七氟烷与肝毒性

以下文章来源于小麻哥的日常 ，作者两只小绵羊

本文由“小麻哥的日常”授权转载

前言

七氟烷是最常用的挥发性麻醉剂之一，特别适用于门诊麻醉，具有出色的安全记录。七氟烷与类似于氟烷性肝炎的罕见严重急性肝损伤的单一病例报告有关。

背景

七氟烷是一种广泛使用的主要麻醉剂，起效快，扩散快。由于其起效迅速且对气道没有刺激性，七氟醚可用于麻醉诱导和麻醉维持。七氟醚于1995年在美国上市。七氟醚必须在受控情况下由经过适当培训和认证的麻醉医师或麻醉护士给药，通常以 2% 至 4% 的浓度与氧气一起给药。

肝毒性

前瞻性连续血液检测通常显示大手术后 1-2 周内血清氨基转移酶水平轻微短暂升高。 然而，ALT水平高于正常上限的10倍是明显不寻常的，并表明存在明显的肝毒性。 临床上明显的七氟醚引起的严重肝损伤非常罕见，仅发表了孤立的病例报告。 损伤的特征是血清转氨酶水平急性升高（5-50 倍）和术后 2-21 天内出现黄疸。 碱性磷酸酶和γ谷氨酰转肽酶水平通常有轻微增加。 黄疸通常先发烧一两天，并可能伴有皮疹和嗜酸性粒细胞增多。 急性肝损伤可能是自限性的，并在 4-8 周内消退，但可能很严重，并伴有急性肝衰竭。 一个强大的危险因素是既往接触过任何卤化麻醉剂，尤其是氟烷性肝炎病史或使用这些药物之一麻醉后不明原因的发热和皮疹。 手术和麻醉后急性肝损伤的鉴别诊断有时很困难，类似于七氟醚诱导的肝炎的临床表现可能由休克或缺血、败血症、其他特异质形式的药物性肝损伤和急性病毒性或疱疹性肝炎引起。 可能性评分：B（极有可能的临床上明显肝损伤的原因）。

损伤机制

七氟烷肝毒性的机制被怀疑与氟烷相似，并且与反应性中间体的产生有关。 七氟醚通过微粒体药物代谢酶CYP 2E1在小程度上代谢为三氟乙酰化反应中间体（TFA），该中间体能够与多种细胞浆蛋白结合，形成潜在的免疫原性加合物。TFA加合物诱导的抗体可以在七氟烷和氟烷肝毒性患者中检测到，并且在暴露于挥发性麻醉剂的医护人员中也存在一定比例。

结局和处理

严重程度从无症状或其他肝损伤证据的轻度和短暂性转氨酶升高，到对严重急性肝衰竭的自限性症状性急性肝炎样反应。 严重程度和预后可能与患者年龄有关，在老年人中更严重，在儿童中更轻且不太常见。 肥胖也可能既是诱发因素，也是结果的预测因素。 七氟烷暴露引起的慢性肝损伤尚未描述。 应警告七氟烷诱发的肝炎患者将来不要暴露于氟化烃麻醉剂，例如氟烷、恩氟烷、异氟烷或地氟烷。 药物类别：卤化麻醉剂   同类其他药物：地氟烷、恩氟烷、氟烷、异氟烷

病例报告

案例1.疑似七氟醚诱发急性肝损伤。

[修改自药物性肝损伤网络数据库中的案例] 一名49岁的女性接受了使用咪达唑仑、芬太尼、丙泊酚和七氟醚的膝关节镜手术。她在手术时接受了头孢唑啉的单次静脉输注。手术后 4 天，她出现恶心、胃灼热和瘙痒，随后出现深色尿液。她过去曾接受过三次全身麻醉，但前一年没有，使用的麻醉剂也不得而知。入院时，她无发热，体格检查显示黄疸和轻度肝压痛。实验室检查显示血清酶升高，总胆红素为4. 0 mg/dL。没有嗜酸性粒细胞增多。甲型、乙型和丙型肝炎以及自身抗体检测结果正常。肝脏超声检查显示胆囊息肉，但没有胆道梗阻的证据。肝活检显示胆汁淤积性肝炎伴轻度胆管损伤。她恢复迅速，无症状，几周后肝脏检查正常。

评论  

该患者在七氟烷麻醉下手术后3周内出现黄疸和肝损伤。虽然审查医生将肝损伤归因于麻醉剂，但发病模式（潜伏期为3周）、临床特征（无发热、早期出现瘙痒）和肝脏组织学（胆汁淤积）是麻醉剂诱导的肝毒性的非典型特征，而青霉素或头孢菌素诱导的肝病更具特征性。尽管最初的肝酶升高是“肝细胞性”，但肝活检提示胆汁淤积性肝炎。事实上，该案后来被重新裁定为很可能是由于头孢唑啉而不是七氟烷引起的。

案例2.七氟醚诱导急性肝损伤。  

[修改自：Singhal S，Gray T，Guzman G，Verma A，Anand K.七氟烷肝毒性：七氟烷肝坏死的病例报告和文献综述。Am J Ther 2010; 17: 219-22. PubMed Citation] 一名37岁男子在咪达唑仑、一氧化二氮、丙泊酚和七氟烷麻醉下接受了腹壁肿块切除术，并于同日出院。手术三天后，他出现了恶心、呕吐、腹痛和黄疸。他没有肝病、药物反应、酗酒或病毒性肝炎危险因素病史。四年前，他在全身麻醉下接受了阑尾切除术，但使用的麻醉剂尚不清楚。其他药物包括使用可待因和对乙酰氨基酚（每天<1克）进行术后疼痛管理。入院时，实验室检查显示轻度黄疸（总胆红素 4.2 mg/dL，直接胆红素 1.8 mg/dL），但血清转氨酶水平显著升高（ALT 3364 U/L，AST 3013 U/L），碱性磷酸酶 （336 U/L） 和轻度嗜酸性粒细胞增多。这些值在一周前进行术前评估时已轻度升高（表）。甲型和乙型肝炎以及自身抗体的检测结果正常。Ebstein Barr病毒检测提示近期感染。肝脏超声检查未显示胆结石或胆道梗阻的证据。在入院后的最初几天，他因黄疸和凝血功能障碍加深而恶化，INR 上升至 4.8。肝活检显示中心眼坏死、炎症和胆汁淤积伴轻微或无纤维化，提示急性药物性肝损伤。考虑过肝移植，但随后他开始自发改善，在接下来的 4 个月里，他的症状消退，肝脏检查结果恢复正常。

评论  

该患者在七氟烷麻醉下手术后3天内出现黄疸和严重肝损伤。临床病程为典型的卤代麻醉性肝损伤，起病迅速，轻度嗜酸性粒细胞增多，肝细胞型损伤，病程严重。危险因素包括既往麻醉（尽管使用的药物尚不清楚）。无法解释的是手术前获得的异常肝脏检查和EBV感染的模棱两可的血清学检查。没有提供丙型和戊型肝炎的测试结果。  

Sevoflurane

Last Update:January 1, 2018.

OVERVIEW  

Introduction  

Sevofurane is one of the most commonly used volatile anesthetic agents, particularly for outpatient anesthesia and has an excellent safety record. Sevoflurane has been implicated in rare single case reports of severe acute liver injury similar to halothane hepatitis.

Background  

Sevoflurane (see' voe flur' ane) is a widely used major anesthetic agent with rapid onset of action and rapid dispersal. Because of its rapid onset of action and lack of irritability to the airways, sevoflurane can be used to both induce and maintain anesthesia. Sevoflurane became available for use in the United States in 1995. Sevoflurane must be administered in a controlled situation by a properly trained and credentialed anesthesiologist or nurse anesthetist and is typically given in concentrations of 2% to 4% with oxygen.

Hepatotoxicity  

Prospective, serial blood testing often demonstrates minor transient elevations in serum aminotransferase levels in the 1 to 2 weeks after major surgery. Appearance ofALT levels above 10 times the upper limit of normal, however, is distinctly unusual and points to significant hepatotoxicity. Clinically apparent, severe hepatic injury from sevoflurane is very rare, only isolated case reports having been published. The injury is marked by acute elevations in serum aminotransferase levels (5- to 50-fold) and appearance of jaundice within 2 to 21 days of surgery. There are usually minimal increases in alkaline phosphatase and gammaglutamyl transpeptidase levels. Jaundice is usually preceded by a day or two of fever and may be accompanied by rash and eosinophilia. The acute liver injury may be self-limited and resolve within 4 to 8 weeks, but can be severe and associated with acute liver failure. A strong risk factor is previous exposure to any of the halogenated anesthetics and particularly a history of halothane hepatitis or unexplained fever and rash after anesthesia with one of these agents. The differential diagnosis of acute liver injury after surgery and anesthesia is sometimes difficult, and a clinical picture similar to sevoflurane induced hepatitis can be caused by shock or ischemia, sepsis, other idiosyncratic forms of drug induced liver injury and acute viral or herpes hepatitis.   Likelihood score: B (highly likely cause of clinically apparent liver injury).  

Mechanism of Injury  

The mechanism of sevoflurane hepatotoxicity is suspected to be similar to that of halothane and associated with creation of reactive intermediates. Sevoflurane is metabolized to a small extent by the microsomal drug metabolizing enzyme CYP 2E1 to a trifluoroacetylated reactive intermediate (TFA) that is capable of binding to multiple intracytoplasmic proteins forming potentially immunogenic adducts. The TFA adducts induce antibodies that can be detected in patients with sevoflurane- as well as halothane hepatotoxicity and are also found in a proportion of health care workers exposed to the volatile anesthetics.

Outcome and Management  

Severity ranges from mild and transient aminotransferase elevations without symptoms or other evidence of liver injury, to a self limited symptomatic acute hepatitis-like reaction to a severe, acute hepatic failure. The severity and prognosis may relate in part of patient age, being more severe in the elderly and both milder and less common in children. Obesity may also be both a predisposing factor and predictor of outcome. Chronic liver injury from sevoflurane exposure has not been described. Patients with sevoflurane induced hepatitis should be cautioned against future exposure to a fluorinated hydrocarbon anesthetic such as halothane, enflurane, isoflurane or desflurane. Drug Class:Halogenated Anesthetics   Other Drugs in the Class:Desflurane, Enflurane, Halothane, Isoflurane  

CASE REPORTS  

Case 1. Suspected sevoflurane induced acute liver injury.  

[Modified from a case in the database of the Drug-Induced Liver Injury Network] A 49 year woman underwent arthroscopic surgery on her knee using midazolam, fentanyl, propofol and sevoflurane. She received a single IV infusion of cefazolin at the time of surgery. Eighteen days after surgery, she developed nausea, heartburn, and pruritus followed by dark urine. She had undergone general anesthesia three times in the past, but not in the previous year and the anesthetics used were not known. On admission, she was afebrile and physical examination revealed jaundice and mild hepatic tenderness. Laboratory tests showed elevations in serum enzymes and a total bilirubin of 4.0 mg/dL. There was no eosinophilia. Tests for hepatitis A, B and C and autoantibodies were normal. A liver ultrasound showed a gall bladder polyp, but no evidence of biliary obstruction. A liver biopsy showed cholestatic hepatitis with mild bile duct injury. She recovered rapidly and was asymptomatic and had normal liver tests a few weeks later.

Comment

This patient developed jaundice and hepatic injury within 3 weeks of surgery under sevoflurane anesthesia. While the liver injury was attributed to the anesthetic by the reviewing physicians, the pattern of onset (latency of 3 weeks), clinical features (absence of fever, early appearance of pruritus) and liver histology (cholestasis) were atypical of anesthetic induced hepatotoxicity and more characteristic of penicillin or cephalosporin induced liver disease. The liver biopsy suggested a cholestatic hepatitis, even though the initial liver enzyme elevations were “hepatocellular”. Indeed, this case was later re-adjudicated as being very likely due to cefazolin rather than sevoflurane.

Case 2. Sevoflurane induced acute liver injury.  

[Modified from: Singhal S, Gray T, Guzman G, Verma A, Anand K. Sevoflurane hepatotoxicity: a case report of sevoflurane hepatic necrosis and review of the literature. Am J Ther 2010; 17: 219-22.PubMed Citation]   A 37 year man underwent resection of an abdominal wall mass under midazolam, nitrous oxide, propofol and sevoflurane anesthesia and was discharged the same day. Three days after surgery, he developed nausea, vomiting, abdominal pain and jaundice. He had no history of liver disease, drug reactions, alcohol abuse or risk factors for viral hepatitis. He had undergone an appendectomy under general anesthesia four years previously, but the anesthetics used were not known. Other medications included postoperative pain management with codeine and acetaminophen (<1 gram daily). On admission, laboratory tests showed mild jaundice (total bilirubin 4.2 mg/dL, direct 1.8 mg/dL), but marked elevations in serum aminotransferase levels (ALT 3364 U/L, AST 3013 U/L) and minimal increase in alkaline phosphatase (336 U/L) and mild eosinophilia. These values had been mildly elevated one week previously at the time of a preoperative evaluation (Table). Tests for hepatitis A and B and autoantibodies were normal. Tests for Ebstein Barr virus suggested recent infection. A liver ultrasound showed no gallstones or evidence of biliary obstruction. During the first few days after admission he worsened with deepening jaundice and coagulopathy, the INR rising to 4.8. A liver biopsy showed centrolobular necrosis and inflammation and cholestasis with minimal or no fibrosis, suggestive of acute drug induced liver injury. Liver transplantation was considered, but he then began to improve spontaneously and over the next 4 months his symptoms resolved and liver test results returned to normal.  

Comment

This patient developed jaundice and severe hepatic injury within 3 days of surgery under sevoflurane anesthesia. The clinical course was typical of halogenated anesthetic liver injury with a rapid onset, mild eosinophilia, a hepatocellular pattern of injury and severe course. Risk factors included previous anesthesia (although the agent used was not known). Unexplained were the abnormal liver tests obtained before surgery and the equivocal serology of EBV infection. Results of tests for hepatitis C and E were not provided.=

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