Sudden Cardiac Arrest- Focusing on the Unsolved Problems

Sudden Cardiac Arrest- Focusing on the Unsolved Problems Wen-Jone Chen MD, PhD, FESC Professor of Medicine, Department of Emergency Medicine, National Taiwan University, Taipei, Taiwan Superintendent, Lotung Poh-ai Hospital, Yilan, Taiwan

Outlines Current status of SCA Adrenaline for cardiac arrest Defibrillation for VF ECMO in refractory cardiac arrest Management of post-cardiac arrest syndrome Hypothermia and PCI Steroid, Erythropoitin, Cyclosporine, NO

Sudden Cardiac Death - A major public health problem 40~50% of CV death 7~8 million deaths annually in global data SCD Incidences USA Netherlands Greece Iceland Canada England Israel Circulation; 2012: 125: 1787-94 53 200/ 100,000/ year 92 97/ 100,000/ year 90/ 100,000/ year 56/ 100,000/ year 56/100,000/ year 51 88/ 100,000/ year 46/ 100,000/ year

Epidemiology of Sudden Cardiac Death in Asia Japan China Thailand Philippine Taiwan* 37 / 100,000 person-year 41 / 100,000 person-year 38 / 100,000 person-year 43 / 100,000 person-year 58 ~ 70 / 100,000 person-year Lower than those in the USA and Europe The proportion of MI is lower in Asia, and the Brugada syndrome is higher than Western countries. Circ J 2013; 77: 2419-31

Regional Variation in Out-of-Hospital Cardiac Arrest Incidence and Outcome JAMA 2008; 300: 1423-31

Out-of-Hospital Cardiac Arrest Incidence (/100,000 population-year) Taipei 2000 Taipei 2010 North America 2008 58 60 56 (40.3 ~86.7) Bystander rate (%) 8 21 25 ~ 40 VF rate (%) 12 10 22.8 (15.4 ~ 32.1) Total survival rate 3.9 7.6 7.9 (3.0 ~ 16.3) (%) VF survival rate (%) 19 25 21 (7.7 ~ 39.9) From Ma MH (unpublished data)

Summary Lower by-stander CPR rate and less VT/VF in our OHCA patients as compared to Western communities. For the past 10 years in Taipei City Registry Increasing by-standard CPR rate More frequent AED use Increased survival rate

Outcomes of In-hospital Resuscitation ROSC Survival to discharge McGrath 1987 14.6 % BRESUS 1992 45 % 21 % Huang 2002 67 % 17.5 % Peberdy 2003 44 % 17 % Nadkarni 2006 47 % 18 % Shih 2007 71 % 18 % Ann Emerg Med 1987;16:1365 Br Med J 1992;304:1347 Resuscitation 2002;53:265 Resuscitation 2003;58:297 JAMA 2006;295:50 Resuscitation 2007;72:394-403

Outcome of In-hospital CPR in NTUH N % Survival VT/VF 74 18 30% PEA 226 54 15% Asystole 121 29 17% Total 421 100% 18% Resuscitation 2002; 53: 265-70 Resuscitation; 2007: 72: 394-403

Trends in survival after in-hospital cardiac arrest. Get with Guidelines-Resuscitation Registry, 2000-2009, n=84,625 Initial rhythm 79.3% asystole or PEA 20.7% VT/VF NEJM 2012; 367: 1912-1920

Changing Incidence of Out-of-Hospital Ventricular Fibrillation, 1980-2000 VF declined by 56% JAMA 2002; 288: 3008-13

Trends in treated ventricular fibrillation out-of-hospital cardiac arrest: A 17-year population-based study VF Incidence ICD implantation 1985 1989 26.3 / 100,000 1990 1994 18.2 / 100,000 5.0 / 100,000 1995 1999 13.8 / 100,000 9.5 / 100,000 2000 2002 7.7 / 100,000 20.7 / 100,000 Heart Rhythm 2004; 3: 255-59

Non-shockable Rhythm is Increasing in OHCA Different resuscitation strategies? Defibrillation: not indicated Hypothermia: not effective? CAB instead of ABC: probable yes? Chest compression only:? PEA is the next focus of SCA research

Is Hypothermia After Cardiac Arrest Effective in Both Shockable and Nonshockable Patients? Circulation; 2011: 123: 877-86

Impact of Changes in Resuscitation Practice on Survival and Neurological Outcome After Out-of-Hospital Cardiac Arrest Resulting From Nonshockable Arrhythmias Circulation; 2012: 125: 1787-94

Adrenaline for Out-of-hospital Cardiac Arrest? (I) Observational studies JAMA 2012; 307:1161-68 BMJ 2013; 347: f6829

Adrenaline for Out-of-hospital Cardiac Arrest? (II) Randomized controlled studies: favorable(but non-significant) effects on improving long-term survival JAMA 2009; 302 : 2222-29

Adrenaline For Out-of-hospital Cardiac Arrest? (III) Randomized controlled studies: favorable(but non-significant) effects on improving long-term survival Resuscitation 2011; 82: 1138-43

Adrenaline (epinephrine) Dosing Period And Survival After In-hospital Cardiac Arrest: A Retrospective Review of Prospectively Collected Data Retrospective review of prospective collected data on in-hospital cardiac arrest, n=20,909 Conclusion: Less frequent average epinephrine dosing than recommended by consensus guideline was associated with improved survival. Resuscitation 2014; 85 : 350-358

Adrenaline for Sudden Cardiac Arrest The epinephrine (adrenaline) should be considered in ACLS guideline 2010 Eagerly awaits new RCT to provide more definite answer Less is more policy New inotropics for ACLS? Epinephrine, vasopressin & steroid Epinephrine + β-blocker Levosimendan

Vasopressin, Steroids, and Epinephrine and Neurologically Favorable Survival After In-Hospital Cardiac Arrest: A Randomized Clinical Trial Randomized, double-blind, placebo-controlled study, n=268 Vesopressin (20IU/CPR cycle)+epinephrine (1mg/ CPR cycle) vs. Epinephrine (1mg/ CPR cycle) for first CPR cycle, then methylprednisolone (40mg) vs. saline then hydrocortisone 300mg for shock vs. saline Survival to discharge with CPC score 1 or 2 13.9% vs. 5.1%, OR=3.28, P=0.02 JAMA 2013; 310: 270-79

Biphasic versus monophasic defibrillation in out-of-hospital cardiac arrest: a systematic review and meta-analysis VF termination after first shock ROSC Survival to discharge Am J Emerg Med 2013; 31: 1472-78

Quantitative Waveform Measures of VF Frequency measures Amplitude spectrum area (AMSA) Angular velocity (AC) Median slope (MS) Cardioversion output predictor (COP) Frequency ratio (FR) Fractal dimension based measures Scaling exponent (ScE) Logarithm of the absolute correlations (LAC) Detrended fluctuation analysis (DFA) Computer assisted waveform analysis to estimate probability of successful defibrillation

Detrended Fluctuation Analysis Predicts Successful Defibrillation for Outof-hospital Ventricular Fibrillation Cardiac Arrest Conclusion: DFA could help predict first-shock defibrillation success in patients with OHCA. The DFAα2 value is probably associated with the organization of VF structure and related to duration of ischemia. Resuscitation 2010; 81: 297-301

A new method to estimate the amplitude spectrum analysis of ventricular fibrillation during cardiopulmonary resuscitation The new algorithm could efficiently filter the CPR related artifact of the VF ECG and preserved the shockability index of the original VF waveform Resuscitation 2013; 84: 1505-11

Predicting defibrillation success in sudden cardiac arrest patients Future perspective: Multi-parameter classification algorithm which combines subsets of predictive features? J Electrocardiol 2013; 46: 473-79

Waveform Analysis Guided Treatment Versus a Standard Shock-First Protocol for the Treatment of Out-of-Hospital Cardiac Arrest Presenting in Ventricular Fibrillation: Results of an International Randomized, Controlled Trial AED study, biphasic, 150J, waveform analysis (n=487) vs. shock-first (n=500) Circulation 2013; 128:995-1002

Nature 2011;475:181-82

Nature 2011, 475:235-39

Terminating ventricular tachyarrhythmias using far-field lowvoltage stimuli: mechanisms and delivery protocols Stimuli applied at 16% or 88% of VT cycle length were most effective in cardioverting VT Stimuli given at 88% of VF cycle length defibrillated successfully. (0.58% of the defibrillation threshold energy for a single strong biphasic shock) Termination of VF using a novel 2-stage defibrillation Heart Rhythm 2013; 10: 1209-17

ECMO for Refractory Cardiac Arrest ECMO may improve outcomes after cardiac arrest, when compared with standard CPR, in case of cardiogenic shock and witnessed arrest, where there is an underlying circulatory disease amenable to immediate corrective interventions. ILCOR 2005 ECMO-CPR should be considered for in-hospital patients in cardiac arrest when the duration of the no-flow arrest is brief and the condition leading to cardiac arrest is reversible (eg. hypothermia or drug intoxication) or amenable to heart transplantation or revascularization. ACLS 2010

The Benefit of ECMO in CPR Chen YS et al, J Am Coll Cardiol. 2003; 41:197-203 Lancet 2008; 372: 554-561

ECMO for Refractory Cardiac Arrest (I) Results are heterogeneous Lack to randomized trial In-hospital vs. out-of-hospital cardiac arrest Duration of cardiac arrest is critical IHCA < 10 min 50% ROSC 10-20 min 25% ROSC > 30 min very few Lancet 2012; 380: 1473-81 OHCA > 15 min < 2% With good neurological outcome Circulation 2013; 128: 2438-94

ECMO for Refractory Cardiac Arrest (II) Selection of candidates for ECMO-CPR seeming to be crucial Intra-arrest PCI vs. delayed PCI 30 day survival 36% vs. 12% Circulation 2012; 126:1605-13 Brain protection and prevention of the post-resuscitation syndrome, eg. hypothermia. Resuscitation 2013; 84:1519-24 Pharmacological intervention to mitigate ischemia/reperfusion injury

What happened after successful resuscitation? Live Happily Ever After 72% died in the hospital in Ontario (Canada) 68% died within 30 days in Goteborg (Sweden) 65% died within 30 days in Rochester (USA) The majority of cardiac arrest patients die after successful resuscitation

Association Between Arterial Hyperoxia Following Resuscitation From Cardiac Arrest and In-Hospital Mortality JAMA 2010: 303: 2165-71

Arterial hyperoxia and in-hospital mortality after resuscitation from cardiac arrest Crit Care 2011; 15: R90

The Effect of Hyperoxia Following Resuscitation From Cardiac Arrest: A Systematic Review and Meta-analysis of Observational Studies Resuscitation 2014 (on-line publication)

Association Between Postresuscitation Partial Pressure of Arterial Carbon Dioxide and Neurological Outcome in Patients With Post Cardiac Arrest Syndrome Retrospective observational study, n=193 Conclusion: hypocapnia and hypercapnia are common after cardiac arrest, and were independently associated with poor neurological outcome Circulation 2013; 127 : 2017-13

Arterial Carbon Dioxide Tension And Outcome in Patients Admitted to The Intensive Care Unit After Cardiac Arrest Retrospective observational cohort study, n=16,542 Conclusion: hypocapnia was independently associated with worse clinical outcome, and hypercapnia a greater likelihood of discharge home among survivors. Resuscitation 2013; 84 : 927-934

Association between Early Arterial Blood Gas Levels and Neurological Outcome in Adult Patients following In-Hospital Cardiac Arrest In submission

The Impact of Oxygen And Carbon Dioxide Management on Outcome After Cardiac Arrest 2010 ACLS guideline O2 saturation 94% Pa CO2 40-50 mmhg In retrospective clinical observational studies Avoid hyperoxia is recommended Hypocapnia associated with worse neurological outcome and mortality Mild hypercapnia (?) Need prospective RCT to verify the hypothesis Curr Opin Crit Care 2014; 20 : 206-72

Hypothermia for Neuroprotection After Cardiac Arrest: Meta-analysis 95% CI of NNT to allow one addition hospital discharge with favorable neurological recovery :4-13 Crit Care Med 2005; 33: 414

台 大 低 溫 治 療 團 隊 之 進 展 於 2004 年 成 立 低 溫 治 療 團 隊 於 2005 年 底 引 進 國 內 首 部 血 管 內 降 溫 之 低 溫 治 療 儀 器 於 2006 年 開 始 進 行 國 內 首 例 : 針 對 OHCA 患 者 之 低 溫 治 療

Survival for 30 days Standard care (n=415) Hypothermia treatment (n=93) Hypothermia treatment P< 0.001 Standard care

% Favorable neurological outcome

PCI Combined with Therapeutic Hypothermia for STEMI After Resuscitation Study N Survival to Hosp discharge Survivors with Intact CNS function Hovdenes 2007 50 41/50 (82%) 34/41 (83%) Knafelj 2007 40 30/40 (75%) 22/30 (73%) Wolfrum 2008 16 12/16 (75%) 11/12 (92%) Peels 2008 44 22/44 (50%) NA Batista 20 8/20 (40%) 6/8 (75%)

About the Future How to cool? When to start cooling? How deep to cool? How long to keep cool?

Effect of Prehospital Induction of Mild Hypothermia on Survival and Neurological Status Among Adults With Cardiac Arrest: Prehospital cooling by 2L of 4ºC normal saline vs. placebo after ROSC N=1359 ( 583 with VF, 776 without VF) 4ºC normal saline reduced core temp, by more than 1ºC and reduced time to achieve goal temp(34ºc) by more than 1 hr Associated with higher re-arrest rate (26% vs. 21%) Increased transient lung edema (41% vs. 30%) JAMA 2013; (e-pub)

Targeted temperature management at 33 C versus 36 C after cardiac arrest Multicentered, randomized trial, n=950 Shockable rhythm about 80% NEJM 2013; 369:2197-2205

Improved Cardiac And Neurologic Outcomes With Postresuscitation Infusion of Cannabinoid Receptor Agonist WIN55, 212-2 Depend on Hypothermia in A Rat Model of Cardiac arrest Crit Care Med 2014; 42 : e42-48

Will the Promise of Drug-induced Therapeutic Hypothermia Be Fulfilled? Cannabinoid (CB) receptor agonists WIN55, 212-2 HU-210 Cholecystokinin octapeptide Poly (adenosine diphosphate-ribose) polymerase inhibitor GPI-6150 X Transient receptor potential vanilloid type I agonist Animal study only, need future translational research. Crit Care Med 2014; 42 : 221-2

Shock 2007:28:53 58

dose dependent response for cardioprotection Drug within ROSC 3 mins Crit Care Med 2008;36:S467 S473

EPO timing Crit Care Med 2008; 36:S467 S473

40000 U EPOalpha i.v. at ROSC then q12h within 48h Resuscitation. 2008;76:397 404.

High dose of EPO after OHCA Multicenter randomized controlled study Witnessed OHCA of presumed cardiac origin No flow<10 min, low flow <50 min 2 groups of 250 patients First case inclusion at Dec. 2008

Eur Heart J. 2011;32:226 35.

Post-cardiac arrest myocardial dysfunction is improved with cyclosporine treatment at onset of resuscitation but not in the reperfusion phase Resuscitation; 2011: 82: S41-47

Inhaled Nitric Oxide Improves Outcomes After Successful Cardiopulmonary Resuscitation in Mice z 1 hr post-cpr Placebo vs. NO (40ppm) for 23 hrs z Mechanism : soluble guanylate cyclase-dependent mechanisms z Circulation; 2011: 124: 1645-53

For A Better Future Perspective of Cardiac Arrest Victims Current CPR guidelines require continuous modification based on researches and regional variations. Although research of CPR is notoriously difficult, it is nevertheless essential if continued improvements are to be made.

Thank you