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Intravenous Amiodarone for the Rapid Treatment

of Life-Threatening Ventricular Arrhythmias
in Critically Ill Patients with Coronary Artery
Disease
Robert P. Ochi, BA, Irvin F. Goldenberg, MD, Adrian Almquist, MD, Marc Pritzker, MD,
Simon Milstein, MD, Wes Pedersen, MD, Fredarick L. Gobel, MD,
and David G. Benditt, MD
m study examined the effectiveness of intra-
venous ambdarane for rapid control and prevention
of m Me-threatening venttiudar tachyar-
rhythmii associated with cardiovascular collapse.
In 22 critically ill patients with coronary artery dis-
ease (mean ejection fraction 27 f 13%), recurrent
ventrkuiar tachyarrhythmias proved refractory to
3.7 l 1.1 (mean f standard deviation) conventional
antian-hythmic drugs. In ths 24-hour period before!
intravenous amkdarone treatment, patients experi-
enced 2.4 f 2.3 (range 1 to 9) episodes of life-
threatening ventricular tachycardii, ventricular fi-
brilktion or both, requiring 4.0 f 3.9 direct current
cardioversions. Within the 24 hours after initiation
of intravenous ambdarone therapy (SO0 to 1,600
n&day), 20 of 22 patients remained alive and had
1.1 f 1.6 episedes of liithreatening ventricular
arrhythmias, requiring 1.9 f 3.1 direct current
cardoversions. In the second 249heur period, there
were19survivorsandlii-thtening
amhythmias were reduced to OA f 0.7 episode/
patisnt requiring 0.4 f 0.9 direct current cardio-
version. Overail, afrhythmiis were controlled in 11
of 22 (60%) patknts within the first 24 hours, and
in 14 of 22 (64%) in the secend 24 hours. Intra-
venous amiodarone therapy was well tolerated.
Twelve pathts were discharged from the hospital
and8remainedaliveatameanto#ow-upof22*
14 months. Thus, in critically ill patients, intrave-
neus amiedarone may be useful for rapid control of
spontaneous, refractory, Iii-threatening ventricu-
lar tachyarrhythmias.
(Am J Cardid 196S;64:SSS-603)
From the Minneapolii Heart Institute and the Department of Medi-
cine, University of Minnesota Medical School, Minneapolii, Minncso-
ta. This study was completed in part during Dr. Benditt’s tenure as an
Established Investigator of the American Heart Association, Dallas,
Texas. Manuscript received January 9, 1989; revised manuscript re-
ceived and accepted June 12,1989.
Address for reprints: Irvin F. Goldenberg, MD, Minneapolis Heart
Institute, 920 East 28th Street, Suite 160, Minneapolis, Minnesota
55407.
0
ral administration of amiodarone is often effec-
tive for suppression of ventricular tachyarrhyth-
mias.1-6 However, the prolonged period of time
usually required to obtain this beneficial effect often
precludes its use for immediate treatment of recurrent
sustained ventricular tachycardia, fibrillation, or both.
On the other hand, rapid achievement of “therapeutic”
plasma amiodarone concentrations is possible by means
of infusion of its parenteral form.7y8 Although the effica-
cy of intravenous amiodarone for preventing inducible
ventricular arrhythmias has been studied in the electro-
physiology laboratory?-l4 only a few reports have as-
sessed the effectiveness of this agent for the emergent
control of spontaneous, refractory, ventricular arrhyth-
mias.15-lg Consequently, this study examined the useful-
ness of intravenous administration of amiodarone for
prompt treatment and prevention of recurrent life-
threatening ventricular tachyarrhythmias in critically ill
patients.
METHOD6
Patient population: Medical records of all patients
receiving intravenous amiodarone were reviewed. Only
patients with coronary artery disease and 11 episodes
of a ventricular tachyarrhythmia associated with cardio-
vascular collapse, for which emergent therapy was re-
quired (direct current countershock, precordial thumps,
overdrive pacing) within 24 hours before administration
of intravenous amiodarone, were included in this study.
Arrhythmias were classified into 2 groups. The first
group comprised patients with unstable ventricular
tachycardia or ventricular fibrillation that was sus-
tained, life-threatening and associated with cardiovascu-
lar collapse. When this arrhythmia occurred, the patient
was unconscious and the arrhythmias required immedi-
ate therapeutic intervention for the patient’s survival.
All patients had multiple episodes of this type of ar-
rhythmia. In the second group were patients with sus-
tained and symptomatic ventricular tachycardia. With
this arrhythmia the patient was always conscious. The
ventricular tachycardia had a duration of 210 beats
and was associated with 11 of the following symptoms:
hypotension, congestive heart failure, diaphoresis, palpi-
tations, shortness of breath or lightheadedness.
THE AMERICAN JOURNAL OF CARDIOLOGY SEPTEMBER 15, 1989 599
INTRAVENDUS AMIDDARDNE WR VERTRICULAR ARRRYTRMIAS
TARLE I Clinical Characteristics
No. of pts
sex (M/F)
Age Cm)
Mean f SD
Range
Ejection fraction (%)
Mean f SD
Range
Antiarrhythmic drugs failed
Mean i SD
Range
Lidocaine
Procainimide
Bretylium
Quinidine
Phenytoin
Disopyramide
Flecainide
Amiodarone (oral)
Mexiliiene
22
12/10
54f13
34-79
27f13
12-57
3.7 f 1.1
2-6
22
21
17
9
3
1
2
2
1
Trea&er~ proto& Informed consent was obtained
from the patient or the patient’s family before adminis-
tration of intravenous amiodarone. Amiodarone was
typically administered as a bolus (average 4 to 6 mg/
kg) followed by a constant infusion. In view .of reports
indicating that transient hypotension may occur with in-
travenous administration of amiodarone,20-22 the hemo-
dynamic status (primarily blood. pressure) of each pa-
Pm241 Post241 Post2411
tient was carefully monitored during drug infusion.
Variations in the amiodarone dose reflected differences
in hemodynamic response during drug administration.
In most patients, previously administered antiarrhyth-
mic agents were continued during the initial phase of
intravenous amiodarone loading.
Statistkw The Fisher’s exact test, chi-square test
and unpaired Student t test were used when comparing
responders to nonresponders. A p value <0.05 was con-
sidered significant. All values are listed as mean & stan-
dard deviation,
RESULTS
Cllnkal fe&ure~ Of 65 patients who received intra-
venous amiodarone from April 1983 to March 1987,22
patients (12 men and 10 women, ages 64 f 13 years)
met selection criteria. Table I liits the patient character-
istics. All patients had ischemic heart disease. Twenty
of the patients sustained myocardial infarctions (2
acute, 18 remote), and in 2 additional patients coronary
artery disease was documented by arteriography. Left
ventricular aneurysms were present in 12 patients. Six
patients had fmt-degree atrioventricular block, 2 had
left bundle branch block and 1 had right bundle branch
block during sinus rhythm. Ejection fraction was mea-
sured by nuclear gated blood pool study, contrast ven-
triculography or echocardiography. The mean ejection
fraction was 27 f 13% (range 12 to 57). Seventeen pa-
tients had severe congestive heart failure requiring ther-
apy during their hospital admission.
wu-
befom intravenous adodamm
therapy: Patients were hospitalized for 7 f 8 days
(range 1 to 28) before initiation of intravenous amioda-
rone therapy. During this period, all patients had multi-
ple, recurrent episodes of ventricular tachyarrhythmias
associated with cardiovascular collapse. These ventricu-
lar arrhythmias were refractory to 3.7 f 1.1 (range 2 to
6) antiarrhythmic drugs (Table I). In the previous 24
hours before intravenous therapy, patients were exposed
to a mean of 2.6 f 0.9 antiarrhythmic drugs (Table II).
In all patients, intravenous amiodarone was given within
15 hours of the last ventricular arrhythmia resulting in
cardiovascular collapse, or an average of 4.5 f 4.9
hours. In the 24 hours before intravenous amiodarone
administration, patients had a mean of 2.4 f 2.3 (range
1 to 9) episodes of life-threatening and hemodynamical-
ly unstable ventricular tachycardia, ventricular tibrilla-
tion or both that required direct current cardioversion
4.0 f 3.9 times/patient (Figure 1). Episodes of sus-
tained symptomatic ventricular tachycardia not requir-
ing immediate therapy were seen in 11 of the 22 pa-
tients, averaging 0.7 f 0.9 episode/patient.
Intravenous amWarene adminhtratlom Fifteen pa-
tients received initial bolus infusions of amiodarone in
doses ranging from 200 to 480 mg (mean dose 346 f
74), or an average of 4 to 6 mg/kg over 5 to 60 minutes
(mean 33 f 21). The patients then received a continu-
ous infusion of 900 to 1,600 mg/day (mean 921 f 162)
of amiodarone for 4.3 f 3.4 days (range 1 to 17). The
total daily dose and duration of therapy varied depend-
800 THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 64
ing on effectiveness of arrhythmia suppression and pa-
tient tolerance of the medication.
Hospital cows0 aftor intrav- amiodarone tbr-
apy: In 19 patients, 1.6 f 1.0 (range 1 to 3) antiar-
rhythmic drugs that had previously failed to prevent
life-threatening arrhythmias were maintained during
the first 24 hours after intravenous amiodarone admin-
istration (Table II). In 2 patients, orally administered
amiodarone therapy (6 and 5 days’ duration) had failed
to suppress arrhythmias before initiation of intravenous
therapy. In 15 patients, treatment with 800 to 1,200
mg/day of oral amiodarone was initiated simultaneous-
ly or within 1 to 3 days after initiation of intravenous
therapy.
Within the first 24 hours after initiation of amioda-
rone infusion, single or combined episodes of hemo-
dynamically unstable and life-threatening ventricular
tachycardia and ventricular fibrillation that required
immediate treatment decreased to 1 .l f 1.6 episodes/
patient, requiring 1.9 f 3.1 direct current cardiover-
sions (Figure 1). The number of patients who experi-
enced episodes of sustained symptomatic ventricular
tachycardia not requiring immediate cardioversion de-
creased from 11 to 5, for an average of 0.4 f 0.8 epi-
sodes/patient. In 11 patients, there were no further re-
currences of hemodynamically unstable and life-threat-
ening ventricular tachycardia, ventricular fibrillation or
both during this time period. By the second day of ami-
odarone infusion, single or combined episodes of life-
threatening ventricular tachycardia and ventricular fi-
brillation requiring immediate therapy decreased to 0.4
f 0.7 event/patient. Concurrently, the number of direct
current shocks delivered decreased to 0.4 f 0.9 times/
patient. Sustained symptomatic ventricular tachycardia
not requiring immediate intervention was seen in only 2
patients, for an average of 0.2 f 0.5 episode/patient.
Hemodynamically unstable and life-threatening ventric-
ular tachycardia, ventricular fibrillation or both were
suppressed in 14 patients for this time period.
Patients were hospitalized for an average of 30 f 20
days (range 1 to 106) after initiation of intravenous
amiodarone. Two patients died in the first 24 hours and
1 patient died in the second 24 hours due to drug fail-
ure. Five other patients died of an arrhythmia 6, 12, 13,
20 and 37 days after intravenous amiodarone adminis-
tration. Two patients who had their arrhythmia con-
trolled died due to progression of their heart failure af-
ter 3 and 9 days of therapy. Neither the presence of
congestive heart failure nor a left ventricular aneurysm
predicted the response to intravenous amiodarone. In
addition, responders had ejection fractions similar to
those of nonresponders (27 f 16 vs 27 f 17% respec-
tively, difference not significant).
Side efkctr: Bradycardia, atrioventricular block or
significant hypotension did not occur during amioda-
rone infusion in these patients. In particular, of the 16
patients who received the initial bolus of intravenous
amiodarone, none developed significant hypotension
(systemic blood pressure <90 mm Hg). Preexisting con-
gestive heart failure did worsen in 2 patients 3 and 9
TABLE II Concomitant Drug Therapy Administered Before
and After Intravenous Amiodarone.
Hours to Intravenous Amiodarone Therapy
48 Hours 24 Hours 24 Hours 48 Hours
Before Before After After
Drug
Lidccaine 15 19 14 12
Procainamide 17 19 9 7
Bretylium 3 12 9 6
Quinidine 2 2 1 1
Phenytoin 1 2 1 0
flecainide 1 0 0 0
Tocainide 0 0 0 1
Amiodarone (oral) 2 2 10 13
Amiodarone 0 0 22 19
(intravenous)
Drug therapy
Mean f SD 1.9zkO.8 2.OztO.9 1.6f l.O* 1.5f0.9*
Range l-4 l-4 O-3 O-3
l Excluding intravenous amiodarone.
SD = standard deviation.
days after initiation of intravenous amicdarone treat-
ment. Thrombophlebitis or inflammation at the infusion
site was avoided due to administration of intravenous
amiodarone through a central venous catheter in most
patients.
Long-term follow-up: Of the 22 patients in this
study, 10 did not survive to hospital discharge (8 died
due to an arrhythmia recurrence, 2 died due to the pro-
gression of underlying heart failure). The remaining 12
patients were followed for an average of 22 f 14
months (Figure 2). Five patients had recurrence of life-
threatening ventricular tachyarrhythmias. Two of these
patients died, 2 underwent subendocardial resection and
aneurysmectomy, and 1 patient *underwent orthotopic
cardiac transplantation. Two additional patients died, 1
due to pacemaker failure and the other from a myocar-
dial infarction. The role, if any, that amiodarone may
241
I I
1
THE AMERICAN JOURNAL OF CARDIOLOGY SEPTEMBER 15, 1989 601
INTRAVENOUS AMIODARONE FOR VENTRICULAR ARRtlYl’RMlAS
have had in affecting the pacemaker threshold in the
patient with pacemaker failure is unknown. The re-
maining 5 patients are alive, have no evidence of symp-
tomatic arrhythmias and are being treated with oral
amiodarone (400 to 600 mg/day).
DISCUSSION
This study demonstrates that intravenous amioda-
rone may be effective for the rapid control and preven-
tion of spontaneously occurring refractory ventricular
tachyarrhythmias associated with hemodynamic insta-
bility in critically ill patients. Alone or in combination
with previously unsuccessful antiarrhythmic drug thera-
pies, we achieved prompt suppression of life-threatening
arrhythmias in 64% of the study population within 48
hours of initiation of intravenous amiodarone therapy.
Despite the severely depressed left ventricular function
of the patients treated, adverse hemodynamic effects
from amiodarone administration were not encountered
in the majority of this study population.
Although numerous small reports support the hy-
pothesis that intravenous amiodarone provides antiar-
rhythmic effects soon after the start of an infusion,22-25
only a small number of critically ill patients similar to
ours have been included in any of these trials.
Mostow et a124 reported a significant reduction in
complex ventricular arrhythmias 24 to 48 hours after
the initiation of an amiodarone infusion. Holt et a123
reported that a bolus of amiodarone (5 mg/kg) resulted
in suppression of ventricular tachyarrhythmias (mainly
nonsustained ventricular tachycardia) in 14 of 16 pa-
tients. Further evidence supporting the concept that in-
travenous loading reduces the latent period preceding
arrhythmic control was reported by Kerin et a1,25 who
demonstrated that the time to suppression of ventricular
arrhythmias was shorter in 10 patients treated with in-
travenous and oral loading versus 10 patients treated
with oral loading alone.
There are only a few reports examining the useful-
ness of intravenous amiodarone for control of life-
threatening arrhythmias in critically ill patients. Leaki
reported the use of intravenous amiodarone in 7 patients
with recurrent ventricular tachycardia or ventricular fi-
brillation. Control of the ventricular tachyarrhythmias
was attained in 6 of these patients. Morady et a117 re-
ported the use of intravenous amiodarone in 15 patients
with ventricular tachycardia, of whom 13 had charac-
teristics similar to those required by our selection crite-
ria. In 10 of these patients, arrhythmias were success-
fully controlled with intravenous amiodarone. In addi-
tion, Installe et all5 treated 5 patients with ventricular
tachycardia, ventricular fibrillation or both. Intravenous
amiodarone controlled the arrhythmia in 4 of these pa-
tients. A brief report’6 of 2 patients with ventricular fi-
brillation controlled by intravenous amiodarone also
supports its application for the immediate management
of ventricular tachyarrhythmias.
Potential adverse effects: Parenteral administration
of amiodarone has been associated with hypoten-
602 THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 64
sion.20-22 Due to its negative inotropic effects, caution
has been advised when administering it to patients with
severe cardiac failure. Nevertheless, despite the poor left
ventricular function of our study population, clinically
significant hypotension did not occur. This may be due
in part to the relatively slow rate of the bolus injection
(average 33 f 21 minutes). On the other hand, 2 of our
patients did die of intractable congestive heart failure.
Clinical implications: Our experience suggests that
intravenous amiodarone may be useful for the rapid
control and prevention of hemodynamically unstable,
refractory ventricular tachyarrhythmias in extremely
ill patients. Furthermore, parenteral administration of
amiodarone can usually be well tolerated by critically ill
patients, even in the presence of poor left ventricular
function. Because of the high recurrence of life-threat-
ening ventricular arrhythmias in these patients after dis-
charge (5 of 12,42%), one should consider them as can-
didates for automatic implantable cardioverter defibril-
lator, arrhythmia surgery, or both.
Acknowiedgment: We are greatly indebted to Nan-
cy Grunz and Terri Hanson for their efforts in prepar-
ing this manuscript.
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