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Amiodarone in the treatment of cardiac arrhythmias in children: One hundred thirty-five cases
Amiodarone in the treatment of cardiac arrhythmias in children: One hundred thirty-five cases
Philippe Coumel, M.D., Loges-en-Josas, France
and Jean
Oral amiodarone was given to 135 (range, 1 day to 6 years) for mainly ECG control or partial ECG control respectively, mechanism, clinical months
regardless resistance signs of heart in 54%). The
discontinuation metabolism hyperthyroid,
than
M.D.
(27%). The onset of drug
(3.3 weeks), and the thiat in adults, with
location (45%) only factor effect (4.1
absence no cardiac
favoring days),
of side effects toxicity and
Les
a mean duration (61%) arrhythmias. obtained in 60% and 16%, presence
improvement the early relapses
was
of 4.1 months Complete 33% of cases,
and ventricular of cardiomegaly a short history after treatment
due to drug accumulation a low incidence of thyroid
15%), (40%) (<
or
2
reflect a faster dysfunction (2
1 hypothyroid).
and methods
The study includes 135 children (SOboys and 55 girls), ages 0 to 15 years (Fig. l), treated and followed up frorn 1971 to 1979, and also includes a previously published study’ of 50 patients. The diagnosis and cause of the arrhythmias are detailed in Tables I and II. The predominance of atria1 (69%) and postoperative arrhythmias (61%) is emphasized, as well as some resistant arrhythmias, such as, permanent reciprocal tachycardia: congenital ectopic His bundle tachycardia” (Figs.
From the Hopital Lariboisiere, Paris, and Chateau des CBtes, Les Loges-en-Josas, France. Reprint requests: P. Coumel, M.D., Hopital Lariboisiere, 2 rue Ambroise-Pare, 75010, Paris, France.
0002~8703/80/131063
and
for
(atrial 6g%, junctional to other drugs, and
Two factors are responsible for the greater difficulty in treating arrhythmias in children compared to adults: (1) the many different types of arrhythmias, some of which are refractory and peculiar to children, and (2) the limitations of therapeutic choice due to greater drug toxicity. This is why amiodarone is a considerable therapeutic asset in children. We report here our experience since 1971. Material
Paris
children (mean age, 10.2 years) idiopathic (25%) and postoperative with clinical improvement was
of the arrhythmia (55%) or sensitivity failure rapid
Fidelle,
+ 07$00.70/O
0 1980 The
C. V. Mosby
Co.
2A and 2B), and catecholamine ventricular tachycardias” (Fig. 3). The arrhythmias were accompanied by clinical cardiac failure in 27%, isolated radiologic cardiomegaly in 40%, and were well tolerated hemodynamically in only 33% of the cases. The arrhythmias were chronic (lasting more than 2 months) in almost half of the cases(46%). In over half (55%), the arrhythmias were resistant to the various antiarrhythmic drugs used in children, i.e., digitalis, disopyramide, beta blockers, atropine, and verapamil. Among the remaining patients, some had no treatment other than amiodarone because they had well-known resistant arrhythmias. The initial treatment was a daily oral dose of 800 mg of amiodarone adjusted according to the child’s surface area. This dose was maintained for an average of 2 weeks, then reduced by half, and was finally given 5 days out of 7. Because of our adult experience and the large predominance of supraventricular arrhythmias, most of the patients were also digitalized. Digitalization was always achieved before amiodarone was given in casesof cardiac failure and was associated with a diuretic. In a small number of cases (eight patients), one single dose of amiodarone was given
American Heart Journal
1063
Fig.
able I. Arrhythmia
diagnosis
I. Age and sex distribution
of the 135 patients.
(n = 135) No. of cases
%
Atria1
Sinus tachycardia Coronary sinus rhythm Extrasystole Ectopic tachycardia Flutter-fibrillation Bradycardia-tachycasdia
syndrome
93
Total JU?ZCtiO?d
Permanent reciprocating Paroxysmal reciprocating (WPW) IIis tachycardia Total Ventricular Extrasystole Ventricular tachycardia Catecholamine-induced tachycardia
tachycardia tachycardia
B 23 32 3 5
7
-z% 6
8
6 5 16% Ii
ventricular
Total WPW = Wolff-Parkinson-White
31 43 4 7’
I 4
1 3
20
15%
syndrome.
to terminate attacks of supraventricular tachycardia and the treatment was discontinued after it was successful. We have no experience with the intravenous route in childhood. The rate monitoring was a pulse curve based on beart rates taken every 2 hours, day and night, and included several daytime and nightime
Idiopathic Congenital cardiopatbies Preoperative Postoperative Wolff-Parkinson-White Valvular diseases Cardiomyopathies
syndrome
34
25
5 82 6 4 4
4 61 4 3 3
controls, many of which bad at least 12 SD taken at normal recording speed with standard amphfication, and then at double these norms to verify the drug’s usual effect on the slow phase. Similar monitoring was progressively spaced for Iongterm treatment in nonhospitalized children. The mean treatment period was 4.1 months, (range, I day to 6 years). For the long-term treatments, the follow-up included height, weight, psychomotor development, ophthalmic state, and serum levels to detect a possible thyroid dysfunction (cholesterol, T,, T,, TS amok&y test).
The results were considered goo sinus rhythm was reestablished, average when the cardiac rate was reduced but the arrhythmia was not perfectly controlled on tbe ECG, and poor when the treatment clinicahy and electrocardio-
December,
1980,
Vd.
100, No.
6, part
2
Amiodarone
;._.
in cardiac
arrhythmias
,
B
0
It
.i “.‘.;
t,.,,
i--
;
,”
.:l .(
I
_
“,
o
;:..I
,.,-:
_I x ,.,
:”
~.
5: g ‘. ,t ,_
:
‘::-.
*
..>.
-., ,. .;’ ,,
Fig. 2A. Resistant His bundle tachycardia in a l-month-old infant. The cardiac insufficiency (see Fig. 2B) is clearly related to the supraventricular tachycardia in this infant, a cousin of whom died several years earlier from the same tachycardia after all antiarrhythmics had failed (amiodarone had not been tried). Tracing A(Dec. 6, 1973) clearly shows the narrow QRS complexes with a second-degree ventriculoatrial block (arrows point to retrograde P’ waves). Two days later (tracing B) the A-V dissociation is complete. Tracings C to E were taken during the following 11 months and show the progressive slowing of the ectopic focus with a persistent A-V dissociation.
Fig. 28. Dramatic regression Fig. 2A. This case is classified
American
Heart
Journal
of the cardiomegaly as an average result
with the progressive slowing (clinical but no ECG control
of the tachycardia of the arrhythmia).
in patient
in
1065
Fig. 3. CatecPlolamin~-renamed severe ventricular tachycardia in an &year-old boy. A strip from the Hoilter monitoring clearly shows the mechanism of the Adams-Stokes syndrome: very rapid and polymorphic attacks of ventricular tachycardia and fibriUation are readily induced by exercise. Beta blockers were only partially effective: and a new G-year treatment with amiodarone did control the arrhythmia.
. 4. Delay before response to amicdarone treatment. In 91 patients in whom the delay could be precisely evaluated, the great majority (83) responded during the first week of treatment (one fourth at the third day). This is in contrast to the necessary 7- to N-day impregnation in adults.
graphically was ineffective. The results were good in $1 cases (SO%), average in 44 (33%), and poor in only 10 (a%), i.e., more than 91)% of the cases totally or partially improved. The cause of the arrhythmia, its mechanism (eetopic focus or reentry), localization (Table HI), and resistance to other ~~ti~~bythrn~~s (Table IV) do not affect ca6y (Pearson d-&square test), &bough a longer duration of the arrhythmia (greater than 2 months) resdted in less drug eiediveness (P c O,lO).
The delay before response to treatment codd be evaluated in 91 patients and is represented in Fig. 4. It ranges from 1 to 16 days, and its mean value is 4.1 days with a peak at day 3. In eight cases of supraventricular taehycardia, a Ml single dose of oral amiodarone was given 2nd rhythm reduction was obtained between 5 and 7 hours in seven patients and after 24 hours in one. Conversely, the delay before relapses after interruption of treatment could be assessedin 34 cases of serious, chronic, and recurring arrhyth-
Amiodarone
01
234
in cardiac
12
8
arrhythmias
16 Weeks
. long-term 0 mean-term o short-term
treatment treatment treatment
( 3 months to 6 years ) ( 2 weeks to 3 months) (2 2 weeks )
Fig. 5. Delay before relapse of chronic arrhythmias after recurrence of the arrhythmia could be evaluated, it occurred 12 to 16 weeks in four.
mias (Fig. 5). Its mean value was 3.3 weeks, and in 24 cases it was 2 weeks or less. The duration of treatment and child’s age affect the delay before relapse. In 10 treatments lasting between 3 months and 6 years, relapses occurred three times in 2 weeks, thres times in 4 weeks, and four times in 2 to 3 months. Concerning children and long-term treatments, particular attention must be paid to drug tolerance. Electrocardiographically, repolarization changes must occur before a treatment failure is accepted, i.e., before the appearance of increased height of U waves and length.ening of the Q-T segment. The sinus rate was steadily reduced, but in only 10 cases was it less than 60/min at rest, and in seven of these patients there was a preexisting atria1 rhythm disturbance. The three cases of sinoatrial block were preexisting. We observed no intra-atria1 conduction disturbances. The P-R lengthening was from 40 to 80 msec in 41 cases, with Wenckebach periods in three cases. We observed no distal A-V conduction disturbance in spite of 52 cases of complete right bundle branch block, 15 of which were associated with a left anterior hemiblock, The QRS duration increased by 20 to 40 msec in two cases of incomplete right bundle branch block. Cornea1 deposition (three cases),photosensitivity (four cases), and bluish skin coloring (one case after 72 months of treatment) were rarely observed and only in older children. In four cases American
Heart Journal
cessation of treatment. In 34 patients in whom the within 2 weeks in 24, after 3 to 4 weeks in six, and after
Table I I I. Amiodarone efficacy according to localization of arrhythmias Atria1
Junctional
Ventricular
Results
93 eases
69% 22 cases
16%
20 cases
15%
Good (81 cases, 60%) Fair (44 cases, 33%) Poor (10 cases, 7%)
55 cases
41%
12 cases
9%
14 cases
10%
31 cases
23%
10 cases
7%
3 cases
2%
3 cases
2%
7 cases
5%
0 cases
IV. Amiodarone efficacy resistance to prior treatment
Table
Prior
treatments
according
to
Anziodarone
as
40 cases 14 cases 7 cases
30% 10% 5%
0 Good (81 cases, 60%) Fair (44 cases, 33%) Poor (10 cases, 7%)
41 cases 30 cases 3 cases
30% 23% 2%
nightmares, hallucinations, and personality problems caused the cessation of treatment. These signs seemedto be precursors of hyperthyroidism; in two other cases they appeared before obvious biologic modifications. Conversely, one patient developed hypothyroidism, which may have reflected a predisposition (control cholesterol was 1067
2.60
/IL). In these three patients,
the thymid
dysfunction (two hyperthyroid, one hypothyroid) completely regress in several weeks with cessation of treatment. iologie surveillance c0nfirms the Jrarity of thyroid complications in the preselle experience: plasma cholesterol leveIs, Hamolsky test, T3> T,, and TSH were monitored bef0re and after a mean duration of 14.5 months of treatment in 40 patients. No variation exceeding the nomad range for these tests was observed except in the three previously mentioned patients.
After amiodarone has been used for more than 10 years as an antiarrhythmic in adults, it is not necessary to emphasize its effectiveness and uniqueness. However, its overall effectiveness does not replace other antizrrhythmics, and moreover, its problems of tolerance or thyroid toxicity should not make it an irntiad simple tlaerapeutic approach. These side effects were carefully considered before this drug was used in children, and only its extraordinary effectiveness and the observed excellent tolerance encouraged us to increase its use over the g-year peri0d. We know of only (one equivalent experience (Kreutzer A: Personal communication). Amiodaron’e cured or imprcaved arrhythmias in six out of ten patients and improved their tolerance in three out of four remaining patients, whatever the mechanism, ?ocalization, ana previous resistance. This is without evidence of poor tolerance or nonreversible toxicity and represents almost all the desirab1.eproperties for an ide21 antiarrhythmic. It is mostly on a matter of principle that one should not use tbis as the first medication in childrens’ rhythm disturbances, even though it is more consistently effective and better tolerated than in l&s. The drug is metaboliz more rapidly in CM&en, with the onset of action in 4 days instead of 10 days as in aadts, and effectiveness after cessation lasts less than a few weeks as opposed to several months in adults. These are the norms found in animal experiments,S from which we a850 know that the drug concentration in the adipose tissue and muscle is 10 to 30 times greater than in the phma. There is no plasma assay to regulate the dosagetxea in a clinical setting and, in any case, the tissue bmding might invalidate normal pharmacokinetic parameters and should not be interpreted as rigorously as for other drugs. The
fact tjhat
Aildren have less adipose tissue than account for the faster metabolism an the former, but probably this is not the only difference and does not explain the unique phenomendln of cornea1 deposits in adults. ‘The drug’s primary and secondary effects ob-viously vary with age, and this is clearPy visible in the oldex child w&o tends to react a5 an adulk. It is in this regard that the younger the chi!d ana t.he more recent the arrhythmia, the more oral amiodarone is iikely to be an effective emergency treatment, able in a few bours to terminate a reciprocal junctional paroxysm4 tachycardia or an atria1 or ventricular tachycardia, while avoiding the dangers 0f other antiarrhythmics. The mechanism of a&ion of amiodarrone is clearly known and it reduces the outward potassium current, a5 well as the rapid anward sodiu.m current, without being classed as a membsanestabilizing agent. Also, it is not a beta Mocker inut nevertheless slows the beta response.’ Finally, j: canal, and its has no e ct on the slow calcium essential action is to lengthen the duration of the action potential and refractory period. A single mechanism of action Seems to fit poorly with the drug3 widespread effectiveness in a great many different arrhythmias. It is rare to combine amiodarone with other antiarrhythmics, with the exception of digitalis, whose supraventricular antiarrhythmic action is synergic. In addition, digitalis alone can compensate for amiodarone’s real, aMrough moderate, depre5sive myoeardiai
adults may
&eCt.7 The demonstration of wide clinical efficacy does not dictate indications for medication. However, one can recognize cases in wbieh one 5hould directly resort to this treatment. In practice, this apphes te all poorly tolerated arrhythmias, as it is the least dangerous m the presence of poor myccardium. In the long sun, it does not necessarily have to be maintained, except in special resistant life or death childhoo arrhythmias as such certam long-term atria1 tachycardias, chronic reciprocal tachycardias, ectopic focus tachycardias in infants, and catecholergic ventricular taehycardias when not controlled by beta-blocking treatment.
1.
Fidelle JE, Attuel P, Toumieux MC, Coumel P: L’ucilisation de l’amiodarone dans Pes troubles rgthmigues graves et sebeiles de l’enfaant. Ann Cardiol Angeiol 25:385, 1976.
Amiodarone
2.
3.
4.
Coumel P, Fidelle JE, Cloup M, Toumieux MC, Attuel P: Tachycardies reciproques a evolution prolongee chez l’enfant. Arch Ma1 Coeur 67:23, 1974. Coumel P, Fidelle JE, Attuel P, Brechenmacher C, et al: Tachycardies hisienne focales congenitales. Etude cooperative de 7 cas. Arch Ma1 Coeur 69899, 1976. Coumel P, Fidelle JE, Lucet V, Attuel P, Eouvrain Y: Catecholamine-induced severe ventricular arrhythmias in children: Report of four cases. Br Heart J 15(Suppl.):28, 1978.
American
Heart
Journal
5. 6. 7.
in cardiac
arrhythmias
Charlier R, Deltour G: Correction des arythmies experimentales par l’amiodarone. J Pharmacot 1:175, 1970. Polster R, Broekhuysen J: The adrenergic antagonism of amiodarone. Biochem Pharmacol 25:131, 1976. Sicart M, Besse P, Choussat A, Bricaud H: Action hemodynamique de l’amiodarone chez l’homme. Arch Ma1 Coeur 70:219, 1977.
1069
Philippe Coumel, M.D., Loges-en-Josas, France
and Jean
Oral amiodarone was given to 135 (range, 1 day to 6 years) for mainly ECG control or partial ECG control respectively, mechanism, clinical months
regardless resistance signs of heart in 54%). The
discontinuation metabolism hyperthyroid,
than
M.D.
(27%). The onset of drug
(3.3 weeks), and the thiat in adults, with
location (45%) only factor effect (4.1
absence no cardiac
favoring days),
of side effects toxicity and
Les
a mean duration (61%) arrhythmias. obtained in 60% and 16%, presence
improvement the early relapses
was
of 4.1 months Complete 33% of cases,
and ventricular of cardiomegaly a short history after treatment
due to drug accumulation a low incidence of thyroid
15%), (40%) (<
or
2
reflect a faster dysfunction (2
1 hypothyroid).
and methods
The study includes 135 children (SOboys and 55 girls), ages 0 to 15 years (Fig. l), treated and followed up frorn 1971 to 1979, and also includes a previously published study’ of 50 patients. The diagnosis and cause of the arrhythmias are detailed in Tables I and II. The predominance of atria1 (69%) and postoperative arrhythmias (61%) is emphasized, as well as some resistant arrhythmias, such as, permanent reciprocal tachycardia: congenital ectopic His bundle tachycardia” (Figs.
From the Hopital Lariboisiere, Paris, and Chateau des CBtes, Les Loges-en-Josas, France. Reprint requests: P. Coumel, M.D., Hopital Lariboisiere, 2 rue Ambroise-Pare, 75010, Paris, France.
0002~8703/80/131063
and
for
(atrial 6g%, junctional to other drugs, and
Two factors are responsible for the greater difficulty in treating arrhythmias in children compared to adults: (1) the many different types of arrhythmias, some of which are refractory and peculiar to children, and (2) the limitations of therapeutic choice due to greater drug toxicity. This is why amiodarone is a considerable therapeutic asset in children. We report here our experience since 1971. Material
Paris
children (mean age, 10.2 years) idiopathic (25%) and postoperative with clinical improvement was
of the arrhythmia (55%) or sensitivity failure rapid
Fidelle,
+ 07$00.70/O
0 1980 The
C. V. Mosby
Co.
2A and 2B), and catecholamine ventricular tachycardias” (Fig. 3). The arrhythmias were accompanied by clinical cardiac failure in 27%, isolated radiologic cardiomegaly in 40%, and were well tolerated hemodynamically in only 33% of the cases. The arrhythmias were chronic (lasting more than 2 months) in almost half of the cases(46%). In over half (55%), the arrhythmias were resistant to the various antiarrhythmic drugs used in children, i.e., digitalis, disopyramide, beta blockers, atropine, and verapamil. Among the remaining patients, some had no treatment other than amiodarone because they had well-known resistant arrhythmias. The initial treatment was a daily oral dose of 800 mg of amiodarone adjusted according to the child’s surface area. This dose was maintained for an average of 2 weeks, then reduced by half, and was finally given 5 days out of 7. Because of our adult experience and the large predominance of supraventricular arrhythmias, most of the patients were also digitalized. Digitalization was always achieved before amiodarone was given in casesof cardiac failure and was associated with a diuretic. In a small number of cases (eight patients), one single dose of amiodarone was given
American Heart Journal
1063
Fig.
able I. Arrhythmia
diagnosis
I. Age and sex distribution
of the 135 patients.
(n = 135) No. of cases
%
Atria1
Sinus tachycardia Coronary sinus rhythm Extrasystole Ectopic tachycardia Flutter-fibrillation Bradycardia-tachycasdia
syndrome
93
Total JU?ZCtiO?d
Permanent reciprocating Paroxysmal reciprocating (WPW) IIis tachycardia Total Ventricular Extrasystole Ventricular tachycardia Catecholamine-induced tachycardia
tachycardia tachycardia
B 23 32 3 5
7
-z% 6
8
6 5 16% Ii
ventricular
Total WPW = Wolff-Parkinson-White
31 43 4 7’
I 4
1 3
20
15%
syndrome.
to terminate attacks of supraventricular tachycardia and the treatment was discontinued after it was successful. We have no experience with the intravenous route in childhood. The rate monitoring was a pulse curve based on beart rates taken every 2 hours, day and night, and included several daytime and nightime
Idiopathic Congenital cardiopatbies Preoperative Postoperative Wolff-Parkinson-White Valvular diseases Cardiomyopathies
syndrome
34
25
5 82 6 4 4
4 61 4 3 3
controls, many of which bad at least 12 SD taken at normal recording speed with standard amphfication, and then at double these norms to verify the drug’s usual effect on the slow phase. Similar monitoring was progressively spaced for Iongterm treatment in nonhospitalized children. The mean treatment period was 4.1 months, (range, I day to 6 years). For the long-term treatments, the follow-up included height, weight, psychomotor development, ophthalmic state, and serum levels to detect a possible thyroid dysfunction (cholesterol, T,, T,, TS amok&y test).
The results were considered goo sinus rhythm was reestablished, average when the cardiac rate was reduced but the arrhythmia was not perfectly controlled on tbe ECG, and poor when the treatment clinicahy and electrocardio-
December,
1980,
Vd.
100, No.
6, part
2
Amiodarone
;._.
in cardiac
arrhythmias
,
B
0
It
.i “.‘.;
t,.,,
i--
;
,”
.:l .(
I
_
“,
o
;:..I
,.,-:
_I x ,.,
:”
~.
5: g ‘. ,t ,_
:
‘::-.
*
..>.
-., ,. .;’ ,,
Fig. 2A. Resistant His bundle tachycardia in a l-month-old infant. The cardiac insufficiency (see Fig. 2B) is clearly related to the supraventricular tachycardia in this infant, a cousin of whom died several years earlier from the same tachycardia after all antiarrhythmics had failed (amiodarone had not been tried). Tracing A(Dec. 6, 1973) clearly shows the narrow QRS complexes with a second-degree ventriculoatrial block (arrows point to retrograde P’ waves). Two days later (tracing B) the A-V dissociation is complete. Tracings C to E were taken during the following 11 months and show the progressive slowing of the ectopic focus with a persistent A-V dissociation.
Fig. 28. Dramatic regression Fig. 2A. This case is classified
American
Heart
Journal
of the cardiomegaly as an average result
with the progressive slowing (clinical but no ECG control
of the tachycardia of the arrhythmia).
in patient
in
1065
Fig. 3. CatecPlolamin~-renamed severe ventricular tachycardia in an &year-old boy. A strip from the Hoilter monitoring clearly shows the mechanism of the Adams-Stokes syndrome: very rapid and polymorphic attacks of ventricular tachycardia and fibriUation are readily induced by exercise. Beta blockers were only partially effective: and a new G-year treatment with amiodarone did control the arrhythmia.
. 4. Delay before response to amicdarone treatment. In 91 patients in whom the delay could be precisely evaluated, the great majority (83) responded during the first week of treatment (one fourth at the third day). This is in contrast to the necessary 7- to N-day impregnation in adults.
graphically was ineffective. The results were good in $1 cases (SO%), average in 44 (33%), and poor in only 10 (a%), i.e., more than 91)% of the cases totally or partially improved. The cause of the arrhythmia, its mechanism (eetopic focus or reentry), localization (Table HI), and resistance to other ~~ti~~bythrn~~s (Table IV) do not affect ca6y (Pearson d-&square test), &bough a longer duration of the arrhythmia (greater than 2 months) resdted in less drug eiediveness (P c O,lO).
The delay before response to treatment codd be evaluated in 91 patients and is represented in Fig. 4. It ranges from 1 to 16 days, and its mean value is 4.1 days with a peak at day 3. In eight cases of supraventricular taehycardia, a Ml single dose of oral amiodarone was given 2nd rhythm reduction was obtained between 5 and 7 hours in seven patients and after 24 hours in one. Conversely, the delay before relapses after interruption of treatment could be assessedin 34 cases of serious, chronic, and recurring arrhyth-
Amiodarone
01
234
in cardiac
12
8
arrhythmias
16 Weeks
. long-term 0 mean-term o short-term
treatment treatment treatment
( 3 months to 6 years ) ( 2 weeks to 3 months) (2 2 weeks )
Fig. 5. Delay before relapse of chronic arrhythmias after recurrence of the arrhythmia could be evaluated, it occurred 12 to 16 weeks in four.
mias (Fig. 5). Its mean value was 3.3 weeks, and in 24 cases it was 2 weeks or less. The duration of treatment and child’s age affect the delay before relapse. In 10 treatments lasting between 3 months and 6 years, relapses occurred three times in 2 weeks, thres times in 4 weeks, and four times in 2 to 3 months. Concerning children and long-term treatments, particular attention must be paid to drug tolerance. Electrocardiographically, repolarization changes must occur before a treatment failure is accepted, i.e., before the appearance of increased height of U waves and length.ening of the Q-T segment. The sinus rate was steadily reduced, but in only 10 cases was it less than 60/min at rest, and in seven of these patients there was a preexisting atria1 rhythm disturbance. The three cases of sinoatrial block were preexisting. We observed no intra-atria1 conduction disturbances. The P-R lengthening was from 40 to 80 msec in 41 cases, with Wenckebach periods in three cases. We observed no distal A-V conduction disturbance in spite of 52 cases of complete right bundle branch block, 15 of which were associated with a left anterior hemiblock, The QRS duration increased by 20 to 40 msec in two cases of incomplete right bundle branch block. Cornea1 deposition (three cases),photosensitivity (four cases), and bluish skin coloring (one case after 72 months of treatment) were rarely observed and only in older children. In four cases American
Heart Journal
cessation of treatment. In 34 patients in whom the within 2 weeks in 24, after 3 to 4 weeks in six, and after
Table I I I. Amiodarone efficacy according to localization of arrhythmias Atria1
Junctional
Ventricular
Results
93 eases
69% 22 cases
16%
20 cases
15%
Good (81 cases, 60%) Fair (44 cases, 33%) Poor (10 cases, 7%)
55 cases
41%
12 cases
9%
14 cases
10%
31 cases
23%
10 cases
7%
3 cases
2%
3 cases
2%
7 cases
5%
0 cases
IV. Amiodarone efficacy resistance to prior treatment
Table
Prior
treatments
according
to
Anziodarone
as
40 cases 14 cases 7 cases
30% 10% 5%
0 Good (81 cases, 60%) Fair (44 cases, 33%) Poor (10 cases, 7%)
41 cases 30 cases 3 cases
30% 23% 2%
nightmares, hallucinations, and personality problems caused the cessation of treatment. These signs seemedto be precursors of hyperthyroidism; in two other cases they appeared before obvious biologic modifications. Conversely, one patient developed hypothyroidism, which may have reflected a predisposition (control cholesterol was 1067
2.60
/IL). In these three patients,
the thymid
dysfunction (two hyperthyroid, one hypothyroid) completely regress in several weeks with cessation of treatment. iologie surveillance c0nfirms the Jrarity of thyroid complications in the preselle experience: plasma cholesterol leveIs, Hamolsky test, T3> T,, and TSH were monitored bef0re and after a mean duration of 14.5 months of treatment in 40 patients. No variation exceeding the nomad range for these tests was observed except in the three previously mentioned patients.
After amiodarone has been used for more than 10 years as an antiarrhythmic in adults, it is not necessary to emphasize its effectiveness and uniqueness. However, its overall effectiveness does not replace other antizrrhythmics, and moreover, its problems of tolerance or thyroid toxicity should not make it an irntiad simple tlaerapeutic approach. These side effects were carefully considered before this drug was used in children, and only its extraordinary effectiveness and the observed excellent tolerance encouraged us to increase its use over the g-year peri0d. We know of only (one equivalent experience (Kreutzer A: Personal communication). Amiodaron’e cured or imprcaved arrhythmias in six out of ten patients and improved their tolerance in three out of four remaining patients, whatever the mechanism, ?ocalization, ana previous resistance. This is without evidence of poor tolerance or nonreversible toxicity and represents almost all the desirab1.eproperties for an ide21 antiarrhythmic. It is mostly on a matter of principle that one should not use tbis as the first medication in childrens’ rhythm disturbances, even though it is more consistently effective and better tolerated than in l&s. The drug is metaboliz more rapidly in CM&en, with the onset of action in 4 days instead of 10 days as in aadts, and effectiveness after cessation lasts less than a few weeks as opposed to several months in adults. These are the norms found in animal experiments,S from which we a850 know that the drug concentration in the adipose tissue and muscle is 10 to 30 times greater than in the phma. There is no plasma assay to regulate the dosagetxea in a clinical setting and, in any case, the tissue bmding might invalidate normal pharmacokinetic parameters and should not be interpreted as rigorously as for other drugs. The
fact tjhat
Aildren have less adipose tissue than account for the faster metabolism an the former, but probably this is not the only difference and does not explain the unique phenomendln of cornea1 deposits in adults. ‘The drug’s primary and secondary effects ob-viously vary with age, and this is clearPy visible in the oldex child w&o tends to react a5 an adulk. It is in this regard that the younger the chi!d ana t.he more recent the arrhythmia, the more oral amiodarone is iikely to be an effective emergency treatment, able in a few bours to terminate a reciprocal junctional paroxysm4 tachycardia or an atria1 or ventricular tachycardia, while avoiding the dangers 0f other antiarrhythmics. The mechanism of a&ion of amiodarrone is clearly known and it reduces the outward potassium current, a5 well as the rapid anward sodiu.m current, without being classed as a membsanestabilizing agent. Also, it is not a beta Mocker inut nevertheless slows the beta response.’ Finally, j: canal, and its has no e ct on the slow calcium essential action is to lengthen the duration of the action potential and refractory period. A single mechanism of action Seems to fit poorly with the drug3 widespread effectiveness in a great many different arrhythmias. It is rare to combine amiodarone with other antiarrhythmics, with the exception of digitalis, whose supraventricular antiarrhythmic action is synergic. In addition, digitalis alone can compensate for amiodarone’s real, aMrough moderate, depre5sive myoeardiai
adults may
&eCt.7 The demonstration of wide clinical efficacy does not dictate indications for medication. However, one can recognize cases in wbieh one 5hould directly resort to this treatment. In practice, this apphes te all poorly tolerated arrhythmias, as it is the least dangerous m the presence of poor myccardium. In the long sun, it does not necessarily have to be maintained, except in special resistant life or death childhoo arrhythmias as such certam long-term atria1 tachycardias, chronic reciprocal tachycardias, ectopic focus tachycardias in infants, and catecholergic ventricular taehycardias when not controlled by beta-blocking treatment.
1.
Fidelle JE, Attuel P, Toumieux MC, Coumel P: L’ucilisation de l’amiodarone dans Pes troubles rgthmigues graves et sebeiles de l’enfaant. Ann Cardiol Angeiol 25:385, 1976.
Amiodarone
2.
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4.
Coumel P, Fidelle JE, Cloup M, Toumieux MC, Attuel P: Tachycardies reciproques a evolution prolongee chez l’enfant. Arch Ma1 Coeur 67:23, 1974. Coumel P, Fidelle JE, Attuel P, Brechenmacher C, et al: Tachycardies hisienne focales congenitales. Etude cooperative de 7 cas. Arch Ma1 Coeur 69899, 1976. Coumel P, Fidelle JE, Lucet V, Attuel P, Eouvrain Y: Catecholamine-induced severe ventricular arrhythmias in children: Report of four cases. Br Heart J 15(Suppl.):28, 1978.
American
Heart
Journal
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in cardiac
arrhythmias
Charlier R, Deltour G: Correction des arythmies experimentales par l’amiodarone. J Pharmacot 1:175, 1970. Polster R, Broekhuysen J: The adrenergic antagonism of amiodarone. Biochem Pharmacol 25:131, 1976. Sicart M, Besse P, Choussat A, Bricaud H: Action hemodynamique de l’amiodarone chez l’homme. Arch Ma1 Coeur 70:219, 1977.
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