SLIDE ANTHOLOGY: Clinical Studies and Perspectives in Cardiac Arrest Management The 2000 Advanced...

SLIDE ANTHOLOGY:SLIDE ANTHOLOGY:

Clinical Studies and Perspectives in Clinical Studies and Perspectives in Cardiac Arrest Management Cardiac Arrest Management

The 2000 The 2000 AAdvanced dvanced CCardiovascular ardiovascular LLife ife SSupport Guidelinesupport Guidelines

Amiodarone IV Amiodarone IV

Jerrold H Levy, MDJerrold H Levy, MDEmory University School of MedicineEmory University School of Medicine

Atlanta, GeorgiaAtlanta, Georgia

ACLS Background: Historical PerspectivesACLS Background: Historical Perspectives

1st, 2nd, & 3rd 1st, 2nd, & 3rd Conference on Conference on

CPRCPR

2000 2000 1st International Guidelines 1st International Guidelines

Conference on CPR and ECC Conference on CPR and ECC

1st Conference 1st Conference on Pediatric on Pediatric

ResuscitationResuscitation

4th CPR and ECC4th CPR and ECCConferenceConference

5th CPR and ECC5th CPR and ECCConferenceConference

1966-19791966-1979

19831983

19851985

19921992

Data from: Data from: CirculationCirculation. 2000;102:1–2.. 2000;102:1–2.

1992 Guidelines for Treatment 1992 Guidelines for Treatment of VF/Pulseless VTof VF/Pulseless VT

Data from: Data from: CirculationCirculation. 2000;102:1-3. . 2000;102:1-3. JAMAJAMA. 1992;268:2199–2241.. 1992;268:2199–2241.

• Reflected scientific knowledge and experience Reflected scientific knowledge and experience in early 1990sin early 1990s

• Defibrillation as key interventionDefibrillation as key intervention

• Three antiarrhythmics as treatment optionsThree antiarrhythmics as treatment options

- LidocaineLidocaine

- ProcainamideProcainamide

- BretyliumBretylium

• No controlled trials existed to help evaluate No controlled trials existed to help evaluate efficacy of antiarrhythmicsefficacy of antiarrhythmics

2000 ACLS Guidelines2000 ACLS Guidelines Primary Goal of the AHA/ECCPrimary Goal of the AHA/ECC

• Establish guidelinesEstablish guidelines

- Based on scientific evidenceBased on scientific evidence

- Prompted by rapid changes and Prompted by rapid changes and advances in knowledgeadvances in knowledge

- Developed as recommendationsDeveloped as recommendations


CollaborateCollaborate with international with international resuscitation authorities on CPR resuscitation authorities on CPR

and ECCand ECC

CollaborateCollaborate with international with international resuscitation authorities on CPR resuscitation authorities on CPR

and ECCand ECC

2000 ACLS Guidelines: Overall Goals2000 ACLS Guidelines: Overall Goals

ReviewReview and revise and revise recommendationsrecommendations

from past conferencesfrom past conferences

ReviewReview and revise and revise recommendationsrecommendations

from past conferencesfrom past conferences

DevelopDevelop a document to explain a document to explainthe guidelinesthe guidelines

DevelopDevelop a document to explain a document to explainthe guidelinesthe guidelines

Data from: Data from: CirculationCirculation. 2000;102:I-2–I-3.. 2000;102:I-2–I-3.

CreateCreate valid, internationally valid, internationally accepted, resuscitation accepted, resuscitation

guidelines using scientific guidelines using scientific evidenceevidence

CreateCreate valid, internationally valid, internationally accepted, resuscitation accepted, resuscitation

guidelines using scientific guidelines using scientific evidenceevidence

International Guidelines International Guidelines 2000 Conference on CPR and ECC: 2000 Conference on CPR and ECC:

ObjectivesObjectives

• Establish ILCOR as the authority for Establish ILCOR as the authority for coordination and communicationcoordination and communication

• Ensure equal representation for AHA and Ensure equal representation for AHA and non-U.S. committeesnon-U.S. committees

• Review and revise recommendations from Review and revise recommendations from past conferences on the basis of accumulated past conferences on the basis of accumulated evidence evidence

• Recommend changes in the methods for Recommend changes in the methods for teaching life-support skillsteaching life-support skills

Data from:Data from: Circulation Circulation. 2000;102:I-2–I-3.. 2000;102:I-2–I-3.

Chain of Survival Chain of Survival


•Early accessEarly access

•Early CPREarly CPR

•Early defibrillationEarly defibrillation

•Early advanced careEarly advanced care

Philosophy: Evidence-Based ReviewPhilosophy: Evidence-Based Review

• Systematically Systematically identify, evaluate,identify, evaluate, andand appraiseappraise evidence to support proposed changesevidence to support proposed changes

• ReviewReview all proposed changes for:all proposed changes for:- Scientific accuracyScientific accuracy- SafetySafety- Cost Cost - EffectivenessEffectiveness- TeachabilityTeachability


Reasons for Modifying GuidelinesReasons for Modifying Guidelines

Lack of evidence to confirm Lack of evidence to confirm effectivenesseffectiveness

Additional evidence to suggest Additional evidence to suggest harm or ineffectivenessharm or ineffectiveness

Evidence that superior therapies Evidence that superior therapies have become availablehave become available

Data from: Data from: CirculationCirculation. 2000;102:I-1.. 2000;102:I-1.

Tools and Principles of Tools and Principles of Evidence-Based ReviewEvidence-Based Review

Search for Search for and gather and gather evidenceevidence

Assess the Assess the quality and level quality and level of the evidence of the evidence

Determine class of Determine class of recommendationrecommendationby evidenceby evidence

Step 1Step 1

Steps 2 & 3Steps 2 & 3

Step 4Step 4

Data from: Data from: CirculationCirculation. 2000;102:I-3.. 2000;102:I-3.

Sorting Studies by Level of EvidenceSorting Studies by Level of Evidence

Level 2Level 2 Neutral RCTs (NS)Neutral RCTs (NS)

Level 3Level 3Prospective, nonrandomized, Prospective, nonrandomized,

observational study with observational study with control groupcontrol group

Level 4Level 4 Retrospective, nonrandomized, Retrospective, nonrandomized, observational study with control groupobservational study with control group

Level 5Level 5 Case series compilation, no control groupCase series compilation, no control group

Level 6Level 6 Animal/mechanical model; 6A – Animal/mechanical model; 6A – higher quality studies, 6B – less powerful designhigher quality studies, 6B – less powerful design

Level 7Level 7 Reasonable extrapolations from data gathered for other purposesReasonable extrapolations from data gathered for other purposes

Level 8Level 8 Common sense; common practices before evidence-based guidelinesCommon sense; common practices before evidence-based guidelines

Level 1Level 1Positive Positive

RCTs RCTs ((PP < 0.05) < 0.05)

Abbreviation: RCT, randomized, controlled trial.Abbreviation: RCT, randomized, controlled trial.Data from: Data from: CirculationCirculation. 2000;102:I-4.. 2000;102:I-4.

Evaluating Quality of EvidenceEvaluating Quality of Evidence

Sort studies by Sort studies by level level

Cross-tabulate by Cross-tabulate by levellevel, , qualityquality, and , and directiondirection

Determine Determine directiondirection of results and statistics of results and statistics (Support proposal, Neutral, Oppose proposal)(Support proposal, Neutral, Oppose proposal)

Assess Assess qualityquality of research design of research design and methods (Excellent, Good, Fair, Poor)and methods (Excellent, Good, Fair, Poor)

Class of RecommendationClass of Recommendation

Data from: Data from: CirculationCirculation. 2000;102:I–4.. 2000;102:I–4.

Classes of RecommendationClasses of Recommendation

Class IClass I Excellent. Proven efficacy, safety, Excellent. Proven efficacy, safety, and usefulnessand usefulness

Acceptable. Good evidence, safe, Acceptable. Good evidence, safe, clinically useful; standard of careclinically useful; standard of care

Acceptable. Fair evidence, safe, Acceptable. Fair evidence, safe, clinically useful; within standardclinically useful; within standardof careof care

Not recommended. Minimal Not recommended. Minimal evidence; preliminary research evidence; preliminary research

Not acceptable. May be harmful; Not acceptable. May be harmful; not clinically usefulnot clinically useful

Data from:Data from: Circulation Circulation. 2000;102:I-5.. 2000;102:I-5.

Class IIaClass IIa

Class IIIClass III

ClassClassIndeterminateIndeterminate

Class IIbClass IIb

Evidence-Based GuidelinesEvidence-Based Guidelines

State a State a proposalproposal

Assess quality Assess quality and level of and level of evidenceevidence

Determine class Determine class of recommendationof recommendation(I, IIa, IIb, (I, IIa, IIb, Indeterminate, III)Indeterminate, III)

SummarizeSummarizerationale rationale

for proposalfor proposal

Step 1Step 1

Steps 2 & 3Steps 2 & 3

Step 4Step 4


Placebo-Controlled MethodologyPlacebo-Controlled Methodology

• Without placebo controls, the value Without placebo controls, the value of antiarrhythmic agents in cardiac of antiarrhythmic agents in cardiac arrest due to VF/pulseless VT cannot arrest due to VF/pulseless VT cannot be determinedbe determined

• Prospective, randomized, placebo-Prospective, randomized, placebo-controlled trials provide objective controlled trials provide objective evaluation of antiarrhythmic agents evaluation of antiarrhythmic agents

Evidence Evaluation TemplateEvidence Evaluation Template

ExcellentExcellent

GoodGood

FairFair

FairFair

GoodGood

ExcellentExcellent

11 22 33 44 55 66 7 87 8

11 22 33 44 55 66 7 87 8LevelLevel

LevelLevel

Su

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ort

ing

Su

pp

ort

ing

+/-

or

+/-

or

Op

po

sin

gO

pp

os

ing

Courtesy of Peter Kudenchuck.Courtesy of Peter Kudenchuck.

Lidocaine in Cardiac Life Support: Lidocaine in Cardiac Life Support: Review of Quality of Evidence Review of Quality of Evidence

• Lidocaine did not fare well under evidence-based Lidocaine did not fare well under evidence-based approachapproach

• Review of evidence showed poor or weak support for Review of evidence showed poor or weak support for lidocaine as beneficial in cardiac arrestlidocaine as beneficial in cardiac arrest

• Supporting evidence primarily consisted of levels 6, Supporting evidence primarily consisted of levels 6, 7, and 87, and 8

• Class indeterminate for shock-refractory VF/pulseless VTClass indeterminate for shock-refractory VF/pulseless VT

• Lack of evidence was key factor in revised lidocaine Lack of evidence was key factor in revised lidocaine classification despite time-honored status and 1992 classification despite time-honored status and 1992 ACLS recommendationACLS recommendation


Quality and Level of Evidence Analysis Quality and Level of Evidence Analysis Lidocaine in Cardiac ArrestLidocaine in Cardiac Arrest

Due to VF/VT Due to VF/VT

Su

pp

ort

ing

Su

pp

ort

ing

2, 3, 6,2, 3, 6,7, 8, 14,7, 8, 14,19, 19, 2222

1313 1818

1010

1111

23, 2423, 24 1,1, 20, 20, 2626

Current Current PracticePractice551212

11 22 33 4 4 5 5 6 6 7 7 8 8

4, 9, 15,4, 9, 15,16, 17,16, 17,21, 2521, 25

ExcellentExcellent

GoodGood

FairFair

FairFair

GoodGood

ExcellentExcellent

11 22 33 4 4 5 5 6 6 7 7 8 8

Author Year (n)Author Year (n)

1.1. Alexander ’99 (43704)Alexander ’99 (43704)2.2. Anastasiou Anastasiou ’’94 (16)94 (16)3.3. Babbs Babbs ’’79794.4. Borer ’76Borer ’765.5. Carden ’56 (23)Carden ’56 (23)6.6. Chow Chow ’’86867.7. Dorian Dorian ’’86868.8. Echt Echt ’’89899.9. Harrison ’63 (12)Harrison ’63 (12)10.10. Harrison ’81 (116)Harrison ’81 (116)11.11. Haynes ’81 (146)Haynes ’81 (146)12.12. Herlitz ’97 (1360)Herlitz ’97 (1360)13.13. Kentsch Kentsch ’’88 (20)88 (20)14.14. Kerber Kerber ’’868615.15. Lazzara ’73Lazzara ’7316.16. Lazzara ’78Lazzara ’7817.17. Lie ’74Lie ’7418.18. Olson ’84 (108)Olson ’84 (108)19.19. Redding Redding ’’68 (105)68 (105)20.20. Sadowski Sadowski ’’99 (903)99 (903)21.21. Spear ’72Spear ’7222.22. Vachiery ’90 (18)Vachiery ’90 (18)23.23. VanWalraven VanWalraven ’’98 (773)98 (773)24.24. Weaver Weaver ’’90 (199)90 (199)25.25. Other MI trialsOther MI trials26.26. MI Meta-analysesMI Meta-analyses

Ne

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Lidocaine in Cardiac Arrest Lidocaine in Cardiac Arrest Due to VF/VT Due to VF/VT

Neutral/Opposing Neutral/Opposing (17) (17)

•Neutral (5)Neutral (5)

- Level 2 (2)Level 2 (2)




•Opposing (12)Opposing (12)





Supporting (10)



- Level 7 (7) Level 7 (7)


Quality and Level of Evidence Analysis Quality and Level of Evidence Analysis Amiodarone in Cardiac Arrest Amiodarone in Cardiac Arrest

Due to VF/VTDue to VF/VT

Su

pp

ort

ing

Su

pp

ort

ing

10101717

1919

ExcellentExcellent

GoodGood

FairFair

1515

99

11 22 33 4 4 5 5 6 6 7 7 8 8

2, 4, 5, 7, 2, 4, 5, 7, 11, 12, 13, 11, 12, 13, 14, 16, 1814, 16, 18

FairFair

GoodGood

ExcellentExcellent

11 22 33 4 4 5 5 6 6 7 7 8 8

1.1. AnastasiNana ’94 (16)AnastasiNana ’94 (16)2.2. Drexler (14)Drexler (14)3.3. Fain ’87 (12)Fain ’87 (12)4.4. Helmy ’88 (46)Helmy ’88 (46)5.5. Horowitz (5)Horowitz (5)6.6. Kentsch ’88 (20)Kentsch ’88 (20)7.7. Klein (13)Klein (13)8.8. Kowey ’95 (228)Kowey ’95 (228)9.9. Kudenchuk ‘99 (504)Kudenchuk ‘99 (504)10.10. Levine ’96 (273)Levine ’96 (273)11.11. Mooss (35)Mooss (35)12.12. Morady (15)Morady (15)13.13. Nalos ’91 (22)Nalos ’91 (22)14.14. Ochi (22)Ochi (22)15.15. Rosalion ’91 (23)Rosalion ’91 (23)16.16. Saksena (9)Saksena (9)17.17. Scheinman ’95 (342)Scheinman ’95 (342)18.18. Schutzenberger ’89 (26)Schutzenberger ’89 (26)19.19. ZhouZhou ’98 (24) ’98 (24)

88

66

1, 31, 3

Author Year (n)Author Year (n)

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Amiodarone in Cardiac Arrest Amiodarone in Cardiac Arrest Due to VF/VT Due to VF/VT

Neutral/Opposing Neutral/Opposing (3) (3)

•Neutral (2)Neutral (2)


•Opposing (1)Opposing (1)


Supporting (16)



- Level 5 (10) Level 5 (10)



2000 ACLS Guidelines: 2000 ACLS Guidelines: Recommended Antiarrhythmic AgentsRecommended Antiarrhythmic Agents

• Amiodarone HCl received a Class-IIb rating Amiodarone HCl received a Class-IIb rating in cardiac arrest; no other antiarrhythmic in cardiac arrest; no other antiarrhythmic agent received a more favorable rating in agent received a more favorable rating in this settingthis setting

• The 2000 ACLS Guidelines recommend The 2000 ACLS Guidelines recommend using only one antiarrhythmic agent in using only one antiarrhythmic agent in resuscitation effortsresuscitation efforts

Data from: Data from: CirculationCirculation. 2000;102:I-115, I-149–I-159.. 2000;102:I-115, I-149–I-159.

2000 ACLS Guidelines VF/Pulseless VT 2000 ACLS Guidelines VF/Pulseless VT Treatment AlgorithmTreatment Algorithm

Guidelines for Dosing and Administration Guidelines for Dosing and Administration for VF and Hemodynamically Unstable VTfor VF and Hemodynamically Unstable VTFirst 24 HoursFirst 24 Hours

FirstFirst Rapid RapidAdd 150 mg (1 ampul) to 100 mL DAdd 150 mg (1 ampul) to 100 mL D55W; administer over FIRST 10 minutes (15 mg/min)W; administer over FIRST 10 minutes (15 mg/min)

PVC,* glass,PVC,* glass,†† or polyolefin container or polyolefin container

Followed by Followed by SlowSlowAdd 900 mg (6 ampuls) to 500 mL DAdd 900 mg (6 ampuls) to 500 mL D55W; administer 33.3 mL/hr over NEXT 6 hours (1 mg/min)W; administer 33.3 mL/hr over NEXT 6 hours (1 mg/min)

GlassGlass†† or polyolefin container or polyolefin container

Reduce to 0.5 mg/min; administer 16.6 mL/hr for REMAINING 18 hoursReduce to 0.5 mg/min; administer 16.6 mL/hr for REMAINING 18 hours

*<10% loss at 2 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 Use of evacuated glass containers for admixing Cordarone I.V. is not recommended, as incompatibility with a buffer in the container may cause precipitation.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 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. 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 Infusions for longer than 3 weeks have not been studied. Transition to oral therapy is recommended at the earliest possible time.time.

Loading InfusionsLoading Infusions

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.

Maintenance InfusionMaintenance Infusion‡‡

The 2000 ACLS Guidelines: The 2000 ACLS Guidelines: Overview and ConclusionOverview and Conclusion

““Amiodarone is recommended after defibrillation and epinephrineAmiodarone is recommended after defibrillation and epinephrinein cardiac arrest with persistent VT or VF (Class IIb).”in cardiac arrest with persistent VT or VF (Class IIb).”

““In summary, evidence supports the use of IV amiodarone,In summary, evidence supports the use of IV amiodarone,following epinephrine, to treat shock-refractory cardiac arrestfollowing epinephrine, to treat shock-refractory cardiac arrest

due to VF or pulseless VT (Class IIb).”due to VF or pulseless VT (Class IIb).”

““The evidence supporting amiodarone is much stronger [than that for The evidence supporting amiodarone is much stronger [than that for lidocaine]. . .and justifies the use of amiodarone before lidocaine. . .”lidocaine]. . .and justifies the use of amiodarone before lidocaine. . .”

““The expert panel members would have no problem with clinicians The expert panel members would have no problem with clinicians routinely using amiodarone as the first-choice antiarrhythmic for routinely using amiodarone as the first-choice antiarrhythmic for

shock-refractory VF/VT”shock-refractory VF/VT”

From:From: Circulation. Circulation. 2000;102(suppl):I-86, I-87, I-117, I-120.2000;102(suppl):I-86, I-87, I-117, I-120.

Preparation of IV Amiodarone Preparation of IV Amiodarone for Cardiac Arrest Due to VF/VTfor Cardiac Arrest Due to VF/VT

• Use 2 ampuls of amiodarone, appropriate size syringe Use 2 ampuls of amiodarone, appropriate size syringe and needle, gauze, sponges or alcohol padand needle, gauze, sponges or alcohol pad

• Check route, dose, dateCheck route, dose, date

• Avoid excessive shaking of ampulsAvoid excessive shaking of ampuls

• Tap top of ampul before opening to promote transfer Tap top of ampul before opening to promote transfer of medication of medication

““In cardiac arrest due to pulseless VT or VF, IV In cardiac arrest due to pulseless VT or VF, IV amiodarone is initially administered as a 300-mg amiodarone is initially administered as a 300-mg

rapid infusion diluted rapid infusion diluted in a volume of 20 to 30 mL of saline or dextrose in in a volume of 20 to 30 mL of saline or dextrose in

water.”water.”

From:From: Circulation. Circulation. 2000;102(suppl):I-121.2000;102(suppl):I-121.

• 900,000 people in the U.S. experience 900,000 people in the U.S. experience an MI annuallyan MI annually

• ~225,000 die~225,000 die

~125,000 die “in the field”~125,000 die “in the field”

Most deaths are arrhythmic in etiologyMost deaths are arrhythmic in etiology

Acute Myocardial InfarctionAcute Myocardial Infarction

Data from: Ryan TJ et al. Data from: Ryan TJ et al. J Am Coll CardiolJ Am Coll Cardiol. 1996;28:1333.. 1996;28:1333.

AAmiodarone in out-of-hospital miodarone in out-of-hospital RResuscitation of esuscitation of REREfractory fractory SSustained ustained

ventricular ventricular TTachyarrhythmias (ARREST)achyarrhythmias (ARREST)

A prospective, randomized, double-blind, A prospective, randomized, double-blind, placebo-controlled study of IV amiodarone in placebo-controlled study of IV amiodarone in patients with out-of-hospital cardiac arrest due patients with out-of-hospital cardiac arrest due to shock-refractory VF/VTto shock-refractory VF/VT

Data from:Data from: Kudenchuk PJ et al. Kudenchuk PJ et al. N Engl J Med.N Engl J Med. 1999;341:871–878. 1999;341:871–878.

ARREST Eligibility CriteriaARREST Eligibility Criteria

• Older than 18 yearsOlder than 18 years

• Nontraumatic out-of-hospital cardiac arrest Nontraumatic out-of-hospital cardiac arrest

• Ongoing or recurrent VF/VT after 3+ shocksOngoing or recurrent VF/VT after 3+ shocks

• Paramedics and study drug on sceneParamedics and study drug on scene

• IV accessIV access

Data from: Kudenchuk PJ et al. Data from: Kudenchuk PJ et al. N Engl J Med.N Engl J Med. 1999;341:871–878. 1999;341:871–878.

• PrimaryPrimary- Admission to hospital with a spontaneously perfusing rhythm (assigned Admission to hospital with a spontaneously perfusing rhythm (assigned

to a hospital bed)to a hospital bed)• Secondary Secondary

- Adverse effectsAdverse effects- Total duration of resuscitative effortsTotal duration of resuscitative efforts- Number of shocks after administration of study drugNumber of shocks after administration of study drug- Need for additional antiarrhythmic drugsNeed for additional antiarrhythmic drugs

• Also evaluated Also evaluated - Survival to hospital discharge*Survival to hospital discharge*- Neurological status at hospital discharge*Neurological status at hospital discharge*

ARREST Study End PointsARREST Study End Points

** By design, the trial did not have sufficient statistical power to demonstrate By design, the trial did not have sufficient statistical power to demonstrate differences in these outcomes. differences in these outcomes.


ARREST Study AlgorithmARREST Study AlgorithmCardiac ArrestCardiac Arrest

VF or Pulseless VTVF or Pulseless VT

Study DrugStudy Drug

Standard ACLS CareStandard ACLS Care

PlaceboPlaceboIV amiodaroneIV amiodarone

ETTETTIVIVEPIEPI

Persistent or Persistent or Recurrent VF/VTRecurrent VF/VT

StableStableRhythmRhythm

AsystoleAsystoleor PEAor PEA

Excluded From StudyExcluded From Study

ETT:ETT: endotracheal intubationendotracheal intubationIV:IV: intravenous access establishedintravenous access establishedEPI:EPI: epinephrineepinephrinePEA:PEA: pulseless electrical activitypulseless electrical activity

Shock x 3Shock x 3

Data from: Kudenchuk PJ et al. Data from: Kudenchuk PJ et al. N Engl J Med.N Engl J Med. 1999;341:871-878. 1999;341:871-878.

November 1994-February 1997November 1994-February 1997Out-of-Hospital Cardiac ArrestOut-of-Hospital Cardiac Arrest

Ineligible/NotIneligible/NotTreatedTreated

(n=3,260)(n=3,260)

Ineligible/TreatedIneligible/Treated(n=27)(n=27)

Eligible/NotEligible/NotTreatedTreated(n=160)(n=160)

Drug AssignmentDrug AssignmentUnknownUnknown

(n=3)(n=3)

(n=3,954)(n=3,954)

Met Study CriteriaMet Study Criteria(n=667)(n=667)

Eligible/TreatedEligible/Treated(n=507)(n=507)

Study GroupStudy Group(n=504)(n=504)


ARREST Patient CharacteristicsARREST Patient Characteristics

MaleMale 187 (76%)187 (76%) 203 (79%)203 (79%) NSNS

Age (yr)Age (yr) 66 66 14*14* 65 65 14*14* NSNS

Cardiac HistoryCardiac History 137 (64%)137 (64%) 135 (59%)135 (59%) NSNS

Other Medical HistoryOther Medical History 101 (47%)101 (47%) 119 (52%)119 (52%) NSNS

Witnessed ArrestWitnessed Arrest 155 (70%)155 (70%) 182 (77%)182 (77%) 0.070.07

Bystander CPRBystander CPR 155 (68%)155 (68%) 138 (59%)138 (59%) 0.060.06

VF Amplitude (mV)VF Amplitude (mV) 0.42 ± 0.2*0.42 ± 0.2* 0.45 ± 0.2*0.45 ± 0.2* NSNS

IV AmiodaroneIV Amiodarone(n=246)(n=246)

PlaceboPlacebo(n=258)(n=258) PP Value Value

** Values shown are means ± SD.Values shown are means ± SD.Data from: Kudenchuk PJ et al. Data from: Kudenchuk PJ et al. N Engl J Med.N Engl J Med. 1999;341:871-878. 1999;341:871-878.

Initial Cardiac Arrest RhythmInitial Cardiac Arrest Rhythm

Abbreviation: PEA, pulseless electrical activity.Abbreviation: PEA, pulseless electrical activity.


0

20

40

60

80

100

VF Asystole VF PEA VF

IV Amiodarone

Placebo

% o

f P

atie

nts

8383 8383

44 551212 1111

Response/Treatment Times Response/Treatment Times in Minutesin Minutes

First unit First unit 4.3 4.3 2.0 (4.0) 2.0 (4.0) 4.4 4.4 2.3 (4.0) 2.3 (4.0) NSNS

Paramedic/ALSParamedic/ALS 8.4 8.4 4.1 (7.8)4.1 (7.8) 8.8 8.8 4.9 (7.9) 4.9 (7.9) NSNS

ShockShock 8.9 8.9 5.4 (7.6) 5.4 (7.6) 9.5 9.5 7.5 (7.4) 7.5 (7.4) NSNS

IV accessIV access 13.1 13.1 4.1 (12.7) 4.1 (12.7) 13.7 13.7 4.1 (13.2) 4.1 (13.2) NSNS

IntubationIntubation 14.3 14.3 5.8 (12.7) 5.8 (12.7) 13.8 13.8 4.6 (13.1) 4.6 (13.1) NSNS

Study drugStudy drug 21.4 21.4 8.3 (19.2) 8.3 (19.2) 20.5 20.5 7.0 (19.3) 7.0 (19.3) NSNS

IVIVAmiodaroneAmiodarone PlaceboPlacebo PP Value Value

Values shown are the means ± SD with medians shown in parentheses.Values shown are the means ± SD with medians shown in parentheses.Abbreviations: ALS, advanced life support; IV, intravenous; NS, not statistically significant; Abbreviations: ALS, advanced life support; IV, intravenous; NS, not statistically significant; SD, standard deviation.SD, standard deviation.


Resuscitation CharacteristicsResuscitation CharacteristicsBefore Study DrugBefore Study Drug

Number of shocksNumber of shocks 5 5 2 (4)* 2 (4)* 5 5 2 (4)* 2 (4)* 0.730.73

Transient ROSCTransient ROSC 55 (22%)55 (22%) 52 (20%)52 (20%) 0.610.61

Antiarrhythmic drugAntiarrhythmic drug 65 (26%)65 (26%) 91 (35%)91 (35%) 0.040.04

Bradycardia treatment Bradycardia treatment 32 (13%)32 (13%) 51 (20%)51 (20%) 0.040.04

Pressor treatmentPressor treatment 19 (8%)19 (8%) 22 (9%)22 (9%) 0.740.74

IVIVAmiodaroneAmiodarone

(n=246)(n=246)PlaceboPlacebo(n=258)(n=258) PP Value Value

Abbreviations: ROSC, return of spontaneous circulation; SD, standard deviation.Abbreviations: ROSC, return of spontaneous circulation; SD, standard deviation.*The values shown are the means ± SD, with the median in parentheses.*The values shown are the means ± SD, with the median in parentheses.


No. Receiving DrugNo. Receiving DrugTotal No.Total No.

0

20

40

60

80

100

Antiarrhythmic Pressor* Bradycardia treatment*

IV Amiodarone

Placebo

Treatment After Study DrugTreatment After Study Drug

** In patients with return of spontaneous circulation.In patients with return of spontaneous circulation.

% o

f P

atie

nts

8080 8282

5959

48484141

2525

246246 258258 153153 145145 153153 145145

P P = 0.70= 0.70

P P = 0.04= 0.04

P P = 0.004= 0.004

Data from:Data from: Kudenchuk PJ et al. Kudenchuk PJ et al. N Engl J Med.N Engl J Med. 1999;341:871-878. 1999;341:871-878.

197197 211211 9191 6969 6363 3636

44

34

49

39

1712

64

4138

33

0

10

20

30

40

50

60

70

All Patients VF Asystole/PEA ROSC No ROSC

IV AmiodaronePlacebo

Admission to Hospital by Admission to Hospital by Arrhythmia CharacteristicsArrhythmia Characteristics

Pat

ien

ts S

urv

ivin

gto

Ad

mis

sio

n (

%)

No. SurvivingNo. Surviving 108 108 8989 101101 8484 77 55 3535 2222 7373 6767Total No. Total No. 246 246 258258 205205 216216 4141 4242 5555 5353 191191 205205

Abbreviations: PEA, pulseless electrical activity; ROSC, return of spontaneous circulation.Abbreviations: PEA, pulseless electrical activity; ROSC, return of spontaneous circulation.Data from:Data from: Kudenchuk PJ et al. Kudenchuk PJ et al. N Engl J Med.N Engl J Med. 1999;341:871-878. 1999;341:871-878.

ARREST Trial ConclusionsARREST Trial Conclusions

• IV amiodarone is effective therapy for IV amiodarone is effective therapy for shock-refractory VFshock-refractory VF

• Adverse effects expected but manageableAdverse effects expected but manageable

• Improving survival from cardiac arrest Improving survival from cardiac arrest remains an important challengeremains an important challenge


A L I V EA L I V E

AAmiodarone Versus miodarone Versus LLidocaine idocaine IIn Pre-hospital Refractory n Pre-hospital Refractory

VVentricular Fibrillation entricular Fibrillation EEvaluationvaluation

Data from:Data from: Dorian PDorian P et al. et al. N Engl J Med.N Engl J Med. 2002;346:884-890. 2002;346:884-890.

..

ALIVE: RationaleALIVE: Rationale• Patients in cardiac arrest due to VF unresponsive Patients in cardiac arrest due to VF unresponsive

to initial defibrillation have a poor prognosisto initial defibrillation have a poor prognosis

• Lidocaine has been the traditional treatment for Lidocaine has been the traditional treatment for shock-resistant VFshock-resistant VF

• No large-scale, controlled clinical trials show lidocaine No large-scale, controlled clinical trials show lidocaine superior to placebo or other antiarrhythmic agents in cardiac superior to placebo or other antiarrhythmic agents in cardiac arrest due to shock-refractory VFarrest due to shock-refractory VF

• Results of the ARREST trial (Kudenchuk et al, Results of the ARREST trial (Kudenchuk et al, N Engl J Med.N Engl J Med. 1999) showed an increase in survival to 1999) showed an increase in survival to hospital admission with IV amiodarone in patients with hospital admission with IV amiodarone in patients with shock-refractory VFshock-refractory VF

• The ALIVE study was designed to compare IV amiodarone The ALIVE study was designed to compare IV amiodarone with IV lidocaine in out-of-hospital with IV lidocaine in out-of-hospital shock-refractory VFshock-refractory VF


ALIVE: HypothesisALIVE: Hypothesis

• Amiodarone can produce better Amiodarone can produce better outcomes than lidocaine in patients outcomes than lidocaine in patients with out-of-hospital cardiac arrest due with out-of-hospital cardiac arrest due to shock-refractory VF to shock-refractory VF


ALIVE: Study DesignALIVE: Study Design

• Blinded, randomized, controlled trial of Blinded, randomized, controlled trial of IV amiodarone (5 mg/kg) vs. IV lidocaine IV amiodarone (5 mg/kg) vs. IV lidocaine (1.5 mg/kg) (1.5 mg/kg)

• Men and women were eligible if they were Men and women were eligible if they were at least 18 years of age and in at least 18 years of age and in documented VF refractory to standard documented VF refractory to standard protocol in the Toronto EMS system protocol in the Toronto EMS system (defibrillations and epinephrine infusion)(defibrillations and epinephrine infusion)

• Eligibility was determined by paramedics Eligibility was determined by paramedics in the City of Toronto EMS system, under in the City of Toronto EMS system, under the direction of a physician the direction of a physician


ALIVE: Outcome MeasuresALIVE: Outcome Measures

• Primary end pointPrimary end point

- Survival to hospital admission Survival to hospital admission

• Subgroup analysesSubgroup analyses

- Survival to hospital admission by initial rhythm (VF, PEA, asystole)Survival to hospital admission by initial rhythm (VF, PEA, asystole)

- Survival to hospital admission by time from EMS crew dispatch to administration of study drugSurvival to hospital admission by time from EMS crew dispatch to administration of study drug

• Secondary end pointSecondary end point

- Survival to hospital discharge Survival to hospital discharge


ALIVE: Study ProtocolALIVE: Study ProtocolVFVF

3 Failed shocks3 Failed shocks

IV epinephrineIV epinephrine

Persistent/recurrent VFPersistent/recurrent VF

1.5 mg/kg Lidocaine/placebo IV 1.5 mg/kg Lidocaine/placebo IV OROR 5 mg/kg Amiodarone/placebo IV5 mg/kg Amiodarone/placebo IV

ALIVE StudyALIVE Study

ACLS treatment as guided by protocolsACLS treatment as guided by protocols

Defibrillation shockDefibrillation shock


Persistent VFPersistent VF

1.5 mg/kg Lidocaine/placebo IV 1.5 mg/kg Lidocaine/placebo IV OROR 2.5 mg/kg Amiodarone/placebo IV2.5 mg/kg Amiodarone/placebo IV

= VF persists or recurs= VF persists or recurs



ALIVE: DemographicsALIVE: Demographics

Amiodarone*Amiodarone* Lidocaine*Lidocaine*Characteristic Characteristic (n=180) (n=180) (n=167) (n=167)

Age (yrs)Age (yrs) 68 ± 1468 ± 14 66 ± 1366 ± 13

Male (%)Male (%) 7676 8181

Weight (kg)Weight (kg) 80 ± 1680 ± 16 82 ± 1382 ± 13

Hx heart disease (%)Hx heart disease (%) 61.161.1 59.359.3Witnessed arrest (%)Witnessed arrest (%) 7676 79.379.3Bystander CPR (%)Bystander CPR (%) 26.326.3 28.728.7

* There were no significant differences between the two study groups for any * There were no significant differences between the two study groups for any

characteristic.characteristic.


ALIVE: Baseline CharacteristicsALIVE: Baseline Characteristics

Abbreviations: VF, ventricular fibrillation; PEA, pulseless electrical activity; VT, ventricular tachycardia; Abbreviations: VF, ventricular fibrillation; PEA, pulseless electrical activity; VT, ventricular tachycardia; SV, supraventricular; SD, standard deviation. SV, supraventricular; SD, standard deviation. * There were no significant differences between the two study groups for any characteristic.* There were no significant differences between the two study groups for any characteristic.†† The values shown are the means ± SD.The values shown are the means ± SD.

Amiodarone*Amiodarone* Lidocaine*Lidocaine*Characteristic Characteristic (n=180) (n=180) (n=167) (n=167)

Initial rhythm (%):Initial rhythm (%):VFVF 77.877.8 79.079.0AsystoleAsystole 11.111.1 9.6 9.6PEAPEA 7.8 7.8 6.6 6.6

Last recorded rhythm before Last recorded rhythm before study drug administration (%):study drug administration (%):

VFVF 88.988.9 91.091.0VTVT 1.7 1.7 2.4 2.4AsystoleAsystole 1.1 1.1 1.2 1.2PEAPEA 5.0 5.0 3.0 3.0SVSV 1.7 1.7 0.6 0.6

Total no. shocksTotal no. shocks 5 ± 1.95 ± 1.9†† 5 ± 2.25 ± 2.2††


Time Intervals From Time Intervals From EMS Crew DispatchEMS Crew Dispatch

** There were no significant differences between the two study groups for any of these There were no significant differences between the two study groups for any of these measurements.measurements.

Amiodarone*Amiodarone* Lidocaine*Lidocaine* Intervals*Intervals* (n=180) (n=180) (n=167) (n=167)

Time from dispatch toTime from dispatch toarrival at patient (min)arrival at patient (min) 7.3 ± 2.7 7.3 ± 2.7 7.5 ± 2.6 7.5 ± 2.6

Time to first defibrillationTime to first defibrillationshock (min)shock (min) 8.4 ± 2.8 8.4 ± 2.8 8.7 ± 3.6 8.7 ± 3.6

Time to IV initiation (min) Time to IV initiation (min) 13.4 ± 4.413.4 ± 4.4 13.6 ± 3.713.6 ± 3.7

Time to study drug (min) Time to study drug (min) 25.2 ± 8.025.2 ± 8.0 24.3 ± 6.824.3 ± 6.8


ALIVE: ResultsALIVE: ResultsBefore Study DrugBefore Study Drug

AmiodaroneAmiodarone Lidocaine Lidocaine PP Value Value Characteristic Characteristic (n=180) (n=180) (n=167) (n=167)

Number of shocksNumber of shocks 5 ± 1.9* (4%)5 ± 1.9* (4%) 5 ± 2.2* (4%)5 ± 2.2* (4%) NSNS

Transient spontaneousTransient spontaneouscirculationcirculation 24 (13.3%)24 (13.3%) 11 (6.6%)11 (6.6%) < 0.04< 0.04

Treatment for bradycardiaTreatment for bradycardia(atropine)(atropine) 98 (54%)98 (54%) 96 (57%)96 (57%) NSNS

Pressor treatmentPressor treatment(dopamine)(dopamine) 2 (1%) 2 (1%) 0 0 NSNS

Antiarrhythmic drugAntiarrhythmic drugtreatment (open label lidocaine) 4 (2%)treatment (open label lidocaine) 4 (2%) 1 (1%) 1 (1%) NSNS

*Values shown are the means ± SD.*Values shown are the means ± SD.


ALIVE: ResultsALIVE: ResultsAfter Study DrugAfter Study Drug

AmiodaroneAmiodarone Lidocaine Lidocaine PP Value ValueCharacteristic Characteristic (n=180) (n=180) (n=167) (n=167)

Treatment for bradycardiaTreatment for bradycardia(atropine)(atropine) 43 (24%)43 (24%) 38 (23%)38 (23%) NSNS

Pressor treatmentPressor treatment(dopamine)(dopamine) 13 (7%) 13 (7%) 6 (4%) 6 (4%) NSNS

Antiarrhythmic drugAntiarrhythmic drugtreatment treatment (open label lidocaine) (open label lidocaine) 11 (6%)11 (6%) 10 (6%) 10 (6%) NSNS


ALIVE: Survival to ALIVE: Survival to Hospital AdmissionHospital Admission

AmiodaroneAmiodarone Lidocaine Lidocaine (n=180)(n=180) (n=167) (n=167) P P ValueValue

Number of patientsNumber of patientssurviving to hospitalsurviving to hospital 41 (22.8%)41 (22.8%) 20 (12.0%)20 (12.0%) 0.0083 0.0083 admissionadmission

Odds ratioOdds ratio 2.17 (1.21, 3.83) 2.17 (1.21, 3.83) (95% CI)(95% CI)

Relative riskRelative riskreductionreduction 53%53%


ALIVE: Survival to ALIVE: Survival to Hospital DischargeHospital Discharge

AmiodaroneAmiodarone Lidocaine Lidocaine (n=180)(n=180) (n=167) (n=167) P P ValueValue

Number of patientsNumber of patientssurviving to hospitalsurviving to hospital 9 (5%)9 (5%) 5 (3%)5 (3%) 0.3427 0.3427 dischargedischarge


ALIVE: Survival by Time from EMS Crew ALIVE: Survival by Time from EMS Crew Dispatch to Study Drug AdministrationDispatch to Study Drug Administration

0

10

20

30

40

50

<24 min to drug ≥24 min to drug

AmiodaroneLidocaine

Per

cen

t S

urv

ival

to

H

osp

ital

Ad

mis

sio

n

28%28%

15%15%18%18%

6%6%

A: 32 +/- 7 minA: 32 +/- 7 minL: 31 +/- 5 minL: 31 +/- 5 min

A: 19 +/- 3 minA: 19 +/- 3 minL: 19 +/- 4 minL: 19 +/- 4 min

((PP=0.05)=0.05)

((PP=0.046)=0.046)


ALIVE: Survival of All Patients ALIVE: Survival of All Patients and Selected Subgroupsand Selected Subgroups

0

10

20

30

40

50AmiodaroneLidocaine

Per

cen

t S

urv

ivin

g

to A

dm

issi

on

VFAll Patients

22.824.8

Asystole or PEA Converting to VF

ROSC No ROSC

12.014.2

12.9

3.7

41.2

27.3

19.9

10.9


ALIVE: Multivariate Predictors of ALIVE: Multivariate Predictors of Survival to Hospital AdmissionSurvival to Hospital Admission

OR (95% CI) OR (95% CI) PP Value ValueTreatmentTreatment(amiodarone(amiodarone 2.5 (1.3, 4.9)2.5 (1.3, 4.9) 0.0071 0.0071 vs. lidocaine)vs. lidocaine)

Time to drugTime to drugadministration (min)administration (min) 0.9 (0.8, 0.9)0.9 (0.8, 0.9) <0.0001<0.0001

Transient return of Transient return of spontaneous circulationspontaneous circulationbefore study drugbefore study drug 5.9 (2.5, 14.3)5.9 (2.5, 14.3) <0.0001<0.0001

Corrected for all factors which may influence outcome: initial rhythm (VF vs. other), 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 witnessed arrest, bystander CPR, BLS shock, age, sex, weight, and number of shocks.shocks.


ALIVE: Conclusions and ALIVE: Conclusions and Clinical SignificanceClinical Significance

• First large-scale direct comparison of amiodarone with First large-scale direct comparison of amiodarone with lidocaine in patients with out-of-hospital VFlidocaine in patients with out-of-hospital VF

• Significantly (Significantly (PP = 0.0083) more patients treated with = 0.0083) more patients treated with amiodarone than with lidocaine (22.8% vs. 12.0%) survived amiodarone than with lidocaine (22.8% vs. 12.0%) survived to hospital admissionto hospital admission

• The difference between amiodarone and lidocaine was The difference between amiodarone and lidocaine was similar in various subgroup analyses (time of dispatch to similar in various subgroup analyses (time of dispatch to administration of study drug, by initial rhythm, and by administration of study drug, by initial rhythm, and by presence or absence of ROSC) of survival to hospital presence or absence of ROSC) of survival to hospital admissionadmission

• Amiodarone is substantially more effective than lidocaine as Amiodarone is substantially more effective than lidocaine as an adjunct to ACLS procedures in patients with cardiac an adjunct to ACLS procedures in patients with cardiac arrest due to shock-refractory VF, with regard to survival to arrest due to shock-refractory VF, with regard to survival to hospital admission hospital admission


Amiodarone I.V. Amiodarone I.V. (Cordarone(Cordarone®® I.V.) I.V.)

IndicationIndicationCordarone I.V. is indicated for initiation of treatmentCordarone I.V. is indicated for initiation of treatmentand prophylaxis of frequently recurring ventricularand prophylaxis of frequently recurring ventricularfibrillation and hemodynamically unstable ventricular fibrillation and hemodynamically unstable ventricular

tachycardia in patients refractory to other therapytachycardia in patients refractory to other therapy

Please see accompanying Prescribing Information.Please see accompanying Prescribing Information.

Data from: Cordarone I.V. Prescribing Information.Data from: Cordarone I.V. Prescribing Information.

• Cordarone I.V. is contraindicated in patients with cardiogenic shock, marked 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 sinus bradycardia, and second- or third-degree AV block in the absence of a functioning pacemaker.functioning pacemaker.

• Cordarone I.V. should be administered only by physicians who are experienced in 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 the treatment of life-threatening arrhythmias, who are thoroughly familiar with the risks and benefits of Cordarone therapy, and who have access to facilities risks and benefits of Cordarone therapy, and who have access to facilities adequate for monitoring the effectiveness and side effects of treatment.adequate for monitoring the effectiveness and side effects of treatment.

• Hypotension is the most common adverse effect seen with Cordarone I.V. and 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 may be related to the rate of infusion. Hypotension should be treated by slowing the infusion or with standard therapy: vasopressor drugs, positive inotropic the infusion or with standard therapy: vasopressor drugs, positive inotropic agents, and volume expansion.agents, and volume expansion.

• In clinical trials, the most important treatment-emergent adverse events were In clinical trials, the most important treatment-emergent adverse events were hypotension (15.6%), bradycardia (4.9%), liver function test abnormalities (3.4%), 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 cardiac arrest (2.9%), VT (2.4%), congestive heart failure (2.1%), cardiogenic shock (1.3%), and AV block (0.5%).shock (1.3%), and AV block (0.5%).

Please see accompanying Prescribing Information.Please see accompanying Prescribing Information.

Data from: Cordarone I.V. Prescribing Information; Data on file, Wyeth-Ayerst Laboratories.Data from: Cordarone I.V. Prescribing Information; Data on file, Wyeth-Ayerst Laboratories.


Amiodarone I.V. Amiodarone I.V. (Cordarone(Cordarone

®® I.V.) I.V.)

• Cordarone I.V. is contraindicated in patients with cardiogenic shock, Cordarone I.V. is contraindicated in patients with cardiogenic shock, marked sinus bradycardia, and second- or third-degree AV block in the marked sinus bradycardia, and second- or third-degree AV block in the absence of a functioning pacemaker.absence of a functioning pacemaker.

• Cordarone I.V. should be administered only by physicians who are Cordarone I.V. should be administered only by physicians who are experienced in the treatment of life-threatening arrhythmias, who are experienced in the treatment of life-threatening arrhythmias, who are thoroughly familiar with the risks and benefits of Cordarone therapy, and thoroughly familiar with the risks and benefits of Cordarone therapy, and who have access to facilities adequate for monitoring the effectiveness and who have access to facilities adequate for monitoring the effectiveness and side effects of treatment.side effects of treatment.

• Hypotension is the most common adverse effect seen with Cordarone I.V. 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 and may be related to the rate of infusion. Hypotension should be treated by slowing the infusion or with standard therapy: vasopressor drugs, by slowing the infusion or with standard therapy: vasopressor drugs, positive inotropic agents, and volume expansion.positive inotropic agents, and volume expansion.

• In clinical trials, the most important treatment-emergent adverse effects In clinical trials, the most important treatment-emergent adverse effects were hypotension (15.6%), bradycardia (4.9%), liver function test were hypotension (15.6%), bradycardia (4.9%), liver function test abnormalities (3.4%), cardiac arrest (2.9%), VT (2.4%), congestive heart abnormalities (3.4%), cardiac arrest (2.9%), VT (2.4%), congestive heart failure (2.1%), cardiogenic shock (1.3%),failure (2.1%), cardiogenic shock (1.3%), and AV block (0.5%).and AV block (0.5%).

Data from: Cordarone I.V.Data from: Cordarone I.V. Prescribing Information; Data on file, Prescribing Information; Data on file, Wyeth-Ayerst Laboratories.Wyeth-Ayerst Laboratories.


IndicationIndication

Cordarone I.V. is indicated for initiation of treatment Cordarone I.V. is indicated for initiation of treatment

and prophylaxis of frequently recurring ventricular and prophylaxis of frequently recurring ventricular

fibrillation and hemodynamically unstable fibrillation and hemodynamically unstable

ventricular tachycardia in patients refractory to ventricular tachycardia in patients refractory to

other therapy.other therapy.


Suppresses Highly Malignant Suppresses Highly Malignant Ventricular Arrhythmias in Patients Ventricular Arrhythmias in Patients

with Severe Underlying Heart Diseasewith Severe Underlying Heart Disease

In clinical studies, IV amiodarone:

• Decreased median number of life-threatening Decreased median number of life-threatening events by 71%events by 71%

• Increased median time to first event to 13.7 hoursIncreased median time to first event to 13.7 hours

• 85% of patients in controlled studies survived the critical first 24 85% of patients in controlled studies survived the critical first 24 hours; without a placebo comparison, a mortality benefit could not be hours; without a placebo comparison, a mortality benefit could not be establishedestablished

• Patients should be monitored carefully for QTc prolongation during Patients should be monitored carefully for QTc prolongation during infusion; <2% incidence of proarrhythmiainfusion; <2% incidence of proarrhythmia

Data from: Kowey PR et al. Data from: Kowey PR et al. CirculationCirculation. 1995;92:3255–3263; Scheinman MM et al. . 1995;92:3255–3263; Scheinman MM et al. CirculationCirculation. 1995;92:3264–3272; Data on file, Wyeth-Ayerst Laboratories.. 1995;92:3264–3272; Data on file, Wyeth-Ayerst Laboratories.

Reduction of VF/VT Events Reduction of VF/VT Events During Double-Blind TherapyDuring Double-Blind Therapy

• The 125-mg dose group was used as a control group.The 125-mg dose group was used as a control group.

• Due to administration of supplemental infusions, the 1,000-mg dose group actually 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 1,185 mg/24 hours compared with the 125-mg dose group, which actually received 428 mg/24 hours.received 428 mg/24 hours.

Reprinted with permission. Reprinted with permission. Circulation. Circulation. Copyright 1995 American Heart Association.Copyright 1995 American Heart Association.Data from: Scheinman MM et al. Data from: Scheinman MM et al. CirculationCirculation. 1995;92:3264–3272; . 1995;92:3264–3272; Data on file, Wyeth-Ayerst Laboratories.Data on file, Wyeth-Ayerst Laboratories.

0.00

0.05

0.10

125 mg 500 mg 1,000 mg

0.070.07

0.020.02

P P = 0.067= 0.06771%71%

ReductionReduction

Eve

nts

/hr

(med

ian

)E

ven

ts/h

r (m

edia

n)

0.040.04

IV Amiodarone Dosing (mg/24 Hours)IV Amiodarone Dosing (mg/24 Hours)

1,000 mg 125 mg Difference frombaseline

Reduction from BaselineReduction from Baselinein VF/VT Eventsin VF/VT Events

No significant difference was observed between the 1,000-mg dose 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 groupsand the 500-mg dose or the 125-mg dose and the 500-mg dose groups

4.04.0

0.480.48

3.03.0

1.681.68

3.523.52(88% reduction)(88% reduction)

1.321.32(44% reduction)(44% reduction)

P = 0.0425

Med

ian

VF

/VT

Eve

nts

Med

ian

VF

/VT

Eve

nts

per

24

Ho

urs

per

24

Ho

urs

Reprinted with permission. Reprinted with permission. Circulation. Circulation. Copyright 1995 American Heart Association.Copyright 1995 American Heart Association.Data from: Scheinman MM et al. Data from: Scheinman MM et al. CirculationCirculation. 1995;92:3264–3272.. 1995;92:3264–3272.

IV amiodarone 1,000 mgIV amiodarone 1,000 mg

BaselineBaseline

IV amiodarone 125 mgIV amiodarone 125 mg

Clinically Manageable Safety ProfileClinically Manageable Safety Profile

~9% Overall discontinuation rate due to ~9% Overall discontinuation rate due to adverse events adverse events

<2% Incidence of proarrhythmia<2% Incidence of proarrhythmia

<1% Discontinuation due to CNS side effects<1% Discontinuation due to CNS side effects

Hypotension is the most common adverse effect seen with CordaroneHypotension is the most common adverse effect seen with Cordarone®® I.V. I.V. (amiodarone HCI) and may be related to the rate of infusion. Hypotension (amiodarone HCI) and may be related to the rate of infusion. Hypotension should be treated by slowing the infusion or with standard therapy: should be treated by slowing the infusion or with standard therapy: vasopressor drugs, positive inotropic agents, and volume expansion.vasopressor drugs, positive inotropic agents, and volume expansion.

Data from: Cordarone I.V. Prescribing Information; Data on file, Wyeth-Ayerst Data from: Cordarone I.V. Prescribing Information; Data on file, Wyeth-Ayerst Laboratories.Laboratories.

Most Important Treatment-Emergent, Most Important Treatment-Emergent, Drug-RelatedDrug-Related

Adverse Events (n=1,836)Adverse Events (n=1,836) % Requiring% Requiring permanent permanent

EventEvent % Incidence % Incidence discontinuationdiscontinuation

HypotensionHypotension 15.6%15.6% 1.6%1.6%

BradycardiaBradycardia 4.9%4.9% <1%<1%

Liver function test abnormalitiesLiver function test abnormalities 3.4%3.4% <1%<1%

Cardiac arrestCardiac arrest 2.9%2.9% 1.2%1.2%

Ventricular tachycardiaVentricular tachycardia 2.4%2.4% 1.1%1.1%

Congestive heart failureCongestive heart failure 2.1%2.1% <1%<1%

Cardiogenic shockCardiogenic shock 1.3%1.3% 1.0%1.0%

AV blockAV block 0.5%0.5% <1% <1%

Data from: CordaroneData from: Cordarone®® I.V (amiodarone HCl) Prescribing Information; Data on file, I.V (amiodarone HCl) Prescribing Information; Data on file, Wyeth-Ayerst Laboratories.Wyeth-Ayerst Laboratories.

IV amiodarone IV amiodarone 1,000 mg1,000 mg(n = 105)(n = 105)

Cardiovascular eventsCardiovascular eventsHypotensionHypotension 3333 (32)(32) 2121 (20)(20) 1717 (18)(18)Heart blockHeart block 44 (4) (4) 00 (0)(0) 22 (2)(2)CHFCHF 55 (5)(5) 00 (0)(0) 00 (0)(0)ProarrhythmiaProarrhythmia 33 (3)(3) 00 (0)(0) 11 (1)(1)Nodal rhythmNodal rhythm 00 (0)(0) 33 (3)(3) 00 (0)(0)PhlebitisPhlebitis 00 (0)(0) 33 (3)(3) 00 (0)(0)

Other eventsOther events NauseaNausea 66 (6)(6) 22 (2)(2) 22 (2)(2)ConfusionConfusion 44 (4)(4) 33 (3)(3) 33 (3)(3)ThrombocytopeniaThrombocytopenia 33 (3)(3) 11 (1)(1) 11 (1)(1)FeverFever 11 (1)(1) 22 (2)(2) 11 (1)(1)DiarrheaDiarrhea 55 (5)(5) 00 (0)(0) 00 (0)(0)

Fewer Drug-Related Adverse Fewer Drug-Related Adverse Events than BretyliumEvents than Bretylium

EventEvent

Treatment GroupTreatment Group

BretyliumBretylium(n = 103)(n = 103)

IV amiodaroneIV amiodarone125 mg125 mg(n = 94)(n = 94)

Values shown are n (%).Values shown are n (%).

Reprinted with permission. Reprinted with permission. Circulation. Circulation. Copyright 1995 American Heart Association.Copyright 1995 American Heart Association.Data from: Kowey PR et al. Data from: Kowey PR et al. CirculationCirculation. 1995;92:3255-3263.. 1995;92:3255-3263.

Antiarrhythmic effects are seen in minutesAntiarrhythmic effects are seen in minutes

Hypotension is the most common adverse Hypotension is the most common adverse effect seen with Cordaroneeffect seen with Cordarone®® I.V. (amiodarone I.V. (amiodarone

HCI) and may be related to the rate of infusion.HCI) and may be related to the rate of infusion.

Data from:Data from: Kadish A, Morady F. Kadish A, Morady F. Prog Cardiovasc DisProg Cardiovasc Dis. 1989;31:281–294; Helmy I et . 1989;31:281–294; Helmy I et al. al. J Am Coll CardiolJ Am Coll Cardiol. 1988;12:1015–1022; Holt P et al. . 1988;12:1015–1022; Holt P et al. Am J Cardiol. Am J Cardiol. 1982;49:1001. 1982;49:1001. Abstract; Benamin R et al. Abstract; Benamin R et al. Arch Mal Coeur. Arch Mal Coeur. 1976;69:513–522.1976;69:513–522.

Rapid Onset of ActionRapid Onset of Action

The Only IV Antiarrhythmic with All The Only IV Antiarrhythmic with All Four Vaughan Williams’ Class EffectsFour Vaughan Williams’ Class Effects

Class I effectClass I effectSodium channel blockadeSodium channel blockade

Class II effectClass II effectNoncompetitive alpha- and Noncompetitive alpha- and beta-adrenergic inhibitionbeta-adrenergic inhibition

Class III effectClass III effectProlongation of repolarization Prolongation of repolarization and refractoriness by increased and refractoriness by increased action potential durationaction potential duration

Class IV effectClass IV effectCalcium channel blockadeCalcium channel blockade

NaNa++

NaNa++NaNa++

NaNa++

NaNa++

NaNa++

NaNa++NaNa++

CaCa++++

CaCa++++

CaCa++++

CaCa++++

CaCa++++

CaCa++++CaCa++++

CaCa++++

Data from: Siddoway LA. Pharmacologic principles of antiarrhythmic drugs. In: Podrid Data from: Siddoway LA. Pharmacologic principles of antiarrhythmic drugs. In: Podrid PJ, Kowey PR, eds. PJ, Kowey PR, eds. Cardiac Arrhythmias: Mechanisms, Diagnosis, and Management.Cardiac Arrhythmias: Mechanisms, Diagnosis, and Management. Baltimore, MD: Williams & Wilkins; 1995:355-368.Baltimore, MD: Williams & Wilkins; 1995:355-368.

Guidelines for Dosing and Administration Guidelines for Dosing and Administration for VF and Hemodynamically Unstable VTfor VF and Hemodynamically Unstable VTFirst 24 HoursFirst 24 Hours

FirstFirst Rapid RapidAdd 150 mg (1 ampul) to 100 mL DAdd 150 mg (1 ampul) to 100 mL D55W; administer overW; administer over FIRST FIRST 10 minutes (15 mg/min)10 minutes (15 mg/min)

PVC,* glass,PVC,* glass,†† or polyolefin container or polyolefin container

Followed by Followed by SlowSlowAdd 900 mg (6 ampuls) to 500 mL DAdd 900 mg (6 ampuls) to 500 mL D55W; administer 33.3 mL/hr overW; administer 33.3 mL/hr over NEXT NEXT 6 hours (1 mg/min)6 hours (1 mg/min)

GlassGlass†† or polyolefin container or polyolefin container

Reduce to 0.5 mg/min; administer 16.6 mL/hr forReduce to 0.5 mg/min; administer 16.6 mL/hr for REMAINING REMAINING 18 hours18 hours

*<10% loss at 2 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 Use of evacuated glass containers for admixing Cordarone I.V. is not recommended, as incompatibility with a buffer in the container may cause precipitation.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 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. 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 Infusions for longer than 3 weeks have not been studied. Transition to oral therapy is recommended at the earliest possible time.time.

Loading InfusionsLoading Infusions

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.

Maintenance InfusionMaintenance Infusion‡‡

Supplemental Infusion*Supplemental Infusion*

Hypotension is the most common adverse effect seen withHypotension is the most common adverse effect seen withCordaroneCordarone®® I.V. (amiodarone HCl) and may be related to the I.V. (amiodarone HCl) and may be related to the rate of infusion.rate of infusion.

Must use volumetric pump when administering Must use volumetric pump when administering Cordarone I.V.; an in-line filter is recommended.Cordarone I.V.; an in-line filter is recommended.

Concentrations greater than 3 mg/mL in DConcentrations greater than 3 mg/mL in D55W have been W have been

associated with a high incidence of peripheral vein phlebitis.associated with a high incidence of peripheral vein phlebitis.

*For the management of breakthrough episodes of life-threatening VT or VF.*For the management of breakthrough episodes of life-threatening VT or VF. Alternatively, the rate of the maintenance infusion may be increased. Alternatively, the rate of the maintenance infusion may be increased.

††<10% loss at 2 hours.<10% loss at 2 hours.

‡‡Use of evacuated glass containers for admixing Cordarone I.V. is not recommended, Use of evacuated glass containers for admixing Cordarone I.V. is not recommended, as incompatibility with a buffer in the container may cause precipitation. as incompatibility with a buffer in the container may cause precipitation.


• Add 150 mg to 100 mL DAdd 150 mg to 100 mL D55W; administer over 10 minutes W; administer over 10 minutes

(15 mg/min); PVC,(15 mg/min); PVC,†† glass, glass,‡‡ or polyolefin container or polyolefin container

Supplemental InfusionSupplemental Infusion (Cont’d.)(Cont’d.)

CordaroneCordarone®® I.V. (amiodarone HCl) has been found to leach out I.V. (amiodarone HCl) has been found to leach out plasticizers, including DEHP, from intravenous tubing (including PVC plasticizers, including DEHP, from intravenous tubing (including PVC tubing). The degree of leaching increases when infusing Cordarone I.V. tubing). The degree of leaching increases when infusing Cordarone I.V. at higher concentrations and lower flow rates than provided in the at higher concentrations and lower flow rates than provided in the Dosage and Administration section of the Prescribing Information.Dosage and Administration section of the Prescribing Information.

Store ampuls in cartons until ready for use to protect from light.Store ampuls in cartons until ready for use to protect from light.

Prepared solutions should not be kept for more than 24 hours.Prepared solutions should not be kept for more than 24 hours.

For infusions longer than 1 hour, Cordarone I.V. concentrations should For infusions longer than 1 hour, Cordarone I.V. concentrations should not exceed 2 mg/mL unless a central venous catheter is used.not exceed 2 mg/mL unless a central venous catheter is used.

Data from: CordaroneData from: Cordarone I.V. Prescribing Information.I.V. Prescribing Information.

Y-Site Injection IncompatibilityY-Site Injection Incompatibility

AmiodaroneAmiodaroneDrugDrug VehicleVehicle ConcentrationConcentration CommentsComments

AminophyllineAminophylline DD55WW 4 mg/mL4 mg/mL PrecipitatePrecipitate

Cefamandole nafateCefamandole nafate DD55WW 4 mg/mL4 mg/mL PrecipitatePrecipitate

Cefazolin sodium Cefazolin sodium DD55WW 4 mg/mL4 mg/mL PrecipitatePrecipitate

Mezlocillin sodium Mezlocillin sodium DD55WW 4 mg/mL4 mg/mL PrecipitatePrecipitate

Heparin sodiumHeparin sodium DD55WW –– PrecipitatePrecipitate

Sodium bicarbonateSodium bicarbonate DD55WW 3 mg/mL3 mg/mL PrecipitatePrecipitate

Data from: CordaroneData from: Cordarone®® I.V. (amiodarone HCl) I.V. (amiodarone HCl) Prescribing Information.Prescribing Information.

SLIDE ANTHOLOGY: Clinical Studies and Perspectives in Cardiac Arrest Management The 2000 Advanced...

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