SHOCKING UPDATES IN ACUTE CARDIAC LIFE SUPPORT (ACLS)

SHOCKING UPDATES IN ACUTE CARDIAC LIFE SUPPORT (ACLS) Reagan Collins, PharmD, BCCCP Clinical Pharmacy Specialist in Critical Care and Nutrition Support The University of Texas MD Anderson Cancer Center

LEARNING OBJECTIVES Identify reversible causes of a cardiovascular emergency Examine ACLS algorithms in order to manage patients experiencing cardiovascular emergencies Select appropriate medications used to treat patients experiencing cardiovascular emergencies

INTRODUCTION Ischemic heart disease is the leading cause of death in the world Cardiac arrest definition: Sudden cessation of organized cardiac electrical activity with hemodynamic collapse Annually in the United States: 326,200 Out-of-hospital Cardiac Arrests (OHCA) 209,000 In-hospital Cardiac Arrests (IHCA) Data to support improving survival rates in cardiac arrest Hazinski MF, et al. Circulation. 2015; 132[suppl 1]: S1-S39.

IHCA/OHCA CHAIN OF SURVIVAL CAB CAB CAB: circulation, airway, breathing Hazinski MF, et al. Circulation. 2015; 132[suppl 1]: S1-S39.

ADULT BASIC LIFE SUPPORT (BLS) Early, High-Quality Cardiopulmonary resuscitation (CPR)* Compression rate: 100 120 compressions/minute Compression depth: 2 2.4 inches Full chest recoil Minimize interruptions in compressions Early defibrillation* Avoid excessive ventilation Compression to ventilation ratio No advanced airway: 30:2 Advanced airway: continuous compressions, 1 breath every 6 seconds Courtesy Wikimedia Commons. Accessed 3/13/2018. Hazinski MF, et al. Circulation. 2015; 132[suppl 1]: S1-S39.

ADULT BASIC LIFE SUPPORT (BLS) Early, High-Quality Cardiopulmonary resuscitation (CPR)* Compression rate: 100 120 compressions/minute Compression depth: 2 2.4 inches Full chest recoil Minimize interruptions in compressions Early defibrillation* Avoid excessive ventilation Compression to ventilation ratio No advanced airway: 30:2 *Quality of CPR and timely defibrillation improve survival Advanced airway: continuous compressions, 1 breath every 6 seconds Courtesy Wikimedia Commons. Accessed 3/13/2018. Hazinski MF, et al. Circulation. 2015; 132[suppl 1]: S1-S39.

REVERSIBLE CAUSES OF CARDIAC ARREST H s T s Hypoxia Hydrogen ions (acidosis) Hypo- / Hyperkalemia Hypovolemia Hypothermia Trauma Toxins Thrombosis (cardiac/pulmonary) Tamponade (cardiac) Tension pneumothorax Hazinski MF, et al. Circulation. 2015; 132[suppl 1]: S1-S39.

Link MS, et al. Circulation. 2015; 132[18 suppl 2]: S444 64.

CURRENT ALGORITHMS FOR ACLS Shockable rhythm Ventricular fibrillation (VF) Courtesy Wikimedia Commons. Accessed 3/13/2018. Pulseless ventricular tachycardia (pvt) Courtesy Wikimedia Commons. Accessed 3/13/2018. Link MS, et al. Circulation. 2015; 132[18 suppl 2]: S444 64.

VF/pVT IV: intravenous, IO: intraosseous, mg: milligram Link MS, et al. Circulation. 2015; 132[18 suppl 2]: S444 64.

CURRENT ALGORITHMS FOR ACLS Non-shockable rhythms Pulseless electrical activity (PEA) Asystole Courtesy Wikimedia Commons. Accessed 3/13/2018. Courtesy Wikimedia Commons. Accessed 3/13/2018. Link MS, et al. Circulation. 2015; 132[18 suppl 2]: S444 64.

PEA / Asystole IV: intravenous, IO: intraosseous, mg: milligram Link MS, et al. Circulation. 2015; 132[18 suppl 2]: S444 64.

Since we are pharmacists, let s focus on pharmacology. Courtesy Wikimedia Commons. Accessed 3/13/2018.

2015 AHA GUIDELINES UPDATE FOR CPR AND ECC: PHARMACOLOGIC THERAPY Vasopressors Epinephrine Vasopressin Antiarrhythmics Amiodarone Lidocaine Magnesium Atropine Beta-blockers Corticosteroids Fibronolytic therapy Sodium bicarbonate Calcium Naloxone Intravenous Lipid Emulsion Goal of pharmacologic therapy: facilitate restoration and maintenance of a perfusing spontaneous rhythm AHA: American Heart Association, ECC: Emergency Cardiovascular Care Link MS, et al. Circulation. 2015; 132[18 suppl 2]: S444 64.

GRADING OF RECOMMENDATIONS Class (strength) of Recommendation I: Strong (benefit >>> risk) IIa: Moderate (benefit >> risk) IIb: Weak (benefit risk) III: No benefit (benefit = risk) III: Harm (risk > benefit) Level of Evidence A High QOE from 1 RCTs, metaanalyses, etc. B-R Moderate QOE from 1 RCTs, metaanalyses, etc. B-NR Moderate QOE of nonrandomized studies C-LD Limited data C-EO Consensus of expert opinion QOE: quality of evidence, RCT: randomized controlled trial Morrison LJ, et al. Circulation. 2015; 132[suppl2]:S-368 82.

2015 GUIDELINE RECOMMENDATIONS: EPINEPHRINE Standard-dose epinephrine (1 mg every 3 5 minutes) may be reasonable for patients in cardiac arrest (Class IIb, LOE B-R) - Updated High-dose epinephrine is not recommended for routine use in cardiac arrest (Class III: No benefit, LOE B-R) New May be reasonable to administer epinephrine as soon as feasible after the onset of cardiac arrest due to an initial non-shockable rhythm (Class IIb, LOE C-LD) Updated Link MS, et al. Circulation. 2015; 132[18 suppl 2]: S444 64.

EPINEPHRINE IN CARDIAC ARREST MOA: alpha-, beta 1, beta 2 -adrenergic receptor agonist 2 Alpha-agonist: vasoconstriction 2 Increase coronary perfusion pressure Increase cerebral perfusion pressure Beta-agonist effects are controversial 2 Increase myocardial workload Two meta-analyses demonstrated epinephrine improved ROSC and survival to hospital admission vs. placebo 1,3 MOA: mechanism of action 1 Lin SL, et al. Resuscitation. 2014; 85: 732 40. 2 Link MS, et al. Circulation. 2015; 132[18 suppl 2]: S444 64. 3 Patanwala AE, et al. Minerva Anesthesiologica. 2014; 80(7): 831 43.

2015 GUIDELINE RECOMMENDATIONS: VASOPRESSIN Vasopressin offers no advantage as a substitute for epinephrine in cardiac arrest (Class IIb, LOE B-R) - Updated Vasopressin in combination with epinephrine offers no advantage as a substitute for standard-dose epinephrine in cardiac arrest (Class IIb, LOE B-R) - New Link MS, et al. Circulation. 2015; 132[18 suppl 2]: S444 64.

VASOPRESSIN IN CARDIAC ARREST MOA: V1a receptor agonist 3 Endogenous vasopressin levels have been demonstrated to be significantly higher in patients who survive a cardiac arrest 1 Maintains activity in acidotic environment 2 In a single-center retrospective analysis, vasopressin + epinephrine combination demonstrated improved ROSC in patients with arterial ph < 7.2 3 MOA: mechanism of action, ROSC: return of spontaneous circulation 1 Lindner KH et al. Anesthesiology. 1992;77(4):662 8. 2 Fox AW, et al. J Cardiovasc Pharmacol. 1992;20:282-9. 3 Turner DW, et al. Ann Pharmacother. 2014;48(8)L986 91.

WENZEL 2004 A Comparison of Vasopressin and Epinephrine for Out-of-Hospital CPR Design Prospective, double-blind, MCT, RCT Aim Evaluate difference in rates of survival to hospital admission and discharge with use of epinephrine vs. vasopressin in OHCA Population N = 1186 OHCA (VF, PEA, or asystole) Initial rhythm: > 40% asystole in both groups Intervention Epinephrine 1 mg IV every 3 min x 2 (n = 597) Vasopressin 40 international units IV every 3 min x 2 (n = 589) + epinephrine 1 mg IV at discretion of MD after first 2 doses Median time to 1st dose: ~9-10 min Outcomes 1 - survival to hospital discharge IV: intravenous, MCT: multicenter, mg: milligram, min: minute(s), RCT: randomized, controlled trial Wenzel V, et al. N Engl J Med. 2004; 250(2): 105 13.

RESULTS Variable Vasopressin (n = 589) No./total no. (%) Epinephrine (n = 597) No./total no. (%) p-value ROSC 145/589 (24.6) 167/597 (28) 0.19 Survival to admission 214/589 (36.3) 186/597 (31.2) 0.06 Survival to discharge - 1 57/578 (9.9) 58/588 (9.9) 0.99 VF hospital discharge 39/219 (17.8) 47.245 (19.2) 0.7 PEA hospital discharge 6/102 (5.9) 7/81 (8.6) 0.47 Asystole hospital discharge 12/257 (4.7) 4/262 (1.5) 0.04 CPC Score of 1 15/46 (32.6) 16/46 (34.8) 0.99 CPC: cerebral performance category score, ROSC: return of spontaneous circulation Wenzel V, et al. N Engl J Med. 2004; 250(2): 105 13.

Data on Patients Who Received Additional Treatment with Epinephrine RESULTS Variable Vasopressin (n = 373) No./total no. (%) Epinephrine (n = 359) No./total no. (%) p-value ROSC 137/373 (36.7) 93/359 (25.9) 0.002 Survival to admission 96/373 (25.7) 59/359 (16.4) 0.002 Survival to discharge 23/369 (6.2) 6/355 (1.7) 0.002 Rate of survival to hospital discharge was improved by: Amiodarone treatment: OR 2.1 (95% CI 1.5 2.9) Fibrinolysis: OR 1.7 (95% CI 1.1 2.6) CI: confidence interval, OR: odds ratio, ROSC: return of spontaneous circulation Wenzel V, et al. N Engl J Med. 2004; 250(2): 105 13.

Data on Patients Who Received Additional Treatment with Epinephrine RESULTS Variable Vasopressin (n = 373) No./total no. (%) Limitations: Epinephrine (n = 359) No./total no. (%) No difference in use of vasopressin or epinephrine on Rate of survival to hospital discharge was improved by: survival to hospital discharge with presenting rhythm Amiodarone of treatment: VF/PEA, OR but 2.1 vasopressin (95% CI 1.5 is 2.9) superior to epinephrine Fibrinolysis: in OR asystole 1.7 (95% CI 1.1 2.6) p-value ROSC 137/373 (36.7) 93/359 (25.9) 0.002 Sample size (Type II error) Overall survival Survival to admission 96/373 (25.7) 59/359 (16.4) 0.002 Survival to discharge 23/369 (6.2) 6/355 (1.7) 0.002 Conclusion: CI: confidence interval, OR: odds ratio, ROSC: return of spontaneous circulation Wenzel V, et al. N Engl J Med. 2004; 250(2): 105 13.

GUEUGNIAUD 2008 Vasopressin and Epinephrine vs. Epinephrine Alone in CPR Design Prospective, double-blind, MCT, RCT Aim Test whether combination of vasopressin and epinephrine is superior to epinephrine alone for OHCA Population N = 2894 OHCA (VF, PEA, or asystole) Initial rhythm: > 80% asystole in both groups Intervention Epinephrine 1 mg IV every 3 min x 2 (n = 1452) Epinephrine 1 mg IV + Vasopressin 40 international units IV every 3 min x 2 (n = 1442) + epinephrine 1 mg IV at discretion of MD after first 2 doses Outcomes Median time to 1st dose: ~21-22 min 1 - survival to hospital admission IV: intravenous, MCT: multicenter, mg: milligram, min: minute(s), RCT, randomized, controlled trial Gueugniaud P, et al. N Engl J Med. 2008;359(1): 21 30.

RESULTS Variable Combination therapy (n = 1442) Epinephrine (n = 1452) p-value ROSC no. (%) 413 (28.6) 428 (29.5) 0.62 Hospital admission no. (%) 299 (20.7) 310 (21.3) 0.69 Hospital discharge no./total no. (%) 24/1439 (1.7) 33/1448 (2.3) 0.24 CPC Score of 1 no./total no. (%) 9/24 (37.5) 17/33 (51.5) 0.29 Post-hoc subgroup analysis: Survival to hospital discharge in PEA favored epinephrine alone group: OR 1.06 (95% CI 1.02 1.11) CI: confidence interval, CPC: cerebral performance category, OR: odds ratio, ROSC: return of spontaneous circulation Gueugniaud P, et al. N Engl J Med. 2008;359(1): 21 30.

RESULTS Variable Combination therapy (n = 1442) Epinephrine (n = 1452) p-value ROSC no. (%) 413 (28.6) 428 (29.5) 0.62 Limitations Overall survival Time to first drug Hospital admission no. (%) 299 (20.7) 310 (21.3) 0.69 Hospital discharge no./total no. (%) 24/1439 (1.7) 33/1448 (2.3) 0.24 CPC Score of 1 no./total no. (%) 9/24 (37.5) 17/33 (51.5) 0.29 Conclusion: The combination of vasopressin + epinephrine vs. epinephrine alone did not improve outcomes in OHCA Post-hoc subgroup analysis: Survival to hospital discharge in PEA favored epinephrine alone group: OR 1.06 (95% CI 1.02 1.11) CI: confidence interval, CPC: cerebral performance category, OR: odds ratio, ROSC: return of spontaneous circulation Gueugniaud P, et al. N Engl J Med. 2008;359(1): 21 30.

ZHANG 2O17 ROSC Question Efficacy of vasopressin + epinephrine to epinephrine alone in OHCA Search Study Selection PubMed, EMBASE, Cochrane Library, Wanfang February 2017 9 RCTs of 5047 patients Study Quality Outcomes Cochrane risk of bias tools ROSC v Epinephrine Combination RCT: randomized, controlled trials, ROSC: return of spontaneous circulation Zhang Q, et al. Am J of Emer Med. 2017; 35: 1555 60.

Question Efficacy of vasopressin + epinephrine to epinephrine alone in OHCA Search Study Selection PubMed, EMBASE, Cochrane Library, Wanfang February 2017 9 RCTs of 5047 patients ZHANG 2O17 Limitations Sample size Poor methodological quality Clinical heterogeneity Lack of confounder evaluation Lack of clinical outcomes Conclusion: ROSC Study Quality Outcomes Cochrane risk of bias tools ROSC Current evidence is insufficient to support the efficacy of vasopressin + epinephrine vs. epinephrine v alone to obtain ROSC Epinephrine Combination RCT: randomized, controlled trials, ROSC: return of spontaneous circulation Zhang Q, et al. Am J of Emer Med. 2017; 35: 1555 60.

IV: intravenous, IO: intraosseous, mg: milligram Link MS, et al. Circulation. 2015; 132[18 suppl 2]: S444 64.

2015 UPDATED GUIDELINE RECOMMENDATIONS: ANTIARRHYTHMICS Amiodarone may be considered for VF/pVT that is unresponsive to CPR, defibrillation, and vasopressor therapy (Class IIb, LOE B-R) Lidocaine may be considered as an alternative to amiodarone for VF/pVT that is unresponsive to CPR, defibrillation, and vasopressor therapy (Class IIb, LOE C-LD) Link MS, et al. Circulation. 2015; 132[18 suppl 2]: S444 64.

ANTIARRHYTHMICS IN CARDIAC ARREST Lidocaine Class Ib antiarrhythmic 1 Amiodarone Class III antiarrhythmic 1 Lidocaine Dosing 2-4 : 1-1.5 mg/kg IV/IO, followed by 0.5 0.75 mg/kg Amiodarone Dosing 3 : 300 mg IV/IO x 1 followed by 150 mg IV/IO x 1 120 mg IV/IO x 1 followed by 60 mg IV/IO x 1 IV: intravenous, IO: intraosseous, Kg: kilogram, mg: milligram 1 Kowey PR. Arch Intern Med. 1998; 158:325 32. Courtesy Wikimedia Commons. Accessed 3/12/18. 2 Kudenchuk P, et al. N Engl J Med. 2016; 374(18): 1711 22. 3 Link MS, et al. Circulation. 2015; 132[18 suppl 2]: S444 64. 4 Lidocaine. Lexi-drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL. Available at: http://online.lexi.com. Accessed March 15, 2018.

VF/pVT IV: intravenous, IO: intraosseous, mg: milligram Link MS, et al. Circulation. 2015; 132[18 suppl 2]: S444 64.

ALIVE TRIAL 50 45 40 Percentage of Patients 35 30 25 20 15 10 5 P = 0.009 P = 0.03 24.8 22.8 14.2 12 P = 0.34 5 3 23.9 P = NS 22.8 0 Survival to Hospital Admission Survival to Hospital Admission - Initial Rhythm VF Survival to Hospital Discharge Results Amiodarone (n = 180) Lidocaine (n = 167) Treatment for bradycardia NS: not significant Dorian PD, et al. New Engl J Med. 2002; 346(12): 884 90.

Amiodarone, Lidocaine, or Placebo in OHCA ROC-ALPS TRIAL Design Prospective, double-blind, MCT, RCT Aim Population N = 3026 OHCA (VF, pvt) Evaluate difference in rates of survival to hospital discharge between amiodarone, lidocaine, or placebo after OHCA due to VF/pVT Intervention Amiodarone (n = 974) 300 mg IV x 1, followed by 150 mg IV x 1 if necessary Lidocaine (n = 993) 120 mg IV x 1, followed by 60 mg IV x 1 if necessary Placebo (n = 1059) Outcomes Median time to first dose: ~ 12 minutes (witnessed) vs. ~19 minutes (unwitnessed) 1 - survival to hospital discharge IV: intravenous, MCT: multicenter, mg: milligram, RCT, randomized, controlled trial Kudenchuk P, et al. N Engl J Med. 2016; 374(18): 1711 22.

RESULTS Outcome Amiodarone (n = 974) Lidocaine (n = 993) Placebo (n = 1059) p-value A vs. Pl L vs. Pl A vs. L ROSC, no. (%) 350 (35.9) 396 (39.9) 366 (34.6) 0.52 0.01 0.07 Survival to admission, no. (%) Survival to discharge - 1, no./total no. (%) 445 (45.7) 467 (47) 420 (39.7) 0.01 <0.001 0.55 237/970 (24.4) 233/985 (23.7) 222/1056 (21) 0.08 0.16 0.7 MRS 3, no./total no. (%) 182/967 (18.8) 172/984 (17.5) 175/1055 (16.6) 0.19 0.16 0.7 Temporary cardiac pacing w/i 24 hours, no. (%) 48 (4.9) 32 (3.2) 29 (2.7) Overall: 0.02 A: amiodarone, L: lidocaine, MRS: modified rankin scale, no.: number, Pl: placebo, ROSC: return of spontaneous circulation, w/i: within Kudenchuk P, et al. N Engl J Med. 2016; 374(18): 1711 22.

RESULTS Outcome Amiodarone (n = 974) Lidocaine (n = 993) Placebo (n = 1059) p-value A vs. Pl L vs. Pl A vs. L ROSC, no. (%) 350 (35.9) 396 (39.9) 366 (34.6) 0.52 0.01 0.07 Survival to admission, no. (%) Survival to discharge - 1, no./total no. (%) MRS 3, no./total no. (%) Limitations: Time to study drug Trial may have been underpowered Conclusion: 445 (45.7) 467 (47) 420 (39.7) 0.01 <0.001 0.55 237/970 (24.4) 233/985 (23.7) 222/1056 (21) 0.08 0.16 0.7 Neither amiodarone or lidocaine results in significantly higher rate of survival to hospital discharge versus placebo among OHCA with VF/pVT 182/967 (18.8) 172/984 (17.5) 175/1055 (16.6) 0.19 0.16 0.7 Temporary cardiac pacing w/i 24 hours, no. (%) 48 (4.9) 32 (3.2) 29 (2.7) Overall: 0.02 A: amiodarone, L: lidocaine, MRS: modified rankin scale, no.: number, Pl: placebo, ROSC: return of spontaneous circulation, w/i: within Kudenchuk P, et al. N Engl J Med. 2016; 374(18): 1711 22.

HUANG 2017 Design Aim Retrospective, observational, Taiwanese nationwide populationbased cohort study Evaluate the impact of amiodarone and lidocaine in patients sent to the EC for OHCA Population N = 27,463 Greater than 60% male Pre-existing diseases include DM, HTN, CAD, HF Intervention Amiodarone + Lidocaine (n = 1487) Amiodarone only (n = 6459) Lidocaine only (n = 1077) Neither (n = 18,440) Outcome 1-year survival EC: emergency center, DM: diabetes mellitus, HTN: hypertension, CAD: coronary artery disease, HF: heart failure Huang C, et al. Int J of Cariol. 2017; 227: 292 98.

Survival to ICU admission, no. (%) Both (n = 1487) RESULTS Amiodarone (n = 6459) Lidocaine (n = 1077) Neither (n = 18440) p-value 507 (34.1) 1755 (27.2) 275 (25.5) 2855 (15.5) <0.0001 Survival to discharge, no. (%) 197 (12.3) 616 (9.5) 90 (8.4) 611 (3.3) <0.0001 One-year survival, no. (%) 165 (11.1) 534 (8.27) 77 (7.15) 602 (3.3) <0.0001 Factors Related to One-year Survival Outcomes Medication use OR (95% CI) via multivariate analysis Both 2.18 (1.71 2.77) Amiodarone 1.84 (1.58 2.13) Lidocaine 1.88 (1.4 2.53) Neither 1 CI: confidence interval, ICU: intensive care unit, OR: odds ratio Huang C, et al. Int J of Cariol. 2017; 227: 292 98.

Survival to ICU admission, no. (%) Both (n = 1487) RESULTS Amiodarone (n = 6459) Lidocaine (n = 1077) Neither (n = 18440) p-value 507 (34.1) 1755 (27.2) 275 (25.5) 2855 (15.5) <0.0001 Limitations: Study design Pre-hospital information not available Lack of evaluation of long-term neurologic outcomes Survival to discharge, no. (%) 197 (12.3) 616 (9.5) 90 (8.4) 611 (3.3) <0.0001 One-year survival, no. (%) 165 (11.1) 534 (8.27) 77 (7.15) 602 (3.3) <0.0001 Conclusion: Factors Related to One-year Survival Outcomes Use of amiodarone, lidocaine, or both are associated with improved 1 year-survival rates Medication use OR (95% CI) via multivariate analysis Both 2.18 (1.71 2.77) Amiodarone 1.84 (1.58 2.13) Lidocaine 1.88 (1.4 2.53) Neither 1 CI: confidence interval, ICU: intensive care unit, OR: odds ratio Huang C, et al. Int J of Cariol. 2017; 227: 292 98.

KHAN 2017 Bayesian Network Meta-Analysis Aim Search Study Selection Assess the effectiveness of antiarrhythmic drugs in shock refractory ventricular arrhythmia in OHCA MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials through 2/2017 11 studies (7 RCTs, 2 prospective observational, 2 retrospective observational) of 5200 patients Study Quality 7 of 11 studies evaluated amiodarone/lidocaine/placebo (N = 4616) Cochrane bias risk assessment tool, Newcastle-Ottawa scale, PRISMA standards Outcomes Survival to hospital discharge PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses, RCT: randomized controlled trial Khan SU, et al. Heart & Lung. 2017;46: 417 24.

RESULTS Survival to Hospital Discharge CI: confidence interval, OR: odds ratio Khan SU, et al. Heart & Lung. 2017;46: 417 24.

RESULTS CONTINUED Traditional analysis on survival to hospital discharge: Amiodarone vs. lidocaine (OR, 1.04; 95% CI 0.85 1.26) Upon evaluation of lidocaine vs. amiodarone for survival to ROSC or survival to hospital admission, no differences noted Sensitivity analysis on RCTs for OHCA due to ventricular arrhythmia: Survival to hospital discharge: Lidocaine superior to amiodarone (OR, 3.01; 95% CI 1.6 4.3) and placebo CI: confidence interval, OR: odds ratio, RCT: randomized controlled trial Khan SU, et al. Heart & Lung. 2017;46: 417 24.

RESULTS CONTINUED Limitations: Heterogeneity in trials and patient populations Procedural variability Traditional analysis Evolution on of survival post-rosc to hospital care discharge: Amiodarone Lack vs. lidocaine of publication (OR, 1.04; bias 95% evaluation CI 0.85 1.26) Upon evaluation of lidocaine vs. amiodarone for survival to ROSC or survival to Conclusion: hospital admission, no differences noted Sensitivity analysis Lidocaine on RCTs is either for OHCA superior due or to ventricular at least equal arrhythmia: in efficacy Survival to hospital amiodarone discharge: for Lidocaine utilization superior in cardiac to amiodarone arrest (OR, 3.01; Revision 95% CI 1.6 of 4.3) guidelines and placebo are warranted regarding amiodarone, where lidocaine can be considered as a first line agent CI: confidence interval, OR: odds ratio, RCT: randomized controlled trial Khan SU, et al. Heart & Lung. 2017;46: 417 24.

MCLEOD 2017 Systematic Review and Network Meta-Analysis (NMA) Aim Search Study Selection Study Quality Assess the use of antiarrhythmic drugs for OHCA resuscitation MEDLINE (Ovid and PubMed), EMBASE, Cochrane Central Register of Controlled Trials, electronic bibliographic databases through 3/2017 8 RCTs of 4464 patients 5 of 8 studies evaluated amiodarone/lidocaine vs. other AAR/placebo (N = 4114) Cochrane Collaboration Tool, GRADE QOE assessment Outcomes ROSC at hospital arrival Survival to hospital admission Survival to hospital discharge Survival to hospital discharge with favorable neurologic status AAR: antiarrhythmic, QOE: quality of evidence, RCT: randomized controlled trial, ROSC: return of spontaneous circulation McLeod SL, et al. Resuscitation. 2017; 121: 90 7.

RESULTS ROSC* Survival to Admission* Survival to Discharge* Neurologically Intact Survival* Lidocaine vs. Placebo 1.15 (1.03 1.28) 1.18 (1.07 1.30) 1.11 (0.95 1.30) 1.05 (0.87 1.27) Amiodarone vs. Placebo 1.06 (0.95 1.18) 1.18 (1.08 1.30) 1.15 (0.99 1.34) 1.13 (0.95 1.36) Amiodarone vs. Lidocaine 0.92 (0.83 1.03) 1.00 (0.91 1.10) 1.04 (0.89 1.21) 1.08 (0.89 1.30) *data presented as NMA estimates odds ratio with 95% confidence interval, high grade quality of evidence ROSC: return of spontaneous circulation McLeod SL, et al. Resuscitation. 2017; 121: 90 7.

RESULTS Lidocaine vs. Placebo Amiodarone vs. Placebo Amiodarone vs. Lidocaine ROSC* 1.15 (1.03 1.28) 1.06 (0.95 1.18) Survival to Admission* Limitations: Trial data spanned over 3 decades Conclusion: 1.18 (1.07 1.30) 1.18 (1.08 1.30) Survival to Discharge* 1.11 (0.95 1.30) 1.15 (0.99 1.34) *data presented as NMA estimates odds ratio with 95% confidence interval, high grade quality of evidence ROSC: return of spontaneous circulation Neurologically Intact Survival* 1.05 (0.87 1.27) 1.13 (0.95 1.36) Amiodarone and lidocaine are associated with improved survival to hospital admission. However, no antiarrhythmic 0.92 improved 1.00 survival to hospital 1.04 discharge (0.83 1.03) (0.91 1.10) (0.89 1.21) or neurologic outcomes. 1.08 (0.89 1.30) McLeod SL, et al. Resuscitation. 2017; 121: 90 7.

SINCE 2015 Amiodarone vs. Lidocaine in OHCA (VF/pVT) ROSC Improved with lidocaine vs. placebo (1 RCT, 1 NMA) 2,4 Survival to hospital admission Improved with amiodarone and lidocaine vs. placebo (1 RCT, 1 NMA) 2,4 Survival to hospital discharge Lidocaine improved outcome over amiodarone and placebo (1 NMA) 1 Survival at 1 year Improved with amiodarone and lidocaine vs. placebo in one observational study 3 1 Khan SU, et al. Heart & Lung. 2017;46: 417 24. 2 McLeod SL, et al. Resuscitation. 2017; 121: 90 7. 3 Huang C, et al. Int J of Cariol. 2017; 227: 292 98. NMA: network meta-analysis, RCT: randomized, controlled trial, ROSC: return of spontaneous circulation 4 Kudenchuk P, et al. N Engl J Med. 2016; 374(18): 1711 22.

VF/pVT OR Lidocaine IV: intravenous, IO: intraosseous Link MS, et al. Circulation. 2015; 132[18 suppl 2]: S444 64.

2015 NEW GUIDELINE RECOMMENDATIONS: STEROIDS IHCA 3 The combination of intra-arrest vasopressin, epinephrine, and methylprednisolone and post-arrest hydrocortisone as described by Mentzelopoulos et al 2 may be considered; however, further studies are needed before recommending the routine use of this therapeutic strategy (Class IIb, LOE C-LD) OHCA 3 Use of steroids is of uncertain benefit (Class IIb, LOE C-LD) CIRCI Guideline Recommendation (2017) 1 Suggest use of corticosteroids in the setting of cardiac arrest (conditional recommendation, very low quality of evidence) CIRCI: Critical Illness-Related Corticosteroid Insufficiency 1 Pastores SM, et al. Crit Care Med. 2018; 46: 146 48. 2 Mentzelopoulos SD, et al. JAMA. 2013; (310)3: 270 79. 3 Link MS, et al. Circulation. 2015; 132[18 suppl 2]: S444 64.

HYPOTHESIS BEHIND THE USE OF STEROIDS Cardiac arrest is associated with lower cortisol levels during and after CPR 1,2 ROSC associated with 2 : Cytokine elevation Endotoxemia Adrenal insufficiency contributing to post-resuscitation shock Corticosteroids during and after CPR may 1-3 : Improve hemodynamics Attenuate post-resuscitation systemic inflammatory response Improve organ dysfunction ROSC: return of spontaneous circulation 1 Hekimian G, et al. Shock. 2004;22(2): 116 19. 2 Adrie C, et al. Curr Opin Crit Care. 2004; 10(3): 208-12. 3 Mentzelopoulos SD, et al. Arch Intern Med. 2009; 169(1): 15 20.

MENTZELOPOULOS 2013 Design Prospective, double-blind, MCT, RCT Aim Vasopressin, steroid, epinephrine (VSE) effect on neurologically favorable survival to hospital discharge in IHCA Population N = 268 All IHCA (> 60% asystole as presenting rhythm) Pre-existing diseases include HTN, CAD, DM Main cause of cardiac arrest: hypotension, hypoxia Intervention VSE (n = 130) Vasopressin 20 100 international units IV in addition to epinephrine 1 mg IV + methylprednisolone 40 mg IV x 1 during 1 CPR cycle Postresuscitation: hydrocortisone 300 mg IVCI daily 7 days Control (n = 138) Outcome ROSC for 20 minutes AND Survival to hospital discharge with favorable neurologic recovery CAD: coronary artery disease, CPR: cardiopulmonary resuscitation, DM: diabetes mellitus, HTN: hypertension, IV: intravenous, IVCI: intravenous continuous infusion, MCT: multicenter, RCT: randomized controlled trial Mentzelopoulos SD, et al. JAMA. 2013; (310)3: 270 79.

Mentzelopoulos SD, et al. Arch Intern Med. 2009; 169(1): 15 20.

RESULTS OR: 3.28 (95% CI 1.17 9.20) NNT = 11 OR: 3.74 (95% CI 1.20 1.62) CI: confidence interval, CPC: cerebral performance category, d: day(s), OR: odds ratio, NNT: number needed to treat Mentzelopoulos SD, et al. JAMA. 2013; (310)3: 270 79.

OR: 3.28 (95% CI 1.17 9.20) RESULTS Limitations: Feasibility of protocol replication Lack of extrapolation to OHCA Role of postresuscitation care on outcomes Low overall survival rates Conclusion: NNT = 11 OR: 3.74 (95% CI 1.20 1.62) VSE combination during CPR and stress-dose hydrocortisone in postresuscitation shock, compared to standard of care epinephrine/placebo, improved survival to hospital discharge with favorable neurologic status CI: confidence interval, CPC: cerebral performance category, d: day(s), OR: odds ratio, NNT: number needed to treat Mentzelopoulos SD, et al. JAMA. 2013; (310)3: 270 79.

VSE VSE IV: intravenous, IO: intraosseous Link MS, et al. Circulation. 2015; 132[18 suppl 2]: S444 64.

SHOULD GUIDELINES CHANGE? Vasopressor recommendations NO Antiarrhythmic recommendations CONSIDER Steroid Recommendations NO

KNOWLEDGE GAPS Vasopressors High-quality, adequately powered trials are needed to determine effectiveness of epinephrine vs. placebo prior to vasopressin Antiarrhythmics High-quality, adequately powered trials are needed to determine effectiveness on long-term outcomes of amiodarone vs. lidocaine Steroids 1-3 High-quality studies are needed to determine the effects of bundled treatment (VSE) or which aspect of bundled treatment is effective 1 Buddineni JP, et al. Crit Care. 2014; 18(308): 1 3. 2 Callaway CW, et al. Circulation. 2015; 132[suppl 1]: S84 145. 3 Rehnberg JV, et al. J of the Inten Care Society. 2015; 16(1): 77-9.

UPCOMING STUDIES Trial Comparison of the Effect of Vasopressin, Steroid, and Epinephrine Treatment in Patients with OHCA Sample Size 834 Prospective, double-blind, placebocontrolled, MCT, RCT, Design Intervention Primary Outcome 4 arms: Epi + PL Epi + Vaso Epi + MP 40 mg Epi + Vaso + MP Survival to hospital discharge with CPC of 1 or 2 CPC: cerebral performance category, Epi: epinephrine, MCT: multicenter, MP: methylprednisolone, OHCA: out-of-hospital cardiac arrest, PL: placebo, RCT: randomized controlled trial, Vaso: vasopressin Comparison of the Effect of Vasopressin, Steroid, and Epinephrine Treatment in Patients with Out-of-Hospital Cardiac Arrest. (2017). Retrieved from http://clinicaltrials.gov/ct2 (Identification No. NCT03317197).

SUMMARY In cardiac arrest, promptly identify reversible causes and treat appropriately High-quality CPR and early defibrillation are key for ROSC and survival Goal of pharmacologic therapy is to facilitate restoration and maintenance of a perfusing spontaneous rhythm Need high-quality, adequately powered RCTs for pharmacological therapy in ACLS algorithms to determine impact on long-term outcomes RCTs: randomized, controlled trials, ROSC: return of spontaneous circulation

POST-ASESSMENT QUESTIONS

You respond to a code on the floor and find a 65 yo F in pulseless ventricular tachycardia (pvt) arrest. The code team immediately provided defibrillation and began high-quality CPR. An advanced airway was placed. What is a potential cause of cardiac arrest that should be ruled out? Hypernatremia Hyperkalemia Hyperglycemia Hypervolemia F: female

You respond to a code on the floor and find a 65 yo F in pulseless ventricular tachycardia (pvt) arrest. The code team immediately provided defibrillation and began high-quality CPR. An advanced airway was placed. What is a potential cause of cardiac arrest that should be ruled out? Hypernatremia Hyperkalemia Hyperglycemia Hypervolemia F: female

You respond to a code in the Emergency Room where a patient presented with an OHCA and the last rhythm check on the cardiac monitor revealed PEA. High-quality CPR is underway and an advanced airway has been placed. Intravenous (IV) access has been obtained. The patient has already received epinephrine 1 mg IV x 1 three minutes ago. The code team leader asks your recommendations for the next medication to be administered. What is the most appropriate medication to administer next for PEA? Atropine 0.5 mg IV x 1 Vasopressin 40 international units IV x 1 Epinephrine 1mg IV x 1 + Vasopressin 40 international units IV x 1 Epinephrine 1 mg IV x 1

You respond to a code in the Emergency Room where a patient presented with an OHCA and the last rhythm check on the cardiac monitor revealed PEA. High-quality CPR is underway and an advanced airway has been placed. Intravenous (IV) access has been obtained. The patient has already received epinephrine 1 mg IV x 1 three minutes ago. The code team leader asks your recommendations for the next medication to be administered. What is the most appropriate medication to administer next for PEA? Atropine 0.5 mg IV x 1 Vasopressin 40 international units IV x 1 Epinephrine 1mg IV x 1 + Vasopressin 40 international units IV x 1 Epinephrine 1 mg IV x 1

PEA / Asystole IV: intravenous, IO: intraosseous, mg: milligram Link MS, et al. Circulation. 2015; 132[18 suppl 2]: S444 64.

A 72 yo M, who weighs 70 kg, develops Ventricular fibrillation (Vfib) cardiac arrest shortly after arrival to the Emergency Center. After 3 full rounds of CPR, 3 defibrillations, and epinephrine 1 mg IV x 1, what is the next most appropriate medication to prepare for administration: Amiodarone 300 mg IV x 1 Lidocaine 300 mg IV x 1 Amiodarone 150 mg IV x 1 Epinephrine 1 mg IV x 1 Kg: kilogram, M: male

A 72 yo M, who weighs 70 kg, develops Ventricular fibrillation (Vfib) cardiac arrest shortly after arrival to the Emergency Center. After 3 full rounds of CPR, 3 defibrillations, and epinephrine 1 mg IVP x 1, what is the next most appropriate medication to prepare for administration: Amiodarone 300 mg IV x 1 Lidocaine 300 mg IV x 1 Amiodarone 150 mg IV x 1 Epinephrine 1 mg IV x 1 Kg: kilogram, M: male

VF/pVT IV: intravenous, IO: intraosseous, mg: milligram Link MS, et al. Circulation. 2015; 132[18 suppl 2]: S444 64.