Update on Hypothermia post Cardiac Arrest. E Hessel, II, MD, FACS

1. Update on Hypothermia post Cardiac Arrest.E Hessel, II, MD, FACS Strive to Revive: Improving Cardiac Resuscitation American Heart Association and UK HealthCare Gill Heart Institute Lexington, KY April 28, 2014 Revised April 28, 2012; 0530 EDST

2. Disclosures • I have no disclosures, financial or otherwise.

3. This is why I am speaking on this topic: Starting in 2003 therapeutic hypothermia (TH) has been strongly recommended following some Cardiac Arrests (CA) by many professional organizations including most recently by the American Heart Association

5. Last year at this meeting I critiqued the use of therapeutic hypothermia (TH) post cardiac arrest especially post in-hospital cardiac arrest (IH-CA) • Pointed out the limitations of the evidence supporting its use for out- of-hospital cardiac arrest (OOH-CA)… • and the lack of any high level evidence of its benefit following cardiac arrest associated with non-shockable rhythms and following in-hospital cardiac arrest (IH-CA).

6. My Objectives For this afternoons presentation • Elaborate and expand on some of the data I presented last year • Review important data which have appeared during in the literature during the past year • Give you my personal current recommendations regarding the use of therapeutic hypothermia post cardiac arrest.

7. I call your attention, and have provided copies for you, of an article of mine recently published on this topic, largely based on my presentation at this meeting last year but including some of the new information which I will present this afternoon. I am referring you to this paper mainly because it provides references to many of the studies I will be commenting on this afternoon J Cardiothoracic and Vascular Anesthesia Epub ahead of print. April 18, 2014

8. Outline • TH for OOH-CA • A new large observational study with concurrent controls • TH for CA associated with non-shockable rhythms • Recent systematic review and some new data • TH for IH-CA • Recent large observational study • Role of simply preventing hyperthermia post CA • Recent large RCT 36o versus 33o C • Role of pre-hospital cooling • Recent RCT • Ongoing Pediatric RCTs • Review limitations of TH • Selection of candidates for TH • Summary

9. Use Therapeutic Hypothermia (TH) following Out-of-Hospital Cardiac Arrest (OOH-CA) • Still no randomized controlled trials since the two major ones published 12 years ago (2002) • There have been • A RCT of benefits of pre-hospital cooling (prior to in-hospital TH) • A RCT comparing a targeted temperature of 36o C versus traditional 33o C • I will review these studies subsequently • In addition the results of a large data registry has been recently reported (see next.)

10. Mader TJ, etal. Therapeutic Hypoth and Temp management 2013; 4(1): 21-31 Retrospective cohort study of patients resuscitated from out-of-hospital Cardiac Arrest using data from the Cardiac Arrest Registry to Enhance Survival (CARES) [CDC and Emory University] ~ 50 sites Nov 1, 2010 through Dec 31, 2012 Adults with CA of presumed cardiac etiology with survival to hospital admission; included shockable and non-shockable l rhythms Propensity score matching to compare patients receiving therapeutic hypothermia or not 6369 patients Shockable 47%; asystole 26%, PEA 20%, other non-shockable 7% Therapeutic hypothermia in 54% (62% of shockable, 50% on non-shockable)

11. Mader TJ, etal. Therapeutic Hypoth and Temp management 2013; 4(1): 21-31

12. Mader TJ, etal. Therapeutic Hypoth and Temp management 2013; 4(1): 21-31

13. Unadjusted outcomes(Mader, et al. 2014) Rhythm n Survived(%) Good Neurologic Outcome(CPC 1 or 2)(%) All • TM 3452 40% 34% • No TM 2917 39 34 Shockable • TM 1851 60 53 • No TM 1141 65 61 Non-shockable • TM 1601 17 12 • No TM 1776 22 16 Note outcome no better or worse with TH

14. Mader TJ, etal. Therapeutic Hypoth and Temp management 2013; 4(1): 21-31

15. Mader TJ, etal. Therapeutic Hypoth and Temp management 2013; 4(1): 21-31

16. Mader TJ, etal. [Therapeutic Hypoth and Temp management 2013; 4(1): 21-31]

18. TH following Cardiac ArrestAssociated with Non-shockable rhythms. • Last year I stated “Although there are conflicting data, most suggest that TH is less beneficial, (or perhaps not even beneficial) post non- shockable rhythms following (either out-of-hospital or in-hospital cardiac arrest)” • Unfortunately this remains true today • There have been three new observational studies, and • Two systematic review and Meta-analyses of this issue • But the definitive answer awaits large well conducted RCT or prospective observational studies.

19. TH following CA associated with non-shockable rhythms • Recent observational studies that provide information • Vaahersalo J, et al. Intensive Care Med 2013; 39: 826-37 • Lindner TW, et al. Critical Care 2013; 17: R147 • Mader, et al. TherHypth and Temp Manag 2014; 4: 21-30 • Recent reviews • Kim Y-M, et al. Resuscitation 2012; 83: 188-96 • Sandroni C, et al. Critical Care 2013:17: 215

20. A recent Systematic Review and Meta-Analysis Sandroni C, etal. Critical Care 2013; 17: 217

21. Death Bad neurologic Outcome Sandroni, et al Critical Care 2013; 17:215

22. TH following CA associated with non-shockable rhythmsMy Summary of these data

23. Studies of effect of therapeutic hypothermia in patients following Cardiac arrest associated with non-shockable rhythms (PEA or asystole) Add Mader, et al’s large observational study in 2014 Hessel, EA. J Cardiothoracic and Vascular Anesthesia Epub ahead of print. April 18, 2014

24. TH following CA associated with non-shockable rhythmsSummary • The Studies • Two small (total of 22 patients in each arm) • 16 non-randomized observations studies • Type of controls • 5 with concurrent controls • 11 with historical controls • Patients • 546 received TH (+ 1601 from Mader, etal 2014) • 1038 did not (+ 1776 from Mader, etal2014)

25. TH following CA associated with non-shockable rhythmsSummary • The Results • Impact on survival (13 studies) • 11 observed no statistically significant difference • 2 observed an improved survival with TH • In aggregate: 12% decrease in mortality with TH (No decrease if include Mader, etal, 2014) • Impact on good neurologic recovery (14 studies) • 13 observed no statistically significant difference • 1 observes an improved outcome with TH • In aggregate: A statistically insignificant 5% increase in good neurologic outcome with TH (No improvement if include Mader, etal, 2014) • Conclusion • There is a suggestion of benefit with use of TH in some studies • Magnitude much less that seen in patients with shockable rhythms • Because of the low quality of the evidence (GRADE) there is need for high quality RCTs to confirm any benefit

26. Unadjusted outcomes(Mader, et al. 2014) Rhythm n Survived(%) Good Neurologic Outcome(CPC1 or 2)(%) Non-shockable • TM 1601 17 12 Worse outcome! • No TM 1776 22 16

27. Mader TJ, etal. Therapeutic Hypoth and Temp management 2013; 4(1): 21-31

28. Mader TJ, etal. [Therapeutic Hypoth and Temp management 2013; 4(1): 21-31]

30. In-Hospital Cardiac Arrest

31. Edelson DP, etal. J Hospital Med 2014 epub ahead of print (90%)

32. NEJM 2012; 367: 1912-20 GWTG-R Investigators 374 hospitals 2000-2009 84,625 cardiac arrests Initial rhythm asystole or PEA in 79% (and increased over time from 69 to 82%) Survival to discharge 17% If VF or VT 34% If Asystole or PEA 10% Neurologic disability in survivors 30% Survival to discharge increased over time while neurologic disability decreased

33. S. Girotra, etal. NEJM 2013.

34. Therpeutic hypothermia after in-hospital Cardiac arrestMikkelsen ME, etal. CCM 2013Additional comments and observations • 210,000 in hospitals cardiac arrests (IHCA) annually in USA • Rate is increasing • Less than 25% have VF/VT as the initial rhythm (and this appears to be declining) • IHCA with initial non-shockable rhythm that transitions to VF/VT is common and outcomes are dismal (Meaney, etal. CCM 2010; 38: 101) • No RCT of TH following IH-CA have been reported

35. TH following In-hospital Cardiac Arrest • Last year I indicated that there was no high level evidence (e.g., RCT or large observational studies demonstrating improved outcome with therapeutic hypothermia when used following in-hospital cardiac arrest. • This remains true, however during the past year the largest retrospective observational study addressing this question was published. I will review this shortly.

36. Hessel, EA. J Cardiothoracic and Vascular Anesthesia Epubahead of print. April 18, 2014

37. Nichol G, et al. Resuscitation 2013; 84: 620-25 Retrospective analysis of multi-center prospective cohort of patients 454 hospitals in USA participating in Get With the Guidelines-Resuscitation (TWTG-R) QI project 2000-2009 Limited to adult patients with ROSC after in-hospital CA on the ward (i.e., excluded if arrest in ER, ICU, OR, procedure areas or recovery areas) 8316 patients 214 (2.6%) received hypothermia, 8102 did not 87% had non-shockable rhythms 41% were unwitnessed 1374 (13%) had shockable rhythms (similar rate in both groups)

38. Nichol G, et al. Resuscitation 2013; 84: 620-25 Primary outcome: Survival to discharge Secondary outcome: Good neurological status at discharge (CPC score 1 or 2) Provided unadjusted and propensity score adjusted Odds Ratios Results: Overall non-statistically significant worse outcome in hypothermia group In those with shockable rhythms [n 1374 (13%] non-statistically significant better outcome with hypothermia

39. Table 2. Effect of hypothermia on survival and favorable neurologic outcome at discharge in entire population Nichol G, et al. Resuscitation 2013; 84: 620-25 Table 4. Effect of hypothermia on survival and favorable neurologic outcome at discharge in patients with shockable rhythms Nichol G, et al. Resuscitation 2013; 84: 620-25 However only 51% of those receiving hypothermia were documented to have been cooled to below 34o C This may explain the lack of benefit

40. Reasons to anticipate thattherapeutic hypothermia might be less effective for In-hospital CA (IHCA) • More than 75% associated with non-shockable rhythms • IH-CA often due to hemorrhage, respiratory insufficiency or pulmonary embolism (instead of primary arrhythmias or AMI) • Victims of In-Hospital CA are often “sicker” and have more co-morbidities • Girotra, etal NEJM 2013 • 44% respiratory insufficiency • 29% hypotension • 20% heart failure • 17% sepsis • 15% pneumonia • 58% in ICU • 31% on mechanical ventilation • 29% receiving intravenous vasopressors

41. Reasons to anticipate thattherapeutic hypothermia might be less effective for In-hospital CA (IHCA) • Diagnosis of cardiac arrest often delayed • Between 12 and 48 % unwitnessed • These patients may be more prone to the complications of TH • Poor outcome following IH-CA less likely to be due to neurologic injury. (See next two slides)

42. Mode of death after admission to an ICU following cardiac arrest.Laver S, etal. Intensive Care Med 2004; 30: 2126-28 Retrospective observational study of 225 patients single ICU in UK, 1998-2003 OOH-CAIH-CA N 113 92 Mean age (years) 63 72 Died (percent) 57% 66% Cause of death (percent) Neurologic 68% 23% Cardiovascular 23 26 Multi-organ failure 9 51

45. So why might patients who experience CA associated with non-shockable rhythms and In-hospital be resistant to the benefits of TH? It is reasonable to assume that the pathophysiology of the neurologic injury (ischemia/reperfusion) is the same regardlessof the rhythm or location of the arrest or these other variables TH modulates this injury and therefore it is plausible to expect it to be beneficial in these other circumstances. However the magnitude of neurologic injury could be much worse in these scenarios, and thus TH, as currently administered, may not be adequate [not a high enough “dose” (e.g., timing, depth and duration), to use the phrase of Dumas, etal(Circulation 2011)

46. So why might patients who experience CA associated with non-shockable rhythms and In-hospital be resistant to the benefits of TH? Possible contributors to worse neurologic injury include: Delayed diagnosis (not infrequently unwitnessed), longer delay in ROSC, and more post resuscitation shock. Since many of these other victims of CA are less likely to have a cardiogenic cause, and the CA is often preceded by periods of cardio-respiratory failure (and associated hypotension and hypoxemia), their brains may have been somewhat ischemic even before the arrest occurs, aggravating the brain injury due to the CA per se.

48. In-hospital Cardiac arrest • But there may be a unique population of patients who experience in-hospital cardiac arrest and this may have implications in our post arrest therapy… • Specificallyperi-operative IH-CA

49. Ramachandran SK, et al. Anesthesiology 2013; 119: 1322-39 Study of outcome of 2524 adults experiencing Cardiac Arrest in the operating room or within 24 hours post-operatively. (2.1 % of all in-hospital cardiac arrests) Obtained from the Get With The Guidelines-Resuscitation (GWTG-R)national in-hospital resuscitation registry (Perioperative arrests occurred in 234 hospitals 2000-2008 Location of arrest OR 1458 (57.5%) PACU 536 ICU 332 Wards 140 Telemetry 58

50. Outcome • ROCS 57.7% • Hospital survival 32% • Neurologically intact( (CPC 1) 19% • (64% of hospital survivors) • Factors associated with survival • Shockable rhythms (better survival) • Occurrence in PACU and telemetry units (better survival) • Arrests attributed to arrhythmias and inadequate natural airway (improved survival) • Trauma and shock worse survival • Number of coexisting diseases (survival decrease with number) • Age (decreases with age) • Duration of arrest (decreases with increase duration) • Time to defibrillation and placement of invasive airway (shorter better)