1. By Greg Gipson 8/30/13

2.  Out-of-hospital ◦ US survival rate 11.4% ◦ King County survival rate 52%  In-hospital ◦ Estimated 6.7 per 1000 admissions ◦ 200,000 patients/year ◦ Neurologic damage ◦ Survival to discharge 24.2%  Still room for improvement American Heart Association, http://www.heart.org/HEARTORG/, accessed 8/27/13http://www.heart.org/HEARTORG/ EMS 2012 Annual Report, available at www.kingcounty.gov/health/ems, accessed 8/27/13www.kingcounty.gov/health/ems

3. AHA 2010 algorithm ◦ CPR ◦ Shock ◦ Drugs  Epi 1mg q3-5min  Vasopressin 40 IU  Amio 300mg  Repeat 150mg ◦ Return of spontaneous circulation (ROSC) American Heart Association, http://www.heart.org/HEARTORG/, accessed 8/27/13http://www.heart.org/HEARTORG/

4. Vasopressin, steroids, and epinephrine and neurologically favorable survival after in- hospital cardiac arrest ◦ Previous trial showed benefit  RCT, single center, n=100  ↑ROSC, ↑survival to discharge, similar ADEs ◦ Neurologically survival ≠ survival ◦ Further investigate treatment algorithm  Published: JAMA - July 2013 Mentzelopoulos S, Malachias S, Chamos C, et al. Vasopressin, steroids, and epinephrine and neurologically favorable survival after in-hospital cardiac arrest. JAMA 2013;310(3):270-279. Mentzelopoulos S, Zakynthinos S, Tzoufi M, et al. Vasopressin, epinephrine, and corticosteroids for in-hospital cardiac arrest

5.  RC, DB, PC, parallel-group, MC ◦ Pharmacists randomized  Sept 1, 2008 – Oct 1, 2010  3 Greek tertiary care hospitals  N=268 consecutive patients  Exclusion ◦ <18 y/o, terminal illness, DNR, exsanguination, arrest before admission, IV steroids, previous enrollment/exclusion Mentzelopoulos S, Malachias S, Chamos C, et al. Vasopressin, steroids, and epinephrine and neurologically favorable survival after in-hospital cardiac arrest. JAMA 2013;310(3):270-279.

6.  Cardiac arrest!  Begin CPR (30:2)  Intervention q 3 minutes, x 5 times ◦ Tx: Vasopressin 20 IU and epi 1mg ◦ Control: Saline placebo and epi 1mg  First cycle ONLY ◦ Tx: Methyprednisolone 40mg IV ◦ Control: Saline placebo Mentzelopoulos S, Malachias S, Chamos C, et al. Vasopressin, steroids, and epinephrine and neurologically favorable survival after in-hospital cardiac arrest. JAMA 2013;310(3):270-279.

7.  No ROSC by 5 th cycle ◦ Follow European resuscitation guidelines ◦ Epi 1mg q3-5min ◦ Option: Amio, atropine, magnesium Nolan JP, Deakin CD, Soar J. European resuscitation council. European resuscitation council guidelines for resuscitation 2005: Section 4, Adult advanced life support. Resuscitation. 2005;37(suppl 1):@39-S86

8.  4 hours post resuscitation ◦ Postresuscitation shock?  Tx: Hydrocortisone 300 mg/d CI, ≤ 7 days, then taper  Unless AMI, then ≤ 3 days  Control: Saline infusions  Could receive open-label hydrocortisone Mentzelopoulos S, Malachias S, Chamos C, et al. Vasopressin, steroids, and epinephrine and neurologically favorable survival after in-hospital cardiac arrest. JAMA 2013;310(3):270-279.

9.  Primary ◦ ROSC x ≥20 minutes ◦ Survival to discharge w/ CPC 1 or 2  Secondary ◦ Atrial pressure 20 min post ROSC ◦ Atrial pressure + ScvO 2 (days 1-10) ◦ Organ failure free days (days 1-60) ◦ Corticosteroid complications  Hyperglycemia, infection, PUD, paresis Mentzelopoulos S, Malachias S, Chamos C, et al. Vasopressin, steroids, and epinephrine and neurologically favorable survival after in-hospital cardiac arrest. JAMA 2013;310(3):270-279. Grenvik A, Safar P. Eds: Brain failure and resuscitation, Churchill Livingstone, New Yortk, 1981; 155-184.

10.  Power calculations ◦ N=244  ITT  Tested ◦ Normality ◦ Heterogeneity Mentzelopoulos S, Malachias S, Chamos C, et al. Vasopressin, steroids, and epinephrine and neurologically favorable survival after in-hospital cardiac arrest. JAMA 2013;310(3):270-279.  Analysis methods ◦ Chi 2 or Fischer exact ◦ T-tests ◦ Linear-mixed model ◦ Logistic regression ◦ Multivariate Cox

11. Mentzelopoulos S, Malachias S, Chamos C, et al. Vasopressin, steroids, and epinephrine and neurologically favorable survival after in-hospital cardiac arrest. JAMA 2013;310(3):270-279.  Figure 1

12.  Comparable baseline characteristics Mentzelopoulos S, Malachias S, Chamos C, et al. Vasopressin, steroids, and epinephrine and neurologically favorable survival after in-hospital cardiac arrest. JAMA 2013;310(3):270-279.

19.  MAP higher on days 1, 2, 4, 5, 10 post resuscitation  ScvO 2 higher on days 1, 2, 4-10 post resuscitation Mentzelopoulos S, Malachias S, Chamos C, et al. Vasopressin, steroids, and epinephrine and neurologically favorable survival after in-hospital cardiac arrest. JAMA 2013;310(3):270-279.

20.  More organ failure free days and ventilator free days in treatment group Mentzelopoulos S, Malachias S, Chamos C, et al. Vasopressin, steroids, and epinephrine and neurologically favorable survival after in-hospital cardiac arrest. JAMA 2013;310(3):270-279.

21.  Adverse events from corticosteroids ◦ Tx group  Used more insulin (p<0.001)  No difference in hyperglycemia (>180mg/dL, p=0.88) ◦ No other ADEs reported Mentzelopoulos S, Malachias S, Chamos C, et al. Vasopressin, steroids, and epinephrine and neurologically favorable survival after in-hospital cardiac arrest. JAMA 2013;310(3):270-279.

22.  Epinephrine ◦ Adrenergic agonist  Vasoconstriction  ↑Cerebral perfusion  ↑Coronary perfusion  ↑HR, ↑CO  ↑Cerebral perfusion  ↑Coronary perfusion  ↑Myocardial O 2 consumption ◦ Effect attenuated in hypoxia and acidosis ◦ T 1/2 = 2-3 min ◦ Peak concentration ~90 sec Papastylianou A, Mentzelopoulos S. Current pharmacological advances in the treatment of cardiac arrest. Emergency Medicine International 2012,815857;9.

23.  Vasopressin ◦ Vasopressin receptor agonist (V 1,2,3 )  V 1 – Vasoconstriction  ↑ Cerebral perfusion  V 2 – Antidiuresis (distal convoluted tubule, medullary collecting duct)  V 3 – Insulin, ACTH, temp, BP, memory (anterior pituitary, islet cells) ◦ Survivors show low vasopressin levels ◦ T 1/2 = 10-35 min ◦ Data shows: Vasopressin = Epi Papastylianou A, Mentzelopoulos S. Current pharmacological advances in the treatment of cardiac arrest. Emergency Medicine International 2012,815857;9. Image from: MCAT Review, http://mcatprep4free.blogspot.com/2011/08/antidiuretic-hormone-adh.html, Accessed 8/28/13http://mcatprep4free.blogspot.com/2011/08/antidiuretic-hormone-adh.html

24.  Corticosteroids ◦ Use is controversial ◦ Adrenal dysfunction possible in shock ◦ Not standard of practice for cardiac resuscitation  ↑ effect of epinephrine  ↑ effect of vasopressin  ↑ myocardial function post arrest ◦ Other possibly beneficial effects  Anti-inflammatory  Increase fluid volume ◦ ADEs Patel G, Balk R. Systemic steroids in severe sepsis and septic shock. American Journal of Respiratory and Critical Care Medicine. 2012;2:133-139 Skyschally A, Haude M, Dorge H, et al. Glucocorticoid treatment prevents progressive myocardial dysfunction resulting from experimental coronary microembloism. Circulation 2004;109(19):2337-2342. Mentzelopoulos S, Malachias S, Chamos C, et al. Vasopressin, steroids, and epinephrine and neurologically favorable survival after in-hospital cardiac arrest. JAMA 2013;310(3):270-279. Image from: http://images.ddccdn.com/drp/images/12/80007201.jpg, Accessed 8/28/13http://images.ddccdn.com/drp/images/12/80007201.jpg

25.  VSE ◦ ↑ ROSC ◦ ↑ Survival and neurologic outcomes ◦ ↑ Hemodynamics ◦ ↓ Organ failure ◦ ? Corticosteroid complications  ↑ Insulin use  ↔ Hyperglycemia

26.  Can we safely apply these results to a US population?  Should we repeat this trial in King County?  What will the next AHA ACLS guidelines recommend? ◦ Will they incorporate this data?