某醫學中心重症病人Amiodarone相關肝傷害之研究

Abstract

Amiodarone為一抗心律不整藥品，其效用及應用廣而常見於臨床使用。然而amiodarone易引起許多副作用，經臨床文獻回顧發現肝毒性並非罕見，其中不乏死亡案例，但臨床使用上此副作用卻常被輕忽，而迄今有關amiodarone引致肝毒性相關危險因子報導極有限。本研究旨在探討國內醫學中心amiodarone處方及相關肝傷害之因子以及臨床上遵照North American Society for Pacing and Electrophysiology (NASPE)治療指引監測相關潛在副作用之比率。 本研究係世代研究，採病歷回顧方式取得相關資料。研究對象為2011年2月至2013年1月新使用amiodarone口服或靜脈注射之加護病房住院患者，包含成人以及小兒。病人若有肝功能異常之相關體質，諸如已存在之肝臟疾病、 病毒性肝炎以及懷孕等皆被排除。本研究定義肝傷害為alanine aminotransferase (ALT)值大於或等於正常值上限3倍以上; total bilirubin (T-bil)值大於正常值上限2倍以上; alkaline phosphatase (ALP)值大於正常值上限1.5倍以上（僅限於成人）。以獨立樣本t檢定、Wilcoxon等級和檢定、卡方檢定以及對數等級檢定分析病例組與對照組之間連續變項分布狀況及類別變項之差異性，並使用存活分析探討時間相依之相關因子。本研究共納入275名病人，其中61名在使用amiodarone後，發生肝功能檢測值異常。在遵照NASPE指引監測各類相關副作用方面，無論是使用藥品前各類應監測之基礎值或是使用藥品期間之相關監測比率皆偏低。研究顯示amiodarone相關肝傷害之因子包含基礎肝功能檢測異常 (HR, 5.31; 95% CI, 3.11-9.06; p < 0.001)、靜脈注射劑量佔肝毒性當日總計量百分比 (HR, 1.01; 95% CI, 1.00-1.02; p = 0.02)、總累積劑量除以體表面積大於3800 mg/m2 (HR 8.11; 95% CI, 1.84-35.84, p = 0.006)、 肝毒性當日之日處方劑量和 (HR 1.00; 95% CI, 1.00-1.00; p = 0.01)、因陣發性上心室心搏過速使用amiodarone (HR, 6.21; 95% CI, 1.39-27.88; p = 0.02)、使用葉克膜 (HR, 3.46; 95% CI, 1.84-6.53; p < 0.001)、住院期間發生過低血壓 (HR, 3.02; 95% CI, 1.64-5.54; p = 0.0004)以及本身有先天性心臟疾病 (HR, 8.95; 95% CI, 3.42-23.40; p < 0.001)、動脈瘤 (HR, 3.93; 95% CI, 1.13-13.70; p = 0.03)或甲狀腺低下 (HR, 8.10; 95% CI, 1.06-62.02; p = 0.04)。多數肝傷害發生於基礎ALT、T-bil或ALP功能表現異常者。本研究找出預測amiodarone相關肝傷害因子之實證，其中總累積劑量除以體表面積為3800 mg/m2之數值或可做為臨床是否持續處方之臨界參考值，可增益amiodarone於臨床上使用之有效性及安全性。

Amiodarone-induced hepatotoxicity is not uncommon and fatal cases have been reported. However, hepatic adverse effects of amiodarone are often neglected in clinical practice. The effectiveness and applicability of amiodarone make it a widely used antiarrhythmic agent. Nonetheless, research to delineate predisposing factors of amiodarone-related liver injury for promoting safe use of amiodarone is still limited. The aims of the study are: (1) to identify risk factors associated with amiodarone-related liver injury, and (2) to examine guideline adherence rate of potential adverse-effect monitoring set by the North American Society for Pacing and Electrophysiology (NASPE) at a 2500-bed medical center in Taiwan. This cohort study was conducted on new users of oral or intravenous (IV) amiodarone, initiated at pediatric or adult intensive care units during February 2011 and January 2013, through medical chart review. Patients with pre-existing liver diseases, viral hepatitis, or pregnancy were excluded. Liver injury was defined as alanine aminotransferase (ALT) higher than or equal to 3 times of upper limit of normal (ULN); total bilirubin (T-bil) exceeding 2 times of ULN; or, alkaline phosphatase (ALP) higher than 1.5 times of ULN (adults only). Two-sample t test, Wilcoxon rank-sum test, chi-square test, and log-rank test were used to examine the differences in the distributions of continuous variables, categorical variables, and time-to-event outcomes between the case and control groups. Cox’s proportional hazards model was applied to estimate the effects of associated factors or predictors on continuous, binary, and time-dependent outcomes. A total of 275 patients were recruited and 61 patients (22.2%) developed liver injury. Adherence to NASPE monitoring guideline was poor, both at baseline and during follow-up periods. Identified predictors for amiodarone-related hepatic injury included baseline liver function test abnormalities (HR, 5.31; 95% CI, 3.11-9.06; p < 0.001), percentage of IV versus total daily amiodarone dosage on the event day (HR, 1.01; 95% CI, 1.00-1.02; p = 0.02), amiodarone cumulative dosage divided by body surface area higher than 3800 mg/m2 (HR, 8.11, 95% CI, 1.84-35.84; p =0.006), amiodarone daily dosage on the event day (HR, 1.00; 95% CI, 1.00-1.00; p = 0.01), with diagnosis of paroxysmal supraventricular tachycardia (HR, 6.21; 95% CI, 1.39-27.88; p = 0.02), under extracorporeal membrane oxygenation (HR, 3.46; 95% CI, 1.84-6.53; p < 0.001), with hypotensive events during hospital stay (HR, 3.02; 95% CI, 1.64-5.54; p = 0.0004), and with comorbid conditions such as congenital heart disease (HR, 8.95; 95% CI, 3.42-23.40; p < 0.001), aneurysm (HR, 3.93; 95% CI, 1.13-13.70; p = 0.03), and hypothyroidism (HR, 8.10; 95% CI, 1.06-62.02; p = 0.04). Liver toxicity with amiodarone may occur at 3800 mg/m2 body surface area. These predictors for amiodarone-related liver injury and threshold of dose-limiting toxicity recognized by the study may help safe and effective use of amiodarone in the future.