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SGEM#82: Melt with You (Targeted Temperature Management)

SGEM#82: Melt with You (Targeted Temperature Management)

Podcast Link: SGEM82
Date:  July 3rd, 2014 

Guest Swedish Skeptics: Katrin Hruska @Akutdok

Case Scenario:  A 72 year old man has witnessed arrest at the Goderich beach. By-standard CPR is started and he shocked out of ventricular fibrillation by emergency medical services but does not regain consciousness. We know from SGEM#54 that cooling in the field does not improve survival. His temperature on arrival to the emergency department is 36°C.

Question: Does cooling to a target temperature of 33°C improve survival to hospital discharge and neurological outcome in unconscious survivors of out-of-hospital cardiac arrest of presumed cardiac cause?

Background: Therapeutic hypothermia post cardiac arrest has received a great deal of attention over the last decade. Two randomized control trials showed that hypothermia post cardiac arrest resuscitation was neuroprotective. One trial (n=273) in NEJM 2002 used cooled air mattress to demonstrate good outcome at 6 months (55% vs. 39%). The smaller Australian study (n=77) also published in NEJM 2002 showed good neurologic outcome at time of hospital discharge (49% vs. 26%).

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Dr. David Newman has calculated the NNT=6 for mild therapeutic hypothermia for neuroprotection following cardiopulmonary resuscitation. The Cochrane Collaboration updated their review on hypothermia for neurporotection in adults after CPR in 2012. They concluded:

  • “Conventional cooling methods to induce mild therapeutic hypothermia seem to improve survival and neurologic outcome after cardiac arrest. Our review supports the current best medical practice as recommended by the International Resuscitation Guidelines.”

cartoon_ambulanceThe SGEM was skeptical after it covered the issue in Episode#21: Ice, Ice Baby. We looked at the paper by Bernard SA et al. called Induction of therapeutic hypothermia by paramedics after resuscitation from out-of-hospital ventricular fibrillation cardiac arrest: a randomized controlled trial, Circulation. 2010;122:737-742. The question was whether pre-hospital therapeutic hypothermia improve patient outcomes after successful resuscitation? The study had 234 patients and used large volumes of ice-cold lactated Ringer’s. The primary outcome was about 50% of patients survived to functional hospital discharge and there was not benefit to cooling.

The SGEM covered the larger pre-hopsital cooling paper by Kim F et al. in JAMA earlier this year. The bottom line was: Scoop and run after cardiac arrest with no cooling required in the field.

Reference: Nielsen N et al. Targeted Temperature Management at 33°C versus 36°C after Cardiac Arrest. NEJM 2013

  • Population: 939 patients from 36 intensive care units (ICUs) in Europe and Australia with OHCA with more than 20 consecutive minutes of spontaneous circulation after resuscitation.
  • Intervention: Cooling to 36 degrees celsius for 36 hours, <37.5 for 72 hs post-arrest
  • Control: Active cooling to 33 degrees celsius
  • Outcome:
    • Primary: Mortality at the end of the trial.
    • Secondary: Mortality, Cerebral Performance Category (CPC) 3-5 or Modified Ranking (mRS) 4-6 at 180 days

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Authors’ Conclusions: In conclusion, our trial does not provide evidence that targeting a body temperature of 33°C confers any benefit for unconscious patients admitted to the hospital after out-of-hospital cardiac arrest, as compared with targeting a body temperature of 36°C.

checklist-cartoonQuality Check List:

  1. The study population included or focused on those in the ED. Unsure
    • Comment: These were all out of hospital cardiac arrests. The emergency department was not mentioned. Some countries such as Sweden patients bypass the emergency department and are admitted directly to the hospital. However, it is reasonable to believe that many patients were admitted through the emergency department.
  2. The patients were adequately randomized.  Yes
  3. The randomization process was concealed.  Yes
  4. The patients were analyzed in the groups to which they were randomized.  Yes
  5. The study patients were recruited consecutively (i.e. no selection bias). Yes
  6. The patients in both groups were similar with respect to prognostic factors. Yes
  7. All participants (patients, clinicians, outcome assessors) were unaware of group allocation. 
    • Health care professionals caring for the trial patients were aware of the intervention assignments because of inherent problems with blinding of body temperature. Physicians performing neurologic prognostication, assessors of neurologic follow-up and final outcome, study administrators, statisticians, and the authors were unaware of the intervention assignments and so were the patients and their families. Manuscript written before randomization code was broken.
  8. All groups were treated equally except for the intervention.  Yes
  9. Follow-up was complete (i.e. at least 80% for both groups). Yes, 100%
  10. All patient-important outcomes were considered. Unsure
    • Little focus on disability. Modified Ranking Scale 0-3 slumped together
  11. The treatment effect was large enough and precise enough to be clinically significant.  No

Results: No difference in mortality. No difference in Cerebral Performance Category (CPC), modified Rankin Score (mRS) or mortality at 180 days.

Dr. Katrin Hruska

Dr. Katrin Hruska

Commentary: This is a well conducted multisite randomized controlled trial on targeted temperature management after out-of-hospital cardiac arrest. They excluded very few patients from the trial. The main reasons for exclusion:

  • Interval from return of spontaneous circulation to screening of >4 hours
  • Unwitnessed arrest with asystole as the initial rhythm
  • Suspected or know acute intracranial hemorrhage or stroke
  • Body temperature of <30°C

A strength of the study was the multiple sites where the trial was conducted and the various sizes of hospitals.

Another strong feature of this study was that temperature was managed in different ways depending on the site’s preferences. The different methods of cooling did not seem to influence the results. This makes the result applicable to different practice settings depending on local protocols.

There was a risk of bias because of the inherent difficulty of blinding the treating physician to the intervention, but this is unlikely to affect mortality.

beer-bubbles-copyThree were lots of bubbles in the FOAMed world as a result of the TTM trial. It is not necessary to go into all the details but you can read more about this issue by clicking on the links:

Comment on Author’s Conclusions: Agree with author’s conclusions.

Bottom Line: This study did not demonstrate a benefit of a targeted temperature 33C vs. 36C for survival of out-of-hospital cardiac arrest.

Case Resolution: The 72 year old man with the out-of-hospital cardiac arrest who arrived at 36°C. He was actively cooled to maintain this temperature but was not cooled further to 33°C. You plan to check in on him in the intensive care unit on your next shift.

Clinical Application: I will start cooling patients to 36°C and admit them to the intensive care unit for further management based on our own local protocols.

What Do I Tell the Patient: I will tell the patient’s wife that her husband had a cardiac arrest. We were able to bring him back but he is still unconscious. We are going to cool him to improve his chances of survival and a good neurological outcome.

KEENER KONTEST: Last weeks winner was Dr. Neil Dattani from Toronto. He knew cocaine was the first local anesthetic isolated from a plant source?

If you want to play the Keener Kontest this week then listen to the podcast for the question. Email me your answer at TheSGEM@gmail.com with “keener” in the subject line. The first person to correctly answer the question will receive a cool skeptical prize.

Upcoming conferences:

  • QueBEEM Quebec City September 29th and 30th
  • EuroBEEM Prague  December 5th and 6th

Remember to be skeptical of anything you learn,

even if you heard it on the Skeptics’ Guide to Emergency Medicine.

5 Comments

  1. I was just wondering if you could comment on the differences between a superiority trial and a equivalence trial? My understanding was that the TTM paper was a failed superiority trial (powered to detect a mortality difference of 11%), and that a negative superiority trial should not be taken to mean no difference exists between groups.

    • Good question and sorry for the delay. Will have a response to you shortly. Keep asking these important/skeptical questions.

    • Here is an article which may help you understand the difference between different trial designs. More to follow…

      http://www.ncbi.nlm.nih.gov/pubmed/18537788

  2. I agree with Medstudent comment below. I have significant concerns on the conclusion that there is “no difference” between 33C and 36C – the study was powered to detect a Hazard ratio reduction of 20%!! between the groups – that is a significant effect size. To presume non-inferiority from this study seems dangerous.

    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC59590/pdf/cvm-1-1-019.pdf

    This seems to be a growing trend in the EM literature – with PROCESS and TTM both constructed with power calculations as superiority trials (PROCESS to detect at 6-7% difference) when in fact their conclusions suggest non-inferiority.

    Would be a great skeptical discussion to have with the EM community – given the recent buzz of TTM and PROCESS

    • Thank you for expressing your concerns. I have updated the bottom line to be more accurate.

      “This study did not demonstrate a benefit of a targeted temperature 33C vs. 36C for survival of out-of-hospital cardiac arrest”.

      An example of FOAM peer review.

      Ken

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