Is It Time to Stop Chilling?

The resuscitation of out of hospital cardiac arrest victims has always been a major goal of EMS. Numerous strategies have come and gone over the last 30 to 40 years in terms of improving resuscitation rates. Among these is the use of induced therapeutic hypothermia (ITH). The concept of ITH was introduced over 15 years ago. In 2003 the American Heart Association made a recommendation to begin cooling as soon as possible after a return of spontaneous circulation (ROSC). However, even with their initial recommendation, they noted that ITH was beneficial even if delayed up to 4 to 6 hours following ROSC. The targeted core temperature was 32–34°C over 4 to 16 hours. Based on this, the idea of beginning ITH in the prehospital setting was introduced and subsequently widely adopted.¹

History of Prehospital ITH

The concept of suspended animation has always been intriguing. That is, slowing down a person’s biological functions to prolong life or prevent death seems almost intuitive. This became more important as we started to learn more about reperfusion injury and oxidative stress. Oxidative stress is a disturbance in the balance between the production of toxic oxidative chemicals (e.g., reactive oxygen species or free radicals) and the body’s antioxidant defenses. Free radical release (oxidative stress) and tissue damage are major factors in poor outcomes following cardiac arrest. Hypothermia appears to reduce oxidative stress and reperfusion injury by slowing the various biochemical processes that cause free radical production.

Hypothermia has been used for over 50 years for neurologic protection in certain conditions and surgical procedures. Its role in cardiac arrest began when it was noted that people who suffered cardiac arrest secondary to accidental hypothermia seemed to tolerate anoxia much longer with less neurologic injury than those who had a normal body temperature (normothermic).² The idea of inducing hypothermia soon after cardiac arrest, in order to minimize oxidative stress, seemed intuitive. Initial animal studies of mild to moderate ITH in dogs, cats, rats and gerbils showed a significant improvement in neurologic outcomes. The first human studies using ITH were published in the late 1950s. These were very small studies (four patients and 19 patients respectively) that showed significant survival benefits for cardiac arrest patients following being therapeutically cooled to 32°C to 34°C.^3–4 The authors concluded their studies warranted the use of hypothermia following cardiac arrest. Of course, at that time, EMS as we know it today did not exist.

A study of ITH following out-of-hospital cardiac arrest was conducted in Melbourne, Australia. Patients who achieved a return of spontaneous circulation (ROSC) in the prehospital setting were cooled following hospital arrival. Overall, 22 patients received ITH using ice packs and neuromuscular blockade (to prevent shivering). The target temperature was 33°C. Survival rates were improved when compared to the control group.⁵ A second small study (33 patients) of out-of-hospital ROSC patients who received ITH (33°C) at the emergency department showed a trend toward improved outcomes but did not reach statistical significance.⁶ The first randomized study of ITH occurred in Europe and enrolled 136 patients. Of these, 55% of patients who received ITH following ROSC had improved neurological outcomes when compared to 39% in the normothermic control group.⁷ A second Australian study of 43 out-of-hospital ROSC survivors also showed improved neurologic outcome for those who received ITH (49% versus 26%).⁸

Despite these promising studies on ITH, none examined the benefit of cooling in the prehospital setting. Five studies completed within the last several years that examined prehospital cooling failed to show any benefit in terms of survival or improved neurologic outcome from prehospital induction of ITH.^9–10 A randomized trial of prehospital ITH of patients with ROSC in Melbourne, Australia, failed to show any benefit from prehospital ITH although the core temperature was modestly decreased.¹¹ The largest trial to date, conducted in King County, WA, enrolled 1,364 patients. They were randomized to receive 2 liters of 4°C saline in the prehospital setting or standard post-resuscitation measures. Interestingly, although prehospital cooling reduced the core temperature at hospital arrival and reduced the overall time it took to reach the target temperature of 34°C, it did not improve overall survival or neurologic status from ROSC patients both with ventricular fibrillation and without ventricular fibrillation. This study also found that the ITH group experienced re-arrest in the field more than the control group (26% versus 21%) which was statistically significant. In addition there was increased diuretic use and pulmonary edema on first chest x-ray (that later resolved) within 24 hours after admission.¹² Furthermore, several studies have shown survival and neurologic outcome in ROSC are just as good if cooling is delayed to the hospital setting.

Why Does It Not Work?

The initial scientific evidence regarding ITH looked promising. At that time, the potential benefit was believed to outweigh the risks. The initial evidence was based on several small human studies. None of these involved prehospital cooling. However, it seemed intuitive that the sooner cooling was started, the sooner the patient would reach the target temperature, and the better the outcome would be. Unfortunately, later studies have refuted this. The subsequent studies, many of which were scientifically more rigorous, looked exclusively at prehospital cooling and failed to find any benefit. There are several reasons for this:

1. The application of cold to a patient, whether IV fluids, cold packs or similar strategies, is extremely ineffective. The second Law of Thermodynamics defines this. The few prehospital ITH studies available have been unable to demonstrate more than a modest cooling of ROSC patients in the prehospital setting. A recent Charlotte study of 132 ROSC patients with prehospital ITH failed to reach the target temperature any faster than waiting until the patient was in the emergency department to begin ITH therapy.¹³ The standard 2 liters of chilled IV fluid does not have the heat transfer capacity to reduce the body temperature of an adult to any significant degree. It is simply limited by the laws of physics. In addition, the differences between the environmental temperature and the ability to cool a patient are extremely variable. This is a particular problem in the desert Southwest where summer temperatures often exceed 38°C to 40°C.
2. The administration of 2 or more liters of chilled IV fluids to a patient with cardiac dysfunction is not without risk. Pulmonary edema, fluid overload and similar problems are common complications of ITH therapy. We have to think beyond the field to the ICU and subsequent care.
3. Prehospital ITH, as commonly practiced, does not address shivering. Shivering is a very primitive response to hypothermia where the skeletal muscles involuntarily rapidly contract and relax in order to generate heat. This response is inevitable with ITH unless medications are given to blunt shivering. These medications include neuromuscular blockade and, in some cases, meperidine (Demerol). Without the ability to block shivering, ITH is considerably less effective.
4. The ability to constantly maintain chilled IV fluids at 4°C in ambulance and rescue vehicles is difficult at best. Furthermore, episodic IV fluid shortages may affect this therapy.
5. More recent research has shown that maintenance of normal body temperature (normothermia) may be more beneficial than hypothermia. One of the largest studies to date demonstrated that patients maintained at 36°C did better than those cooled to 33°C. This multi-center study enrolled 950 unconscious adults with ROSC after cardiac arrest. The overall mortality rate for those cooled to 33°C was 50% while those maintained at 36°C had a mortality rate of 48% (no significant difference). There was also no significant difference in neurologic function or deaths at 180 days out between the two groups.¹⁴ Based on this many centers are concentrating on maintaining normothermia rather than attempting hypothermia. This strategy makes the utility of prehospital cooling considerably less important.

Summary

The evidence is quite clear that ITH in the prehospital setting is of dubious benefit. But, what is the harm in continuing the practice? Well, prehospital ITH most likely takes away from more beneficial therapies such as high-quality CPR, rapid defibrillation, recognition of ST-segment elevation myocardial infarction (STEMI), and similar essential treatments. Several studies have shown prehospital ITH, in many cases, delays hospital transport.

When the initial studies of ITH were released, I was immediately on the ITH bandwagon. Interestingly, the American Heart Association (AHA) has never recommended prehospital ITH.¹ Even the position paper on ITH by the National Association of EMS Physicians (NAEMSP) was cautious when they wrote, “A lack of evidence on induced hypothermia in the prehospital setting currently precludes recommending this treatment modality as standard of care for all emergency medical services (EMS) patients resuscitated from cardiac arrest.”¹⁵ A systematic review of ITH recently published states, “In cardiac arrest, the initiation of therapeutic hypothermia in the out-of-hospital environment has not been shown to improve neurologic outcomes, although studies to date have been limited.”¹⁶

We now know that caution exercised by the AHA and NAEMSP was appropriate. One of my mentors in residency always said, “Never be the first doctor to prescribe a new drug or the last doctor to prescribe an old one.” Like many things in EMS, ITH is something that was put in place with good intent but limited scientific evidence. But we now know ITH is probably not a good practice and it is time to abandon it. However, we should still carry chilled IV fluids for hyperthermia, excited delirium and to maintain normothermia in patients in cardiac arrest where transport times are long.

References

1. Nolan JP, Morley PT, Vanden Hoek TL, et al. Therapeutic hypothermia after cardiac arrest: an advisory statement by the advanced life support task force of the International Liaison Committee on Resuscitation. Circulation, 2003; 108: 118–121.
2. Eisenburger P, Sterz F, Holzer M, et al. Therapeutic hypothermia after cardiac arrest. Curr Opin Crit Care, 2001; 7: 184–188.
3. Williams GR Jr., Spencer FC. The clinical use of hypothermia following cardiac arrest. Ann Surg, 1958; 148: 462–468.
4. Benson DW, Williams GR Jr., Spencer FC, et al. The use of hypothermia after cardiac arrest. Anesth Analg, 1959; 38: 423–428.
5. Bernard SA, Jones BM, Horne MK. Clinical trial of induced hypothermia in comatose survivors of out-of-hospital cardiac arrest. Ann Emerg Med, 1997; 30: 146–153.
6. Yanagawa Y, Ishihara S, Norio H, et al. Preliminary clinical outcome study of mild resuscitative hypothermia after out-of-hospital cardiopulmonary arrest. Resuscitation, 1998; 39: 61–66.
7. The 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.
8. Bernard SA, 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.
9. Hunter BR, O’Donnell DP, Allgood KL, Seupaul RA. No benefit to prehospital initiation of therapeutic hypothermia in out-of-hospital cardiac arrest: a systematic review and meta-analysis. Acad Emerg Med, 2014; 21: 355–364.
10. Diao M, Huang F, Guan J, et al. Prehospital therapeutic hypothermia after cardiac arrest: a systematic review and meta-analysis of randomized controlled trials. Resuscitation, 2013; 84: 1021–1028.
11. Bernard SA, Smith K, Cameron P, et al. 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.
12. Kim F, Nichol G, Maynard C, et al. Effect of Prehospital Induction of Mild Hypothermia on Survival and Neurological Status Among Adults With Cardiac Arrest: A Randomized Clinical Trial. JAMA, 2013.
13. Schenfeld EM, Studnek J, Heffner AC, Nussbaum M, Kraft K, Pearson DA. Effect of prehospital initiation of therapeutic hypothermia in adults with cardiac arrest on time-to-target temperature. CJEM, 2014; 16: 23–33.
14. 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.
15. National Association of EMS Physicians. Induced therapeutic hypothermia in resuscitated cardiac arrest patients. Prehosp Emerg Care, 2008; 12: 393–394.
16. Bucher J, Koyfman A. Does Initiation of Therapeutic Hypothermia on the Out-of-Hospital Environment Improve Neurologic Outcomes? Ann Emerg Med, 2015.

Bryan E. Bledsoe, DO, FACEP, FAAEM, is a professor of emergency medicine and EMS fellowship director at the University of Nevada School of Medicine in Las Vegas.