The Efficacy and Employment of Targeted Temperature Management

2015 - 3 June – Targeted Temperature Management
Marvin A. Wayne, MD, FACEP, FAAEM, FAHA
In this article, an expert addresses the low use of TTM by evaluating various studies conducted on TTM.

Beginning with the study by Bernard et al and that of the Hypothermia after Cardiac Arrest Study Group in 2002, targeted temperature management (TTM) has enjoyed prominence following resuscitation from cerebral ischemic events, primarily from cardiac arrest.(1,2) For the ensuing 13 years, TTM has been given status as a proven therapy to improve neurologic outcomes for unconscious patients who have survived out-of-hospital cardiac arrest (OHCA). Several landmark studies have continued to support this therapy.(3-5) Furthermore, the 2010 American Heart Association guidelines and the International Liaison Committee on Resuscitation Consensus Statement recommend cooling for resuscitated post-OHCA patients.(3,6)   More recent work published by Cronberg et al has reinforced the neurologic benefits of TTM in patients cooled to both 330C and 360C.(7)  This study further confirms that although a 2013 study by Nielsen et al (8) has challenged the ideal temperature for TTM, no literature evidence has demonstrated an adverse outcome. Whether using 360C or 330C, Nielsen et al clearly outline the continued need for prevention of hyperthermia and maintenance of mild or moderate hypothermia. Another recent paper has emphasized that without some form of controlled TTM, post-anoxic arrest patients will spontaneously develop hyperthermia, which is a disaster neurologically. Unfortunately, while the majority of post-arrest patients are candidates for TTM, the actual percentage of patients receiving this therapy sits at a dismal 2.49%.(9) While this is an improvement over previous data  (<1% received appropriate therapy), it shows how far we have to go.(10)
So, if agreement generally exists on the need for TTM, at whatever degree and using whatever method is preferred, why do so few TTM-eligible patients receive this acknowledged neuroprotective therapy?(9-11) Toma et al conducted a study to identify barriers to implementing TTM.(11) Their findings revealed that healthcare workers lacked familiarity with the therapy. The investigators also noted a dearth of concrete protocols related to TTM and a lack of agreement among various healthcare workers in accepting the supporting evidence. The workers also feared an increased workload without clear evidence of benefit, not receiving the necessary education, and potential difficulties arising from multidisciplinary coordination.

Controversy exists over when to initiate cooling. Looking at the various articles on this topic leads to confusion rather than clarification. The work of Bernard et al was primarily based on pre-hospital cooling with positive results. On the other hand, a recent study by Kim et al suggested no clear benefit as pertains to pre-hospital cooling.(1,4) I would argue the Kim study was flawed since it neither began the cooling process during resuscitation nor ensured subjects were continued on a cooling protocol at the hospital.  Pre-hospital cooling does help select candidates who meet predetermined criteria and alerts the receiving facility that a candidate is en route.  Additionally, emergency medical service (EMS) and hospital systems need to acknowledge that these patients should be taken to a facility capable of around-the-clock percutaneous coronary intervention and that has protocols in place to initiate TTM.(12-14)

TTM can be initiated before hospital arrival and be carried through the emergency department, cardiology care and the intensive care unit. It begins with bystander cardiopulmonary resuscitation (CPR) and EMS resuscitation of OHCA victims. This can be improved with community CPR training programs, publically available automatic defibrillators and well-trained dispatchers capable of coaching CPR over the telephone. The receiving hospitals must be committed to coordinating care with cardiology, as approximately 70% of OHCA patients have an occult lesion not evidenced by electrocardiogram, troponins or age.(3,13,14)

The biggest question surrounding TTM centers on the temperature target for cooling. Prior to the study by Nielsen et al, which compared 33˚C and 36˚C, parameters of 32˚C to 34˚C had been used. However, this study showed that the outcomes for patients cooled to 36˚C were basically the same as the outcomes for those cooled to 33˚C. At no time did the authors suggest not to cool. In fact, they kept tight control with both groups being cooled and no group allowed to remain normothermic or hyperthermic, as this would not be in the patients’ best interests.(12) A more recent study by Polderman et al referred to specific strengths and weaknesses of the Nielsen study.(15) Strengths included large enrollment numbers, a predefined protocol for withdrawal of therapy, and meticulous patient follow-up. Weaknesses included possible selection bias, a long delay before initiating cooling, a time of 10 hours to achieve target temperature, rapid rewarming, and sicker patients in the 33˚C arm. Polderman et al suggest that it is best to continue to cool patients to 32˚C or 33˚C, pending the results of further studies, which should compare different temperature levels and examine optimal duration and rewarming rates. Some of the authors of the Nielsen study have written that the "most interesting aspect of the TTM trial may be that it indicates substantial knowledge gaps in post-cardiac arrest fever and temperature management. The optimal temperature, duration of temperature management, and target population remain to be defined.”(16) Both Polderman et al and Nielsen et al recommend more studies, not less treatment.(15,16)

Confusion remains regarding the “best” method of cooling: surface versus intravascular. Of course, the "best" method of cooling is simply the one that is actually used. The literature suggests that both surface and intravascular methods have proven benefit. Cooling by whatever means should be continued for a time at a target temperature that is supported by the institution.(17-19) After achievement of TTM, warming should be slow, no greater than 0.30C per hour. Neuroprognostication should not begin before 48 hours post-warming. The literature suggests that the simplest and most reliable methods include spontaneous eye opening, corneal reflex and somatosensory evoked potentials.(17,18)

The success of a TTM system of care begins with EMS and is carried through the emergency department, the cardiac catheterization lab and the intensive care unit. It partners all care providers and provides them with care bundles. The results are neurologically intact survivors of OHCA, many of whom return to their baseline activity.  This outcome will only occur if each of us joins with our fellow providers to make it happen.  The greatest enemy we face in this process is our own apathy. Cool is “cool” only if we provide it.

1. Bernard S, Gray TW, Buist MD, et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med. 2002; 346:557-563.
2. Hypothermia after Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med. 2002;346:549-556.
3. Field JM, Sayre MR, Chameides L, et al. 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science Part 1: Executive Summary: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care.  Circulation. 2010;122:S640-S656.
4. Kim F, Nichol G, Maynard C, et al. Effect of pre-hospital induction of mild hypothermia on survival and neurological status among adults with cardiac arrest.  JAMA. 2014;311:45-52.
5. Lopez-de-Sa E, Rey J, Armada E, et al. Hypothermia in comatose survivors from out-of-hospital cardiac arrest: pilot trial comparing 2 levels of target temperature. Circulation. 2012;126:2826-2833.
6. Neumar R, Nolar J, Adrie C, et al. Post cardiac arrest syndrome epidemiology, pathophysiology, treatment and prognostication. Circulation. 2008;118: 2452-2483.
7. Cronberg T, Lilja G, Horn J, et al. Neurologic function and health-related quality of life in patients following targeted temperature management at 33°C vs 36°C after out-of-hospital cardiac arrest: a randomized clinical trial. JAMA Neurol. 2015 Jun 1;72(6):634-641.
8. Nielsen N, Wetterslev J, Cronberg T, et al. Targeted temperature management at 33˚C versus 36˚C after cardiac arrest. N Engl J Med. 2013; 369: 2197-2206.
9.  Dresden S, O'Connor L, Pearce G, et al. National trends in the use of post cardiac arrest therapeutic hypothermia and hospital factors influencing its use therapeutic hypothermia and temperature management. Ther Hypothermia Temp Manag. 2015 Mar;5(1):48-54.
10. Patel PV, John S, Gsarg RK, et al.  Therapeutic hypothermia after cardiac arrest is underutilized in the United States. Ther Hypothermia Temp Manag. 2011;1(4):199-203.
11. Toma A, Bensimon CM, Danty KN, et al. Perceived barriers to therapeutic hypothermia for patients resuscitated from cardiac arrest: a qualitative study of emergency departments and critical care workers. Crit Care Med. 2010; 38(2): 504-509.
12. Nielsen N, Hordenes J, Nilsson F, et al. Outcomes, timing, and adverse events in therapeutic hypothermia after out-of-hospital cardiac arrest. Acta Anaesthesiol Scand. 2009;53: 926-934.
13. Batista LM, Lima FO, Januzzi JL, et al. Feasibility and safety of combined percutaneous coronary intervention and therapeutic hypothermia following cardiac arrest. Resuscitation. 2010;81:398-403.
14. Gonzalez MR, Esposito EC, Leary M, et al. Initial clinical predictors of significant coronary lesions after resuscitation from cardiac arrest. Ther Hypothermia Temp Manag. 2012;2(2): 73-77.
15. Polderman K, Varon J. How low should we go? Hypothermia or strict normothermia after cardiac arrest. Circulation. 2015; 131:669-675.
16. Wise M, Horn J, Aneman A, et al. Targeted temperature management after out-of-hospital cardiac arrest: certainties and uncertainties. Crit Care. 2014; 18:459.
17. Grossestreuer AV, Abella BS, Leary M, et al. Time to awakening and neurologic outcome in therapeutic hypothermia-treated cardiac arrest patients. Resuscitation. 2013;84(12):1741-1746.
18. Levy D, Caronna J, Singer B, et al. Predicting outcome from hypoxic ischemic coma. JAMA. 1985 Mar 8;253(10):1420-1426.
19. Oh SH, Oh JS, Kim YM, et al. An observational study of surface versus endovascular cooling techniques in cardiac arrest patients: a propensity-matched analysis. Crit Care. 2015;19:85.