Why we do What we do? Critical Care Edition: Therapeutic hypothermia

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          Cardiac arrest to this day continues to be a major cause of death even this advanced technological age of medicine. According to the AHA as of 2013 there is incidence of Out-of-Hospital Cardiac Arrest (OHCA) of 359,400 a slight decrease from 2012 (382,800). Even with bystander CPR at 40% the overall survivor rate from this deadly disease is only 9.5%. There is not much improvement in survival with in hospital cardiac arrest (incidence 209,000; 23.9 % survival rate with adults and 40% with children. With survivors there is also the concern of meaningful neurologic function. Often described as having a cerebral performance category (CPC) score of 1 or 2. CPC score of 1 indicates a patient is conscious, alert, and able to work. CPC score of 2 indicates some one who is conscious and  able to carry out independent activities. CPC 3 indicates  someone who is dependent on others for daily support. CPC score of 4 indicates a vegetative state while 5 correlates to a patient who is dead (1). The one therapy that has showed promise in many animal and a few randomized controlled human studies is therapeutic hypothermia to improve neurologic outcome in post-arrest patients (2). Many national organizations recommend this treatment as standard of care after achieving ROSC (return of spontaneous circulation) but why. Well to answer this question its important to know what are the neurological pathologic processes occurring after cardiac arrest.

 

            Now bare with me we will have to review biochemistry quickly. After suffering cardiac arrest and successful ROSC patients suffer neurologically two fold. The term is coined ischemia-reperfusion injury. The effects are deleterious on the cellular level which include increased mitochondrial injury with a resultant dramatic decrease in ATP production. The lack of ATP shifts metabolism to anaerobic glycolysis, which leads to ion pump dysfunction and increased intracellular calcium which leads to intracellular kinase and protease activation. Fat metabolism is also increased with concomitant rises in ketonic acids and lactate further contributing to metabolic acidosis. Also extremely elevated levels of the excitatory neurotransmitter glutamate is released which in high levels is severely neurotoxic. Other detrimental systemic causes of ischemia-reperfusion injury includes cell membranes leakage and cytotoxic edema, production of free radicals, coagulation activation and micro-thrombi formation, and non-convulsive status epileptic activity(3). Needless to say the brain damage is severe and is multi-factorial, but luckily numerous studies show that hypothermia can reduce or eliminate all of these processes.

 

            So now we have touched on why hypothermia may improve post-arrest neurologic dysfunction lets review how to achieve it. There are three steps therapeutic hypothermia. The three phases include induction, maintenance and re-warming phase. The goals are to quickly achieve induction phase which is to bring the core body temperature to 32-34 degrees celsius rapidly. This can be done via ice cold normal saline typically cooled to 4 degrees celsius, ice packs, cooling blankets, or surface air cooling (such as the Arctic Sun). Each method has been studying and none has proven to be superior to another with the exception of rapidity to achieving target temperature (4). The Arctic Sun has been compared to cooling blankets and ice packs in one trial which did show a faster cooling time to 34 degrees celsius (5). In order to accurately measure core temperature many devices have been used such as the more common bladder, rectal, tympanic membrane, and esophageal temperature probes and even more invasive iliac-femoral and pulmonary arterial devices have even been implemented. With the exception of tympanic membrane temperature more closely associating with brain temperature no other device provides a substantial benefit over another (14). Currently  Its been proposed that the earlier to achieve target temperature the better the neurologic outcome. There have been a few studies that looked at pre-hospital cooling via EMS to see if patients had better neurological and mortality outcomes. There was a randomized controlled single center trial that looked to see if pre-hospital cooling improved  neurological outcome at discharge but did not find a benefit even though patients reached target temperature earlier (6). Achieving target temperature is just the beginning during the maintenance phase goal is to keep fluctuations of temperature between 0.2 and 0.5 degrees celsius and the biggest challenge is physiologic shivering. To prevent shivering neuromuscular blockade and sedation medications are often administered such as vecuronium, versed, fentanyl and meperidine as some examples. Most studies and hypothermia protocols have used the length of cooling between 12-24 hours with few lasting to 72 hours although the exact timing has not been well established (7). The next phase is active rewarming which is mostly achieved with heated blankets. It is crucial in controlling the rapidity of rewarming with a recommended 0.2-0.5 degree/hr to 37 degrees celsius and prevention of hyperthermia.(8) This is due to the fact that large changes in volume status and even more concerning electrolyte shifts can be fatal (9). Now that we have gone over how to cool we will wrap up with who to cool.

 

            Two landmark trials in the early 2000s lead to widespread implementation and adaptation by many US and Eurasian societies in incorporating therapeutic hypothermia as standard of care following ROSC after cardiac arrest. These include Bernard and HACA (Hypothermia After Cardiac Arrest Study Group) trials.  In summary both were randomized controlled trials with relatively small sample sizes that had inclusion criteria of initial rhythm of Ventricular fibrillation, age of greater than 18 and persistent coma following ROSC. HACA study showed patients treated with mild hypothermia had improved CPC scores (1 or 2) at discharge (10). While the Bernard trials described a favorable outcome as good neurologic outcome discharged home or to a rehab facility (7). From these two trials there was consensus that patients with VF should receive hypothermia and would have successful outcomes.

 

            For patients whose initial rhythm was asystole or PEA (pulseless electrical activity) it was unclear whether or not they would benefit from hypothermia treatment. One retrospective trial by Oddo et al included all cardiac arrest despite the rhythm patients including those in cardiogenic shock. This study was from a single ICU with 109 patients with 86 in VF and 23 in PEA or asystole. The study concluded that patients with cardiogenic shock treated with hypothermia had favorable outcomes but in those with initial rhythms of PEA or asytole prognosis was still dismal therefore it could not be suggested that TH would be of benefit. One of the obvious limitations of this study was its small sample size (11). Therefore the same author participated in a prospective  study over 2 years  in a single ICU to determine what early predictors were associated with positive outcome in cardiac arrest. The predictors analyzed were the initial rhythm, presence of shock, blood lactate levels, and time to ROSC. Only 74 patients met inclusion criteria and this study found that initial rhythm was not statistically significant to be a a predictor of survival, although looking at the raw numbers patients with initial rhythm of VF after cardiac arrest did perform better neurologically and had increase survival. The only independent predictors that were statistically significant were time to from collapse to ROSC and blood lactate levels. When ROSC was achieved in less than 25 minutes survival to hospital discharge was 65.7 % and good neurological outcome (CPC scores of 1 or 2) was 57.9% (Oddo 2). With the findings of these two papers it could be reasonably assumed that patients whose initial rhythm is PEA or asystole do not have favorable outcomes following cardiac arrest although a larger randomized controlled center study should be conducted before making this conclusion.

 

            As this article was being written a new larger study examining the benefits of therapeutic hypothermia was released in NEJM. Nielsen et al compared targeted temperature management of 33 degrees celsius vs 36 degrees in an international trial consisting of 36 ICUs in Europe and Australia with 950 patients. The patients included were cardiac arrest patients greater than age of 18 irrespective of initial rhythms. The authors using standard hypothermia treatment found there was no benefit in all cause mortality (primary outcome) or survival and neurologic function at 180 days (secondary outcome) when comparing targeted temperature between 33 and 36 degrees celsius and concluded it was prevention of fever and not necessarily hypothermia contributes to neurologic benefit. The study also did not find any harm when targeting the temperature of 33 degrees. So what does this mean well this study did not compare normothermia (37 degrees Celsius) to hypothermia so the only major benefit this author concluded for this study is that moderate hypothermia is comparable to mild hypothermia (32-34 degrees celsius) and is likely easier to induce and maintain and can be considered a targeted temperature in cardiac arrest patients. Overall any hyperthermia following ischemia-reperfusion injury is neurologically deleterious and should be avoided at all cost. In summary although a very promising therapeutic modality for treatment of post-arrest patients there are still many questions to be answered to optimize this treatment such as how long to cool and still who will benefit from cooling. All in all hypothermia is a relatively easy and cost-effective treatment option  and in this author’s opinion should remain standard of care in treating suspected cardiac post-arrest patients. 

 

 

 

References

  1. Cronberg,T. et al, 2009. Long-term neurological outcome after cardiac arrest and therapeutic hypothermia. Resuscitation, 80, 1119-1123.
  2. Holzer, M. et al, 2005, Hypothermia for neuroprotection after cardiac arrest: Systematic review and individual patient data meta-analysis. Critical Care Medicine, 33(2), 414-418.
  3. Polderman, K.H., 2009. Mechanisms of action, physiological effects, and complications of hypothermia. Critical Care Medicine, 37(7), S186-S202.
  4. Bernard,S.,et al, 2003. Induced hypothermia using large volume, ice-cold intravenous fluid in comatose survivors of out-of-hospital cardiac arrest: a preliminary report. Resuscitation, 56, 9-13.
  5. Heard,K.J., et al, 2010. A randomized controlled trial comparing the Arctic Sun to standard cooling for induction of hypothermia after cardiac arrest. Resuscitation, 81,9-14.
  6. Kim,F., et al, 2013. Effect of Prehospital Induction of Mild Hypothermia on Survival and Neurological Status Among Adults With Cardiac Arrest A Randomized Trial. Journal of American Medical Association, E1-E8.
  7. Bernard, S., et al, 2002, Treatment of Comatose Survivors of Out-Of-Hospital Cardiac Arrest with Induced Hypothermia. New England Journal of Medicine, 346 (8), 557-563.
  8. Bouwes,A., et al, 2012. The influence of rewarming after therapeutic hypothermia on outcome after cardiac arrest. Resuscitation, 83, 996-1000.
  9. Polderman,K.H., et al, 2009. Therappeutic hypothermia and controlled normothermia in the intensive care unit: Practical considerations, side effects, and cooling methods. Critical Care Medicine, 37(3), 1101-1120.
  10. The Hypothermia After Cardiac Arrest Study Group, 2002. Mild Therapeutic Hypothermia To Improve the Neurologic Outcome After Cardiac Arrest. The New England Journal of Medicine, 346 (8), 549-556.
  11. Oddo,M., et al, 2008. Early predictors of outcome in comatose survivors of ventricular fibrillation and non-ventricular fibrillation cardiac arrest treated with hypothermia: A prospective study. Critical Care Medicine, 36(8), 2296-2301.
  12. Oddo, M., et al, 2006. From evidence to clinical practice: Effective implementation of therapeutic hypothermia to improve patient outcome after cardiac arrest. Critical Care Medicine, 34 (7), 1865-1873.
  13. Nielsen, N., et al, 2013. Targeted Temperature Management at 33 degrees Celsius versus 36 degrees Celsius after Cardiac Arrest. The New England Journal of Medicine, 1-10. doi:10.1056/NEJMoa1310519.
  14. Alzaga, A., Cerdan, M., Varon, J., 2006. Therapeutic Hypothermia. Resuscitation, 70, 369-380.

Contribution by Dr. Moses Washington MD

One Comment

  • sannman

    Can we post up the Jacobi and Monte criterion for hypothermia protocol? We recently had a cardiac arrest to ROSC pt who did not meet the downtime cutoff for JMC (he was down for 30min). It would be nice to see the guidelines for our practice compared to current literature.

    Anyway great read.

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