clinical applications and acute Hepatotoxicity of Intravenous Amiodarone

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1 The Journal of International Medical Research 2009; 37: [first published online as 37(6) 4] Clinical Applications and Acute Hepatotoxicity of Intravenous Amiodarone X HUANG, Y YANG, J ZHU, X GAO, G WANG, H TAN, Y LIANG AND J LI Emergency Centre of Cardiovascular Institute and Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China This cross-sectional, retrospective study was designed to evaluate the current clinical applications and acute hepatotoxicity of intravenous amiodarone administration at a hospital in China. Clinical data were collected from 1214 patients receiving intravenous amiodarone treatment between October 2003 and September Baseline patient characteristics, drug indications, administration records and acute hepatotoxicity associated with the drug were examined. Amiodarone was used primarily in arrhythmic patients with obvious cardiac dysfunction. Atrial fibrillation and ventricular arrhythmia were the two most commonly treated dysfunctions. Incorrect indications and administration methods were also noted. Hepatotoxicity occurred in 12.6% of the patients, but was mild in most cases. Males showed a higher incidence of hepatotoxicity than females. The use of amiodarone was considered to be reasonable and standardized, but there was still considerable room for improvement, particularly in the standardization of administration guidelines. Intravenous amiodarone can cause hepatotoxicity and hepatic function tests should be performed soon after giving amiodarone intravenously. KEY WORDS: AMIODARONE; INTRAVENOUS INJECTION; INDICATIONS; ARRHYTHMIA; HEPATOTOXICITY; ATRIAL FIBRILLATION Introduction Amiodarone is a class III anti-arrhythmic drug commonly used for the treatment of both ventricular and supraventricular arrhythmias. 1 3 The North American Society of Pacing and Electrophysiology (NASPE) has standardized the use of amiodarone and provided guidelines for its administration. 1,2 The guidelines used in China for the use of amiodarone have been revised in line with those suggested by the NASPE; 3 however, the unique pharmacokinetic characteristics of amiodarone and its adverse effects on the cardiovascular and other systems still make clinical applications potentially problematic. Moreover, the clinical use of amiodarone has not been studied in detail. Amiodarone is associated with many adverse effects, such as thyroid dysfunction, corneal microdeposits, and hepatic and pulmonary toxicities during long-term therapy. 4 6 Intravenous administration of 1928

2 amiodarone can lead to phlebitis at the injection site, sweating, heat sensation, nausea, sinus bradycardia, atrioventricular block and severe hypotension. 7 Long-term administration of amiodarone is associated with two types of liver toxicity. Asymptomatic elevation of transaminases is frequent, with a reported incidence of approximately 24 26%; 7 9 this is usually transient and returns to a normal level after dose reduction or withdrawal. Symptomatic liver injury is rare and potentially fatal; acute hepatotoxicity during intravenous amiodarone treatment has been described in case reports. 7,8,10 12 To investigate the indications and acute hepatotoxicity of intravenous amiodarone, clinical data from patients receiving intravenous amiodarone therapy at Fuwai Hospital, China, between 2003 and 2005, were reviewed retrospectively and variables such as the incidence, severity and resolution time of acute hepatotoxicity were analysed. By gathering this information, it is hoped that this study may offer guidance and suggestions for the future use of intravenous amiodarone in various clinical settings. Patients and methods PATIENTS AND CLINICAL DATA COLLECTION This was a cross-sectional, retrospective analysis of cardiovascular patients who received intravenous amiodarone for the treatment or prevention of arrhythmia. Using the medical records of Fuwai Hospital, Beijing, China, all patients who had received amiodarone intravenously between October 2003 and September 2005 were identified. Patients who had never used intravenous amiodarone, those who had used only oral amiodarone, those who had received amiodarone in the emergency department or prior to hospitalization, patients aged < 14 years and patients with incomplete medical information were excluded. Clinical data and medication administration records for intravenous amiodarone were analysed. Hepatotoxicity was evaluated from alanine transaminase (ALT) and bilirubin levels. Arrhythmias were recorded by type. If more than one type of arrhythmia was present, only the main type was recorded. Heart disease was classified according to the cardiac functional classification of the New York Heart Association (NYHA). 13 AMIODARONE PREPARATION AND ADMINISTRATION Amiodarone was prepared for intravenous injection by diluting in ml of 5% glucose solution. The loading dose was defined as the total dose of amiodarone received in the first 30 min and was decided at the physician s discretion. It was administered as a single intravenous bolus injection into a peripheral or central vein over min or it was injected continuously through a syringe pump over 30 min. 3 In some cases a repeat dose was administered in the first 30 min if required. The maintenance dose was given by intravenous drip using an infusion pump and was defined as the dose required to maintain the desired plasma level of amiodarone (as determined by the individual physician). It was normally lower than the loading dose. In some cases, the loading dose and maintenance dose were given in a single intravenous injection, e.g. 150 mg amiodarone as a bolus was administered at the same time as a maintenance dose of 1 mg/min. HEPATOTOXICITY Abnormal hepatic function was defined as elevated levels of ALT and/or bilirubin due to 1929

3 intravenous administration of amiodarone. Mild hepatic abnormality was defined as an ALT level 2 10 times the upper limit of normal, 8,14 with or without a bilirubin level greater than twice the upper limit of normal. Severe hepatic abnormality was defined as an ALT level > 10 times the upper limit of normal. 7,11 To standardize the diagnostic criteria for amiodarone-induced hepatotoxicity, the method of causality assessment developed by Maria and Victorino 15 was used to classify drug-induced hepatic reactions in clinical practice. The score was confirmed by two independent investigators and an expert with relevant clinical experience was consulted when contradictory scores were given. STATISTICAL ANALYSIS Data are expressed as ranges and means ± SD, and were analysed using the SPSS statistical package, version 13.0 (SPSS Inc., Chicago, IL, USA) for Windows. The χ 2 test was used to analyse the constituent ratio in various measured parameters between the two groups, i.e. the ratio between the normal and abnormal hepatic function groups. Analysis of variance was used to analyse the difference between groups. A P-value of < 0.05 was considered to be statistically significant. Results BASELINE CHARACTERISTICS A search of the hospital records of Fuwai Hospital, Beijing, China, identified 1487 patients treated with intravenous amiodarone. In total, 106 patients who were aged < 14 years and 167 patients who lacked complete medical information were excluded, leaving 1214 patients who were included in the analysis. The mean ± SD age of the study group was 56.3 ± 13.2 years (range years); 831 (68.5%) were males aged 57.1 ± 13.2 years and 383 (31.5%) were females aged 54.7 ± 13.0 years. The patients NYHA cardiac functional classification 13 was: class I, 83 (6.8%) patients; class II, 686 (56.5%); class III, 314 (25.9%); and class IV, 131 (10.8%). DISTRIBUTION OF CARDIAC ARRHYTHMIAS The distribution of types of cardiac arrhythmias and the doses of amiodarone given to patients with different types of arrhythmias are shown in Table 1. The number of patients treated with intravenous amiodarone during the peri-operative period in the surgical department was 979/1214 (80.6%); 736/1214 (60.6%) patients had atrial fibrillation or atrial flutter and this occurred early in the post-operative period in 637/736 (86.5%) of these patients. The 24-h and total overall doses received by patients with ventricular fibrillation and sustained ventricular tachycardia were statistically significantly higher than those given to patients with all other types of arrhythmia (P < 0.001). Moreover, the 24-h and total overall doses given to patients with atrial fibrillation and atrial flutter were also statistically significantly higher than those given to patients with premature ventricular contraction and non-sustained ventricular tachycardia, paroxysmal supraventricular tachycardia, premature atrial contraction, sinus tachycardia, atrial tachycardia, and arrhythmia in the peri-operative period (before operation) (P < 0.05). Intravenous amiodarone was used to treat 118/1214 (9.7%) of the patients with malignant arrhythmias (sustained ventricular tachycardia and ventricular fibrillation). AMIODARONE ADMINISTRATION Of the 1214 patients, 190 (15.7%) received 1930

4 TABLE 1: Distribution of cardiac arrhythmias and the doses of intravenous amiodarone given to patients with different types of arrhythmias at Fuwai Hospital, China, between October 2003 and September 2005 Total dose in first 24 h (mg), Total dose (mg), Type of arrhythmia No. (%) of patients mean ± SD mean ± SD Atrial fibrillation 672 (55.3) ± 402.1* ± 578.3* Atrial flutter 64 (5.3) ± 557.8* ± 601.8* Premature ventricular contraction and non-sustained ventricular tachycardia 172 (14.2) ± ± Ventricular fibrillation and sustained ventricular tachycardia 118 (9.7) ± 697.4*** ± *** Paroxysmal supraventricular tachycardia 53 (4.4) ± ± Premature atrial contraction 52 (4.3) ± ± Sinus tachycardia 50 (4.1) ± ± Peri-operative period (before operation) 19 (1.6) ± ± Atrial tachycardia 14 (1.2) ± ± *P < 0.05 for atrial fibrillation and atrial flutter versus premature ventricular contraction and non-sustained ventricular tachycardia, paroxysmal supraventricular tachycardia, premature atrial contraction, sinus tachycardia, atrial tachycardia, and arrhythmia in the peri-operative period (before operation). ***P < versus all other types of arrhythmia. only an intravenous loading dose of amiodarone, 384 (31.6%) received only maintenance doses and the remaining 640 (52.7%) received both loading and maintenance doses of the drug. For the total of 830 (68.4%) patients who received an intravenous loading dose, the loading dose was in the range of mg (mean ± SD 98.1 ± 50.6 mg) and 565 of these 830 patients (68.1%) received < 150 mg. The 384 patients who received only maintenance doses constituted 37.5% of the total 1024 patients who received maintenance doses. The dose range and retention time of the maintenance dose were mg/min (mean ± SD 1.16 ± 0.44 mg/min) and h (39.9 ± 44.8 h), respectively. The total dose of intravenous amiodarone during the first 24 h ranged from 50 to 2550 mg (mean ± SD ± mg). A drug retention time of > 24 h was seen in 643 (62.8%) of the 1024 patients who received maintenance doses. Of the 640 patients who received both loading and maintenance doses, 486 (75.9%) received the maintenance dose immediately after the loading dose and, in 154 (24.1%) patients, there was a delay before the maintenance dose was given, with an interval of h (mean ± SD 10.1 ± 22.7 h) between the two doses. COMBINED MEDICATIONS β-receptor blockers were used in combination with intravenous amiodarone in 888/1214 (73.1%) patients. Lidocaine was combined with amiodarone in 305/1214 (25.1%) patients. ABNORMAL HEPATIC FUNCTION Of the 1214 patients reviewed, 802 (66.1%) 1931

5 had liver function tests performed before and after intravenous amiodarone therapy. Baseline ALT concentration was in the range 3 79 IU/l (mean ± SD 37.1 ± 16.5 IU/l) and baseline bilirubin concentration was in the range µmol/l (mean ± SD 20.4 ± 6.5 µmol/l). After intravenous amiodarone therapy, 548/802 (68.3%) patients had both ALT and bilirubin tests performed, 236/802 (29.4%) had only ALT tests and 18/802 (2.2%) had only bilirubin tests. A total of 236/802 (29.4%) patients had abnormal results; in 135/802 (16.8%) patients the abnormal results were attributed to causes other than intravenous administration of amiodarone. In the remaining 101/802 (12.6%) patients the abnormal results were considered to be the consequences of intravenous amiodarone; 92/802 (11.5%) patients were mildly affected and the remaining 9/802 (1.1%) had severe hepatic abnormality, with ALT levels > 10 times the upper limit of normal. Of the 92 mildly affected patients, 78/802 (9.7%) had mildly elevated ALT (one of these patients also had an elevated bilirubin level of 44.9 µmol/l) and 14/802 (1.7%) had only elevated bilirubin levels. The mean ± SD age of the patients with mildly elevated ALT levels was 57.3 ± 9.6 years. The ALT concentration was in the range IU/l (mean ± SD ± 80.1 IU/l; median of 127 IU/l). The cumulative intravenous amiodarone dose ranged from 50 to 6000 mg ( ± mg) in patients with elevated ALT levels. The interval from the initial intravenous amiodarone injection until the increase in ALT level was observed was 0 7 days (mean ± SD 3.6 ± 2.4 days; median 3 days). Elevated ALT levels occurred in 26 patients in the recovery stage. The mean ± SD time to recover from ALT elevation was 4.1 ± 3.2 days and the mean ± SD ALT level after recovery was 80.6 ± 50.5 IU/l. Seventeen (2.1%) out of 802 patients had mild increases in bilirubin level; one patient also had mildly elevated ALT and two had significantly elevated ALT. The mean ± SD age of these patients was 53.5 ± 14.0 years. Bilirubin levels ranged from 38.1 to µmol/l with a mean ± SD of 55.4 ± 26.5 µmol/l. Nine (1.1%) out of 802 patients (eight males) were found to have severe hepatic function abnormalities that were probably attributable to intravenous amiodarone treatment (Table 2). Three of these patients had ventricular premature contraction, two had atrial fibrillation, three had ventricular tachycardia (one each with idiopathic, nonsustained and sustained ventricular tachycardia) and one had aortic dissection. Their total amiodarone dose ranged from 500 to mg, given over a period of h. In these patients, the ALT level increased from a baseline level of up to 42 IU/l to > 400 IU/l within 2 days after amiodarone infusion and reached a peak value of 2554 IU/l. The ALT level started to decrease < 3 days after stopping amiodarone and starting hepatoprotection treatment (i.e. hepatoprotective medications such as glucuronolactone or polyene phosphatidylcholine capsules or injections). One patient demonstrated a continued ALT increase that peaked on the seventh day after infusion. The ALT elevation resolved in 5 18 days in these nine patients (Table 2). Logistic regression was used to analyse the relationships between hepatic function and clinical parameters in 667 patients, including the 101 patients in whom abnormal liver function was attributed to intravenous administration of amiodarone (Table 3). The data showed that sex may be a risk factor leading to abnormal hepatic function in patients receiving intravenous amiodarone 1932

6 TABLE 2: Patient data for cases of severe hepatotoxicity attributed to intravenous amiodarone treatment (n = 9) Period of Recovery Age, sex, Total dose administration Baseline Highest Onset ALT value Recovery type of arrhythmia (mg) (h) ALT (IU/l) ALT (IU/l) (days) (IU/l) (days) 42, male, VPC , male, VPC , male, aortic dissection No test , male, idiopathic VT , male, AF , male, AF , male, VPC , male, unsustained VT , female, sustained VT ALT, alanine transaminase; VPC, ventricular premature contraction; VT, ventricular tachycardia; AF, atrial fibrillation. therapy, as males were significantly more susceptible than females to abnormal hepatic function (odds ratio 1.81, P = 0.03, 95% confidence interval 1.09, 3.00). Discussion This study revealed unsuitable indications and administration methods for intravenous amiodarone in the study population. More importantly, acute abnormal hepatic function was also seen in some patients. Amiodarone is becoming the drug of choice in the treatment of atrial fibrillation, particularly in the post-surgical setting, 4,6 and has been shown to be more effective than lidocaine against ventricular fibrillation, sustained ventricular tachycardia and electronic defibrillation The present study showed that intravenous amiodarone was used in 8.6% of patients with premature atrial contraction and sinus tachycardia, and in 14.2% cases of premature ventricular contraction and nonsustained ventricular tachycardia, which are not indications for amiodarone. A loading dose, but no maintenance dose, was given to 15.7% of the patients; a loading dose alone is usually not sufficient to control arrhythmias. A maintenance dose with no loading dose was given to 31.6% of the patients; this approach may produce a rate of increase in blood levels of the drug that is too slow. Among those patients who received both loading and maintenance doses, 24.1% (154/640) experienced a significant delay (10.1 ± 22.7 h) before being given the maintenance dose, a practice which may cause fluctuations in the blood level of the drug. The mean loading dose of intravenous amiodarone was 98.1 mg, which is much lower than the recommended guidelines, whereas the mean initial maintenance dose in the present study was 1.16 mg/min, similar to 1933

7 TABLE 3: Hepatic function analysis in patients who had liver function tests performed before and after intravenous amiodarone therapy and in whom abnormal liver function was attributed to intravenous administration of amiodarone Normal hepatic Abnormal hepatic function function (n = 566) (n = 101) a Males, n (%) 374 (66.1) 79 (78.2)* Age (years) 57.0 ± ± 9.6 Basic diseases, n (%) Coronary heart disease 266 (47.0) 46 (45.5) Valvular heart disease 195 (34.5) 35 (34.7) Other 105 (18.6) 20 (19.8) Cardiac function (NYHA class), n (%) I 52 (9.2) 4 (4.0) II 293 (51.8) 60 (59.4) III 158 (27.9) 27 (26.7) IV 63 (11.1) 10 (9.9) Type of arrhythmia, n (%) Atrial fibrillation 328 (58.0) 61 (60.4) Premature ventricular contraction 92 (16.3) 17 (16.8) Sustained VT/VF 50 (8.8) 12 (11.9) Other 96 (17.0) 11 (10.9) Total dose in the first 24 h (mg) ± ± Total overall dose (mg) ± ± b a Of the 236 patients with abnormal hepatic function, 135 of these patients were excluded from this table because it was attributed to reasons other than intravenous administration of amiodarone. b Total overall dose from onset of therapy until elevated hepatic enzymes were seen. *P = 0.03 (odds ratio 1.81, 95% confidence interval 1.09, 3.00) for the abnormal versus the normal hepatic function group. Data are number and percent of patients or mean ± SD. NYHA, New York Heart Association; VF, ventricular fibrillation; VT, ventricular tachycardia. the recommended guidelines. 1 3 Intravenous amiodarone combined with a β-receptor blocker was used in 73.7% of the patients. β- Receptor blockers are useful not only in treating coronary heart disease and heart failure, but also in treating arrhythmias. Although different methods of administration of amiodarone may lead to different clinical presentations of hepatic toxicity, the incidence rate of hepatic abnormality induced by intravenous amiodarone found in the present study was different from that reported for oral amiodarone. 8,9,11 The acute hepatic toxicity of intravenous amiodarone has not been well studied. Elevation of ALT has been suggested as a good example of exposure to amiodarone, and ALT was the critical index in evaluating the hepatotoxicity of amiodarone. 19 In the present study, 12.6% (101/802) of patients had hepatotoxicity that was probably due to intravenous amiodarone administration. Most patients with hepatotoxicity had a mild or moderate ALT elevation, with onset 3.6 ± 2.4 days after the first intravenous injection of amiodarone. They often presented with no symptoms in the clinic, and transient hepatotoxicity resolved within a few days after dose reduction or withdrawal. Similar 1934

8 findings have been seen with oral amiodarone therapy. 20 Some patients in the present study used hepatoprotective medications, such as glucuronolactone or polyene phosphatidylcholine capsules or injections, to protect hepatic function. In previous studies, intravenous amiodarone has led to severe hepatotoxicity and even death. 7,10 12,21 Nine patients in the present study showed severe hepatotoxicity, but it did not lead to death in these cases. The hepatic abnormalities in these patients subsided after amiodarone treatment had been replaced by symptomatic treatment. Furthermore, no other factors that could predict the severity of hepatic toxicity were found in these patients. The mechanism of hepatotoxicity of intravenous amiodarone is still unclear. It may be due to polysorbate 80, which is the solvent used at a concentration of 10% to solubilize the lipophilic amiodarone. 7,12 Tisdale et al. 22 proposed that the left ventricular ejection fraction may be a risk factor for the hepatic side-effects associated with amiodarone. There was no significant correlation between cardiac function and hepatotoxicity in the present study. A significant sex difference was noted, however; the ratio of males to females who developed hepatic toxicity was Lewis et al. 8 proposed that men were more susceptible than women to amiodarone hepatotoxicity and suggested a possible genetic basis for amiodarone hepatotoxicity. Compared with women, men may consume more alcohol, which may increase the likelihood of liver injury. The present study revealed that there is still inappropriate use of intravenous amiodarone therapy and improper dosing practices. All physicians and clinicians should follow the guidelines for the clinical treatment of patients with amiodarone. Hepatic abnormality is one of the most common acute adverse effects of amiodarone treatment; fortunately, in cases of mild ALT elevation, this abnormality can be resolved by reducing the dose or discontinuing the drug. Males showed a higher incidence of hepatic toxicity than females; a rate of 1.1% for severe hepatotoxicity was observed in the present study. Since hepatic function tends to change quickly after intravenous amiodarone treatment, we recommend that blood levels of markers of hepatotoxicity should be monitored closely, perhaps on the first and third days after starting intravenous amiodarone therapy. Conflicts of interest The authors have no conflict of interest to declare in relation to this article. Received for publication 19 June 2009 Accepted subject to revision 13 July 2009 Revised accepted 26 October 2009 Copyright 2009 Field House Publishing LLP References 1 Goldschlager N, Epstein AE, Naccarelli G, et al: Practical guidelines for clinicians who treat patients with amiodarone. Practice Guidelines Subcommittee, North American Society of Pacing and Electrophysiology. Arch Intern Med 2000; 160: Goldschlager N, Epstein AE, Naccarelli GV, et al: A practical guide for clinicians who treat patients with amiodarone: Heart Rhythm 2007; 4: Jiang WP: Amiodarone guideline for arrhythmia in China. Chin J Cardiol 2004; 32: [In Chinese]. 4 Bagshaw SM, Galbraith PD, Mitchell LB, et al: Prophylactic amiodarone for prevention of atrial fibrillation after cardiac surgery: a metaanalysis. Ann Thorac Surg 2006; 82: Podrid PJ: Amiodarone: reevaluation of an old drug. Ann Intern Med 1995; 122: Vassallo P, Trohman RG: Prescribing amiodarone: an evidence-based review of clinical indications. JAMA 2007; 298:

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