Presentation on theme: "Update on Hypothermia post Cardiac Arrest. E Hessel, II, MD, FACS"— Presentation transcript:
1Update on Hypothermia post Cardiac Arrest. E Hessel, II, MD, FACS Strive to Revive:Improving Cardiac ResuscitationAmerican Heart Association andUK HealthCare Gill Heart InstituteLexington, KYApril 28, 2014Revised April 28, 2012; 0530 EDST
2DisclosuresI have no disclosures, financial or otherwise.
3This is why I am speaking on this topic: Starting in 2003 therapeutic hypothermia (TH) has beenstrongly recommended following some Cardiac Arrests (CA) bymany professional organizations including most recentlyby the American Heart Association
5Last 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 followingin-hospital cardiac arrest (IH-CA).
6My Objectives For this afternoons presentation Elaborate and expand on some of the data I presented last yearReview important data which have appeared during in the literature during the past yearGive you my personal current recommendations regarding the use of therapeutic hypothermia post cardiac arrest.
7J Cardiothoracic and Vascular Anesthesia I call your attention, and have provided copies for you, ofan article of mine recently published on this topic, largely based onmy presentation at this meeting last year but including some of the new informationwhich I will present this afternoon.I am referring you to this paper mainly because it provides references to many ofthe studies I will be commenting on this afternoonJ Cardiothoracic and Vascular AnesthesiaEpub ahead of print. April 18, 2014
8Outline TH for OOH-CA TH for CA associated with non-shockable rhythms A new large observational study with concurrent controlsTH for CA associated with non-shockable rhythmsRecent systematic review and some new dataTH for IH-CARecent large observational studyRole of simply preventing hyperthermia post CARecent large RCT 36o versus 33o CRole of pre-hospital coolingRecent RCTOngoing Pediatric RCTsReview limitations of THSelection of candidates for THSummary
9Use 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 beenA RCT of benefits of pre-hospital cooling (prior to in-hospital TH)A RCT comparing a targeted temperature of 36o C versus traditional 33o CI will review these studies subsequentlyIn addition the results of a large data registry has been recently reported (see next.)
10Mader TJ, etal. Therapeutic Hypoth and Temp management 2013; 4(1): 21-31 Retrospective cohort study of patients resuscitated from out-of-hospitalCardiac Arrest using data from theCardiac Arrest Registry to Enhance Survival (CARES) [CDC and Emory University]~ 50 sitesNov 1, 2010 through Dec 31, 2012Adults with CA of presumed cardiac etiology with survival to hospital admission;included shockable and non-shockable l rhythmsPropensity score matching to compare patients receivingtherapeutic hypothermia or not6369 patientsShockable 47%; asystole 26%, PEA 20%, other non-shockable 7%Therapeutic hypothermia in 54% (62% of shockable, 50% on non-shockable)
18TH following Cardiac Arrest Associated 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 todayThere have been three new observational studies, andTwo systematic review and Meta-analyses of this issueBut the definitive answer awaits large well conducted RCT or prospective observational studies.
19TH following CA associated with non-shockable rhythms Recent observational studies that provide informationVaahersalo J, et al. Intensive Care Med 2013; 39:Lindner TW, et al. Critical Care 2013; 17: R147Mader, et al. Ther Hypth and Temp Manag 2014; 4: 21-30Recent reviewsKim Y-M, et al. Resuscitation 2012; 83:Sandroni C, et al. Critical Care 2013:17: 215
20A recent Systematic Review and Meta-Analysis Sandroni C, etal. Critical Care 2013; 17: 217
21Death Bad neurologic Outcome Sandroni, et al Critical Care 2013; 17:215
22TH following CA associated with non-shockable rhythms My Summary of these data
23Studies 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 2014Hessel, EA. J Cardiothoracic and Vascular Anesthesia Epub ahead of print. April 18, 2014
24TH following CA associated with non-shockable rhythms Summary The StudiesTwo small (total of 22 patients in each arm)16 non-randomized observations studiesType of controls5 with concurrent controls11 with historical controlsPatients546 received TH ( from Mader, etal 2014)1038 did not ( from Mader, etal 2014)
25TH following CA associated with non-shockable rhythms Summary The ResultsImpact on survival (13 studies)11 observed no statistically significant difference2 observed an improved survival with THIn 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 difference1 observes an improved outcome with THIn aggregate: A statistically insignificant 5% increase in good neurologic outcome with TH (No improvement if include Mader, etal, 2014)ConclusionThere is a suggestion of benefit with use of TH in some studiesMagnitude much less that seen in patients with shockable rhythmsBecause of the low quality of the evidence (GRADE) there is need for high quality RCTs to confirm any benefit
26Unadjusted outcomes (Mader, et al. 2014) Rhythm n Survived(%) Good NeurologicOutcome(CPC1 or 2)(%)Non-shockableTM Worse outcome!No TM
31Edelson DP, etal. J Hospital Med 2014 epub ahead of print (90%)
32NEJM 2012; 367: 1912-20 GWTG-R Investigators 374 hospitals 2000-2009 84,625 cardiac arrestsInitial 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
34Therpeutic hypothermia after in-hospital Cardiac arrest Mikkelsen ME, etal. CCM 2013 Additional comments and observations210,000 in hospitals cardiac arrests (IHCA) annually in USARate is increasingLess 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
35TH 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.
36Hessel, EA. J Cardiothoracic and Vascular Anesthesia Epub ahead of print. April 18, 2014
37Nichol G, et al. Resuscitation 2013; 84: 620-25 Retrospective analysis of multi-center prospective cohort of patients454 hospitals in USA participating in Get With the Guidelines-Resuscitation (TWTG-R) QI projectLimited 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 patients214 (2.6%) received hypothermia,8102 did not87% had non-shockable rhythms41% were unwitnessed1374 (13%) had shockable rhythms (similar rate in both groups)
38Nichol G, et al. Resuscitation 2013; 84: 620-25 Primary outcome: Survival to dischargeSecondary outcome: Good neurological status at discharge(CPC score 1 or 2)Provided unadjusted and propensity score adjusted Odds RatiosResults:Overall non-statistically significant worse outcome inhypothermia groupIn those with shockable rhythms [n 1374 (13%]non-statistically significant better outcome with hypothermia
39Table 2. Effect of hypothermia on survival and favorable neurologic outcome at discharge in entire populationNichol G, et al. Resuscitation 2013; 84:Table 4. Effect of hypothermia on survival and favorableneurologic outcome at discharge in patients with shockable rhythmsNichol G, et al. Resuscitation 2013; 84:However only 51% of those receiving hypothermiawere documented to have been cooled to below 34o CThis may explain the lack of benefit
40Reasons to anticipate that therapeutic hypothermia might be less effective for In-hospital CA (IHCA) More than 75% associated with non-shockable rhythmsIH-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-morbiditiesGirotra, etal NEJM 201344% respiratory insufficiency29% hypotension20% heart failure17% sepsis15% pneumonia58% in ICU31% on mechanical ventilation29% receiving intravenous vasopressors
41Reasons to anticipate that therapeutic hypothermia might be less effective for In-hospital CA (IHCA) Diagnosis of cardiac arrest often delayedBetween 12 and 48 % unwitnessedThese patients may be more prone to the complications of THPoor outcome following IH-CA less likely to be due to neurologic injury. (See next two slides)
42Mode of death after admission to an ICU following cardiac arrest Mode of death after admission to an ICU following cardiac arrest. Laver S, etal. Intensive Care Med 2004; 30:Retrospective observational study of 225 patients single ICU in UK,OOH-CA IH-CANMean age (years)Died (percent) % 66%Cause of death (percent)Neurologic % 23%CardiovascularMulti-organ failure
45So 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 regardless of 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)
46So 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.
48In-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…Specifically peri-operative IH-CA
49Ramachandran SK, et al. Anesthesiology 2013; 119: 1322-39 Study of outcome of 2524 adults experiencing Cardiac Arrest in the operating room orwithin 24 hours post-operatively. (2.1 % of all in-hospital cardiac arrests)Obtained from the Get With The Guidelines-Resuscitation (GWTG-R) nationalin-hospital resuscitation registry (Perioperative arrests occurred in 234 hospitalsLocation of arrestOR 1458 (57.5%)PACU 536ICU 332Wards 140Telemetry
50Neurologically intact( (CPC 1) 19% OutcomeROCS %Hospital survival 32%Neurologically intact( (CPC 1) 19%(64% of hospital survivors)Factors associated with survivalShockable 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 survivalNumber 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)
51Factors associated with worse neurologic outcome Poor pre arrest neurological statusOlder ageInadequate natural airwayPre-arrest ventilator supportLonger duration of eventNOT the initial CA rhythm
52In survivorsGood Neurological OutcomeAmong all patients 16.1% 19.9% %
53Comparison of Perioperative with All In-hospital Cardiac arrests (Get with the Guidelines-Resuscitation Registry)All Periop CA*Initial rhythmShockable % 24%Non-shockableOutcomeSurvival to DischargeGood neurologic outcomeAll patientsIn survivorsSurvival per initial rhythmShockableNon-shockable@Girotra S, et al. NEJM 2012; 367:*Ramachandran SK, et al. Anesthesiology 2013; 119:
54Why better outcome following Perioperative cardiac arrest? Hypotheses Shorter time to defibrillation, epinephrine and until invasive airway placementSurgical causes for cardiac arrest are more likely to be reversible including medication and airway causesImmediate availability of skilled physicians
59Last year I posited that “Intriguingly, it may be that simply preventing hyperthermia may be as effective as inducing mild hypothermia following resuscitation from cardiac arrest.”A recent large RCT has been published that seems to support this hypothesis.
60Nielsen N, et al. NEJM 2013; 369 (23): 2197-2206 Prospective RCT 939 unconscious patients following Out-of Hospital Cardiac ArrestNote that this included nearly 3 times as many patients as the two prior RCTs of TH combined (350)36 ICUs in Europe and AustraliaInclusion criteria≥18 year old, Admitted to hospitalUnconscious (GCS < 8)after Out-of-Hospital cardiac arrestof presumed cardiac causewith any rhythm (but 80% shockable, 12% asystole. 7% PEARandomized to temperature target of-33o or-36oPrimary outcome: All cause mortality to end of trialSecondary outcomes:Neurologic outcome (blinded assessors)Cerebral Performance Category (CPC) at discharge from ICU, Hospital, and end of trialSerious adverse events
61Nielsen N, et al. NEJM 2013; 369 (23): 2197-2206 Temperature managementCooled to assigned temperature (33o or 36o C) as rapidly as possible and maintained for 28 hrsThen rewarmed at 0.5o/ hourThen, if unconscious, kept below 37.5o for 72 hrs post arrest.Sedated until end of intervention.Results:No difference in any outcome measures between the two groups.
62Note that by aiming for a temperature of 36o, Nielsen N, et al. NEJM 2013; 369 (23):Note that by aiming for a temperature of 36o,temperature was kept below 37.2o in 97.5% of the patients in that group
63Nielsen N, et al. NEJM 2013; 369 (23): 2197-2206
76TH following IH-CA Even if we don’t know for sure that it will help… What’s the harm in trying? Potential complications of THInfection, pneumonia, sepsis, hemodynamic instability, arrhythmias, hyperglycemia, coagulopathy, bleeding, electrolyte abnormalities, polyuria, seizures, altered drug metabolismComplicates other care (e.g., angiography, interventional cardiology )Expensive, labor intensiveDiverts resources (staff, ICU beds, money)False sense of hope for familyConversely, failure to use may suggest to the family that the hospital/physicians are not providing optimal care (they have heard about TH in lay press)Inhibits the ability to conduct badly needed RCTs.
77Complications of TH Recent Reviews: Soleimanpour H et al. Review. J CV Thor Res 2013; 6(1): 1-8Noyes AM and Lundbye JB. J Intens Care Med 2014, epub ahead of print.In Nielsen, et al’s recent RCT comparing 33o with 36oC, found no significant differences in complication rate.One potentially troublesome problem…
78Joffe J, et al. Resuscitation 2014, epub ahead of print Compared stent thrombosis (ST) rate after PCI for AMIST155 without Cardiac Arrest 2.0%55 with CA (all received TH at 33oC for 24 hours 10.9Not known if true and if so if related to CA per se or TH, or bothTH could have contributedDid not receive oral DAT drugs pre procedureHypothermia may activate plateletsHypothermia may inhibit effect of ClopidogrelHypothermia may alter pharmacokinetics and dynamics of drugs
79Stent thrombosis following PCI post TH Penela, D. JACC 2013; 61: 201331% in TH group (5/11) vs. 0.7 in othersIbrahim, K. Eur Heart J 2011, 32: (suppl): 25314.8% in TH (4/27)Rosillo SO, et al. JACC 2014; 63(9):2..3% in TH (2/77)
81Furthermore, even if we opt to employ it, We really don’t know how implement it optimally! Time window of therapeutic effectivenessOptimal method of inducing and maintaining coolingOptimal temperatureOptimal durationHow to rewarmWhere/ how to measure temperatureProper sedation and muscle relaxationNeed for EEG monitoringSeizure detection and managementManagement of shivering, hypotension, hypertensionNeurologic assessmentHow to assess neurologic prognosisCriteria for and when to withdraw
86(i.e Kim et al’s pre hospital cooling trial, and Nielsen etal’s 36o vs 33o C TTM trial)
87Thus I believe there is an increase skepticism being raised about the benefit of therapeutic hypothermia post cardiac arrest, if not questions about how it should be applied and to whom.
88Despite what I and some others consider to be limited evidence supporting the use of Therapeutic Hypothermia post Cardiac Arrest there are still many (perhaps a majority) who are strong advocatesNolan JP. Clin Med 2011, BMJ 2011Kern KB. JACC Caridvasc Interv 2012Boutsikaris D Emerg Med Clin NA 2012Delhaye C etal. JACC 2012Varon J, et al. Am J Emerg Med 2012Scirica BM Circulation 2013Da Silva and Frontera. Cardiol Clinic 2013; 31:Perman SM, et al. Chest 2014; 145(2):
90Intra-Arrest Hypothermia CBS Sunday Morning, yesterday, April 27, 2014“Brought back from the dead” segmentSam Parnia, MD, PhD. Director of CPR research at Stony Brook School of Medicine; Director of AWARE“Today, cooling devices do much the same thing as that icy stream: it chills people whose hearts have stopped and preserves their brains until doctors can figure out how to get their hearts going again.“Cooling buys us time. So, for example, if somebody were to suddenly collapse and die at home, what we could do is go into the freezer and take out our frozen peas, frozen vegetables, put them on the body, and try to do CPR at the same time, so we can slow down the rate by which they're getting brain damage.“ !!!I could find no reference to any published work on Intra-arrestHypothermia in PubMed by Dr. Parnia although he has published a book for the general public on this topic (“Erasing Death”, Harper, 2013)
95Ongoing Pediatric RCTs (Children <18 years old) THAPCA TrialsComparison groupsHypothermia (32-34oC) for 48hrs followed by 3 days of “normothermia” ( oC) versus5 days of “normothermia”Primary outcome: Neurological outcome at 12 monthsTwo studiesNCT (n = 350): In-hospital CANCT (n = 500): Out-of-hospital CATwo pilot studiesNCT (Phase II, n = 40)48 hours of hypothermia versus 48 hours normothermiaNCT (Phase II, N = 40)72 hours of hypothermia versus 24 hours of hypothermiaOutcome: Brain injury per plasma biomarkers and MRI
100Ebell MH, et al. JAMA Intern Med 2013; 173: 1-7 Used the GWTG-R Registry51,240 IHCA in 366 hospitalsDetermined which pre-arrest characteristicspredicted good neurologic outcome (CPC 1) at dischargeThen tested in a validation groupDesigned to help patients/families make an informed DNR decision(? Could it also be used to help inform the decision as towho to utilize aggressive post arrest therapies)
101Ebell MH, et al. JAMA Intern Med 2013; 173: 1-7
102Ebell MH, et al. JAMA Intern Med 2013; 173: 1-7
10327%1.4%Ebell MH, et al. JAMA Intern Med 2013; 173: 1-7
105SummaryThe use of TH is based upon the presumed pathophysiology of neurologic injury (e.g., coma) post cardiac arrest, and animal data suggesting that this can be ameliorated by hypothermia and two RCTs reported in 2002This has led to it to be recommended by many organizations including the AHALast year at this meeting I indicated that the evidence supporting its use post OOH CA associated with shockable rhythm's thought to be due to cardiac disease was weak..And that the evidence supporting its use following cardiac arrest associated with non-shockable rhythms, and following in-hospital cardiac arrest was even weaker.The later may be due to the possibility that these patients have sustained more severe neurologic injury which is not amenable benefit from TH as currently practice.
106Summary, continued As I have just reviewed In the past year no new evidence has appeared supporting the use of TH for any indicationIf anything, new studies have reinforced the skepticism I expressed last year, and others are voicing similar concerns.
107Summary (continued)Based upon data I presented last year and new information which has become available during this past year, and until more definitive information becomes available, I recommend:TH following out-of-hospital cardiac arrest TH should be limited to patients meeting the strict criteria of the original RCTs (witnessed, presenting with shockable rhythms, and thought to be of cardiac origin)TH following in-hospital cardiac arrest TH should be limited to patients with the best likelihood of benefit (witnessed, shockable rhythms*, due to a reversible cause, who are without severe pre-existing disease or impaired neurologic status. (Consider using the GO-FAR score)*Non-shockable rhythms could be considered if arrest occurred peri-operativelyAnd finally, Instead of cooling to 32-34o, we should instead simply strictly keep body temperature no higher than 37.0o for the 30 hours after decision to treat and below 37.5o until 72 or more hours post arrest.