Therapeutic Hypothermia: An old treatment gets a new look

Imagine you are on a suburban paramedic crew that responds to a 60-year-old woman who collapsed in front of her husband as she attempted to get out of bed to use the bathroom. Telephone CPR is in progress. On arrival, you find the patient in v-fib. You administer three shocks, and your partner begins intubating the patient. Eventually, you’re able to get back a working rhythm. Sounds pretty routine so far, but here’s where it gets interesting: En route to the hospital, as part of your local protocol, you begin an infusion of ice-cold saline. Sound strange? Perhaps not.

Clinical use of therapeutic hypothermia has been around for over 70 years. After waxing and waning in popularity, therapeutic hypothermia has reemerged as a potentially lifesaving tool in the fight to save the hypoxic brain. Although there is a growing body of evidence to support this treatment, further research on therapeutic hypothermia is needed to see if this treatment option should become the new standard of care.

Emergency medical services have gone through dramatic changes in the last 25 years. Cutting-edge drugs and diagnostic equipment give patients the best possible chance of survival, especially when it comes to out-of-hospital cardiac arrests. Despite these advances, however, the statistical chance of a patient making full neurological recovery following an out-of-hospital cardiac arrest is still very poor. The medical community needs to consider how to help these patients not only survive, but have a quality life. Further research on therapeutic hypothermia, a relatively new treatment that may increase the odds of neurological recovery, may be the answer. A coordinated effort between EMS and hospitals to research the use of therapeutic hypothermia to treat cardiac arrests should be explored.

History

It is well known that the brain responds poorly to hypoxic events. In most situations, the 4–6-minute “point of no return” still applies. Part of the problem (perhaps not realized by many responders) is that brain damage will continue for several hours following resuscitation; it doesn’t simply stop because the patient’s heart starts beating again.1 In fact, only a fraction of cardiac arrest patients fully recover from this brain damage. One study showed that while 17%–25% of cardiac arrest patients survived to hospital admission, only 4%–9% left the hospital neurologically intact.2 Some research has shown, however, that therapeutic hypothermia can help increase the odds of these patients recovering completely.

Medical application for hypothermia actually began thousands of years ago with the ancient Egyptians, Greeks and Romans.3 Even then, practitioners recognized that hypothermia could slow bleeding. Anecdotal evidence of the therapeutic effects of hypothermia can also be seen in children who drown in an ice-covered lake, only to be revived 30 minutes later without brain damage.

The mechanism of how hypothermia protects brain tissue is not clearly understood and is beyond the scope of this article. Suffice it to say that hypothermia is believed to decrease cerebral oxygen requirements and reduce the production of free radicals that can cause permanent brain damage.4

Clinicians began seriously exploring medical use of induced hypothermia in the 1930s, when cases were published citing favorable outcomes in patients resuscitated after long periods of apnea following cold-water drowning.3 Animal studies subsequently carried out in the 1950s were able to show a benefit from induced hypothermia in dogs with brain trauma and ischemia. These early studies led to human trials in the 1960s, but the human experiments were largely abandoned due to serious complications and difficulty in proving efficacy.3 The complications were serious enough to stall further therapeutic hypothermia research for decades. A review of severe hypothermia side effects includes:

• Decreased level of consciousness
• Hypoxia
• Loss of motor reflexes
• Acid-base disturbances
• Decreased cerebral blood flow
• Hypotension
• Bradycardia
• Increased ventricular fibrillation risk
• Asystole.

In the last 10 years, however, therapeutic hypothermia has again caught the interest of clinicians. Physicians have renewed their exploration of how hypothermia can assist in minimizing or negating the debilitating neurological effects of cardiac arrest, stroke and brain trauma. Many problems encountered in the early studies were found to be surmountable when researchers discovered that the deep hypothermia used in previous trials (below 30ºC) was unnecessary (see Table I for general metric conversions). Mild forms of hypothermia (32º–35ºC) were found to have the same benefits without the serious side effects.3

The EMS Role

Paramedics played an important role in beginning this potentially lifesaving treatment. EMS is mentioned in several studies as being a vital link in the therapeutic hypothermia treatment process, which usually must continue for a minimum of 12 hours following cardiac arrest. Since therapeutic hypothermia benefits decrease drastically after a delay of even a few minutes following successful cardiac arrest resuscitation,5 EMS may be in the best position to begin immediate treatment.

Current research has shown, almost universally, that therapeutic hypothermia indeed reduces brain damage following cardiac arrest.1,4,6,7-12 Where studies differ is in determining at what point such hypothermia should be initiated and what method should be used.

Timing

Determining the appropriate time to implement hypothermia is a matter of some debate, although most researchers agree that such treatment should be initiated as soon as possible following reperfusion.2,5,6 Some clinicians are concerned that beginning therapeutic hypothermia during cardiopulmonary arrest (as opposed to after reperfusion) could lead to negative cardiovascular effects.6 While some animal studies have shown no untoward effect with initiation of hypothermia during resuscitative efforts,6,12 Dr. Stephen Bernard, an Australian physician who has pioneered much of the current research, states that there is a very real danger of affecting defibrillation thresholds if the patient is cooled too aggressively during cardiac arrest.13

Conducting such a procedure at the onset of ACLS activities may not be realistic in any case. With the flurry of activity focused on intubation, starting an IV, initiating DC shock (if necessary) and administering necessary cardiac drugs, therapeutic hypothermia may be forced to take a backseat. In addition, implementation of such forced cooling may be a waste of time, equipment and personnel if the patient never regains spontaneous circulation. Thus, hypothermic treatment may best be initiated en route to the hospital, after primary ACLS duties have been completed and return of spontaneous circulation has been achieved.

Cooling Techniques

Focused cranial cooling versus total systemic cooling is another subject of debate. Some have hypothesized that since the brain is the focus of the hypothermic protection, cooling efforts should be directed there. Such focused cooling may also be able to reduce the potential negative cardiac effects of total systemic cooling. There are questions, however, whether isolated cranial cooling is even possible. While one study showed that packing bags of ice around the neck and head of swine can significantly reduce brain temperature,2 a field EMS study carried out in Pittsburgh was unable to reproduce the same effect.14 The authors of the Pittsburgh study suggested that one of the reasons for this may be that circulation of warmer blood from the core may in part negate the effects of isolated cranial cooling. Another problem with isolated brain cooling is that EMS and hospitals are often ill- equipped to initiate such cooling techniques.

Systemic cooling appears to be a better method for implementing therapeutic hypothermia. One concern about systemic cooling is that total body cooling could negatively affect the cardiovascular system. The risk of severe cardiovascular effects, however, is rarely a problem unless the body temperature falls below 28º–30ºC.15 One researcher was able to show that by infusing ice-cold saline IV at 30 ml/kg, core temperature could be reduced to between 35.5º and 33.8ºC without adverse effects.16 This technique, reproduced in other studies,15 may hold the best promise as a safe, inexpensive and fast method to induce therapeutic hypothermia.

Potential Side Effects

Therapeutic hypothermia is not without potential side effects. Some researchers believe, however, that such side effects are minor and acceptable, considering the overwhelming evidence of benefits.7 Research has shown the following potential side effects of therapeutic hypothermia:

• Higher rate of infection7
• Increase in blood glucose1
• Increased potassium levels1
• Lower cardiac index1
• “Pneumatic complications”10
• Abnormal clotting factors10
• Theoretical possibility of pulmonary edema if chilled fluids are used to induce hypothermia (this has not been witnessed thus far)
• Uncontrolled shivering may negate induced hypothermia benefits (several studies have used paralytics to offset this problem).

These symptoms were observed in the case studies cited in this article. To minimize potential side effects, care must be taken not to overcool the patient. Temperature must be monitored constantly.

Discussion

In EMS, much of the recent focus in treating out-of-hospital cardiac arrest has centered on drugs and equipment to revive the heart and deliver the patient to the emergency department with a return of spontaneous circulation. Little attention has been given to ensuring these patients have the best possible chance of returning to a “normal” lifestyle. Our patients deserve the best possible chance of walking out of our hospitals neurologically intact.

An important study from the New England Journal of Medicine showed promising results with therapeutic hypothermia. Study groups were broken into two post-cardiac arrest groups. One received therapeutic hypothermia, the other did not. Over half (55%) of the hypothermic group showed “favorable outcomes” compared with 39% of the normothermic group. Even more telling is the mortality rate. Six-month mortality was 41% in the hypothermic group compared with 55% of the normothermic group.7 This study, among others, caused Canadian researchers to conclude that therapeutic hypothermia should be considered the standard of care for selected patients with anoxic brain injury post cardiac arrest.4 Much of the published research (both on animals and humans) on therapeutic hypothermia has shown similar results.

Multiple animal and human studies have shown that mild hypothermia (33º–35ºC), initiated as soon as possible following cardiac arrest, can dramatically improve the survival rate of patients, with few side effects. Large human clinical trials continue.7,13 Therapeutic hypothermia is already considered the post- cardiac arrest standard of care in several hospitals worldwide and is finding its way into EMS care in Australia. Implementation of such cooling in the prehospital field is challenging, but not impossible. A few bags of ice-cold saline could easily be kept in a small, portable, 12-volt cooler in most ambulances.

Early research seems to demonstrate significant benefits of therapeutic hypothermia. Medical program directors and EMS agencies in the United States should actively coordinate with their local hospitals to implement more field and clinical studies of therapeutic hypothermia.

References

1. Bernard SA, Gray TW, Buist MD, et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. New Engl J Med 346(2):557–563, 2002.
2. Tadler SC, Callaway CW, Menegazzi JJ. Noninvasive cerebral cooling in a swine model of cardiac arrest. Acad Emerg Med 5(1):25–30, 1998.
3. Polderman K. Application of therapeutic hypothermia in the ICU: Opportunities and pitfalls of a promising treatment modality. Part I: Indications and evidence. Intensive Care Med 30(2):556–575, 2004.
4. Olafson K, Selaman M, Easton DW. Best evidence in critical care medicine: Therapeutic hypothermia to improve neurologic outcome after cardiac arrest. Can J Anesth 51(1):76, 2004.
5. Kuboyama K, Safar P, Radovsky A, et al. Delay in cooling negates the beneficial effects of mild resuscitative cerebral hypothermia after cardiac arrest in dogs: A prospective randomized study [Abstract]. Crit Care Med 21(9):1348–1358, 1993.
6. Hagioka S, Takeda Y, Takata K, et al. Nasopharyngeal cooling selectively and rapidly decreases brain temperature and attenuates neuronal damage, even if initiated at the onset of cardiopulmonary resuscitation in rats. Crit Care Med 31(10):2502–2508, 2003.
7. Holzer M. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest: The hypothermia after cardiac arrest study group. N Engl J Med 346(2):549–556, 2002.
8. Sterz F, Holzer M, Roine R, et al. Hypothermia after cardiac arrest: A treatment that works. Current Opinion in Critical Care 9(3):205–210, 2003.
9. Behringer W, Prueckner S, Safar P, et al. Rapid induction of mild cerebral hypothermia by cold aortic flush achieves normal recovery in a dog outcome model with 20-minute exsanguination cardiac arrest. Acad Emerg Med 7(12):1341–1348, 2000.
10. Zeiner A, Holzer M, Sterz F, et al. Mild resuscitative hypothermia to improve neurological outcome after cardiac arrest: A clinical feasibility trial. Stroke 31(1):86, 2000.
11. Sterz F, Safar P, Tisherman S, et al. Mild hypothermic cardiopulmonary resuscitation improves outcome after prolonged cardiac arrest in dogs. Crit Care Med 19(3):379–389, 1991.
12. Xiao F, Safar P, Radovsky A. Mild protective and resuscitative hypothermia for asphyxial cardiac arrest in rats. Am J Emerg Med 16(1):17–23, 1998.
13. Bernard SA. Dandenong Hospital, Australia. Interview with the author. April 25, 2004.
14. Callaway CW, Tadler SC, Katz LM, et al. Feasibility of external cranial cooling during out-of-hospital cardiac arrest. Resuscitation 52(2):159–165, 2002.
15. Polderman K. Application of therapeutic hypothermia in the intensive care unit: Opportunities and pitfalls of a promising treatment modality. Part 2: Practical aspects and side effects. Intensive Care Medicine online: (2):1–31, 2004.
16. Bernard SA, Buist M, Monteiro O, et al. Induced hypothermia using large volume, ice-cold intravenous fluid in comatose survivors of out-of-hospital cardiac arrest. Resuscitation 56(1):9–13, 2003.