Transcript New Perspectives in Cardiac Arrest Management: The 2000

Intravenous Amiodarone for
Supraventricular Tachycardias
Jerrold H Levy, MD
Emory University School of Medicine
Atlanta, Georgia
Supraventricular Tachycardias:
Therapeutic Objectives
• Determine the mechanism of the
arrhythmia
• Restore sinus rhythm with the simplest
technique and approach as possible
• Eliminate or significantly reduce
arrhythmia recurrences and underlying
cause
Singh 2002.
Types of Supraventricular
Tachyarrhythmias
Sinus Node Reentry
Atrial Flutter
RA
LA
Automatic Atrial Tachycardia
Reentrant Atrial Tachycardia
Atrioventricular Nodal
Reentry (AVNRT)
LV
RV
AV Reentry via an Accessory
AV Connection (AVRT)
Atrial Fibrillation (Not Shown)
Singh 2002.
Types of Paroxysmal
Supraventricular Tachycardia
AV Reciprocating
Tachycardia
Sinus Nodal Reentry
Intra-atrial Reentry
Automatic Atrial
Tachycardia
AV Nodal
Reentry
Mechanisms of Paroxysmal
Supraventricular Tachycardias
Enhanced Automaticity:
• Paroxysmal and Acute
• Chronic
Re-entry without Bypass Tracts:
• AV Nodal Re-entry: Slow – Fast/Fast – Slow
• Sinoatrial Nodal Re-entry
• Intra-atrial Re-entry
Re-entry in Association with Bypass Tracts:
• Re-entry with Anterograde AV Conduction (Orthodromic)
– With Evidence of Pre-excitation of 12-Lead ECG
– Concealed WPW (Bypass Tract Conducting
Only Retrogradely)
• Re-entry with Anterograde Conduction Over Bypass
Tract (Antidromic) During Tachycardia
Accessory Pathways: Concealed
Bypass Tract AV Reentrant Tachycardia
Concealed Bypass
Tract
AV Node
Bundle of His
Right Bundle Branch
Left Bundle Branch
P
Singh 2002.
Electrical Conduction in
Atrial Flutter
AV Node
ECG of Flutter
Ventricular Rate 150-160 (Most Often 2:1 AV Block)
Atrial Fibrillation
Electrocardiogram
Coarse Fibrillation
Fine Fibrillation
Baseline Coarsely or Finely Irregular; P Waves Absent.
Ventricular Response (QRS) Irregular, Slow or Rapid
Scheidt S, Erlebacher JA, Netter FH. Basic Electrocardiography ECG. Ciba-Geigy: First Printing, 1986, p23.
AF is Associated With
CV Diseases
Systemic Diseases
• CT surgery
• Age
• Valvular or
congential disease
• DTs, sympathetic storm
• Hypertension
• Cardiomyopathy
• Heart failure
• Myocardial ischemia/MI
• Peri/myocarditis
• Infiltrative heart disease
• Cardiac trauma
• Electrolyte disorders
• Thyrotoxicosis
• Fever/hypothermia
• Hypovolemia
• Diabetes
• Anemia
• Pulmonary disease
• Cerebrovascular disease
Antiarrhythmic Drugs
vs. Therapeutic Goal
Vagal Stimulation
Digoxin
b-Blocking Drugs
Verapamil
Diltiazem
Adenosine
Ibutilide
Atrium
AV Node
Quinidine
Procainamide
Disopyramide
Flecainide
Propafenone
Sotalol
Amiodarone
His Purkinje
Ventricle
Singh 2002.
AP
Simulated Drug Level Curves
= “Full” loading dose
= Half loading dose and infusion
Plasma Drug Level
= Infusion without loading dose
Therapeutic
Concentration
Range
0
Levy 2002.
1
2
3
4
Time (Half-life)
5
6
Agents Used in the Treatment of SVT
Tachycardias by Vaughan Williams Class
1A: Quinidine, procainamide, disopyramide
1C: Flecainide, propafenone
2: Esmolol, propranolol, metoprolol,
atenolol, (et al)
3: Amiodarone, sotalol
4: Diltiazem, verapamil
– Glycosides: digoxin
– Purinergic: adenosine
Singh 2002.
Amiodarone Historical
Landmarks (1)
1962: Synthesized as an anti-anginal
compound (Charlier)
1968: Novel action with new biological
profile (Charlier)
1970: Unusual electrophysiology profile
(Singh & Vaughan Williams)
74/76: Unusual clinical potency as an
antiarrhythmic drug (Rosenbaum M)
Amiodarone Historical
Landmarks (2)
1983: First US Symposium on Amiodarone
(Singh & Zipes)
1984: FDA Approval
1993: Efficacy Unparalleled; Mode of
Action Unknown
1995: Amiodarone IV approved
1999: Symposium, the last 15 years
(Singh, AJC (Suppl))
Singh 2002.
Unique Features of Amiodarone
as an Anti-arrhythmic Drug
• Long elimination half-life
• Can be administered to anephric patients
on dialysis
• Well tolerated in advanced CHF
• Manageable drug-drug interactions
(ie, digoxin, coumadin)
• Very low incidence of torsades de pointes
even with diuretic therapy
Singh 2002.
Unique Features of Amiodarone
as an Anti-arrhythmic Drug (Cont’d.)
• Has Class 1 properties without the
associated proarrhythmic actions or
negative impact on mortality
• Has antisympathetic actions without
beta-blocker side effects
• Increases LVEF and improves CHF
• Antifibrillatory actions in the ventricles may
be augmented by addition of beta-blockade
Singh 2002.
Intravenous Amiodarone
Pharmacokinetics
• Peak levels after single 5 mg/kg
15 min infusions: 5-41 mg/L
• After 10 min 150 mg load for VF/VT:
7-26 mg/L
• Levels decline to 10% of peak within
30-45 min at the end of the infusion
• After 48 hrs of continued infusions,
levels 0.7 to 1.4 mg/L
Singh 2002.
Pharmacokinetics of
Oral Amiodarone
• Absorption: Tmax:2-12 h (lab 0.4-3 h)
• Extent of absorption: Poor and slow
• Bioavailability: Variable (22-86%)
• Protein binding: 96.3 ± 0.6%
• Volume of distribution: 1.3-65.8 l/kg
• Negligible renal excretion
• Biotransformation: Hepatic and intestinal
• Elimination half-life: 3.2-20.7 h (acute),
13.7-52.6 day (chronic)
Singh 2002.
Pharmacokinetics of
Oral Amiodarone
• Total body clearance: 0.10-0.77 l/min
• Pattern of elimination: First order
• Metabolites: Major: mono Ndesethylamiodarone, Minor: bis-Ndesethylamiodarone, deiodinated
metabolites
• Therapeutic levels: 1.0-2.5 µg/mL range
• Special factors: Slow onset and offset
of action
Singh 2002.
Actions of IV Amiodarone vs
Chronic Amiodarone
Actions
IV Amio
Chronic Amio
Repolarization (QT
interval) prolongation
(atria & ventricles)
±
++++
Conduction velocity
(atria & vent) reduced
++
++
(function of rate)
Sinus rates reduced
+
+++
AV nodal
conduction slowed
+
++
Actions of IV Amiodarone vs
Chronic Amiodarone
Actions
IV Amio
Chronic Amio
++
++++
Atrial refactoriness
increased
±
+++
Ventricular refactoriness
increased
±
+++
Noncompetitive alpha
and beta blocking activity
+
+
AV nodal refactoriness
increased
Singh 2002.
Pharmacokinetics of
IV Amiodarone
Summary: More rapid onset and offset
of action with IV versus oral
Comparison of Oral vs. IV Amiodarone:
Conversion of Atrial Fibrillation
• N=52 patients with atrial fibrillation
– 86 episodes of attempted cardioversion
with oral, intravenous, or DC
cardioversion
• Conversion to sinus rhythm achieved
– 29% of pts treated with oral amiodarone
– 42% of pts treated with DC cardioversion
– 64% of pts treated with intravenous
amiodarone
– Overall statistical significance: P = 0.032
Horner SM. Acta Cardiol. 1992;47:473.
Efficacy of IV Amiodarone for the
Conversion of Atrial arrhythmia
Vietti-Ramus
et al. 1992
44 pts
86% w/ SVT reverted to SR <24 h
100% w/ PSVT reverted to SR <24 h
75% w/ AFL reverted to SR <24 h
85.7% w/ AF reverted to SR <24 h
Strasberg
et al. 1985
26 pts
100% reverted to SR (P<0.001)
46% reverted <30 min
23% converted 2-8 h
27% no conversion
4% reverted to AFL < 10 min; to SR 40 min later
Faniel and
Schoenfeld
1983
26 pts
80.8% reverted to SR <24 h and maintained >48 h
Mean time from treatment to SSR = 171 min
Total dose = 6.9 ± 2.3 mg/kg
Management of Atrial Tachyarrhythmias in the
Critically Ill: a Comparison of Intravenous
Procainamide and Amiodarone
24 pts atrial fibrillation more than 1 h evaluated – 10 Amiodarone,
14 Procainamide
Methods:
• Amiodarone IV 3 mg/kg then 10 mg/kg/24 h with repeat dose of 3
mg/kg at 1 h if no response or Procainamide IV 10 mg/kg at 1
mg/kg/min then 2-4 mg/min for 24 h with repeat dose of 5mg/kg
at 1 h if no response
Results:
• 7/10 Amiodarone-treated patients, 10/14 Procainamide-treated
patients converted to sinus rhythm by 12 hours
• No significant change in SBP from baseline
Chapman MJ et al Intensive Care Med 1993;19:48-52.
Amiodarone Versus Propafenone for Conversion
of Chronic Atrial Fibrillation: Results of a
Randomized, Controlled Study
118 pts with atrial fibrillation lasting more than 3 weeks,
34 amiodarone, 32 propafenone, 35 control
Methods:
• IV amiodarone 300 mg over 1 h, then 20 mg/kg over 24 hours
plus 600 mg orally, in 3 doses for 1 week, then 400 mg/day
orally for 3 weeks. IV propafenone 2 mg/kg over 15 minutes,
then 10 mg/kg over 24 h and then 450 mg/day orally for 1
month. All patients received digoxin and anticoagulation
(INR 2-3)
Results:
• 16/34 (47.05%) amiodarone-treated patients vs. 13/32 (40.62%)
propafenone-treated
• Patients converted to sinus rhythm, P<0.001
• 1 propafenone-treated patient discontinued treatment because
of QRS widening
Kochiadakis GE et al J Am Coll Cardiol 1993;33:966-71.
PIAF Trial
Rhythm or Rate Control in Atrial Fibrillation Pharmacological
Intervention in Atrial Fibrillation (PIAF): a Randomized Trial
• 252 pts enrolled, 125 diltiazem, 127 amiodarone
Methods:
Pts randomized to diltiazem or amiodarone
Results:
• 76 pts on diltiazem, 70 on amiodarone reported
improved symptoms, P=0.317
• 23% of amiodarone pts returned to sinus rhythm
• amiodarone-treated pts did better on 6 min walk test than diltiazem
Conclusion:
In patients with atrial fibrillation, the therapeutic strategies of rate
versus rhythm control yielded similar clinical results overall
1. Hohnloser et al. Lancet. 2000;356:1789-94.
IV Amiodarone Treatment for Acute Heart
Rate Control in Critically Ill Patients
Methods
• Retrospective study of 38 ICU patients
– Pts received IV amiodarone for resistant
atrial tachyarrhythmias
• Onset of rapid heart rate (mean 149 ± 13
beats/min was associated with decrease in
systolic blood pressure of 20 ± 5 mm Hg
(P<0.05)
Clemo HF, Wood MA, Gilligan DM, Ellenbogen KA. Am J Cardiol. 1998;81:594-8.
IV Amiodarone Treatment for Acute Heart
Rate Control in Critically Ill Patients
• Intravenous diltiazem (n=34), esmolol
(n=4), and digoxin (n=24) had no effect,
while reducing systolic blood pressure
of 6 ± 4 mm Hg (P<0.05)
• Infusion of amiodarone (242 ± 137 mg
over 1 hr decreased heart rate by 37 ± 8
beats/min and increased systolic blood
pressure by 24 ± 6 mm Hg (P<0.05)
– Beneficial outcomes noted in
pulmonary artery occlusive pressure
and cardiac output
Clemo HF, Wood MA, Gilligan DM, Ellenbogen KA. Am J Cardiol. 1998;81:594-8.
Caveats Regarding
Amiodarone Dosing
• Complex PK/PD with extremely long
half life
• Different efficacy rates with studies due
to dosing issues, and different patient
populations
Amiodarone IV for Atrial
Arrhythymias: Summary
• Effective in SVT, but best studied in AF
• Acute IV therapy is different than
chronic oral administration: dosing and
PK needs
to be considered
• In critically ill patients, IV therapy
is required
Questions and Answers