1994;105;1642-1645 Chest Demedts W Van Mieghem, L Coolen, I Malysse, LM Lacquet, GJ Deneffe and MG lung surgery Amiodarone and the development of ARDS after

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1642 Amiodarone and ARDS After Lung Surgery (Van Mieghem eta!)

�_i1 clinical investigationsLTI �J Amiodarone and the Development of

ARDS After Lung Surgery*

Walter Van Mieghem, M.D., F.C.C.P.; Luc Coolen, M.D.; Ines Malysse, M.D.;

LuJovic M. Lacquet, M.D.; Georges J.D. Deneffe, M.D., F.C.C.P.; and

Maurits G.P. Demedts, M.D., F.C.C.P.

An evaluation of amiodarone as prophylactic treatmentfor supraventricular tachyarrhythmias after pulmonarysurgery was stopped because of a high incidence of theadult respiratory distress syndrome (ARDS) after apneumonectomy. Retrospective analysis of all cases ofresection for pulmonary neoplasm in our hospital be-tween 1987 and 1991 indicates that amiodarone may be

trial dysrhythmias-fibrillation, flutter, or parox-

ysmal atrial tachycardias-are frequently occur-

ring arrhythmias after thoracic surgery. Besides the

hemodynamic consequences and the need for im-

For editorial comment see page 1635

mediate treatment, atrial fibrillation has severe prog-

nostic implications for patients after pneumonec-

tomy, of which a postoperative mortality of 25 per-

cent has been reported.’

Several prophylactic strategies with antiarrhyth-

mic drugs, mostly digitalis or beta-blocking agents,

have been evaluated for the prophylaxis of atrial fi-

brillation after coronary artery bypass surgery and

were not found superior to placebo.2’3In the last 4 years, 242 pneumonectomies and 310

lobectomies have been performed in our hospital,

and postoperative atrial dysrhythmias were regularly

seen with sometimes important hemodynamic con-

sequences for the patient.

We, therefore, decided to prospectively evaluate a

prophylactic regimen consisting of amiodarone or

verapamil, since either one has been reported safe

and effective in the prevention of postoperative atrial

arrhythmias.4’5

METHODS

A prospective open randomized study was planned for 100

consecutive pneumonectomy and 200 consecutive lobectomy

*From the Limburgs Hartcentrum (Dr. Van Mieghem), Genk,

Belgium; and U.Z. Gasthuisberg (Drs. Coolen, Malysse, Lacquet,Deneffe, and Demedts), Department of Pneumology, Leuven,Belgium.

Manuscript received October 21, 1993; revision accepted Febru-ary 24, 1994.Reprint requests: Dr. Van Mieghern, Lirnburgs Hartcentrum, Stfans Ziekenhuis, Schiepse Box 3600 Genk, Belgium

implicated in the development of ARDS after lung sur-

gery. (Che8t 1994; 105:1642-45)

[ ARDSadult respiratory distress syndrome

Key words: amiodarone; ARDS; atrial dysrhythmias; lung

surgery

cases, comparing amiodarone, verapamil, or placebo as prophy-

lactic treatment for atrial fibrillation.

All patients in whom a pulmonary resection was performed

were considered for the study, within 1 h of return from surgery

to the ICU. Exclusion criteria consisted of a heart rate of less than

50 beats per minute, systolic blood pressure below 100 mm Hg,

atrial dysrhythmias, heart failure, or thyroid dysfunction.

Amiodarone was administered in a bolus of 150 mg IV over 2

mm, followed by a continuous infusion of 1,200 mg over 24 h for

3 consecutive days. Serial blood samples for amiodarone and de-sethylamiodarone were taken before the administration of the

amiodarone bolus and every 12 h for 60 h. Verapamil was

administered as a bolus of 10 mg IV for 2 mm followed by a 30-

mm infusion of 0.375 mg per mm and afterwards 0.125 mg per

mm for 3 days.6

The treatment routinely used after a pulmonary operation, ie,

prophylactic antibiotics, subcutaneous low molecular weight

heparin, and an H2 antagonist IV, was given as usual. Other forms

of treatment were given as required.

The prophylactic antiarrhythmic treatment was interrupted

when side effects occurred, which were thought to be related to

the antiarrhythmic drug such as rhythm or conduction distur-

bances and hypotension, or when other and more effective

antiarrhythmic therapy seemed needed.After the recognition of severe complications in some of the

patients treated with amiodarone, it was decided to make a ret-

rospective evaluation of the incidence of adult respiratory distress

syndrome (ARDS) after pulmonary surgery in our institution

from January 1987 until September 1991.

Adult respiratory distress syndrome was defined as extensive

newly occurring patchy alveolar consolidation in the remaininglung parenchyma not caused by an infection, cardiac decompen-

sation, or pulmonary embolism, leading to acute respiratory fail-

ure with severe hypoxemia for which artificial ventilation with

high oxygen concentration was necessary.7

RESULTS

The prospective study was interrupted on July 29,

1992, because of severe life threatening side effects in

three postpneumonectomy patients in the amio-

darone treatment group. At that time, 64 patients had

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Table 1-Incidence of Atrial Fibrillation and SideEffects in Patients After Lobectomy (n64) orPneumonectomy (n82) During the 3 Days of

Postoperative Treatment5

Table 3-Clinical Data and Lung injury Score (7) inthe 3 Patients With ARDS After Amiodarone Therapy5

Table 2-Plasma Levels (�.sg/L) of Amiodarone (A) and Desethylamiodarone (D) in Patients

With (1) and Without (N) ARDS5

Drug ARDS 12 hf 24 h 36 h 48 h 60 h

A N 1,587± 1,094 1,451 ± 159 2,069±561 2,188±485 2,483±822

A Y 1,136±480 1,1461 1,562±176 1,635±99 2,261±341

D N 144±116 157±51 248±104 216±34 293±99

D Y 71±49 1041 251±130 190±12 189±63

(Mean ± SD). Differences are not significant.

fhhours after the start of the amiodarone therapy.

�Only one sample available.

CHEST I 105 1 6 1 JUNE, 1994 1643

Lobectomy Pneumonectomy

P A V P A V

No. of patients

AFHARDS

7Pplacebo; Aamiodarone; Vverapamil; AFatrial fibrillation;

and Hhypotension.

been included after lobectomy and 32 patients after

pneumonectomy.The results are summarized in Table 1 . Systemic

hypotension occurred shortly after the start of the

infusion of verapamil in nine patients and subsidedrapidly after the cessation of verapamil therapy and

fluid replacement.

Adult respiratory distress syndrome developed af-

ter right pneumonectomy in three patients in theamiodarone group, two occurrences on the second

postoperative day, and the third one at the end of thethird postoperative day.

Right-heart catheterization was performed in thesethree patients and showed normal pulmonary wedgepressures and normal cardiac output on each occa-

sion. Treatment with amiodarone was stopped after

a total dose of 2,150 mg in the first, 3,750 mg in the

second, and 3,350 mg in the third patient.Plasma levels of amiodarone and desethylamio-

darone (Table 2) were similar and within expectedlimits in all pneumonectomy patients of the amio-

darone group, whether they developed ARDS or not.Other treatment of these patients consisted of ar-

tificial ventilation, fluid restriction, diuretics, meth-ylprednisolone for 24 h, and hemodynamic supportwith dobutamine and dopamine.

The first two patients died during the course oftheir ARDS because of intractable hypoxemia despite

ventilatory treatment with a high fraction of inspired

oxygen (F1o2) and positive end-expiratory pressure

(PEEP), and the third one recovered.An autopsy was performed on patient 1 and

showed typical characteristics of ARDS in the re-

22 21 21 10 11 11

6 1 0 1 0 0

0 1 3 1 0 0

0 0 0 0 3 0

Patient No. 1 No. 2 No. 3

Age 62 72 46

Tumor stage T2NO T2NO T3NO

FEy1, % of pred 90 86 95

Dco, % of pred 81 1 1 1 73

Hypoxemia score 4 4 4

Chest roentgenogram score 4 3 4

PEEPscore 2 2 2Lung injury score 3 3 3

Cardiac output, L/min 6.5 4 5.5

Mean pulmonary artery pressure, 29 23 34

mm Hg

Pulmonary capillary wedge pressure, 13 5 9

mm Hg

Pulmonary vascular resistance, 200 360 360

dynes 5 cm5Systolic arterial pressure, 86 122 106

mm HgSystemic vascular resistance, 800 1,300 1,440

dynes 5 cm5Amiodarone total dose, mg 2,150 3,750 3,350

Amiodarone plasma levels, 1,476 2,020 2,503

�sg/L

Artificial ventilation, d 1 8 5Outcome Died Died Recovered

#{149}Sincethe patients had only 1 remaining lung, a chest x-ray film score

of 4 was given for alveolar consolidation in the whole remaining lung

parenchyma, a score of 3 for consolidation of three-fourths of the

lung.

maining left lung. The macroscopic picture was thatof a red-blue heavy lung and elastic consistency not

collapsing on incision. On microscopic examination,an elastoid degeneration of the lung parenchyma wasseen with lymphocytic reaction and hyaline mem-branes.

Clinical and hemodynamic data of these threepatients are summarized in Table 3; all patients weremen and none had hepatic or renal dysfunction.

From January 1987 until September 1991, a totalof 310 lobectomies and 108 right-sided and 134 left-

sided pneumonectomies were performed. The results

are summarized in Table 4. The incidence of atrialfibrillation varied from 16 percent in the lobectomygroup to 23 percent after left-sided pneumonectomy..The overall incidence of ARDS was 1 1 percent in thepatients treated with amiodarone compared with 1.8percent in the nonamiodarone group, a difference

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1644 Amlodarone and ARDS After Lung Surgery (Van M!egtiern etaO

which is highly significant (x2 33; p<O.0001). The

incidence of ARDS after the right pneumonectomywas 7.4 percent in all patients compared with 1.6percent in the other types of lung surgery (x2 11.2;p<O.OO1), and in our retrospective study, ARDS wasalmost exclusively seen after the administration ofamiodarone except after right-sided pneumonec-tomy. The evaluation of prophylactic antiarrhythmictreatment with amiodarone was stopped because thedevelopment of ARDS seemed related to amiodaroneadministration.

DIsCussIoN

Pulmonary toxicity is the most serious noncardiacside effect attributed to amiodarone therapy. Theoverall incidence of amiodarone pulmonary toxicityhas been estimated at 5 to 10 percent of treated pa-tients.8

Amiodarone-induced pulmonary disease usuallyappears as a subacute or chronic disease, although insome cases there may be rapid progression towardrespiratory failure.9

The most common presentation is that of a rela-tively benign subacute illness, characterized bycough, dyspnea, and sometimes weight loss. Thechest roentgenogram of these patients most often

shows diffuse parenchymal infiltrates, typically in an

interstitial pattern.Other patients may have a more abrupt onsej of an

acute illness. These patients characteristically havesignificant fever, and the chest roentgenogram oftenshows localized opaque areas in an acinar pattern.

The clinical presentation may strongly mimic an in-fectious pneumonia or in extreme cases, ARDS.’#{176}

The mechanisms of amiodarone pulmonary toxic-ity are not completely understood.” Currently, atleast two different pathways of toxicity may exist: (1)an indirect mechanism characterized by influx ofinflammatory or immune effector cells to the lung,

similar to the findings described with other “hyper-sensitivity” reactions associated with inhalation oforganic antigen that are seen in farmer’s lung or pi-geon breeder’s disease; and (2) a direct toxic mech-anism that results in lung parenchymal cell injuryand a subsequent fibrotic response. Several mecha-nisms of direct toxicity have been proposed. Regard-less of the mechanism of initial toxicity to the cell,Martin et al’2 suggest an amiodarone-mediated in-crease in cytosolic-free calcium may be the ultimateintercellular mediator of cell injury. Direct toxic in-jury of lung parenchymal cells by amiodarone,regardless of the specific mechanisms, can trigger arepair process with widespread deposition of collagenthat further deranges the alveolar capillary struc-tures. Additionally, amiodarone may directly inducefibroblast replication in vitro, potentially facilitating

Table 4-Retrospective Analysis of the Incidence ofAtrial Fibrillation (AF), Amiodarone Administration

(AM), Total Number of ARDS Cases, and ConcomitantAM Followed by the Occurrence of ARDS After

Right�Slded Pneumonectomy (RP), Left-SidedPneumonectomy (LP), and Lobectomy (LOB) From

January 1987 until September 1991

No. AF (%) AM (%) ARDS (%) AM + ARDS

RP 108 21 (19.4) 13 (12) 8 (7.4) 1LP 134 31 (23) 16 (11) 2 (1.5) 2

LOB 310 52(17) 26(8) 5(1.6) 3

the fibrotic response to amiodarone-mediated inju-

ry.13 As pulmonary fibrosis occurs, gas exchange isfurther impaired and the chance for reversibility of

the disorder is significantly lessened. In part, differ-ent mechanisms of toxicity may relate to differingclinical presentations. On the other hand, it is possi-

ble that toxicity from amiodarone or desethylamio-darone represents a spectrum of toxic reactions thatare interrelated and interdependent, and that themajor factor responsible for differing clinical pre-sentations is the genetically determined response of

the individual.Acute pulmonary toxicity has been described after

both cardiac and noncardiac operations in patientsreceiving preoperative amiodarone therapy. Consis-tently, the pulmonary abnormalities appear 1 to 4days after extubation and progress rapidly with a

high mortality rate.14’15 The mechanism by which

surgery may initiate this acute lung reaction to ami-odarone is not known; cardiopulmonary bypass,peroperative oxygen toxicity, congestive heart fail-ure, and superimposed infection have all been pro-posed.

In our three postpneumonectomy patients or in

other patients with acute amiodarone-related pul-monary toxicity after noncardiac surgery, cardio-pulmonary bypass or congestive heart failure cannotbe implicated.

To our knowledge, development of ARDS in con-junction with postoperative initiation of amiodaronetherapy has not been previously reported. On thecontrary, intravenous prophylactic administration of

amiodarone in doses comparable with those used inour study were reported safe and effective in patientsundergoing coronary artery bypass surgery.5 Serialplasmalevels of amiodarone and desethylamiodaroneare summarized in Table 2. None exceeded theaccepted therapeutic range.

It is well known that ARDS occurs more frequentlyafter right-sided pneumonectomy compared withother types of lung surgery.’6”7 The pathogenesis isunclear and several possible mechanisms have beenproposed. In our retrospective evaluation, the mci-dence of ARDS after right-sided pneumonectomy

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CHESTI1O5/6/JUNE,1994 1645

was 7.4 percent compared with 1.6 percent in the

other types of lung surgery. In the small group of 11patients who received amiodarone after right-sidedpneumonectomy in the prospective evaluation ofprophylactic amiodarone therapy, ARDS occurred in3 out of 1 1 patients.

Greenspan etal’4 described ARDS occurring aftercardiac surgery for malignant arrhythmias in three ofa series of eight patients, when the surgery was per-

formed immediately after the administration ofamiodarone, 1,200 mg per day for 7 to 14 days, sug-gesting that recent administration of a high dose of

amiodarone before major cardiac surgery is poten-tially pulmotoxic. Furthermore, 6 of 1 1 patients in

their series who were preoperatively receiving long-term amiodarone therapy for malignant ventriculararrhythmias developed ARDS as well, immediately

after cardiac surgery.Kay et al’5 reported ARDS with fatal evolution in

4 of 33 patients receiving prolonged amiodaronetherapy without signs of preoperative pulmonarydisease after cardiac and noncardiac surgery.

We are not aware of reports of increased amio-darone-induced pulmonary toxicity in patientstreated for cardiac arrhythmias late after pneu-monectomy. One of our patients in whom a leftpneumonectomy was performed in October 1988,

however, developed ARDS 5 months after initiationof amiodarone therapy for recurrent atrial fibrilla-

tion in December 1989.Another patient, who survived ARDS after a right

pneumonectomy in 1990, was treated afterwardswith amiodarone for recurrent atrial fibrillation andafter 2 weeks developed another episode of ARDSwith fatal outcome.

The risk of amiodarone pulmonary toxicity may berelated to the drug’s concentration in the lung. It ispossible, when the amount of pulmonary tissue has

decreased, which is the case after lung parenchymaresection, standard doses of amiodarone may causehigher concentrations in the remaining lung, increas-ing the risk of pulmonary toxicity.

In view of our findings and data from the litera-ture, we suggest avoiding the use of amiodarone totreat cardiac arrhythmias after pulmonary surgery,and to observe carefully all patients requiring amio-

darone treatment for serious cardiac arrhythmias

after any type of thoracic or nonthoracic surgery.

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1994;105;1642-1645 ChestW Van Mieghem, L Coolen, I Malysse, LM Lacquet, GJ Deneffe and MG Demedts

Amiodarone and the development of ARDS after lung surgery

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