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Jerrold H Levy, MD Emory University School of Medicine Atlanta, Georgia

SLIDE ANTHOLOGY: Clinical Studies and Perspectives in Cardiac Arrest Management The 2000 A dvanced C ardiovascular L ife S upport Guidelines Amiodarone IV . Jerrold H Levy, MD Emory University School of Medicine Atlanta, Georgia. ACLS Background: Historical Perspectives. 2000

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Jerrold H Levy, MD Emory University School of Medicine Atlanta, Georgia

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  1. SLIDE ANTHOLOGY:Clinical Studies and Perspectives in Cardiac Arrest Management The 2000 Advanced Cardiovascular Life Support GuidelinesAmiodarone IV Jerrold H Levy, MD Emory University School of Medicine Atlanta, Georgia

  2. 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 1985 1983 1st, 2nd, & 3rd Conference on CPR 1966-1979 Data from: Circulation. 2000;102:1–2.

  3. 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.

  4. 2000 ACLS GuidelinesPrimary 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.

  5. 2000 ACLS Guidelines: Overall Goals Create valid, internationally accepted, resuscitation guidelines using scientific evidence Develop a document to explainthe 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.

  6. 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.

  7. Chain of Survival • Early access • Early CPR • Early defibrillation • Early advanced care Data from: Circulation. 2000;102:I-22–I-23.

  8. Philosophy: Evidence-Based Review • Systematically identify, evaluate,andappraise evidence to support proposed changes • Reviewall proposed changes for: • Scientific accuracy • Safety • Cost • Effectiveness • Teachability Data from: Circulation. 2000;102:1–3.

  9. 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.

  10. 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 recommendationby evidence Data from: Circulation. 2000;102:I-3.

  11. Sorting Studies by Level of Evidence Positive RCTs (P < 0.05) Level 1 Level 2 Neutral RCTs (NS) Prospective, nonrandomized, observational study with control group Level 3 Retrospective, nonrandomized, observational study with control group Level 4 Level 5 Case series compilation, no control group Animal/mechanical model; 6A – higher quality studies, 6B – less powerful design Level 6 Level 7 Reasonable extrapolations from data gathered for other purposes Level 8 Common sense; common practices before evidence-based guidelines Data from: Circulation. 2000;102:I-4. Abbreviation: RCT, randomized, controlled trial.

  12. Evaluating Quality of Evidence Sort studies by level Assess qualityof 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.

  13. Class I Excellent. Proven efficacy, safety, and usefulness Acceptable. Good evidence, safe, clinically useful; standard of care Acceptable. Fair evidence, safe, clinically useful; within standardof care Not recommended. Minimal evidence; preliminary research Not acceptable. May be harmful; not clinically useful Classes of Recommendation Class IIa Class IIb ClassIndeterminate Class III Data from: Circulation. 2000;102:I-5.

  14. 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) Summarizerationale for proposal Data from: Circulation. 2000;102:I-3–I-5.

  15. Placebo-Controlled Methodology • Without placebo controls, the value of antiarrhythmic agents in cardiac arrest due to VF/pulseless VT cannot be determined • Prospective, randomized, placebo-controlled trials provide objective evaluation of antiarrhythmic agents

  16. Evidence Evaluation Template Level 1 2 3 4 5 6 7 8 Excellent Good Fair Fair Good Excellent Supporting +/- orOpposing Level 1 2 3 4 5 6 7 8 Courtesy of Peter Kudenchuck.

  17. 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.

  18. Excellent Good Fair Fair Good Excellent Quality and Level of Evidence Analysis Lidocaine in Cardiac ArrestDue to VF/VT 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 Supporting 4, 9, 15,16, 17,21, 25 12 5 Current Practice 1 2 3 4 5 6 7 8 10 2, 3, 6,7, 8, 14,19, 22 Neutral/Opposing 13 18 23, 24 1, 20, 26 11 1 2 3 4 5 6 7 8

  19. 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)

  20. 1 2 3 4 5 6 7 8 Quality and Level of Evidence Analysis Amiodarone in Cardiac Arrest Due to VF/VT Author Year (n) Excellent Good Fair 9 8 1. AnastasiNana ’94 (16) 2. Drexler (14) 3. Fain ’87 (12) 4. Helmy ’88 (46) 5. Horowitz (5) 6. Kentsch ’88 (20) 7. Klein (13) 8. Kowey ’95 (228) 9. Kudenchuk ‘99 (504) 10. Levine ’96 (273) 11. Mooss (35) 12. Morady (15) 13. Nalos ’91 (22) 14. Ochi (22) 15. Rosalion ’91 (23) 16. Saksena (9) 17. Scheinman ’95 (342) 18. Schutzenberger ’89 (26) 19.Zhou ’98 (24) 1, 3 15 Supporting 2, 4, 5, 7, 11, 12, 13, 14, 16, 18 6 Fair Good Excellent 10 17 19 Neutral/Opposing 1 2 3 4 5 6 7 8

  21. 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)

  22. 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.

  23. 2000 ACLS Guidelines VF/Pulseless VT Treatment Algorithm

  24. Guidelines for Dosing and Administration for VF and Hemodynamically Unstable VT First 24 Hours First Rapid Add 150 mg (1 ampul) to 100 mL D5W; administer over FIRST 10 minutes (15 mg/min) 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 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. Loading 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 Infusion‡

  25. The 2000 ACLS Guidelines: Overview and Conclusion “Amiodarone is recommended after defibrillation and epinephrinein 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 arrestdue 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.

  26. 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.

  27. 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.

  28. 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.

  29. 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.

  30. 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.

  31. ARREST Study Algorithm VF or Pulseless VT Cardiac Arrest Shock x 3 Persistent or Recurrent VF/VT Stable Rhythm Asystole or PEA ETT IV EPI Excluded From Study Placebo IV amiodarone Study Drug ETT: endotracheal intubation IV: intravenous access established EPI: epinephrine PEA: pulseless electrical activity Standard ACLS Care Data from: Kudenchuk PJ et al. N Engl J Med. 1999;341:871-878.

  32. November 1994-February 1997Out-of-Hospital Cardiac Arrest (n=3,954) Ineligible/NotTreated(n=3,260) Ineligible/Treated(n=27) Met Study Criteria (n=667) Eligible/NotTreated(n=160) Eligible/Treated (n=507) Drug AssignmentUnknown (n=3) Study Group (n=504) Data from: Kudenchuk PJ et al. N Engl J Med. 1999;341:871–878.

  33. ARREST Patient Characteristics IV Amiodarone(n=246) Placebo(n=258) P Value Male 187 (76%) 203 (79%) NS Age (yr) 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 * Values shown are means ± SD. Data from: Kudenchuk PJ et al. N Engl J Med. 1999;341:871-878.

  34. Initial Cardiac Arrest Rhythm 83 83 % of Patients 12 11 5 4 Abbreviation: PEA, pulseless electrical activity. Data from:Kudenchuk PJ et al. N Engl J Med. 1999;341:871–878.

  35. Response/Treatment Times in Minutes IVAmiodarone 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.

  36. Resuscitation CharacteristicsBefore Study Drug IVAmiodarone(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.

  37. 197 211 91 69 63 36 246 258 153 145 153 145 Treatment After Study Drug P = 0.70 82 80 P = 0.04 59 P = 0.004 48 % of Patients 41 25 No. Receiving Drug Total No. * In patients with return of spontaneous circulation. Data from:Kudenchuk PJ et al. N Engl J Med. 1999;341:871-878.

  38. Admission to Hospital by Arrhythmia Characteristics Patients Surviving to Admission (%) No. Surviving 108 89 101 84 7 5 35 22 73 67 Total No. 246 258 205 216 41 42 55 53 191 205 Abbreviations: PEA, pulseless electrical activity; ROSC, return of spontaneous circulation. Data from:Kudenchuk PJ et al. N Engl J Med. 1999;341:871-878.

  39. 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.

  40. Amiodarone Versus Lidocaine In Pre-hospital Refractory Ventricular Fibrillation Evaluation A L I V E Data from:Dorian P et al. N Engl J Med. 2002;346:884-890. .

  41. 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.

  42. 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.

  43. 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.

  44. 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.

  45. 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 = VF persists or recurs Data from:Dorian P et al. N Engl J Med. 2002;346:884-890.

  46. ALIVE: Demographics Amiodarone* Lidocaine* Characteristic (n=180) (n=167) Age (yrs) 68 ± 14 66 ± 13 Male (%) 76 81 Weight (kg) 80 ± 16 82 ± 13 Hx heart disease (%) 61.1 59.3 Witnessed arrest (%) 76 79.3 Bystander CPR (%) 26.3 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.

  47. ALIVE: Baseline Characteristics Amiodarone* Lidocaine*Characteristic (n=180) (n=167) Initial rhythm (%): VF 77.8 79.0 Asystole 11.1 9.6 PEA 7.8 6.6 Last recorded rhythm before study drug administration (%): VF 88.9 91.0 VT 1.7 2.4 Asystole 1.1 1.2 PEA 5.0 3.0 SV 1.7 0.6Total no. shocks 5 ± 1.9† 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.

  48. Time Intervals From EMS Crew Dispatch Amiodarone* Lidocaine* Intervals* (n=180) (n=167) Time from dispatch toarrival at patient (min) 7.3 ± 2.7 7.5 ± 2.6 Time to first defibrillationshock (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.

  49. ALIVE: ResultsBefore Study Drug Amiodarone Lidocaine P Value Characteristic (n=180) (n=167) Number of shocks 5 ± 1.9* (4%) 5 ± 2.2* (4%) NS Transient spontaneouscirculation 24 (13.3%) 11 (6.6%) < 0.04 Treatment for bradycardia(atropine) 98 (54%) 96 (57%) NS Pressor treatment(dopamine) 2 (1%) 0 NS Antiarrhythmic drugtreatment (open label lidocaine) 4 (2%) 1 (1%) NS *Values shown are the means ± SD. Data from:Dorian P et al. N Engl J Med. 2002;346:884-890.

  50. ALIVE: ResultsAfter Study Drug Amiodarone Lidocaine P ValueCharacteristic (n=180) (n=167) Treatment for bradycardia(atropine) 43 (24%) 38 (23%) NS Pressor treatment(dopamine) 13 (7%) 6 (4%) NS Antiarrhythmic drugtreatment (open label lidocaine) 11 (6%) 10 (6%) NS Data from:Dorian P et al. N Engl J Med. 2002;346:884-890.

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