Amiodarone-induced Pneumonitis·
Assessment of Risk Factors and Possible Risk Reduction Glenn D. Adams, M.D., F.G.G.P.; Richard Kehoe, M.D.; Michael Lesch, M.D.; andJeffrey Glassroth, M.D., F.G.G.P.
Problems with pulmonary toxicity have emerged as a potentially limiting factor for amiodarone use. We prospectively studied 33 subjects treated with amiodarone for refractory arrhythmias. Serial clinical, radiographic and pulmonary function tests were correlated with the dose and duration of amiodarone treatment to define: a) prevalence of lung toxicity, b) subgroups of patients at particular risk for toxicity, c) potential interaction between amiodarone dose and toxicity. Considering all subjects, no significant change in lung volumes or airflow indices were noted; carbon
monoxide diffusing capacity (Dco) underwent a mean reduction of 20.3 percent during treatment. Symptoms of possible pulmonary toxicity occurred in 27.3 percent of subjects. No type or degree of pretreatment cardiopulmonary dysfunction predicted lung toxicity. However, maintenance dose was correlated with toxicity; patients treated with doses of s400 mg per day from the start of treatment had insignificant reductions in Dco and did not develop symptoms.
Niodarone hydrochloride is a benzofuran derivative which has been used in Europe since 1967 for the treatment of angina pectoris as well as ventricular and supraventricular arrhythmias. 1 The drug has been available experimentally in the United States for several years for treatment of refractory arrhythmias. 2-5 Concentrations of the drug in tissues such as fat, skin and lung may be many times greater than therapeutic serum levels. Prior to 1980, there was no report of pulmonary complications related to therapy with amiodarone. Since that time, there have been several accounts of apparent amiodarone-related pulmonary toxicity including interstitial pneumonitis and alveolar infiltrates.":" However, because many of these patients were also prone to develop congestive heart failure, there is uncertainty as to whether the pulmonary process was cardiac related, drug related, or somehow due to a combination of these factors. We have prospectively studied 33 patients treated with amiodarone in order to determine the effect of the drug on serial pulmonary function tests and to determine if these changes could be attributed solely to amiodarone or whether other cardiopulmonary disorders were responsible. Additionally, we sought to identify the characteristics of those individuals at increased risk of developing pulmonary function ab-
normalities.
·From the Department of Medicine (Sections of Pulmonary Medicine and Cardiology), Northwestern University Medical School and Northwestern Memorial Hospital, Chicago. This work was supported in part by Pulmonary Academic Award No. HL 01208-03 from the National Heart, Lung and Blood Institute. Manuscript received May 22; revision accepted August 6. Reprint requests: Dr: Classroth, 456 Wesley, 250 East Superior, Chicago 60611
254
MATERIAL AND METHODS
Consecutive patients treated with amiodarone hydrochloride between January 1982, and October 1983, at Northwestern Memorial Hospital were considered for this study. All patients had an arrhythmia, either ventricular, supraventricular or both, refractory to conventional therapy. The need for amiodarone therapy was documented by a control electrophysiologic study (EPS) in a drugfree state. Patients were considered candidates for amiodarone therapy if EPS continued to elicit arrhythmias despite treatment with conventional drugs. The study was approved by the Institutional Review Board of Northwestern University and informed consent was obtained in all cases. Treatment Protocol
After baseline testing was performed, patients initially received a loading dose of800 to 1,200 mg/day of amiodarone by mouth for three to 24 days based on the type and severity of arrhythmia, resting heart rate, and body surface area. H arrhythmia control was inadequate, the loading dose could be increased within the first several days at the discretion of the managing cardiologist. Individual patient dosages were then adjusted based on arrhythmia response, heart rate, and clinical course including possible side effects. In general, it was attempted to attain a 600 mg/day maintenance dose within six weeks of starting therapy. If adequate control of the arrhythmia and heart rate were maintained at this dosage, an attempt was made to further reduce maintenance doses to 400 mg/day or less. In five patients a deviation from protocol occurred; these patients were treated with amiodarone doses that never exceeded 400 mg/day. Clinical Evaluation
Complete medical histories were obtained including cardiopulmonary symptoms prior and subsequent to initiation of amiodarone therapy. Recent episodes of congestive heart failure or myocardial infarction were specifically documented because of their potential effect on pulmonary function. 16-19All medications were reviewed and other antiarrhythmic drugs were discontinued prior to starting amiodarone with the exception of digitalis and beta-blockers. All patients were examined by a cardiologist initially (RK) and at a Amlodarone-Induced Pneumonitis (Adams st 81)
minimum of every three months thereafter. At these visits the dose of amiodarone was adjusted based upon the patients' clinical and electrocardiographic response. Other medication dosages were adjusted as needed. All cardiopulmonary symptoms and 6ndings were recorded during the examination period, as were other potentially drug-related effects. Prior to the introduction of amiodarone therapy, the following studies were obtained: continuous 24-hour electrocardiographic recording, left ventricular ejection fraction with gated equilibrium radionuclide technique, PA and lateral chest radiographs, complete blood count (CaC), SMA-20, thyroid function tests, anti-nuclear antibody and ophthalmologic evaluation including slit-lamp examination. Pulmonary function testing (PIT) was performed prior to therapy when possible or immediately after control of life-threatening arrhythmias had been achieved. A water-sealed spirometer (Collins computerized modular lung analyzer, Warren Collins Co, Braintree, MA) was used. Testing included Bow rates, lung volumes and single breath carbon monoxide diffusing capacity (Dco). The Dco was hemoglobin-corrected in all individuals." The normal values of Morris et alll were used for comparison of lung volumes and spirometric results. The regression equation of Gaensler and Smith22 was used for comparison of the Dco results. Equipment used in volume and Dco measurements were calibrated daily and results of Dco measurements were reproducible to within ± 3 percent. These studies were repeated at three- to six-month intervals, or sooner if clinically indicated. Only pulmonary function test results obtained at our institution were used for analysis. Patients were followed-up while receiving amiodarone for an average of 41.8 weeks (SEM, 3.3 weeks). The last available pulmonary function test has been termed the "final" test. Chest radiographs were obtained prior to therapy in all patients and within three days of the subsequent serial pulmonary function test. They were reviewed by a pulmonologist OG) who was not informed about the patients' clinical status. Each set of chest radiographs was graded and the scores were summed according to the following grading scale: O-nonnal I-increased heart size I-pulmonary vascular engorgement or redistribution 2-mild interstitial abnormalities including Kerley B lines 3-moderate to severe interstitial abnormalities 4-interstitial abnormalities and alveolar changes 4-pleural effusion (unilateral or bilateral) The baseline and last available chest radiographs were used for analysis except when considering the effect of dosage, in which case serial scores were compared. The last available chest radiograph has been termed the "final" radiograph.
Diagnosis ofAmiodarone Toxicity A diagnosis of probable amiodarone pulmonary toxicity was made when respiratory tract symptoms (cough or dyspnea) lasting> four weeks developed in previously stable patients. Other causes for the symptoms were clinically excluded using appropriate techniques. In that regard, determinations of ejection fraction, when performed, were compared to pretreatment results to aid in the exclusion of congestive heart failure. Radiographic or pulmonary function changes were not required for a diagnosis of probable amiodarone toxicity.
Statistical Analysis Statistical analysis was performed using a two-tailed Wilcoxon signed rank test, Students t-test, or chi square test where appropriate. A p value of <0.05 was considered significant. 13
Exclusions Patients were considered ineligible for purposes of analysis if they
Table I-Patient Population and Summary of Teat Reaulta Group" and Patient No
Sex
CHF
Change inCXR
16 61 51 60 59 61 71 69 74
CAD CAD CAD CAD CAD Cardiomypathy AVR CAD VSDrepair CAD Cor triatrium CAD and AVR AVR CAD CAD CAD CAD and MVR
no yes yes no no yes no yes no yes no yes no no no no no
W I I W S S S S S W S I S I W I I
68 72 67 48 57 25
AVR CAD CAD None CAD None
yes no yes no no no
S
71 58 36
CAD CAD CAD
yes yes no
I I W
66 64 66 43 77 51 60
CAD AVR CAD None mitral prolapse CAD and AVR CAD
yes no no no no yes yes
W S S S
Age
1. Fall in Dco >15% 1 F M 2 3 M 4 F 5 M F 6 7 M 8 M
9
Underlying Cardiac Disease
M
M 10 11 M 12 M M 13 14 M 15 M 16 M 17 M 2. Fall in Dco 0-15% 18 M 19 F 20 M 21 F 22 M 23 M 3. Rise in Dco 0-15% 24 M M 25 26 M 4. Rise in Dco > 15% 27 M 28 M 29 M 30 M 31 F 32 M 33 M
84 58 61 76 62 62 70 63
S S I S
W I W
CAD = coronary artery disease; AVR= aortic valve replacement; MVR = mitral valve replacement; VSD = ventricular septal defect; W=worse; I=imhroved; S=same. *Groupings by c ange in Dco compare hemoglobin corrected baseline to most recent value. were unavailable for serial study or if the initial pulmonary function evaluation was performed at another institution. RESULTS
Patient Population Fifty-one patients were treated with amiodarone at our institution during the 22-month period of the study. Thirteen patients were either lost to follow-up or had initial pulmonary function testing (PFI) performed at other institutions and were excluded. None of these patients is known to have subsequently developed signs or symptoms of pulmonary disease. Two other patients had the drug discontinued prior to obtaining baseline pulmonary function testing within four days of initiation of therapy because of recurrent ventricular tachycardia. Finally, three patients expired CHEST I 93 I 2 I FEBRUARY, 1988
255
within three months of the initiation of amiodarone therapy and serial testing was not obtained. Two of these patients died of cardiac arrest and one of a previously diagnosed metastatic carcinoma. The remaining 33 patients constitute the final study population. There were 27 men and 6 women, ranging in age from 16 to 84 years (mean 60.3 years). Twenty-two of these patients had coronary artery disease documented by cardiac catheterization, three with associated valvular disease; five had valvular heart disease only. The remaining six patients included three who had ventricular arrhythmias with no other documented cardiac dysfunction (Table 1). Pulmonary Function Status
Five patients had baseline PFT prior to the start of amiodarone therapy and the remaining 28 within several days of controlling a life-threatening arrhythmia with the drug. Of the 33 patients studied, one had a history of asthma. His PFT during the study period demonstrated no evidence of airway obstruction. There were seven patients with mild chronic airflow obstruction based on baseline PFT data (FEV/ FVC < 75 percent) and history. None of these subjects received corticosteroids during the period of this study. Four of the seven also had a history of documented congestive heart failure. Eleven patients (33 percent) had initial PIT compatible with a restrictive defect. Six of the 11 had a Dco < 80 percent of their predicted normal value. Fourteen additional patients had an isolated reduction in the Dco with no evidence of a restrictive defect. The mean baseline Dco for these 20 subjects was 49 percent of predicted normal (Table 2). Comparing the baseline and final pulmonary function test of the 33 patients, there was no significant change in mean values of airflow or lung volume parameters (Table2). However; more than half of these patients had a reduction in Dco (Table 1). For all 33
patients, the mean reduction in hemoglobin-corrected Dco was 20.3 percent. Thirteen patients with a baseline Dco ~ 80 percent of the predicted normal value had a significant reduction in Dco at the end of the study period which averaged 23 percent for the group. The remaining 20 patients, who had an initial Dco < 80 percent of predicted, had a somewhat more modest decrease in 16.6 percent which did not attain statistical significance when compared to their initial results (Table 2). Radiographic Correlation
Thirty-two of the 33 patients had serial chest radiographs available for evaluation. All films were obtained within three days of PIT Most patients' interval chest radiograph scores had some variability in either direction. Pleural effusions were noted in three patients, one during an obvious episode of congestive heart failure, one possibly due to amiodarone, and the third had an effusion with no other cardiopulmonary symptom or finding. All three had a history of prior congestive heart failure. Fourteen of the 32 patients (43.8 percent) had an unchanged chest radiograph score upon comparing their baseline and final films. Eight patients' chest radiographs worsened while on therapy from a mean baseline score of2.00 to a mean final score of 4.38. Ten patients had radiographic improvement during therapy from a mean baseline score of 4.00 to a final score of 2.20. Patients' graded chest radiographs were then correlated with their level of PIT performance (Tables2-5). Although patients with a baseline Dco < 80 percent of their predicted normal value were significantly more likely (p<. OS) to have abnormal chest radiographic findings and an elevated radiographic score, there was no difference between these patients and subjects with a normal baseline Dco with respect to change in radiographic score after the institution of amiodarone therapy. Moreover, there was no statistically significant
Table i-Serial Pulmonary Function and Chest X-ray Film in 33 Patients Test Forced vital capacity FEV 1* FEV/FVC (%) Max mid exp flow* Total lung capacity* Diffusing capacity (Dco)* Initial Dcoi:!:80%* Initial Dco<80% Chest x-ray score CXR-initial Dcoi:!:80% CXR-initial Dco<80%
Patients
Baseline ± SEM
Final±SEM
Percent Change
P-value
33 33 33 33 33 33 13 20
79.45±2.39 86.36±2.90 76.52± 1.40 81.10±5.95 85.40±2.62 68.64±4.99 98.95±3.71 49.00±3.44 2.57±.34 1.31 ± .41 3.26± .41
BO.66±2.34 86.39±2.96 76.00± 1.42 76.27±5.66 82.60±2.41 54.73±4.79 76.08±8.01 40.85±3.40 2.50±.42 1.62± .38 3.11± .62
+ 1.5 +0.03 -0.7 -5.9 -3.3 -20.3 -23.0 -16.6 +1.2 +23.7 -4.6
NSt NS NS NS NS <.02 <.05 NS NS NS NS
32 13 19
*Mean percent of predicted normal values. tNS =not significant
258
Amlodarone-Induced Pneumonitis (Adams st 81)
Table 3-11esults ofClinicalTesting in AmiodaroneTreated Patients with and without a Hiltory of Prior Congeative Heart Failure Patients without History of CHF (n =20)
Patients with History of CHF (n = 13) Test
No. Patients
Baseline
Final
Mean Change
No. Patients
13 11 2 13 6 7 13
51.7±5.8 45.9±5.1 84.0±2.0 79.6±4.5 65.5±2.8 91.7 ±4.3 3.6 ± 0.4
43.3±4.4 39.7±4.3 58.0±8.1 79.6±4.1 70.0±4.4 88.0±4.6 3.6±0.8
-18.4 -6.2 -26.0 0.0 +4.5 -3.7 0.0
20 9 11
Dco
Initial Dco<8O%
Initial Dcoi:!:80% TLC Initial TLC<8O% Initial TLCi:!:8O% Chest X-ray score
20
5 15 19
Mean
Baseline
Final
Change
75.0±5.8 52.8±4.5 101.5±3.8 89.2±2.9 74.8±2.6 94.0±2.9 1.6±0.3
62.1 ±6.9 41.1±5.3 79.4±9.1 84.5±2.9 68.7±4.1 89.8±2.5 1.7±0.3
-17.1t -22.1 -21.9 -5.3 -8.3 -4.5 +3.5
Data are mean ± SEM percent of predicted normal value. p =value <0.02 patients without history of CHF baseline vs final. t = % increase ( + ) or decrease (- ) between baseline and final test results.
correlation between radiographic score or any of the PFT parameters studied (other than initial Dco) regardless of whether the baseline results, final values or a change between the two was considered.
Patients with Congestive Heart Failure Thirteen of the 33 patients with a history of documented congestive heart failure received amiodarone for a mean duration of 9.75 months. There was one episode of mild congestive heart failure in five of these patients during amiodarone therapy. Four of the five were treated as outpatients. No patient was in acute left ventricular failure, clinically or radiographically, when baseline or final PFrs were obtained. All 13 of these patients had or developed an abnormal Dco during the study with a mean decrease ofB.4 percent of predicted; this reduction did not attain statistical significance (Table 3). Baseline PFT data were not predictive of the magnitude of the subsequent reduction in Dco (Table 3). Similar results were obtained when only the 11 patients in this group with angiographically documented coronary artery disease were considered. There was no change in the chest radiograph score of these (13) patients with congestive
heart failure during treatment with amiodarone. Patients without Congestive Heart Failure There were 20 patients without a history of congestive heart failure. The mean duration of amiodarone treatment for these patients was 12.4 months, not significantly different from the group with congestive heart failure. None of these patients developed congestive heart failure during amiodarone therapy and none had a significant change in TLC or radiographic score (Table 3). There was a significant reduction (7.1 percent, p<0.02) in the mean Dco for this group when final and baseline values were compared. There was no correlation between the baseline Dco value and the magnitude of the subsequent reduction in this group (Table 3). However, the presence of documented coronary artery disease did correlate with the likelihood of a fall in Dco while on amiodarone. Thus, 11 of these 20 patients had documented coronary artery disease and a significant reduction of28.6 percent (p<0.05) in the Dco developed when compared to baseline. There were nine patients with angiographically normal coronary arteries; none of these patients had a history of congestive heart failure. No significant reduction in the Dco was noted in this group.
Table 4-Effect ofAmiodarone DOBtJge in Clinical Tea" (Serial Reduction in Maintenance DOBtJge) Test
No. Patients
1. Baseline to 600 mglday* Dco Dco pt hx of CHF Dco no hx of CHF TLC
TLC pt hx of CHF TLC no hx of CHF 2. 600 mglday to 400 mgldayt Dco Dco no hx of eHF TLC
hx=history, CHF =congestive heart failure.
Baseline± SEM
Final±SEM
Change (%)
P Value
63.13±9.96 35.83 ± 11.55 78.60± 11.36 SO.OO±2.25 84.17± 11.91 82.5±2.99
-16.9 -19.2 -12.3 -5.1 +6.3 -6.3
<0.05
10 18 6 12
76.00±8.88 44.33±9.15 89.00±9.53 84.33±2.45 79.67±5.95 88.00±3.23
9 6 11
67.22± 10.42 78.00±9.44 81.64±3.20
57.11±7.76 66.83±8.28 SO.45±4.46
-15.0 -14.3 -1.5
16 6
<0.05
*Only those PFTs performed within one month prior to reduction from initial dose to 600 mglday are included. tOnly patients with PITs performed at least 3 months after reduction to 400 mglday are included. CHEST I 93 I 2 I FEBRUARY, 1988
217
Table 5-Effect ofDoae and Duration ofAmiodarone TlaerGPfI Oft Diffuaing CaptJCity Group and Patient
No
1. Fall in Dco >15% 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Mean (±SEM) 2. Fall in Dco 0-15% 18 19
20 21
22
23 Mean (±SEM) 3. Rise in Dco 0-15%
24
25 26 Mean (±SEM) 4. Rise in Dco >15% 27 28 29
30 31 32 33
Mean (±SEM)
Duration (Weeks)
Loading Dose
Maintenance Dose
Maintenance Dose
Total Rx
16 2 5 3 4 2 4 1 4 2 4 1 2 5 12 8
35 23 12 2 11 0 8 0
4 28 4 40
55 53
(>6OOmglday)
(6OOmglday)
«4OOmglday)
26
21 45 41
4.5(1.0)
~ 14.2(3.9)
32 28 32 16 0 32 12 51 0 16 7 10 19.9(3.7)
3 1 2 3 2 ~ 2.7(0.6)
9 0 10 20 25 25 14.8(4.1)
15 63 52 12 28 27 32.8(8.3)
57 50.3(6.4)
1 3
15 1
19 24 28 28.7(2.7)
35 28 29 30.7(2.2)
..!
44 2 7 12 11
55
8 5
..!
.J!
1.6(0.7)
5.3(4.9)
2 0 4 11 2 8
2 0 5
~ 4.4(1.5)
58
54
21 11 81 24
22 0 28
~ 8.6(4.4)
.J.
36.6(10.7)
34
40 33
64 4
43 25 64 60 36 20
19 36.8(4.8) 27 64 64
35 55
62
54 30
44 83
60 14 49.6(8.7)
See text for discussion.
Effects of Dosage
The effect of dosage and duration of amiodarone treatment are summarized in Tables 4 and 5. When all patients were considered, there was a reduction in the mean Dco and mean TLC of 16.9 and 5.1 percent, respectively, between baseline and peak dosages; both of these changes were statistically significant. Although no further significant reduction in TLC occurred as amiodarone was decreased from >600 mglday to <400 mg/day, the mean Dco declined an additional 15 percent. When the changes in Dco were analyzed according to dose and duration of amiodarone therapy (Table 5), no Significantcorrelation between Dco and the total duration of amiodarone treatment was ob218
served. However, when comparing groups having the largest decline or increase in Dco (groups 1 and 4, respectively, in Table 5) patients experiencing a large decline averaged a significantly longer duration of time on a maintenance dose of 600 mg/day than patients in group 4, (p<.Ol). Likewise, group 1 patients had a shorter mean duration of treatment on maintenance doses of <400 mglday than group 4 patients, although this difference did not achieve statistical significance (.lO>p>.05). When viewed as percentage of the total duration of amiodarone treatment, group 1 patients received <400 mglday an average of 54 percent of the time, while group 4 patients were maintained at those doses an average of73.8 percent of their total period of AmIodarone-lnduced Pneumonitis (Adama et tIJ)
Table 6-Statua ofDifferent ClinictJl Parameters during
Amiodarone TheraPfl Among Patientl with Symptomatic
Pulmonary ToDcity
Patient No. Sex Age
1
7
8 13 10 28 4 30 32
M M M M M M F M M
66 70 63 59 61 64
76 43 51
Symptom Cough Cough Cough Cough Cough, Dyspnea Dyspnea Dyspnea Dyspnea Dyspnea
Change in Dco· (> 15 percent)
Change in CXR worse unchanged unchanged unchanged
+ + +
worse
unchanged
worse
unchanged improved
• + = increase, - = decrease. See text for discussion.
treatment. Despite the protocol, there were five patients who received a single loading dose of amiodarone and were then placed on a maintenance dose that never exceeded 400 mglday. In this group, only a slight and insignificant change in the Dco of 8.4 percent was noted when baseline and final PIT values were compared. Signs and Symptoms of Possible Drug Toxicity
Nine of the 33 patients (27.3 percent) developed transient or persistent pulmonary symptoms which were attributed to amiodarone (Table 6). Five patients (15.2 percent) developed mild dyspnea. This was transient in two patients requiring no therapeutic intervention. In two patients, the dyspnea has been stable but continues despite a reduction in amiodarone to 200 mg/day and 400 mglday five days per week. The fifth patient (number 10) developed probable amiodarone pulmonary toxicity, with a dry cough, dyspnea, fatigue, a pleural effusion and bilateral anterior upper lobe infiltrates four weeks after initial therapy while on a maintenance dose of 600 mg/day. The pleural effusion in this patient was transudative in nature. Discontinuing amiodarone therapy resulted in some improvement of symptoms. No other procedures were performed and congestive heart failure could not definitively be excluded as the cause of deterioration. Amiodarone was never restarted. He died several months later after a massive cerebrovascular accident complicated by pulmonary edema. An autopsy was not performed and no pulmonary function test results were available. Of the five patients with dyspnea, two had serial decreases in the Dco of 15 percent while three showed an increase (Table 6). Chest radiographs were unchanged in two of five, worsened in two and improved in one. Five patients (15.2 percent) developed a dry cough which was transient in three requiring no therapeutic
intervention, and persistent in one. The fifth patient was noted to have minimal bilateral pleural thickening of unknown etiology prior to therapy. He developed a progressive increase in pleural thickening associated with mild dyspnea on exertion during amiodarone treatment. No infectious or inflammatory etiology was found. Low dose therapy (400 mg five days per week) with amiodarone and close observation continues and symptoms have improved. All five of these patients had a decrease in the Dco of> 15 percent (Table 6). Chest radiographs were unchanged in three of the five and deteriorated in the remaining two. the 33 patients in the study, 30 are still taking amiodarone. All 30 are receiving 400 mg/day or less and have had good control of their arrhythmia. Three patients died, including the previously mentioned patient with possible amiodarone lung toxicity. A second patient also died with a cerebrovascular accident and pulmonary edema and the third died suddenly at home. Autopsies were not performed on any of these patients.
or
DISCUSSION
Since the introduction of amiodarone into the United States, there has been an increasing number of reports of pulmonary toxicity associated with the use of this drug.6-14 Toxicityhas been manifested as a variety of symptoms such as cough, dyspnea, chest pain, malaise and fever, Radiographic abnormalities, usually consisting of interstitial and/or alveolar infiltrates, have also been noted. However, because many of these patients suffer from severe underlying heart disease and congestive heart failure, there has been some difficulty in determining whether the process is cardiac, drug-related or a combination of the two acting independently or synergistically. Attempts to relate clinical and radiographic abnormalities to amiodarone have utilized pulmonary function testing. Typically, these studies revealed restrictive changes with a reduced total lung capacity and a decreased diffusing capacity.e.8-14.13 These changes were presumed to be acute and due to amiodarone, although baseline pulmonary function was not evaluated in most series. In fact, there are few data available describing the effect of amiodarone on serial pulmonary function tests. Rakita and coworkers" performed sequential pulmonary function tests in 35 patients taking amiodarone over a 52-month period and round no significant deterioration of pulmonary function regardless of whether the initial function tests were normal or abnormal. They concluded that serial changes in .pulmonary function tests did not predict the development of pulmonary toxicity. Radiographic status and the presence of congestive heart failure were not described. CHEST I 93 121 FEBRUARY, 1988
251
Kudenchuk et al25 recently reported the evaluation of 69 patients taking an average maintenance dose of 564 mg/day of amiodarone. In this group there was no statistically significant change in pulmonary function, although 10 percent of patients had at least a 15 percent decline in TLC and 28 percent developed more than a 15 percent fall in the Dco. Furthermore, 15 percent of the chest films showed new or worsening interstitial abnormalities. These investigators concluded that patients with pretreatment abnormalities in the Dco, TLC, or chest radiograph may be at an increased risk of developing amiodarone pulmonary toxicity and therefore should be considered for alternative therapy. The pretreatment abnormalities noted in pulmonary function test results or chest films were not explained, and the prevalence of congestive heart failure was not described. Although these studies have attempted to evaluate the role of pulmonary function tests in defining amiodarone pulmonary toxicity, many issues remain unresolved. In particular, the potential contributions of other underlying pulmonary or cardiac abnormalities to the physiologic parameters studied is unclear; raising the possibility that the impact of amiodarone on pulmonary function may be overestimated. The effect of amiodarone dose on possible toxicity has also not been thoroughly studied. Our results suggest that symptoms of possible amiodarone pulmonary toxicity are common but these symptoms are often subtle and difficult to distinguish from those of congestive heart failure. Moreover, no single test or group of tests is predictive of amiodarone pulmonary toxicity. Like Rakita et al24 we found no significant change in the spirometric values for our study population except for a slight decline in mean TLC at a dose of greater than 600 mg/day of amiodarone. However, in contrast to the results of Rakita and coauthors, there was a reduction in the mean hemoglobin-corrected Dco during treatment of up to 28.6 percent in every clinical subgroup we evaluated. A notable exception, however, was those patients who never received more than 400 mg per day of the drug: the reductions in Dco were very small and statistically insignificant. Despite changes in the Dco, we were unable to demonstrate a correlation between these changes, the serial chest radiograph score or patients' symptoms. Our chest radiograph grading scale was designed to evaluate congestive heart failure as well as amiodarone-related changes. Indeed, except for cardiomegaly and vascular engorgement in congestive heart failure and anterior upper lobe infiltrates associated with amiodarone toxicity, radiographic findings are similar for both processes. Consequently, radiographic deterioration could reflect either etiology. While 25 percent (8 of 32) of our total group demon280
strated radiographic deterioration during therapy, only three of eight had a history of congestive heart failure. Although unlikely, we cannot exclude congestive heart failure as the cause of these changes. In the absence of underlying structural heart disease (patients with isolated atrial arrhythmia), such changes are more suggestive of a drug-related effect. It is also unlikely that some patients with low baseline Dco and high radiographic scores initially had these results on the basis of a cardiac problem that was replaced by an equally extensive process secondary to amiodarone. In ten subjects (Table 5) the Dco actually increased during the course of the study. The reasons for these increases are unclear. Possibilities include Huctuations in cardiac output and hydrostatic pressure in the pulmonary circulation;" and variation in ventilationperfusion matching unrelated to cardiac status. Seventy-five percent (24 of 32) of our total group demonstrated radiographic improvement or stability during therapy regardless of any decline in the Dco. Our study population also included eight patients who maintained normal chest radiographs throughout therapy (grade 0) but whose Dco significantly decreased. It is also well documented that interstitial processes may present with a normal chest radtograph.f" Had observation continued, radiographic deterioration might have occurred. The diagnosis of amiodarone pulmonary toxicity was made on "clinical" grounds in our patients. This is a problem with many studies of amiodarone toxicity. Indeed, the only definitive standard of such pulmonary toxicity is lung biopsy material. Although additional diagnostic studies, including gallium scanning and transbronchial biopsy, might have been pursued, they were not deemed clinically indicated. Moreover, the utility of such tests for distinguishing amiodarone pulmonary toxicity as opposed to amiodarone therapy without toxicity has not been defined. By our criteria, nine patients developed symptoms of either cough or dyspnea; one patient complained of both symptoms (Table 6). Again, there was no clear correlation between symptoms and either Dco or chest radiograph status. However; in each of the three symptomatic patients with worsening on chest film, the Dco did fall by more than 15 percent. Three other subjects had a reduction in Dco with no radiographic change. In the remaining three of these nine subjects the Dco was noted to increase during treatment with ainiodarone. All three complained of dyspnea which improved in one patient (No. 32) with a reduction in the dose of amiodarone to 400 mg per day. The mild dyspnea experienced by the other two subjects (patients 28 and 30) has remained unchanged. Although patient 32 had documented coronary artery disease and a history of congestive heart failure, he was not felt to have clinical evidence of heart failure during the study period and Amiodaron.lnduced Pneumonitis (Adams st 8/)
the improvement in his symptoms noted after the reduction in daily dose of amiodarone together suggest drug toxicity as the basis for his symptoms. Similarly, both patients 28 and 30 had no history or clinical evidence of congestive heart failure as an explanation of their symptoms. If all nine of these subjects did indeed experience amiodarone toxicity, the calculated sensitivity and specificity of a >15 percent reduction in Dco for detecting (or excluding) amiodarone pulmonary toxicity would be only 66 and 54 percent, respectively. Moreover, the proportion of all subjects manifesting such a reduction who actually had pulmonary toxicity (the predictive value of a "positive" test) would be only 35 percent. However, the proportion of subjects without pulmonary toxicity who did not experience such a reduction (predictive value of a negative test) would be 81 percent. Thus, the greatest utility of the Dco in this context may be in identifying persons who are unlikely to have amiodarone toxicity. Our results differ substantially from those of Kudenchuk et al." There are s~veral possible explanations for these differences. First, their diagnosis of"amiodarone toxicity" was frequently based on minimal radiographic changes or symptoms that did not always change from the pretreatment baseline. This renders uncertain the actual incidence of amiodarone toxicity. Second, the patients studied by Kudenchuk et al had a rather high prevalence of both pretreatment pulmonary function abnormalities and radiographic pulmonary interstitial abnormalities. The etiology of these abnormalities, especially the radiographic changes, was uncertain as was their potential for spontaneous progression. Since a comparable control group, not treated with amiodarone, is not available for comparison, the conclusion that amiodarone accounted for the observed clinical deterioration seems somewhat tenuous. Finally, although these investigators cite the utility of serial pulmonary function tests, particularly Dco, as a means of monitoring amiodarone toxicity, their data do not clearly support that position. Indeed, the two patients they report as dying with amiodarone pulmonary toxicity did not appear to have significant serial reductions in Dco. Our data suggest that underlying cardiac disease does not predispose individuals to amiodarone-related changes in pulmonary function. Specifically, development of symptoms and the reductions in Dco were similar in patients with and without a history of congestive heart failure, regardless of baseline Dco, chest radiograph score or amiodarone dosage (Table 3). Similar results were obtained when only those subjects with angiographically documented coronary artery disease were studied. The explanation for the reduction in diffusing capacity among our patients is not clear Amiodarone does
not appear to have a significant effect on cardiac function, nor does it precipitate or aggravate cardiac failure regardless of underlying cardiac disease. 29 While acute congestive heart failure may cause a reduction in the Dco, the most consistent pulmonary function alterations with congestive heart failure are a decrease in the FEVb FVC and small airway tests. 16-19 These changes were not present in our congestive heart failure patients. Amiodarone pulmonary toxicity is, of course, another possibility. Although the mechanism for this toxicity is undefined, there is evidence to support both a drug-induced immunologic mechanism and a direct toxic mechanism.l2.13·30-32 One striking finding of our study was that as maintenance doses were lowered from >600 mg/day to <400 mg/day the decline of Dco slowed or stopped. It is possible that the extremely long half-life and tissue binding properties of amiodarone" caused a continued decline in Dco during the initial phase of treatment at <400 mg/day (Table 4). At this lower dose one may expect less accumulation of amiodarone and with serial testing perhaps an increase in the Dco toward baseline. Indeed, among patients demonstrating the greatest increase in Dco, there was a clear pattern of early reduction of amiodarone dosage to <400 mg/day (Table 5). Finally, among the five patients in the study who were treated, with the exception of a single loading dose, with <400 mg/day of amiodarone, no significant reduction in Dco or symptoms suggestive of pulmonary toxicity occurred. Since it was still unclear if amiodarone toxicity was dose-related, we evaluated five other patients since the close of our study period whose maintenance dose never exceeded 400 mg/day. These patients met the same criteria for inclusion in our study as the original 33. Again, there was only a small and insignificant reduction in the Dco (9.6 percent) between baseline and final PFL When all ten patients' PIT data were analyzed, the mean decrease in the Dco was 9.0 percent, the smallest reduction in the Dco for any group evaluated. These patients had no change in other PIT parameters and had no symptom suggestive of pulmonary toxicity. Other investigators have raised the possibility that pulmonary toxicity may relate most closely to total cumulative dose of amiodarone. A recent report of 1,307 patients from the Amiodarone Toxicity Study Group stated that the incidence of toxicity correlated with cumulative dose. However, that preliminary report deals with all forms of toxicity and does not provide information regarding loading doses of drug. 33 Our own experience has not indicated a problem relating to cumulative dose but rather to the initial dosing schedule. We have now altered our treatment protocol from a slow gradual decrease in loading and maintenance dose as outlined in our methods, to a higher loading dose (1,400-1,600 mg/day) followed by CHEST I 93 I 2 I FEBRUARY. 1988
281
an immediate reduction to a maintenance dose of 400 mg/day, However, it must be noted that the efficacyof "low dose" amiodarone regimens as compared to "high dose" regimens has not been conclusively proven. Decisions concerning amiodarone dosage will continue to be individualized. Based on these results, we suggest that baseline testing, including lung volumes, Dco and chest radiograph should be obtained prior to amiodarone therapy. Serial chest radiographs should not be routinely obtained nor should Dco be regularly repeated in patients receiving s400 rng per day of amiodarone. While alterations in serial chest x-ray films may occur, that test appears to be rather insensitive and nonspecific with regard to amiodarone pulmonary toxicity. The Dco may be a more sensitive parameter to follow, but also should be regarded as nonspecific for amiodarone toxicity. When pulmonary symptoms arise, chest radiographs should be obtained and the patient re-evaluated as to the possible relation of amiodarone to these symptoms. In the majority of patients, this drug is well tolerated and produces good arrhythmia control. Only a minority of patients developed pulmonary symptoms and since these are not usually incapacitating it is inappropriate to completely withdraw amiodarone because of minor complaints. In such patients, our approach has been a dose reduction rather than a discontinuation of amiodarone with close clinical and radiographic follow-up. Amiodarone should be discontinued when there is documentation of drug-related disease progression despite low dose therapy «400 mg/day). In cases of severe pulmonary toxicity, steroid therapy should be considered" although its efficacy remains unproven. Pre-existing congestive heart failure or lung disease should not preclude utilization of amiodarone in life-threatening arrhythmias. Many questions regarding amiodarone pulmonary toxicity remain. A better understanding of the kinetics of amiodarone distribution and metabolism coupled with prospective, randomized controlled treatment trials using strict criteria for the diagnosis of toxicity will be needed to answer them. REFERENCES
1 Marcus FI, Fontaine GH, Frank R, Grosgogeat ~ Clinical pulmonary and therapeutic applications of the antiarrhythmic agent, amiodarone. Am Heart J 1981; 101:480-93 2 Rowland E, Krilder OM. Electrophysiological assessment of amiodarone in treatment of resistant supraventricular arrhythmias. Br Heart J 1980; 44:83-90 3 Rosenbaum MB, Chiale PA, Ryba D, Elizari M~ Control of tachyarrhythmias associated with the Wolf Parkinson White syndrome by amiodarone hydrochloride. Am J Cardiol 1974; 34:215-23 4 Wheeler PJ, Camm AJ. Amiodarone-A treatment for resistant ventricular arrhythmias. In: Amiodarone in cardiacarrhythmias, Royal Society of Medical International Congress and Symposium, series 26. London: Academic Press, 1978;35-8
282
5 Rosenbaum MB, Chiale PA, Halpern MS, Nau GJ, Przybylski J, Levi RJ, et ale Clinical efficacy of amiodarone as an antiarrhythmia agent. Am J Cardioll976; 38:934-44 6 Robnensch HH, Liron M, Tupilski M, Laniado S. Possible association of pneumonitis with amiodarone therapy. Am Heart J 1980; 100:412-13 7 Heger JJ, Prystowsky EN, Jackman MD, Naccarelli S~ Warfel KA, Rinkenberger RL, et ale Amiodarone clinical efficacy and electrophysiology during long-term therapy for recurrent ventricular tachycardia or ventricular fibrillation. N Engl J Med 1981; 305:539-45 8 Sobol SM, RakitaL. Pneumonitis and pulmonary fibrosis associated with amiodarone treatment: a possible complication of a new antiarrhythmic day. Circulation 1982; 65:819-24 9 Marchlinski FE, Gansler TS, Waxman HL, Josephson ME. Amiodarone pulmonary toxicity. Ann Intern Med 1982; 97:82945 10 Riley SA, Williams SE, Cooke NJ. Alveolitis after treatment with amiodarone. Br Med J 1982; 284:161-62 11 McGovern B, Garan H, Kelly E, Ruskin J. Adverse reactions during treatment with amiodarone hydrochloride. Br Moo J 1983; 287:175-80 12 Suarez LO, Poderoso JJ, Elsner B, Bunster AM, Esteva H, Bellotti M. Subacute pneumopathy during amiodarone therapy. Chest 1983; 83:566-68 13 Harris L, McKenna WJ, Rowland E, Holt O~ Storey GCA, Krikler OM. Side effects of long-term amiodarone therapy. Circulation 1983; 67:45-51 14 Wright AJ, Brackenridge RG. Pulmonary infiltration and bone marrow depression complicating treatment with amiodarone. Br Med J 1982; 284:1303 15 Zheutlin TA, Roth H, Chua w Steinman A, Summers C, Lesch MD, et ale Programmed electrical stimulation to determine the need for antiarrhythmic therapy in patients with complex ventricular ectopic activity. Am Heart J 1986; 111:860-67 16 Bedell GN, Suzuk l Wilson WR. Pulmonary abnormalities in congestive heart failure. J Lab Clio Med 1961; 58:798-803 17 Hales CA, Kazemi H. Pulmonary function after uncomplicated myocardial infarction. Chest 1977; 72:350-58 18 Light RW, George RB. Serial pulmonary function in patients with acute heart failure. Arch Intern Med 1983; 143:429-33 19 Collins ~ Clark TJH, Brown OJ. Airway function in healthy subjects and patients with left:heart disease. Clin Sci Mol Med 1975; 49:217-28 20 Cotes JE, Dabbs JM, Elwood PC, Hall AM, McDonald A, Saunders MJ. Iron deficiency anemia: Its effect on transfer factor for the lung (diffusing capacity) and ventilation and cardiac frequency during submaximal exercise. Clin Sci 1972; 42:325-35 21 Morris JF, KoskI A, Johnson LC. Spirometric standards for healthy, nonsmoking adults. Am Rev Respir Dis 1971; 103:57-67 22 Gaensler EA, Smith AA. Attachment for automated single breath diffusing capacity measurement. Chest 1973; 63:36-45 23 Romaker A, Ries A, Olson L, Curtis G, Clausen J. Pulmonary toxicity associated with amiodarone therapy (abstract). Am Rev Respir Dis 1983; 127:91 24 Rakita L, Sobol SM, Mostow N, Vrobell: Amiodarone pulmonary toxicity. Am Heart J 1983; 106:906-14 25 Kudenchuk PJ, Pierson OJ, Greene HL, Graham EL, Sears GK, 'Irobaugh GB. Prospective evaluation of amiodarone pulmonary toxicity. Chest 1984; 86:541-48 26 Burgess JH. Pulmonary diffusing capacity in disorders of the pulmonary circulation. Circulation 1974; 49:541-60 27 Sahn SA, Schwartz MI. Oesquamative interstitial pneumonia with a normal chest radiograph. Br J Dis Chest 1974; 68:228-34 28 Epler GR, McLoud Te, Gaensler EA, Mikus J~ Carrington CB. Normal chest roentgenogram in chronic diffuse infiltrative lung disease. N Engl J Med 1978; 298:934-39 Amlodarone-Induced Pneumonitis (Adams st 8/)
29 Schwartz A, Shen E, Morady F, Gillespie K, Scheinman M, Chattersee K. Hemodynamic effects of intravenous amiodarone in patients with depressed left ventricular function and recurrent ventricular tachycardia. Am Heart} 1983; 106:848-55 30 Akoun GM, Gautheir-Rahman S, Millerson B}, Perrot ~ Mayoud CM. Amiodarone induced hypersensitivity pneumonitis. Chest 1984; 85:33-35 31 Israel-Diet D, Venet A, Caubarrere I, et ale Bronchoalveolar
lavage in amiodarone pneumonitis. Cellular abnormalities and their relevance to pathogenesis. Chest 1987; 91:214-21 32 Martin WJ II, Howard DM. Amiodarone-induced lung toxicity. In vitro evidence for the direct toxicity of the drug. Am } Pathol 1985; 120:344-50 33 Mason JW Toxicity of amiodarone (abstract). Circulation 1985; 72(suppl lli):272
second International Meeting on Respiratory Allergy The Department of Pulmonary Diseases, Cardarelli Hospital, Naples, will present this second international meeting April 22 and 23 in Sorrento at the Sorrento Palace Congress Center For information, contact the organizing secretariat: Jean Cilder, Casella Postale Aperta, NapoliVomero, 80128 Naples, Italy.
Critical Care Medicine The 26th Annual Symposium of the University of Southern California School of Medicine, Postgraduate Division, will be held March 14-17 at Caesars Palace Hotel, Las Vegas. For information, contact the Associate Dean, USC School of Medicine, Postgraduate Division, 1975 Zonal Avenue, KAM 307, Los Angeles 90033 (213:224-7051).
CHEST I 93 I 2 I FEBRUARY. 1988
213