a metabolic product. Isoflurane and, to an even lesser extent, desflurane, are biotransformed to TFA [7,8]. However, the degree of biotransformation of these anesthetics is much less than that of halothane, which may prevent--or greatly reduce--the production of hapten sufficiently to prevent an immune response Figure 1. Sevoflurane appears to have an extremely low potential to initiate such a cascade. Absorbed sevoflurane is biotransformed to a lesser degree than halothane (3%-5% vs 18%-25%), and less total mass of metabolite is produced [9,10]. Another mode of decreasing hepatotoxic potential is a qualitative, rather than quantitative, change in metabolite production. As shown in Figure 2, the organic metabolite of sevoflurane is not TFA, but a unique compound, hexafluoroisopropanol (HFIP). Based on chemical reactivity, this compound has much less protein binding capability than TFA. In addition, the HFIP produced does not accumulate, but rapidly undergoes phase II biotransformation, specifically glucuronidation to form HFIP-glucuronide. This compound is rapidly excreted in the urine. Most is excreted in 12 h and none is present beyond 2 days after anesthesia [9,11]. This is in contrast to halothane, where TFA is detectable in urine for up to 12 days after 75 min of anesthesia [10]. In a study by Strum et al. [12], sevoflurane was compared to isoflurane, with or without soda lime, to evaluate the potential for hepatic toxicity in rats. The authors found that sevoflurane had no more hepatotoxic potential than isoflurane in these animals. An early investigation in human volunteers [13] showed that there were no changes in serum aminotransferase levels after sevoflurane anesthesia. In direct comparison with isoflurane in surgical patients [14], or enflurane anesthesia in volunteers [15], sevoflurane produced no differences in plasma aspartate aminotransferase or alanine aminotransferase levels. Recently, Green et al. [16] evaluated the degree of organic fluoride binding to hepatic protein in rats after anesthesia using a sodium fusion analytical technique. In contrast to halothane, sevoflurane and desflurane did not show an increase in covalently bound fluorine over control (unanesthetized) values Figure 3. These results suggest that the ability of free HFIP, and HFIP-glucuronide, to bind to liver macromolecules is low and may preclude the initiation of an immune-mediated response. Based on current data, it appears that the hepatotoxic potential of sevoflurane is quite low.Figure 2: Hepatic cytochrome P-450 biotransformation of sevoflurane leads to the production of inorganic fluoride ion and the organic product hexafluoroisopropanol, which is rapidly glucuronidated.Figure 3: Amount of fluorine bound to hepatic protein after exposure to 1.5 minimum alveolar anesthetic concentration sevoflurane, halothane, or desflurane in rats. [Data from Green WB et al. [16].] *Differs from control value (P < 0.05).Effects on Hepatic Perfusion All inhaled anesthetics now in use reduce hepatic perfusion, generally in a dose-related fashion. Altered hepatic blood flow and oxygenation may have an impact on hepatocellular damage, as well as hepatocellular function and hepatic drug clearance. Halothane has generally been shown to reduce both hepatic arterial and portal venous blood flow with increasing anesthetic concentrations [17]. Isoflurane, however, reduces portal blood flow and maintains hepatic arterial blood flow, or may actually increase it over unanesthetized values [18,19]. Sevoflurane has been well studied with respect to its influence on hepatic perfusion. Initial studies by Manohar and Parks [20] evaluated organ blood flow using radiolabeled microspheres in a porcine model. Exposure to 1.0 or 1.5 minimum alveolar anesthetic concentration (MAC) sevoflurane with 50% nitrous oxide produced an increase in hepatic arterial flow at both anesthetic levels, whereas there were modest decreases in intestinal blood flow. Crawford et al. [21] studied hepatic blood flow in sevoflurane-anesthetized rats and found preservation of total hepatic blood flow with increases in hepatic arterial flow (25% at 1.0 MAC; 31% at 1.5 MAC). However, these animals had concomitant hypercarbia during spontaneous ventilation. In a subsequently study by Conzen et al. [22], sevoflurane and isoflurane maintained total liver blood flow at an anesthetic concentration that reduced mean arterial pressure to 70 mm Hg, but decreased total liver flow when mean arterial pressure was reduced to 50 mm Hg. Fujita et al. [23] evaluated the effects of 1.5 MAC halothane, isoflurane, or sevoflurane on portal venous blood flow and hepatic oxygenation in a beagle dog model. In this model the hepatic artery was ligated so that there was no contribution of arterial flow to hepatic perfusion, in order to mimic the interruption of hepatic arterial flow in clinical practice. Sevoflurane reduced portal flow and oxygen delivery more than isoflurane, but did not reduce hepatic oxygen (O2) consumption as much as halothane. The hepatic O2 supply/uptake ratio was less with sevoflurane than with halothane or isoflurane. The results suggest that if hepatic arterial flow is compromised, there may be a smaller margin of safety against hypoxia with sevoflurane compared to halothane or isoflurane. Sevoflurane appears to be similar to isoflurane in terms of preserving or increasing hepatic arterial blood flow compared to unanesthetized values. The effect of sevoflurane on hepatic blood flow has recently been compared to other inhaled drugs in a chronically instrumented greyhound model [24]. This type of study allows evaluation of anesthetic influence on blood flow without the effects of surgical intervention and permits awake, unanesthetized control measurements for comparison. Results of this investigation showed that sevoflurane and isoflurane preserved hepatic arterial blood flow better than enflurane and significantly better than halothane Figure 4. All anesthetics reduced portal blood flow, with halothane producing the most pronounced results. Sevoflurane maintained hepatic blood flow and O2 delivery at concentrations less than 2.0 MAC, comparable to results observed with isoflurane. Sevoflurane 2.0 MAC anesthesia reduced O2 delivery, which was not balanced by a further reduction in hepatic O2 consumption, as occurred with isoflurane anesthesia. Other signs of hepatic impairment, such as hepatic lactate uptake, have not been examined with sevoflurane anesthesia. These results were substantiated by Bernard et al. [25] in a similar model using mongrel dogs that compared the effects of isoflurane and sevoflurane on hepatic blood flow. Portal venous blood flow was reduced substantially only at the 2.0 MAC level. Hepatic arterial flow, which was shown to be well maintained in the study by Frink et al. [18], was actually increased over control values with increasing anesthetic depth (this same phenomenon has been noted in other studies during isoflurane anesthesia). Data from these animal models suggest that sevoflurane maintains good hepatic blood flow and liver oxygenation at concentrations less than 2.0 MAC in a fashion comparable to that observed with isoflurane anesthesia. Although there are no available data on hepatic blood flow measurements in humans, previous studies in animals with other inhaled anesthetics (e.g., halothane and isoflurane) have generally mirrored the effects found in subsequent studies in humans.Figure 4: Dose-dependent effect of inhaled anesthetics on hepatic arterial blood flow in chronically instrumented dogs in the absence of surgical stress. Sevoflurane and isoflurane preserve hepatic arterial blood flow even at higher minimum alveolar anesthetic concentration (MAC) levels. [Data from Frink et al. [24].] dagger Differs from sevoflurane at same MAC value (P < 0.05); *differs from sevoflurane and isoflurane at same MAC values (P < 0.05).Hepatic Metabolic Function The effects of inhaled anesthetics on metabolic function have been studied by evaluating either altered drug clearance (e.g., when halothane administration alters the clearance of another concomitantly administered drug) or the protein manufacturing/secretory capability of the liver. Franks et al. [26] evaluated the potential for inhaled anesthetics, including sevoflurane, to depress protein synthesis by the liver using an isolated perfused rat liver system. All inhaled anesthetics (halothane, sevoflurane, isoflurane, and enflurane) at 1.3 MAC were capable of decreasing the albumin, transferrin, and fibrinogen synthesis during the 4-h liver perfusion, but there were no statistical differences between the four anesthetics. Sevoflurane decreased synthesis of the three proteins by 60%-70%. The clinical implications of these results are at present unclear. Sevoflurane and desflurane were studied with regard to hepatic metabolism and albumin binding of diazepam using an in vitro rat liver slice model [27]. In the absence of albumin in this model there was evidence that both sevoflurane and desflurane reduced diazepam elimination (possibly due to reduced hepatic enzyme activity); however, the inhibition with both anesthetics was less than the reduction in diazepam elimination reported with halothane exposure in a previous investigation by these authors using the same model [28]. When albumin was added to the system, as would be the case in vivo, both sevoflurane and desflurane actually increased elimination of diazepam, presumably by displacement of diazepam from albumin, producing an increase in the free fraction of diazepam. Diazepam is a low extraction drug, and the clearance of drugs with a higher hepatic extraction ratio could be decreased by changes in liver blood flow produced by sevoflurane. The clinical relevance of these in vitro observations on protein binding is uncertain [29]. Fujita et al. [23] evaluated indocyanine green (ICG) clearance and portal blood flow during sevoflurane anesthesia. ICG clearance was less altered with sevoflurane anesthesia than with halothane anesthesia. ICG clearance did not differ between sevoflurane and isoflurane anesthesia. The authors interpreted these results to indicate that hepatic metabolic function was better preserved with sevoflurane than with halothane anesthesia. There are no human data regarding hepatic drug metabolizing capability during the administration of sevoflurane anesthesia. In summary, insight gained with previously developed inhaled anesthetics allows us to evaluate new inhaled anesthetics with greater accuracy. Although the possibility for the unexpected exists, many of the principles of inhaled anesthetic physiologic effects and potential for toxicity remain the same. Research thus far indicates that the effect of sevoflurane on the liver in terms of hepatic perfusion and metabolic function is similar to that of isoflurane. Available data support sevoflurane as having a low potential to produce hepatotoxicity from metabolism by cytochrome P-450 enzymes. At present, it appears that sevoflurane has no detrimental effect on overall hepatic function.