In this study, both the patients with grade B liver dysfunction and normal liver function inhaled sevoflurane with 1.5 MAC during the maintenance of anesthesia. Free HFIP could be detected in the two groups at 0.5 hour after inhalation of sevoflurane. It indicates that sevoflurane can be rapidly metabolized by the liver, which has been confirmed in some related studies[,].The increase of free HFIP content in the initial phase should be due to the increase of its generation from sevoflurane in the liver. The subsequent reduction of free HFIP content in the blood may mainly relate to its excretion from the kidney with a conjugated form. It implied that the level of free HFIP in the blood did not continuously increase with the prolongation of anesthesia time. Although no significant difference was found in the peak concentration of free HFIP between the two groups, the time to reach the peak concentration in the group with grade B liver dysfunction was delayed for 1 h when compared with that in the group with normal liver function. It indicates that the liver function of grade B still has some influence on the metabolism of sevoflurane, which may be associated with some changes in the biological enzyme about sevoflurane metabolism. Studies have shown that the activity of enzyme CYP 2E1 related to sevoflurane metabolism is normal in cirrhotic patients with liver dysfunction[,], and the expression of CYP 2E1 decreased significantly only in patients with severe cirrhosis[]. However, the content of uridine diphosphoglucuronyl transferase (UDPGT) involved in phase Ⅱ reaction of sevoflurane metabolism increased significantly in patients with liver cirrhosis[]. Therefore, we speculate that the delayed peak time of free HFIP in patients with grade B liver dysfunction may result from the up-regulation of UDPGT. Glucuronidation is beneficial to the excretion of sevoflurane metabolites, which may be a compensatory response after liver injury. The concentrations of free HFIP in the group with grade B liver dysfunction were slightly lower than those in the group with normal liver function in the initial stage of inhalation. However, they had no significant difference after discontinuation of inhalation anesthesia. It indicates that grade B liver dysfunction has no significant effect on the total metabolic level of sevoflurane. The blood/gas partition coefficient of HFIP (452) measured in this study is about 680 times of sevoflurane (0.66)[]. It means the elimination of HFIP from the body will become very slow. Some studies have shown that HFIP can still be detected in the blood at 24 hours after sevoflurane anesthesia [][4]. However, the complete elimination time of HFIP needs further study.
HFIP may affect the recovery from anesthesia due to its central nervous system inhibitory action. It may delay the anesthesia recovery time, even result in the occurrence of emergence agitation during recovery. In this study, longer recovery time and deeper sedation and analgesia were found in the patients with grade B liver dysfunction than the patients with normal liver function during the period of anesthesia recovery (Table 4–5). Is this phenomenon caused by the retained free HFIP in the body? Our results indicate that the concentrations of free HFIP both in the two groups are deficient, and have no statistically significant difference in the period of recovery. Therefore, even if the free HFIP content influences the recovery of anesthesia, it should be consistent and slight in the two groups. The relatively deep sedation and analgesia in patients with grade B liver dysfunction may be mainly related to slow metabolism of intravenous anesthetics and the accumulation of sevoflurane in the body. Studies have shown that the metabolism of intravenous anesthetics is often affected by poor liver function, impaired hepatic perfusion, increased extrahepatic shunt and decreased plasma protein synthesis, etc.[][]
As all know, the metabolism of drugs is mainly mediated by the cytochrome P450 (CYPs) in the liver[]. The contents and activities of enzymes, such as CYP 1A,2C19 and 3A mainly involved in the metabolism of propofol, midazolam and opioids, are easily affected by liver diseases[19,20]. Intravenous anesthesia with propofol is easy to cause hemodynamic fluctuation, which has a significant individual difference. Studies have confirmed that the pharmacokinetics of propofol is not affected by a single intravenous injection in cirrhotic patients[][]. However, the elimination half-life of fentanyl prolonged 4–5 times and the blood free concentration of diazepam increased obviously in patients with liver cirrhosis[]. Patients with liver dysfunction may delay drugs’ metabolism and affect patient’s recovery quality from anesthesia. Therefore, the dosage of these intravenous anesthetic drugs should be reduced appropriately, especially in the period of postoperative analgesia for those patients with liver dysfunction. The result of this study shows that almost no difference exists in the degree of sevoflurane metabolism in the two groups, except the delay of HFIP’s peak time in the group with grade B liver dysfunction. Therefore, patients with liver dysfunction are recommended to use inhalation anesthesia with sevoflurane and reduce the amount of intravenous anesthetics, especially fentanyl.
This study only observed one trend of free HFIP in the blood for one inhaled sevoflurane concentration, and did not study the effects of more severe liver dysfunction, such as grade C, on the metabolism of sevoflurane. Therefore, the effects of different inhaled sevoflurane concentrations and different liver function status on the level of HFIP and anesthesia recovery quality needs further study.
In summary, the status of grade B liver dysfunction can significantly delay the peak time of HFIP, but not affect the degree of sevoflurane metabolism when compared with normal liver function.