Download Review on Flecainide poisoning - Hong Kong College of Emergency

Hong Kong Journal of Emergency Medicine
Review on Flecainide poisoning
ITF Cheung and CY Man
Flecainide acetate is a Vaughn-Williams class IC antiarrhythmic. It is used mainly for treatment of
supraventricular arrhythmias due to reentry and is highly effective in suppressing frequent premature
ventricular depolarization and nonsustained ventricular tachycardia (VT). Although less than 1% of drug
overdoses are fatal, severe intoxication with Vaughn-Williams class IC antiarrhythmics is associated with
average mortality of 22.5% and the rate of mortality after flecainide overdose is approximately 10%. Severe
flecainide overdose is frequently fatal because of the rapid onset of hypotension and ventricular arrhythmias.
Its cardiotoxicity is mainly due to its sodium and potassium channels blocking effects. Commonly
recommended therapies like haemolysis or haemoperfusion is not helpful because of its large volume of
distribution. As a result, the treatment goals are to decrease the amount of blockade; correct aggravating
conditions for arrhythmias, such as electrolytes disturbances or hypoxia; avoid drugs with sodium channels
blocking effects. Recently, there are some successful data on using peripheral cardiopulmonary bypass
technique in the treatment of severe flecainide intoxication. This may be a promising treatment option in
this type of drug overdose. (Hong Kong j.emerg.med. 2002;9:150-153)
Keywords: Class IC antiarrhythmic, flecainide, overdose, poisoning
Flecainide acetate is a Vaughn-Williams class IC
antiarrhythmic. (Table 1) It is used mainly for
treatment of supraventricular arrhythmias due to
reentry and is highly effective in suppressing frequent
premature ventricular depolarization and
nonsustained ventricular tachycardia ( VT ). 1-3
Although less than 1% drug overdoses are fatal, severe
i n t ox i c a t i o n w i t h Va u g h n - Wi l l i a m s c l a s s I C
antiarrhythmics is associated with average mortality
of 22.5% and the rate of mortality after flecainide
overdose is approximately 10%. 4 Severe flecainide
overdose is frequently fatal because of the rapid onset
of hypotension and ventricular arrhythmias. 2,4 Its
cardiotoxicity is mainly due to its sodium and
potassium channels blocking effects.
Correspondence to:
Cheung Tsz Fung, Ian, MBChB(CUHK), FRCSEd(A&E)
Prince of Wales Hospital, Accident and Emergency Department,
30-32 Ngan Shing Street, Shatin, N.T., Hong Kong
Email: [email protected]
Man Chi Yin, FRCSEd, FHKCEM, FHKAM(Emergency Medicine)
Mechanism of toxic effects
Class 1 antiarrhythmics block sodium channels in
cardiomyocytes and cardiac conducting tissue. Sodium
channel is responsible for phase 0 or the rapid upstroke
of the action potential and is reflected in the QRS
duration of the ECG. Drugs that block the sodium
channel will increase QRS duration. (Table 2)
Class 1A drugs lengthen the duration of action
potential, where class 1B drugs shorten it, and class
1C drugs have little or no effect on action potential
Table 1. Vaughn-Williams classification
Class I
Ia - Procainamide, Quinidine, Disopyramide
Ib -Lidocaine, Mexiletine, Tocainide
Ic - Encainide, Flecainide (Tambocor), Propafenone
(Rhythmol)
Class II - Acebutalol, Propranolol, Esmolol
Class III - Bretyllium, Amiodarone, Sotalol (also class II),
Ibutilide
Class IV - Verapamil, Diltiazem
Cheung et al./Review on Flecainide poisoning
Table 2. Drugs that block the sodium channel
Quinine
Quinidine
Procainamide
Disopyramide
Lidocaine
Phenytoin
Mexiletine
Tocainide
Flecainide
Propafenone
Moricizine
Class 1A
Class 1B
Class 1C
Tricyclics
Phenothiazines
Thioridazine
Cocaine
Diphenhydramine
Benadryl
Propoxyphene
Dologesic
Carbamazepine
Amantadine
duration. Class 1B antiarrhythmics have rapid offset
kinetics, thus the sodium channel is reactivated between
contractions. On the other hand, Class 1C has slow offset
kinetics and causes complete blockade of any particular
sodium channel for a much longer duration.5
Potassium channel is primarily responsible for phase
III or rapid repolarization of the action potential and
is reflected in the QT interval of the ECG. Drugs that
cause potassium channel blockade will result in an
increase in the QT duration. Class III antiarrhythmics
are potassium channel blockers and result in QT
prolongation. Class 1A and 1C drugs, in addition to
their effects on the sodium channel, also have
potassium channel blocking effects, thus they cause
both QRS and QT prolongation.
151
The reminder 70% is converted by the liver to
metabolites, which exert weak electro-physiologic
effect. 6,7 The main metabolite meta-0-dealkylated
lactum contribute little to the efficacy or toxicity of
the drug. Renal clearance is enhanced in acidic urine,
however, a systemic acidosis is likely to exacerbate
cardiac toxicity and must be avoided.
Clinical features of flecainide overdose
Daily therapeutic dose of flecainide is 200-300 mg.
Doses in excess of 400 mg per day are associated with
a high incidence of adverse effects and are usually not
required for the control of arrhythmias.
In the first 30 minutes after overdose, nausea and
vomiting are common early symptoms. After 30
minutes to 2 hours of ingestion, cardiotoxicity will
appear and bradyarrhythmias are more common than
tachyarrhythmias. Other cardiac arrhythmias include
various heart block, Torsade de pointes, other
ventricular arrhythmias, VF and asystole. Cardiac
arrest has been reported in 1/4 of all patients with
flecainide overdose. 4,8
Serious ventricular tachyarrhythmias may be provoked
in 5-25% of patients, who had depressed left
ventricular function, sustained VT or taking a daily
dose of more than 400 mg. Other clinical features like
dizziness, headache, blurred vision, seizure and
hypotension had been reported.
Flecainide may elevate pacing or defibrillation
thresholds, therefore, higher energy level will be
required during resuscitation.
Kinetics in overdose
Investigation
Flecainide is well absorbed with bioavailability of
95%. It is a weak base with moderate protein binding
(40%) and has a high volume of distribution of
9 L/kg. Its distribution half-life is 10 mins whereas its
elimination half-life is dose dependent, ranging from
7 to 23 hours. After complete absorption, about 30%
of an oral dose is excreted unchanged by the kidneys.
Urgent electrolytes and acid-base (Na +, K + , Mg 2+ ,
HCO3-) should be measured and corrected, in order
to prevent exacerbating toxicity.
ECG will show progressive prolongation of QRS,
often well over 200 ms. Some authors suggested that
152
prolongation of PR or QRS of more than 50%
indicates toxicity. 2
Drug level may be of prognostic significance though
are unlikely to alter initial management.
Treatment
As an emergency physician, the paramount initial
treatment is supportive, which includes the basic
Airway, Breathing and Circulation. The aim is to
prevent hypoxia and maintain fluid balance, which
will aggravate the toxicity.
Secondly, we should decrease further drug absorption.
Gastrointestinal decontamination like gastric lavage
should be considered in all patients who are
unconscious and presented within 1 hour after
ingestion of more than two times the recommended
daily dose. However, atropine or pacing should be
given prior to intubation and lavage, in order to
prevent vagal stimulation. Activated charcoal should
be given to ALL patients unless contraindicated.8
Thirdly, we need to minimize cardiac toxicity by
1) decreasing the amount of blockade (e.g. NaHCO3
for sodium channel blockade); 2) correct aggravating
conditions for arrhythmias, such as electrolytes
disturbance or hypoxia; 3) avoid drugs with sodium
channel blocking effects. (Table 2)
Early and large doses of NaHCO 3 should be given.
Total doses of 3-6 mEq/kg NaHCO 3 showed efficacy
in animal studies.9-12 We should aim at maintaining a
pH of 7.5-7.55. Some authors recommended that
NaHCO 3 should be given in patients with QRS>160
ms or any arrhythmias.10
Lastly, we need to increase the elimination of the
drugs. Forced diuresis should be avoided because this
may be complicated by the antiarrhythmic-induced
cardiac insufficiency. Urinary acidification will
increase flecainide elimination, however, a systemic
acidosis is likely to exacerbate cardiac toxicity and
must be avoided. Haemoperfusion and haemodialysis
Hong Kong j. emerg. med.
!
Vol. 9(3)
!
Jul 2002
is unlikely to be helpful as flecainide has a very large
volume of distribution, although there is one case
report in which this seems to be more effective.13,14
Although cardiopulmonary bypass (CBS) continues
to be an experimental procedure in the treatment of
poisoning, 15,16 there are two recently published cases
of successful use of CBS in the treatment of flecainide
overdose. In May 1997 Annals of Emergency Medicine
published the first reported use of CBS in flecainide
overdose.17 The patient had an agonal rhythm and a
flecainide level of 5.4 mug/ml (normal range
0.2-1.0 mug/ml). After 10 hours of CBS, the level
dropped to 1.4 mug/ml and the patient had a stable
rhythm and blood pressure. However, treatment was
discontinued because the patient already sustained an
irreversible neurologic damage before effective
circulation was restored. In 2001 Crit Care Med
published a successful case of using extracorporeal
membrane oxygenation (ECMO) in treatment of
flecainide overdose. 18 The patient had a pulseless
electrical activity after a fatal dose of flecainide
intoxication. After 26 hours of ECMO, the patient
had a stable cardiac function with decreasing pump
flow and an almost normalized conscious state. This
patient finally survived without neurological sequelae
upon hospital discharge.
For treatment of arrhythmias, ALL class 1A
antiarrhythmics are contraindicated. Class 1B
(lignocaine and phenytoin), which may be used, may
still exacerbate sodium channel blockade and
potentially exacerbate arrhythmias. Therefore, they
should be avoided. Magnesium is normally the drug
of choice for treating Torsade de pointes, however, its
calcium channel blocking activities may aggravate the
hypotension and heart block. For these reasons,
isoprenaline or over-drive pacing should be preferred.
Second or third degree heart block should be treated
with atropine, NaHCO3 and isoprenaline followed by
a pacemaker.
Seizures should be treated by diazepam 5-20 mg
intravenously followed by phenobarbitone 15 mg/kg
intravenously.
Cheung et al./Review on Flecainide poisoning
Late complications and prognosis
In a large retrospective review of 120 cases of 1C
antiarrhythmics overdose, 2 the average mortality was
22.5% (8-36%), whereas the overall mortality of drug
overdose in general was less than 1%. The overall
mortality rate for flecainide overdose was 10%. All
patients with flecainide overdose should have cardiac
monitoring for at least 24 hours or until ECG changes
have resolved. Long-term sequelae have not been
reported, although there is one report of persistent
ECG changes.
153
References
1.
2.
3.
4.
5.
6.
Summary
Flecainide has a large volume of distribution and
negative inotropic effect. In cases of overdose, PR and
QRS inter vals correlate well with drug level.
Prolongation of PR or QRS intervals of more 50% of
normal indicate toxicity. 3 Cardiac complications can
occur as early as 30 minutes and bradyarrhythmias
are more common. In flecainide overdose, the
threshold for pacing and defibrillation will be
increased and class 1 antiarrhythmics and magnesium
should be avoided. Aggressive use of NaHCO3 should
be considered early, and atropine and pacing should
be given before gastric lavage. Recent reports indicate
the potential usefulness of CBS/ECMO in the
treatment of flecainide overdose.
7.
8.
9.
10.
11.
12.
13.
Conclusion
14.
Flecainide overdose carries a high mortality. Early
recognition of its cardiac toxicity and aggressive
treatments in minimizing them are paramount. Avoid
treating arrhythmias induced by antiarrhythmics with
another antiarrhythmics. If we can improve the vital
organ perfusion, maintain adequate renal and hepatic
blood flow to enhance drug clearance, and allow time
for drug redistribution, the chance of survival will be
markedly improved.
15.
16.
17.
18.
Roden DM, Woosley RL. Drug therapy. Flecainide. N
Engl J Med 1986;315(1):36-41.
Winkelmann BR, Leinberger H. Life-threatening
flecainide toxicity. A pharmacodynamic approach. Ann
Intern Med 1987;106(6):807-14.
Suttorp MJ, Kingma JH, Jessurun EH, et al. The value of
class 1C antiarrhythmic drugs for acute conversion of
paroxysmal atrial fibrillation or flutter to sinus rhythm. J
Am Coll Cardiol 1990;16(7):1722-7.
Koppel C, Oberdisse U, Heinemeyer G. Clinical course
and outcome in class 1C antiarrhythmic overdose. J Toxicol
Clin Toxicol 1990;28(4):433-44.
Ranger S, Nattel S. Determinants and mechanisms of
flecainide-induced promotion of ventricular tachycardia
in anesthetized dogs. Circulation 1995;92(5):1300-11.
Boriani G, Strocchi E, Capucci A, et al. Flecainide: evidence
of non-linear kinetics. Eur J Clin Pharmacol 1991;41(1):57-9.
Funck-Brentano C, Becquemont L, Kroemer HK, et al.
Variable disposition kinetics and electrocardiographic
effects of flecainide during repeated dosing in humans:
contribution of genetic factors, dose-dependent clearance,
and interaction with amiodarone. Clin Pharmacol Ther
1994;55(3):256-69.
Gotz D, Pohle S, Barckow D. Primary and secondary
detoxification in severe flecainide intoxication. Intensive
Care Med 1991;17(3):181-4.
Bajaj AK, Woosley RL, Roden DM. Acute electrophysiologic effects of sodium administration in dogs treated
with O-desmethyl encainide. Circulation 1989;80(4):9941002.
Goldman MJ, Mowry JB, Kirk MA. Sodium bicarbonate
to correct widened QRS in a case of flecainide overdose. J
Emerg Med 1997;15(2):183-6.
Keyler DE, Pentel PR. Hypertonic sodium bicarbonate
partially reverses QRS prolongation due to flecainide in
rats. Life Sci 1989;45(17):1575-80.
Salerno DM, Murakami MM, Johnston RB, et al. Reversal
of flecainide-induced ventricular arrhythmia by hypertonic
sodium bicarbonate in dogs. Am J Emerg Med 1995;13
(3):285-93.
Wu r z b e r g e r R , Wi t t e r E , Ave n h a u s H , e t a l .
Hemoperfusion in flecainide poisoning. Klin Wochenschr
1986;64(9):442-4.
Borgeat A, Biollaz J, Freymond B, et al. Hemofiltration
clearance of flecainide in a patient with acute renal failure.
Intensive Care Med 1988;14(3):236-7.
Goodwin DA, Lally KP, Null DM. Extracorporeal
membrane oxygenation support for cardiac dysfunction
from tricyclic antidepressant overdose. Crit Care Med
1993;21(4):625-7.
McVey FK, Corke CF. Extracorporeal circulation in the
management of massive propanolol overdose. Anaesthesia
1991;46(9):744-6.
Yasui RK, Culclasure TF, Kaufmann D, et al. Flecainide
overdose: is cardiopulmonary support the treatment? Ann
Emerg Med 1997;29(5):680-2.
Auzinger GM, Scheinkestel CD. Successful extra-corporeal
life support in a case of severe flecainide intoxication. Crit
Care Med 2001;29(4):887-90.