Transcript New Perspectives in Cardiac Arrest Management: The 2000

SLIDE ANTHOLOGY:
Clinical Studies and Perspectives in
Cardiac Arrest Management
The 2000 Advanced Cardiovascular Life
Support Guidelines
Amiodarone IV
Jerrold H Levy, MD
Emory University School of Medicine
Atlanta, Georgia
ACLS Background: Historical Perspectives
2000
1st International Guidelines
Conference on CPR and ECC
5th CPR and ECC
Conference
1992
4th CPR and ECC
Conference
1st Conference
on Pediatric
Resuscitation
1st, 2nd, & 3rd
Conference on
CPR
1983
1966-1979
Data from: Circulation. 2000;102:1–2.
1985
1992 Guidelines for Treatment
of VF/Pulseless VT
• Reflected scientific knowledge and experience
in early 1990s
• Defibrillation as key intervention
• Three antiarrhythmics as treatment options
- Lidocaine
- Procainamide
- Bretylium
• No controlled trials existed to help evaluate
efficacy of antiarrhythmics
Data from: Circulation. 2000;102:1-3. JAMA. 1992;268:2199–2241.
2000 ACLS Guidelines
Primary Goal of the AHA/ECC
• Establish guidelines
- Based on scientific evidence
- Prompted by rapid changes and
advances in knowledge
- Developed as recommendations
Data from: Circulation. 2000;102:1–3.
2000 ACLS Guidelines: Overall Goals
Create valid, internationally
accepted, resuscitation
guidelines using scientific
evidence
Develop a document to explain
the guidelines
Review and revise
recommendations
from past conferences
Collaborate with international
resuscitation authorities on CPR
and ECC
Data from: Circulation. 2000;102:I-2–I-3.
International Guidelines
2000 Conference on CPR and ECC:
Objectives
• Establish ILCOR as the authority for
coordination and communication
• Ensure equal representation for AHA and
non-U.S. committees
• Review and revise recommendations from
past conferences on the basis of accumulated
evidence
• Recommend changes in the methods for
teaching life-support skills
Data from: Circulation. 2000;102:I-2–I-3.
Chain of Survival
• Early access
• Early CPR
• Early defibrillation
• Early advanced care
Data from: Circulation. 2000;102:I-22–I-23.
Philosophy: Evidence-Based Review
• Systematically identify, evaluate, and
appraise evidence to support proposed
changes
• Review all proposed changes for:
- Scientific accuracy
- Safety
- Cost
- Effectiveness
- Teachability
Data from: Circulation. 2000;102:1–3.
Reasons for Modifying Guidelines
 Lack of evidence to confirm effectiveness
Additional evidence to suggest
 harm or ineffectiveness
Evidence that superior therapies
 have become available
Data from: Circulation. 2000;102:I-1.
Tools and Principles of
Evidence-Based Review
Step 1
Search for
and gather
evidence
Steps 2 & 3
Assess the
quality and level
of the evidence
Step 4
Determine class of
recommendation
by evidence
Data from: Circulation. 2000;102:I-3.
Sorting Studies by Level of Evidence
Level 1
Level 2
Level 3
Level 4
Level 5
Level 6
Level 7
Level 8
Positive
RCTs
(P < 0.05)
Neutral RCTs (NS)
Prospective, nonrandomized,
observational study with
control group
Retrospective, nonrandomized,
observational study with control group
Case series compilation, no control group
Animal/mechanical model; 6A –
higher quality studies, 6B – less powerful design
Reasonable extrapolations from data gathered for other purposes
Common sense; common practices before evidence-based guidelines
Data from: Circulation. 2000;102:I-4.
Abbreviation: RCT, randomized, controlled trial.
Evaluating Quality of Evidence
Sort studies by level
Assess quality of research design
and methods (Excellent, Good, Fair, Poor)
Determine direction of results and statistics
(Support proposal, Neutral, Oppose proposal)
Cross-tabulate by level, quality, and direction
Class of Recommendation
Data from: Circulation. 2000;102:I–4.
Classes of Recommendation
Class I
Excellent. Proven efficacy, safety,
and usefulness
Class IIa
Acceptable. Good evidence, safe,
clinically useful; standard of care
Class IIb
Acceptable. Fair evidence, safe,
clinically useful; within standard
of care
Class
Indeterminate
Not recommended. Minimal
evidence; preliminary research
Class III
Not acceptable. May be harmful;
not clinically useful
Data from: Circulation. 2000;102:I-5.
Evidence-Based Guidelines
Step 1
State a
proposal
Steps 2 & 3
Assess quality
and level of
evidence
Step 4
Determine class
of recommendation
(I, IIa, IIb,
Indeterminate, III)
Data from: Circulation. 2000;102:I-3–I-5.
Summarize
rationale
for proposal
Placebo-Controlled Methodology
•
Without placebo controls, the value
of antiarrhythmic agents in cardiac
arrest due to VF/pulseless VT cannot
be determined
•
Prospective, randomized, placebocontrolled trials provide objective
evaluation of antiarrhythmic agents
Evidence Evaluation Template
Supporting
Level
1
2
3
4
5
6
7
8
Excellent
Good
Fair
Fair
Good
Excellent
Level
1
2
Courtesy of Peter Kudenchuck.
3
4
5
6
7
8
Lidocaine in Cardiac Life Support:
Review of Quality of Evidence
• Lidocaine did not fare well under evidence-based
approach
• Review of evidence showed poor or weak support for
lidocaine as beneficial in cardiac arrest
• Supporting evidence primarily consisted of levels 6,
7, and 8
• Class indeterminate for shock-refractory VF/pulseless VT
• Lack of evidence was key factor in revised lidocaine
classification despite time-honored status and 1992
ACLS recommendation
Data from: Circulation. 2000;102:I-86–I-87.
Supporting
Quality and Level of Evidence Analysis
Lidocaine in Cardiac Arrest
Due to VF/VT
Excellent
Good
Fair
1
2
3
4
5
6
10
Fair
Good
5
12
4, 9, 15, Current
16, 17, Practice
21, 25
7
8
13
Excellent
23, 24
18
2, 3, 6,
7, 8, 14,
19, 22
1, 20,
26
6
7
11
1
2
3
4
5
8
Author Year (n)
1. Alexander ’99 (43704)
2. Anastasiou ’94 (16)
3. Babbs ’79
4. Borer ’76
5. Carden ’56 (23)
6. Chow ’86
7. Dorian ’86
8. Echt ’89
9. Harrison ’63 (12)
10. Harrison ’81 (116)
11. Haynes ’81 (146)
12. Herlitz ’97 (1360)
13. Kentsch ’88 (20)
14. Kerber ’86
15. Lazzara ’73
16. Lazzara ’78
17. Lie ’74
18. Olson ’84 (108)
19. Redding ’68 (105)
20. Sadowski ’99 (903)
21. Spear ’72
22. Vachiery ’90 (18)
23. VanWalraven ’98 (773)
24. Weaver ’90 (199)
25. Other MI trials
26. MI Meta-analyses
Lidocaine in Cardiac Arrest
Due to VF/VT
Supporting (10)
-
Level 4 (1)
Level 6 (1)
Level 7 (7)
Level 8 (1)
Neutral/Opposing (17)
• Neutral (5)
- Level 2 (2)
- Level 3 (1)
- Level 6 (1)
- Level 7 (1)
• Opposing (12)
- Level 1 (1)
- Level 4 (2)
- Level 6 (7)
- Level 7 (2)
Supporting
Quality and Level of Evidence Analysis
Amiodarone in Cardiac Arrest
Due to VF/VT
Excellent
9
Author Year (n)
8
1, 3
Good
Fair
6
1
2
3
4
2, 4, 5, 7,
11, 12, 13,
14, 16, 18
5
6
15
7
8
Fair
10
17
Good
19
Excellent
1
2
3
4
5
6
7
8
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
AnastasiNana ’94 (16)
Drexler (14)
Fain ’87 (12)
Helmy ’88 (46)
Horowitz (5)
Kentsch ’88 (20)
Klein (13)
Kowey ’95 (228)
Kudenchuk ‘99 (504)
Levine ’96 (273)
Mooss (35)
Morady (15)
Nalos ’91 (22)
Ochi (22)
Rosalion ’91 (23)
Saksena (9)
Scheinman ’95 (342)
Schutzenberger ’89 (26)
Zhou ’98 (24)
Amiodarone in Cardiac Arrest
Due to VF/VT
Supporting (16)
-
Level 1 (2)
Level 2 (1)
Level 5 (10)
Level 6 (2)
Level 7 (1)
Neutral/Opposing (3)
• Neutral (2)
- Level 2 (2)
• Opposing (1)
- Level 7 (1)
2000 ACLS Guidelines:
Recommended Antiarrhythmic Agents
• Amiodarone HCl received a Class-IIb rating
in cardiac arrest; no other antiarrhythmic
agent received a more favorable rating in
this setting
• The 2000 ACLS Guidelines recommend
using only one antiarrhythmic agent in
resuscitation efforts
Data from: Circulation. 2000;102:I-115, I-149–I-159.
2000 ACLS Guidelines VF/Pulseless VT
Treatment Algorithm
Guidelines for Dosing and Administration
for VF and Hemodynamically Unstable VT
First 24 Hours
Loading Infusions
First Rapid
Add 150 mg (1 ampul) to 100 mL D5W; administer over FIRST 10 minutes (15 mg/min)
NOTE: In cardiac arrest due to shock-refractory VF/pulseless VT, the initial dose should be
300 mg, I.V. push, as recommended in the VF/pulseless VT algorithm in the 2000 ACLS guidelines.
PVC,* glass,† or polyolefin container
Followed by Slow
Add 900 mg (6 ampuls) to 500 mL D5W; administer 33.3 mL/hr over NEXT 6 hours (1 mg/min)
Glass† or polyolefin container
Maintenance Infusion‡
Reduce to 0.5 mg/min; administer 16.6 mL/hr for REMAINING 18 hours
*<10% loss at 2 hours.
†Use of evacuated glass containers for admixing Cordarone I.V. is not recommended, as
incompatibility with a buffer in the container may cause precipitation.
‡After the first 24 hours, the maintenance infusion rate of 0.5 mg/min (720 mg/24 hours) should
be continued utilizing a concentration of 1–6 mg/mL; concentrations greater than 2 mg/mL
should be administered via a central venous catheter. Infusions for longer than 3 weeks have
not been studied. Transition to oral therapy is recommended at the earliest possible time.
The 2000 ACLS Guidelines:
Overview and Conclusion
“Amiodarone is recommended after defibrillation and epinephrine
in cardiac arrest with persistent VT or VF (Class IIb).”
“In summary, evidence supports the use of IV amiodarone,
following epinephrine, to treat shock-refractory cardiac arrest
due to VF or pulseless VT (Class IIb).”
“The evidence supporting amiodarone is much stronger [than that for
lidocaine]. . .and justifies the use of amiodarone before lidocaine. . .”
“The expert panel members would have no problem with clinicians
routinely using amiodarone as the first-choice antiarrhythmic for
shock-refractory VF/VT”
From: Circulation. 2000;102(suppl):I-86, I-87, I-117, I-120.
Preparation of IV Amiodarone
for Cardiac Arrest Due to VF/VT
“In cardiac arrest due to pulseless VT or VF, IV amiodarone
is initially administered as a 300-mg rapid infusion diluted
in a volume of 20 to 30 mL of saline or dextrose in water.”
• Use 2 ampuls of amiodarone, appropriate size syringe
and needle, gauze, sponges or alcohol pad
• Check route, dose, date
• Avoid excessive shaking of ampuls
• Tap top of ampul before opening to promote transfer
of medication
From: Circulation. 2000;102(suppl):I-121.
Acute Myocardial Infarction
• 900,000 people in the U.S.
experience an MI annually
• ~225,000 die
~125,000 die “in the field”
Most deaths are arrhythmic in etiology
Data from: Ryan TJ et al. J Am Coll Cardiol. 1996;28:1333.
Amiodarone in out-of-hospital
Resuscitation of REfractory Sustained
ventricular Tachyarrhythmias (ARREST)
A prospective, randomized, double-blind,
placebo-controlled study of IV amiodarone in
patients with out-of-hospital cardiac arrest due
to shock-refractory VF/VT
Data from: Kudenchuk PJ et al. N Engl J Med. 1999;341:871–878.
ARREST Eligibility Criteria
• Older than 18 years
• Nontraumatic out-of-hospital cardiac arrest
• Ongoing or recurrent VF/VT after 3+ shocks
• Paramedics and study drug on scene
• IV access
Data from: Kudenchuk PJ et al. N Engl J Med. 1999;341:871–878.
ARREST Study End Points
•
•
•
Primary
- Admission to hospital with a spontaneously perfusing
rhythm (assigned to a hospital bed)
Secondary
- Adverse effects
- Total duration of resuscitative efforts
- Number of shocks after administration of study drug
- Need for additional antiarrhythmic drugs
Also evaluated
- Survival to hospital discharge*
- Neurological status at hospital discharge*
* By design, the trial did not have sufficient statistical power to demonstrate
differences in these outcomes.
Data from: Kudenchuk PJ et al. N Engl J Med. 1999;341:871–878.
ARREST Study Algorithm
Cardiac Arrest
VF or Pulseless VT
Shock x 3
Persistent or
Recurrent VF/VT
Stable
Rhythm
ETT
IV
EPI
Study Drug
Standard ACLS Care
Asystole
or PEA
Excluded From Study
Placebo
IV amiodarone
ETT: endotracheal intubation
IV: intravenous access established
EPI: epinephrine
PEA: pulseless electrical activity
Data from: Kudenchuk PJ et al. N Engl J Med. 1999;341:871-878.
November 1994-February 1997
Out-of-Hospital Cardiac Arrest
(n=3,954)
Ineligible/Not
Treated
(n=3,260)
Met Study Criteria
(n=667)
Eligible/Treated
(n=507)
Study Group
(n=504)
Ineligible/Treated
(n=27)
Eligible/Not
Treated
(n=160)
Drug Assignment
Unknown
(n=3)
Data from: Kudenchuk PJ et al. N Engl J Med. 1999;341:871–878.
ARREST Patient Characteristics
IV Amiodarone
(n=246)
Male
Placebo
(n=258)
P Value
187 (76%)
203 (79%)
NS
66 ± 14*
65 ± 14*
NS
Cardiac History
137 (64%)
135 (59%)
NS
Other Medical History
101 (47%)
119 (52%)
NS
Witnessed Arrest
155 (70%)
182 (77%)
0.07
Bystander CPR
155 (68%)
138 (59%)
0.06
VF Amplitude (mV)
0.42 ± 0.2*
0.45 ± 0.2*
NS
Age (yr)
* Values shown are means ± SD.
Data from: Kudenchuk PJ et al. N Engl J Med. 1999;341:871-878.
Initial Cardiac Arrest Rhythm
100
83
83
IV Amiodarone
% of Patients
80
Placebo
60
40
12
20
4
5
Asystole
VF
11
0
VF
PEA
Abbreviation: PEA, pulseless electrical activity.
Data from: Kudenchuk PJ et al. N Engl J Med. 1999;341:871–878.
VF
Response/Treatment Times
in Minutes
IV
Amiodarone
Placebo
P Value
First unit
4.3  2.0 (4.0)
4.4  2.3 (4.0)
NS
Paramedic/ALS
8.4  4.1 (7.8)
8.8  4.9 (7.9)
NS
Shock
8.9  5.4 (7.6)
9.5  7.5 (7.4)
NS
IV access
13.1  4.1 (12.7)
13.7  4.1 (13.2)
NS
Intubation
14.3  5.8 (12.7)
13.8  4.6 (13.1)
NS
Study drug
21.4  8.3 (19.2)
20.5  7.0 (19.3)
NS
Values shown are the means ± SD with medians shown in parentheses.
Abbreviations: ALS, advanced life support; IV, intravenous; NS, not statistically significant;
SD, standard deviation.
Data from: Kudenchuk PJ et al. N Engl J Med. 1999;341:871–878.
Resuscitation Characteristics
Before Study Drug
IV
Amiodarone
(n=246)
Placebo
(n=258)
P Value
Number of shocks
5  2 (4)*
5  2 (4)*
0.73
Transient ROSC
55 (22%)
52 (20%)
0.61
Antiarrhythmic drug
65 (26%)
91 (35%)
0.04
Bradycardia treatment
32 (13%)
51 (20%)
0.04
Pressor treatment
19 (8%)
22 (9%)
0.74
Abbreviations: ROSC, return of spontaneous circulation; SD, standard deviation.
*The values shown are the means ± SD, with the median in parentheses.
Data from: Kudenchuk PJ et al. N Engl J Med. 1999;341:871–878.
Treatment After Study Drug
100
P = 0.70
80
IV Amiodarone
82
Placebo
80
% of Patients
P = 0.04
59
60
P = 0.004
48
41
40
25
20
0
Antiarrhythmic
No. Receiving Drug
Total No.
197
246
211
258
Pressor*
91
153
69
145
* In patients with return of spontaneous circulation.
Data from: Kudenchuk PJ et al. N Engl J Med. 1999;341:871-878.
Bradycardia treatment*
63
153
36
145
Admission to Hospital by
Arrhythmia Characteristics
70
IV Amiodarone
Placebo
64
Patients Surviving
to Admission (%)
60
50
49
44
41
39
40
38
34
33
30
17
20
12
10
0
All Patients
No. Surviving
Total No.
108
246
89
258
VF
101
205
Asystole/PEA
84
216
7
41
5
42
ROSC
No ROSC
35
55
73
191
22
53
67
205
Abbreviations: PEA, pulseless electrical activity; ROSC, return of spontaneous circulation.
Data from: Kudenchuk PJ et al. N Engl J Med. 1999;341:871-878.
ARREST Trial Conclusions
• IV amiodarone is effective therapy for
shock-refractory VF
• Adverse effects expected but manageable
• Improving survival from cardiac arrest
remains an important challenge
Data from: Kudenchuk PJ et al. N Engl J Med. 1999;341:871–878.
ALIVE
Amiodarone Versus Lidocaine
In Pre-hospital Refractory
Ventricular Fibrillation Evaluation
Data from: Dorian P et al. N Engl J Med. 2002;346:884-890.
.
ALIVE: Rationale
• Patients in cardiac arrest due to VF unresponsive
to initial defibrillation have a poor prognosis
• Lidocaine has been the traditional treatment for
shock-resistant VF
• No large-scale, controlled clinical trials show lidocaine
superior to placebo or other antiarrhythmic agents in
cardiac arrest due to shock-refractory VF
• Results of the ARREST trial (Kudenchuk et al,
N Engl J Med. 1999) showed an increase in survival to
hospital admission with IV amiodarone in patients with
shock-refractory VF
• The ALIVE study was designed to compare IV
amiodarone with IV lidocaine in out-of-hospital
shock-refractory VF
Data from: Dorian P et al. N Engl J Med. 2002;346:884-890.
ALIVE: Hypothesis
• Amiodarone can produce better
outcomes than lidocaine in patients
with out-of-hospital cardiac arrest due
to shock-refractory VF
Data from: Dorian P et al. N Engl J Med. 2002;346:884-890.
ALIVE: Study Design
• Blinded, randomized, controlled trial of
IV amiodarone (5 mg/kg) vs. IV lidocaine
(1.5 mg/kg)
• Men and women were eligible if they were
at least 18 years of age and in
documented VF refractory to standard
protocol in the Toronto EMS system
(defibrillations and epinephrine infusion)
• Eligibility was determined by paramedics
in the City of Toronto EMS system, under
the direction of a physician
Data from: Dorian P et al. N Engl J Med. 2002;346:884-890.
ALIVE: Outcome Measures
• Primary end point
- Survival to hospital admission
• Subgroup analyses
- Survival to hospital admission by initial rhythm
(VF, PEA, asystole)
- Survival to hospital admission by time from EMS
crew dispatch to administration of study drug
• Secondary end point
- Survival to hospital discharge
Data from: Dorian P et al. N Engl J Med. 2002;346:884-890.
ALIVE: Study Protocol
VF
3 Failed shocks
IV epinephrine
Defibrillation shock
Persistent/recurrent VF
ALIVE Study
1.5 mg/kg Lidocaine/placebo IV OR
5 mg/kg Amiodarone/placebo IV
Defibrillation shock
Persistent VF
1.5 mg/kg Lidocaine/placebo IV OR
2.5 mg/kg Amiodarone/placebo IV
Defibrillation shock
ACLS treatment as guided by protocols
Data from: Dorian P et al. N Engl J Med. 2002;346:884-890.
= VF persists or recurs
ALIVE: Demographics
Characteristic
Age (yrs)
Male (%)
Weight (kg)
Hx heart disease (%)
Witnessed arrest (%)
Bystander CPR (%)
Amiodarone*
(n=180)
68 ± 14
76
80 ± 16
61.1
76
26.3
Lidocaine*
(n=167)
66 ± 13
81
82 ± 13
59.3
79.3
28.7
* There were no significant differences between the two study groups for any
characteristic.
Data from: Dorian P et al. N Engl J Med. 2002;346:884-890.
ALIVE: Baseline Characteristics
Characteristic
Amiodarone*
(n=180)
Initial rhythm (%):
VF
Asystole
PEA
Last recorded rhythm before
study drug administration (%):
VF
VT
Asystole
PEA
SV
Total no. shocks
Lidocaine*
(n=167)
77.8
11.1
7.8
79.0
9.6
6.6
88.9
1.7
1.1
5.0
1.7
5 ± 1.9†
91.0
2.4
1.2
3.0
0.6
5 ± 2.2†
Abbreviations: VF, ventricular fibrillation; PEA, pulseless electrical activity; VT, ventricular tachycardia;
SV, supraventricular; SD, standard deviation.
* There were no significant differences between the two study groups for any characteristic.
† The values shown are the means ± SD.
Data from: Dorian P et al. N Engl J Med. 2002;346:884-890.
Time Intervals From
EMS Crew Dispatch
Intervals*
Amiodarone*
(n=180)
Lidocaine*
(n=167)
Time from dispatch to
arrival at patient (min)
7.3 ± 2.7
7.5 ± 2.6
Time to first defibrillation
shock (min)
8.4 ± 2.8
8.7 ± 3.6
Time to IV initiation (min)
13.4 ± 4.4
13.6 ± 3.7
Time to study drug (min)
25.2 ± 8.0
24.3 ± 6.8
* There were no significant differences between the two study groups for any of these
measurements.
Data from: Dorian P et al. N Engl J Med. 2002;346:884-890.
ALIVE: Results
Before Study Drug
Amiodarone
(n=180)
Lidocaine
(n=167)
P Value
Number of shocks
5 ± 1.9* (4%)
5 ± 2.2* (4%)
NS
Transient spontaneous
circulation
24 (13.3%)
11 (6.6%)
< 0.04
Treatment for bradycardia
(atropine)
98 (54%)
96 (57%)
NS
Characteristic
Pressor treatment
(dopamine)
2 (1%)
Antiarrhythmic drug
treatment (open label lidocaine) 4 (2%)
*Values shown are the means ± SD.
Data from: Dorian P et al. N Engl J Med. 2002;346:884-890.
0
NS
1 (1%)
NS
ALIVE: Results
After Study Drug
Characteristic
Amiodarone
(n=180)
Lidocaine
(n=167)
P Value
Treatment for bradycardia
(atropine)
43 (24%)
38 (23%)
NS
Pressor treatment
(dopamine)
13 (7%)
6 (4%)
NS
Antiarrhythmic drug
treatment
(open label lidocaine)
11 (6%)
10 (6%)
NS
Data from: Dorian P et al. N Engl J Med. 2002;346:884-890.
ALIVE: Survival to
Hospital Admission
Number of patients
surviving to hospital
admission
Odds ratio
Relative risk
reduction
Amiodarone
(n=180)
Lidocaine
(n=167)
P Value
41 (22.8%)
20 (12.0%)
0.0083
2.17 (1.21, 3.83)
(95% CI)
53%
Data from: Dorian P et al. N Engl J Med. 2002;346:884-890.
ALIVE: Survival to
Hospital Discharge
Amiodarone
(n=180)
Number of patients
surviving to hospital
discharge
9 (5%)
Data from: Dorian P et al. N Engl J Med. 2002;346:884-890.
Lidocaine
(n=167)
5 (3%)
P Value
0.3427
ALIVE: Survival by Time from EMS Crew
Dispatch to Study Drug Administration
Percent Survival to
Hospital Admission
50
40
30
20
Amiodarone
Lidocaine
A: 19 +/- 3 min
L: 19 +/- 4 min
(P=0.05)
28%
A: 32 +/- 7 min
L: 31 +/- 5 min
(P=0.046)
18%
15%
6%
10
0
<24 min to drug
≥24 min to drug
Data from: Dorian P et al. N Engl J Med. 2002;346:884-890.
ALIVE: Survival of All Patients
and Selected Subgroups
50
Percent Surviving
to Admission
40
Amiodarone
Lidocaine
30
41.2
27.3
24.8
22.8
19.9
20
14.2
12.0
10
0
12.9
10.9
3.7
All Patients
VF
Asystole or PEA
Converting to VF
Data from: Dorian P et al. N Engl J Med. 2002;346:884-890.
ROSC
No ROSC
ALIVE: Multivariate Predictors of
Survival to Hospital Admission
OR (95% CI)
Treatment
(amiodarone
vs. lidocaine)
P Value
2.5 (1.3, 4.9)
0.0071
Time to drug
administration (min)
0.9 (0.8, 0.9)
<0.0001
Transient return of
spontaneous circulation
before study drug
5.9 (2.5, 14.3)
<0.0001
Corrected for all factors which may influence outcome: initial rhythm (VF vs. other),
witnessed arrest, bystander CPR, BLS shock, age, sex, weight, and number of shocks.
Data from: Dorian P et al. N Engl J Med. 2002;346:884-890.
ALIVE: Conclusions and
Clinical Significance
• First large-scale direct comparison of amiodarone with
lidocaine in patients with out-of-hospital VF
• Significantly (P = 0.0083) more patients treated with
amiodarone than with lidocaine (22.8% vs. 12.0%)
survived to hospital admission
• The difference between amiodarone and lidocaine was
similar in various subgroup analyses (time of dispatch
to administration of study drug, by initial rhythm, and by
presence or absence of ROSC) of survival to hospital
admission
• Amiodarone is substantially more effective than
lidocaine as an adjunct to ACLS procedures in patients
with cardiac arrest due to shock-refractory VF, with
regard to survival to hospital admission
Data from: Dorian P et al. N Engl J Med. 2002;346:884-890.
Amiodarone I.V.
®
(Cordarone I.V.)
Indication
Cordarone I.V. is indicated for initiation of treatment
and prophylaxis of frequently recurring ventricular
fibrillation and hemodynamically unstable ventricular
tachycardia in patients refractory to other therapy
Please see accompanying Prescribing Information.
Data from: Cordarone I.V. Prescribing Information.
Amiodarone I.V.
®
(Cordarone I.V.)
•
Cordarone I.V. is contraindicated in patients with cardiogenic shock, marked
sinus bradycardia, and second- or third-degree AV block in the absence of a
functioning pacemaker.
•
Cordarone I.V. should be administered only by physicians who are experienced in
the treatment of life-threatening arrhythmias, who are thoroughly familiar with
the risks and benefits of Cordarone therapy, and who have access to facilities
adequate for monitoring the effectiveness and side effects of treatment.
•
Hypotension is the most common adverse effect seen with Cordarone I.V. and
may be related to the rate of infusion. Hypotension should be treated by slowing
the infusion or with standard therapy: vasopressor drugs, positive inotropic
agents, and volume expansion.
•
In clinical trials, the most important treatment-emergent adverse events were
hypotension (15.6%), bradycardia (4.9%), liver function test abnormalities (3.4%),
cardiac arrest (2.9%), VT (2.4%), congestive heart failure (2.1%), cardiogenic
shock (1.3%), and AV block (0.5%).
Please see accompanying Prescribing Information.
Data from: Cordarone I.V. Prescribing Information; Data on file, Wyeth-Ayerst Laboratories.
Amiodarone
I.V.
®
(Cordarone I.V.)
•
Cordarone I.V. is contraindicated in patients with cardiogenic shock,
marked sinus bradycardia, and second- or third-degree AV block in the
absence of a functioning pacemaker.
•
Cordarone I.V. should be administered only by physicians who are
experienced in the treatment of life-threatening arrhythmias, who are
thoroughly familiar with the risks and benefits of Cordarone therapy, and
who have access to facilities adequate for monitoring the effectiveness and
side effects of treatment.
•
Hypotension is the most common adverse effect seen with Cordarone I.V.
and may be related to the rate of infusion. Hypotension should be treated
by slowing the infusion or with standard therapy: vasopressor drugs,
positive inotropic agents, and volume expansion.
•
In clinical trials, the most important treatment-emergent adverse effects
were hypotension (15.6%), bradycardia (4.9%), liver function test
abnormalities (3.4%), cardiac arrest (2.9%), VT (2.4%), congestive heart
failure (2.1%), cardiogenic shock (1.3%), and AV block (0.5%).
Data from: Cordarone I.V. Prescribing Information; Data on file,
Wyeth-Ayerst Laboratories.
Amiodarone I.V.
®
(Cordarone I.V.)
Indication
Cordarone I.V. is indicated for initiation of treatment
and prophylaxis of frequently recurring ventricular
fibrillation and hemodynamically unstable
ventricular tachycardia in patients refractory to
other therapy.
Data from: Cordarone I.V. Prescribing Information.
Suppresses Highly Malignant
Ventricular Arrhythmias in Patients
with Severe Underlying Heart Disease
In clinical studies, IV amiodarone:
•
Decreased median number of life-threatening
events by 71%
•
•
Increased median time to first event to 13.7 hours
•
Patients should be monitored carefully for QTc
prolongation during infusion; <2% incidence of
proarrhythmia
85% of patients in controlled studies survived the critical
first 24 hours; without a placebo comparison, a mortality
benefit could not be established
Data from: Kowey PR et al. Circulation. 1995;92:3255–3263; Scheinman MM et al.
Circulation. 1995;92:3264–3272; Data on file, Wyeth-Ayerst Laboratories.
Events/hr (median)
Reduction of VF/VT Events
During Double-Blind Therapy
0.10
0.07
P = 0.067
71%
Reduction
0.04
0.05
0.02
0.00
125 mg
500 mg
1,000 mg
IV Amiodarone Dosing (mg/24 Hours)
• The 125-mg dose group was used as a control group.
• Due to administration of supplemental infusions, the 1,000-mg dose group actually
received 1,185 mg/24 hours compared with the 125-mg dose group, which actually
received 428 mg/24 hours.
Reprinted with permission. Circulation. Copyright 1995 American Heart Association.
Data from: Scheinman MM et al. Circulation. 1995;92:3264–3272;
Data on file, Wyeth-Ayerst Laboratories.
Reduction from Baseline
in VF/VT Events
P = 0.0425
Median VF/VT Events
per 24 Hours
Baseline
IV amiodarone 1,000 mg
IV amiodarone 125 mg
4.0
3.52
(88% reduction)
3.0
1.68
1.32
(44% reduction)
0.48
1,000 mg
125 mg
Difference from
baseline
No significant difference was observed between the 1,000-mg dose
and the 500-mg dose or the 125-mg dose and the 500-mg dose groups
Reprinted with permission. Circulation. Copyright 1995 American Heart Association.
Data from: Scheinman MM et al. Circulation. 1995;92:3264–3272.
Clinically Manageable Safety Profile
~9% Overall discontinuation rate due to
adverse events
<2% Incidence of proarrhythmia
<1% Discontinuation due to CNS side effects
Hypotension is the most common adverse effect seen with Cordarone® I.V.
(amiodarone HCI) and may be related to the rate of infusion. Hypotension
should be treated by slowing the infusion or with standard therapy:
vasopressor drugs, positive inotropic agents, and volume expansion.
Data from: Cordarone I.V. Prescribing Information; Data on file, Wyeth-Ayerst
Laboratories.
Most Important Treatment-Emergent,
Drug-Related
Adverse Events (n=1,836)
Event % Incidence
% Requiring
permanent
discontinuation
Hypotension
15.6%
1.6%
Bradycardia
4.9%
<1%
Liver function test abnormalities
3.4%
<1%
Cardiac arrest
2.9%
1.2%
Ventricular tachycardia
2.4%
1.1%
Congestive heart failure
2.1%
<1%
Cardiogenic shock
1.3%
1.0%
AV block
0.5%
<1%
Data from: Cordarone® I.V (amiodarone HCl) Prescribing Information; Data on file,
Wyeth-Ayerst Laboratories.
Fewer Drug-Related Adverse
Events than Bretylium
Treatment Group
Event
Cardiovascular events
Hypotension
Heart block
CHF
Proarrhythmia
Nodal rhythm
Phlebitis
Other events
Nausea
Confusion
Thrombocytopenia
Fever
Diarrhea
Bretylium
(n = 103)
IV amiodarone IV amiodarone
1,000 mg
125 mg
(n = 105)
(n = 94)
33
4
5
3
0
0
(32)
(4)
(5)
(3)
(0)
(0)
21
0
0
0
3
3
(20)
(0)
(0)
(0)
(3)
(3)
17
2
0
1
0
0
(18)
(2)
(0)
(1)
(0)
(0)
6
4
3
1
5
(6)
(4)
(3)
(1)
(5)
2
3
1
2
0
(2)
(3)
(1)
(2)
(0)
2
3
1
1
0
(2)
(3)
(1)
(1)
(0)
Values shown are n (%).
Reprinted with permission. Circulation. Copyright 1995 American Heart Association.
Data from: Kowey PR et al. Circulation. 1995;92:3255-3263.
Rapid Onset of Action
Antiarrhythmic effects are seen in minutes
Hypotension is the most common adverse
effect seen with Cordarone® I.V. (amiodarone
HCI) and may be related to the rate of infusion.
Data from: Kadish A, Morady F. Prog Cardiovasc Dis. 1989;31:281–294; Helmy I et
al. J Am Coll Cardiol. 1988;12:1015–1022; Holt P et al. Am J Cardiol. 1982;49:1001.
Abstract; Benamin R et al. Arch Mal Coeur. 1976;69:513–522.
The Only IV Antiarrhythmic with All
Four Vaughan Williams’ Class Effects
Class I effect
Class II effect
Sodium channel blockade
Noncompetitive alpha- and
beta-adrenergic inhibition
Na+
Na+
Na+
Na+
Na+
Na+
Na+
Na+
Ca++
Ca++
Ca++
Ca++
Ca++
Ca++
Ca++
Ca++
Class III effect
Class IV effect
Prolongation of repolarization
and refractoriness by increased
action potential duration
Calcium channel blockade
Data from: Siddoway LA. Pharmacologic principles of antiarrhythmic drugs. In: Podrid
PJ, Kowey PR, eds. Cardiac Arrhythmias: Mechanisms, Diagnosis, and Management.
Baltimore, MD: Williams & Wilkins; 1995:355-368.
Guidelines for Dosing and Administration
for VF and Hemodynamically Unstable VT
First 24 Hours
Loading Infusions
First Rapid
Add 150 mg (1 ampul) to 100 mL D5W; administer over FIRST 10 minutes (15 mg/min)
NOTE: In cardiac arrest due to shock-refractory VF/pulseless VT, the initial dose should be
300 mg, I.V. push, as recommended in the VF/pulseless VT algorithm in the 2000 ACLS guidelines.
PVC,* glass,† or polyolefin container
Followed by Slow
Add 900 mg (6 ampuls) to 500 mL D5W; administer 33.3 mL/hr over NEXT 6 hours (1 mg/min)
Glass† or polyolefin container
Maintenance Infusion‡
Reduce to 0.5 mg/min; administer 16.6 mL/hr for REMAINING 18 hours
*<10% loss at 2 hours.
†Use of evacuated glass containers for admixing Cordarone I.V. is not recommended, as
incompatibility with a buffer in the container may cause precipitation.
‡After the first 24 hours, the maintenance infusion rate of 0.5 mg/min (720 mg/24 hours) should
be continued utilizing a concentration of 1–6 mg/mL; concentrations greater than 2 mg/mL
should be administered via a central venous catheter. Infusions for longer than 3 weeks have
not been studied. Transition to oral therapy is recommended at the earliest possible time.
Supplemental Infusion*
• Add 150 mg to 100 mL D5W; administer over 10 minutes
(15 mg/min); PVC,† glass,‡ or polyolefin container
Hypotension is the most common adverse effect seen with
Cordarone® I.V. (amiodarone HCl) and may be related to the
rate of infusion.
Must use volumetric pump when administering
Cordarone I.V.; an in-line filter is recommended.
Concentrations greater than 3 mg/mL in D5W have been
associated with a high incidence of peripheral vein phlebitis.
*For the management of breakthrough episodes of life-threatening VT or VF.
Alternatively, the rate of the maintenance infusion may be increased.
†<10%
loss at 2 hours.
‡Use
of evacuated glass containers for admixing Cordarone I.V. is not recommended,
as incompatibility with a buffer in the container may cause precipitation.
Data from: Cordarone I.V. Prescribing Information.
Supplemental Infusion (Cont’d.)
Cordarone® I.V. (amiodarone HCl) has been found to leach out
plasticizers, including DEHP, from intravenous tubing (including PVC
tubing). The degree of leaching increases when infusing Cordarone I.V.
at higher concentrations and lower flow rates than provided in the
Dosage and Administration section of the Prescribing Information.
Store ampuls in cartons until ready for use to protect from light.
Prepared solutions should not be kept for more than 24 hours.
For infusions longer than 1 hour, Cordarone I.V. concentrations should
not exceed 2 mg/mL unless a central venous catheter is used.
Data from: Cordarone I.V. Prescribing Information.
Y-Site Injection Incompatibility
Drug
Amiodarone
Vehicle Concentration Comments
Aminophylline
D5W
4 mg/mL
Precipitate
Cefamandole nafate
D5W
4 mg/mL
Precipitate
Cefazolin sodium
D5W
4 mg/mL
Precipitate
Mezlocillin sodium
D5W
4 mg/mL
Precipitate
Heparin sodium
D5W
–
Precipitate
Sodium bicarbonate
D5W
3 mg/mL
Precipitate
Data from: Cordarone® I.V. (amiodarone HCl) Prescribing Information.