Why does inducing therapeutic hypothermia (TH) increase survival rates for out-of-hospital cardiac arrests triggered by ventricular fibrillation? And why have healthcare agencies, particularly EMS, been slow to implement this treatment?
Annually, nearly 450,000 people in the U.S. are victims of sudden death from cardiac arrest (CA).1 Despite numerous treatment options, survivals to hospital discharge have remained relatively unchanged over the last 50 years.2 While technological advances are increasing the survivability of cardiac arrest, patients are still not living long enough to be discharged from the hospital.
Therapeutic hypothermia has been associated with improving the survival rate of cardiac arrest patients, as well as helping reduce their neurological impairment. However, it may need to be implemented as soon as possible for maximal benefit. The earliest stage in the chain of survival at which TH can be implemented is in the EMS system. But EMS agencies can't begin TH if it can't be continued by receiving hospitals.
Several factors impede the implementation of TH in hospitals. This article evaluates the physiology of TH and analyzes the factors preventing its implementation.
Annually, around 300,000 adults in the United States experience out-of-hospital cardiac arrests.3 These patients have a variety of treatment regimens available. With the pharmacological therapy, intra-aortic balloon pumps, state-of-the-art intensive care units and extracorporeal membrane oxygenation treatments we have today,2 cardiac arrest care has progressed tremendously. However, according to the University of Pennsylvania's Raina M. Merchant, MD, "TH is the only post-resuscitation therapy shown to improve both survival and reduce disability after cardiac arrest."3
Within the past decade, several research papers focusing on the use of TH after CA have been published.4 However, there are only four trials of mild hypothermia after CA that describe any kind of comparative study, and as treatment could not be blinded, only two of these studies were randomized controlled trials (RCTs).5 Here are brief descriptions of these four studies.
- Bernard, et al, 1997: A prospective study using a historic control group of 22 adult patients who remained unconscious following initial VF out-of-hospital cardiac arrest (OHCA). The hypothermic group was cooled to 33 degrees [all temperatures Centigrade] for 12 hours with surface cooling and icepacks. Patients were then actively rewarmed over 6 hours. Findings: Good neurological outcome (GOS 1 or 2) in 11/22 of hypothermic group. Limitations: Study was not an RCT or multicenter, but a prospective study with a small sample size of 22 historic control. This was a pilot study for a later RCT.
- Yanagawa, et al, 1998: A prospective study from one site in Japan involving 28 adult patients who sustained OHCA and ROSC. Thirteen were selected for TH of 33-34 degrees for 48 hours. Cooling was achieved using cooling blankets. Patients were passively rewarmed at 1 degree a day. Findings: More survivors (7/13 vs. 5/15) and improved neurological outcomes in TH group. However, 11/13 in the TH group vs. 6/15 in the control group developed pneumonia. Limitations: Not an RCT. Used historic controls rather than randomization. Small scale, single center. Predominantly male sample, and TH group was 6 years younger than historic control group.
- Bernard, et al, 2002: Multicenter RCT involving 4 hospitals in Australia with 77 patients remaining unconscious following OHCA. Of these, 43 received TH to 33 degrees for 12 hours. Cooling was achieved using icepacks. Findings: TH group had good neurological recovery (21/43 vs. 9/34 for normothermic group). TH increased survival (21/43 vs. 11/34). Limitations: Odd and even day randomization may be difficult to achieve outside a controlled hospital environment. Strict inclusion criteria, only involved shockable CAs. Excluded women below age 50.
- HACA Study Group, 2002: Multicenter RCT across Europe involving 275 adult patients who sustained OHCA and ROSC. Of these, 137 received TH to 32-34 degrees. for 24 hours with an external cooling device consisting of a mattress and cover that deliver cold air to the entire body. After 24 hours, they were passively rewarmed over 8 hours. Findings: Of TH group, 55% had good neurological outcomes vs. 39% in the normothermic group. Six-month mortality was 41% in the TH group, 55% in the normothermic group. Limitations: Study ended prematurely because of funding difficulties. Strict inclusion criteria caused a delay in sample recruitment.
The earliest of these studies was the preliminary clinical trial led by Australian physician Stephen A. Bernard in 1997, which was the pilot for his 2002 RCT.4 Bernard's team studied 22 adult patients who remained comatose after an initial out-of-hospital VF CA. The TH group was cooled to 33 degrees using icepacks and maintained in TH for 12 hours before being actively rewarmed. Neurological outcomes were assessed using the Glasgow Outcome Score (GOS). The results were compared with a historical sample of 22 patients who did not receive TH after CA. The study found that 11 of 22 TH patients had good neurological recoveries, with Glasgow scores of 1 or 2, compared to 3 of 22 patients in the normothermia historical control group.4
In 1998, Japanese physician Youichi Yanagawa aimed to compare the effects of hypothermia following out-of-hospital cardiac arrest. His group involved 28 patients; the hypothermia group was cooled to 34 degrees for 48 hours, while the control group was treated per standard practice without hypothermia.4 The study found that 54% of the hypothermic patients survived, compared to 33% of the normothermic group. Yet while only 40% of the normal group developed pneumonia, 85% of the hypothermic patients did. This suggests that although TH improves outcomes after CA, it also increases the incidence of pneumonia.4
The two randomized controlled trials that served as the basis of the International Liaison Committee on Resuscitation's recommendation in support of TH were the Hypothermia After Cardiac Arrest (HACA) trial and Bernard's 2002 trial.6 The HACA trial was conducted in nine centers across five European nations; Bernard's work was undertaken in four hospitals in Melbourne.7 These trials were similar in that they enrolled comatose patients resuscitated from ventricular fibrillation or pulseless ventricular tachycardia. All patients received advanced cardiac life support with post-resuscitation care; all were sedated, paralyzed to prevent shivering, and ventilated.6 The TH groups of both trials were cooled to 32-34 degrees within six hours of arrest. The hypothermia protocols differed slightly.
In the European study, 75 of 136 (55%) patients in the hypothermia group had favorable neurological outcomes and were able to live and work independently six months post-arrest, compared to 54 of 137 (39%) of the normothermic patients.7 After six months, death occurred in 41% of the hypothermic group and 55% of the normothermic group.7 The Australian study focused on neurological function at the time of hospital discharge. Of the 43 patients treated with hypothermia, 21 (49%) had good neurological function, compared to 9 of 34 (26%) who did not receive TH.7
Reperfusion Injury and the Physiology of Hypothermia
Why does therapeutic hypothermia lead to this improved outcome in patients? To understand this effect, it is important to understand two concepts: reperfusion injury and the physiology of hypothermia.
When cardiac arrest occurs, blood flow to the brain ceases. As a result, cerebral tissue becomes ischemic, and oxygen levels are depleted.8 Immediately post-resuscitation, there is an excessive increase in cerebral blood flow; however, for the 90 minutes to 12 hours following this, blood flow is decreased to only 50% of the baseline value before CA.8 Scientists have known for decades that cellular oxygen deprivation causes cell damage and can lead to cellular death. However, due to the work of Lance Becker, MD, of the University of Pennsylvania, we now have a better understanding of the physiology behind this.2 When a cell becomes ischemic, a cycle of three critical reactions occurs within it. These lead to further tissue injury and ischemia even after perfusion returns to baseline values--thus the term reperfusion injury.2 These reactions include the production of oxygen free radicals (reactive oxygen species), excitatory amino acid release, and calcium shifts.7 In turn, they lead to mitochondrial damage and apoptosis (programmed cell death).7
Within the cell, mitochondria use oxygen to produce energy. Once the oxygen is used, the mitochondrion releases an oxygen free radical. These free radicals are highly reactive due to an unpaired valence electron.2 The reaction of these radicals triggers a chemical chain reaction that uses adenosine triphosphate (ATP) and produces lactic acid.2 The decreased availability of ATP and increased levels of lactic acid--which cannot be removed with the decreased perfusion--cause muscle death. Under normal conditions, the body produces antioxidants to counteract free radicals. However, during major injury or ischemia, the production of these antioxidants is drastically reduced, and thus the free radicals become a major problem.2
Reperfusion injury causes hypotension, vascular and organ dysfunction, cerebral edema and apoptosis.2 Hypothermia suppresses many of the chemical reactions associated with reperfusion injury and thus counteracts some of the negative physiological effects that result after resuscitation.7 For each 1-degree drop in temperature, the cerebral metabolic rate is decreased 6%-7%.8 This is advantageous because it decreases oxygen demands in the same cells that are being deprived of oxygen supplies.9
Approximately 30% of cardiac arrest survivors endure severe brain damage.8 Three distinct stages of cerebral damage follow anoxic insult: early, intermediate and late.2 The early stage starts from the moment of insult and lasts an hour after injury. During this stage, metabolic demands increase while perfusion decreases. Despite a dramatic loss in supplies, the consumption of oxygen, glucose and ATP continues. Hypothermia works to significantly reduce metabolic demands on the brain.2 It is most beneficial when applied early, within 15 minutes of the onset of ischemia.9
The intermediate stage spans from 1 to 12 hours post-resuscitation. Excitatory amino acids and glutamate are released, triggering the ion channels in the brain and causing a calcium ion rush into the intercellular space. This activates cytotoxic cascades within the cells, causing neuronal cell death. Increased levels of nitric oxides in the brain after cardiac arrest can cause vascular dysfunction. Hypothermia decreases the release of excitatory amino acids and glutamate while also decreasing the production of nitric oxide.2
The late stage is from 12 to 24 hours post-resuscitation. Markers of this stage include cerebral edema, breakdown of the blood-brain barrier, seizures and neuronal death. At this point, hypothermia helps by slowing the breakdown and decreasing intracranial pressure and cerebral edema.2
For each hour TH is delayed, the odds of neurological impairment increase by 30%.2 This is why it is essential to start TH in the prehospital setting. As of September 2008, out of roughly 24,000 EMS agencies in the United States, about 100 had implemented therapeutic hypothermia protocols.2 Furthermore, in a survey led by Benjamin Abella, MD, 265 physicians were questioned regarding their use of TH, methods used and/or why they had not incorporated TH into their practices. Of these physicians, 87% said they had not used TH: 49% felt there was not enough supporting data, 32% cited a lack of incorporation into ACLS protocols, and 28% said the methods for cooling were too difficult or too slow.10
In October 2002, the Advanced Life Support Task Force of the International Liaison Committee on Resuscitation (ILCOR) recommended that comatose adult patients with spontaneous circulation after out-of-hospital cardiac arrest caused by an initial VF rhythm should be cooled to 32° to 34 degrees for 12 to 24 hours. The American Heart Association (AHA) recommended therapeutic hypothermia induction in 2003 and again in its 2005 Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care.3 Despite the multitude of benefits an induced TH protocol can present for cardiac arrest patients (as well as other trauma patients), several factors inhibit implementation in the hospital setting, and therefore within EMS.
Factors Limiting Implementation of TH
EMS is a liaison between out-of-hospital patients and medical centers. Any treatment or care started in the field must not possess a potential of harm to the patient. If induced hypothermia is ended prematurely, the patient might be harmed. Therefore, for EMS systems to use TH, it is crucial they have a medical center that can continue the treatment.11
It is thus important to analyze the factors inhibiting the implementation of TH protocols in both hospitals and EMS systems. These include a lack of evidence, cost, concern about the continuum of care, induction methodology, time, resources and uncertainty about adverse effects. In addition, personal barriers such as unawareness or simple resistance to change may be significant inhibiting factors.12
Lack of evidence--It is important to note that although many studies have been conducted examining the effects of in-hospital therapeutic hypothermia, few have researched the effects of inducing TH in the prehospital setting.2 The National Association of EMS Physicians believes the lack of evidence on the induction of TH in the prehospital setting precludes the recommendation of a protocol as the standard of care for EMS patients resuscitated from cardiac arrest.11 In addition, British physician G.C. Fisher has argued that a lack of thorough detail in the two major foundational studies allows the clinically skeptic to claim the trials invalid and therefore resist using TH.13 To overcome this, additional research may have to be conducted. The European Resuscitation Council believes prehospital hypothermia is safe and effective "even if there is a lack of experience."2
Adverse effects--To analyze the advantages of TH, known beneficial effects must be balanced against known adverse effects.7 Hypothermia triggers the body's natural response mechanisms; vasoconstriction is the primary autonomic defense. Shivering soon follows and leads to tachycardia, hypertension and increased oxygen and glucose consumption. This counteracts the benefits of TH by leading to an increase in metabolic demand by as much as 300% and a buildup of lactic acid, which leads to cell death. Shivering can be prevented by the use of such drugs as Demerol (meperidine) and oral buspirone.9 In addition, there is a risk of overcooling, which increases the risk of infection and threatens coagulopathy. This leads to harmful atrial and ventricular dysrhythmias.1
Continuum of care--The continuum of care is an important concept in emergency medicine. To ensure the greatest quality of care, each link of the continuum must be quick, trained and able to communicate with the subsequent link. EMS will care for many CA victims in the prehospital setting. The sooner TH is initiated, the better;14 however, any implementation of prehospital cooling must be done in conjunction with a hospital program that will continue the treatment.11 Furthermore, EMS communications with medical centers and cardiac care programs should be improved to ensure proper transfer of care.15
EMS can help drive medical centers to implement TH protocols. Austin-Travis County EMS in Texas is a prime example. Jeff Hayes, chief of staff for the service's medical director's office, explains that when his agency stated that its units would bypass nearby medical centers and transport farther to a center that could induce hypothermia, those medical centers began to feel a sense of competition and started to implement hypothermia.16Time--Inducing TH is a lengthy process, as different cooling methods decrease the body temperature at different rates. Actively cooling both internally and externally can achieve a 3-degree drop in 30 minutes.2 However, many urban EMS agencies have transport times less than this. This makes the implementation of TH a highly individualized consideration for EMS agencies. Although agencies with longer transport times may find it beneficial to implement TH, agencies with shorter transport times may find a swift transport to a medical center with TH more feasible. Transportation should not be delayed to start cooling. (Hayes, Jeff. RE: Research Paper on Induced Therapeutic Hypothermia. 12/3/09. E-mail to Pedram Rahmanian, 7/30/10.)
Cost--Spread of new treatments is often slow. However, two specific concerns may be limiting adoption of TH. Regardless of treatment, out-of-hospital cardiac arrest has a poor survival rate, and hypothermia is costly. Thus it is unclear if the benefits of TH justify the cost.17 The quality of life of the survivors is another concern.
To the first doubt, a study led by Merchant used a complex mathematical design to measure quality-adjusted survival after cardiac arrest, the costs of hypothermia and post-hospital costs, and incremental cost-effectiveness ratios.3 Patients were considered in one of three states six months post-arrest: alive with favorable neurological outcome (little to no disability), alive with poor neurological outcome (severe disability or vegetative), or dead.17 Costs were then assigned over the average life expectancy of a CA survivor. Some factors affecting costs included additional nursing care required during cooling, extra time spent in the ICU and hospital ward, and post-discharge care.3 Cooling methods add another cost; this study focused on the use of cooling blankets.17
The incremental cost effectiveness ratio (ICER) for TH compared with conventional post-resuscitation care without TH was $47,168 per quality adjusted life year (QALY).3 Other studies have shown the ICER of kidney dialysis is $55,000/QALY. Placing AEDs in public places has an ICER of $44,000/QALY, while placing them on all commercial planes has an estimated cost of $94,700/QALY.3 Comparison to these other medical treatments demonstrates that by current standards, the benefits of TH justify its costs.17
Induction methodology--Prehospital implementation of therapeutic hypothermia requires a method usable in the field by paramedics.14 Many methods that would typically be feasible in a medical center are not for EMS; they may be too bulky, too expensive or too slow. Cooling strategies shown to be feasible and effective for EMS include fans, cooling blankets, icepacks, and the injection of 2 liters of 4-degree saline solution.18 The ability to maintain these resources on hand varies between EMS agencies. When transport times are short and these techniques hinder other post-resuscitation care, it may be more realistic simply to avoid post-resuscitation rewarming rather than induce hypothermia in the field.14
Resource limitations--Resource barriers include a shortcoming of trained personnel and the expense and availability of cooling systems. Limited human and financial resources are often perceived as a major issue; however, they are frequently a logistic issue.12 Therapeutic hypothermia does not require paramedics to learn new skills.2 Rather, all EMS personnel just need to become familiar with their specific protocol and practice. In addition, although expensive catheter cooling systems have specific advantages, they are not essential for inducing TH in EMS.12 Inexpensive icepacks could also be effectively used.
Personal barriers--Personal barriers are a major impediment to implementation of TH. These may include a lack of awareness about its benefits or just an inherent resistance to change.12 Counteracting any awareness deficit requires an increased informative effort. Therapeutic hypothermia should be incorporated into continuing education programs, and individual agencies should work to educate their personnel. Protocols including TH should be reviewed by agencies to address any concerns and ensure each person fully understands the procedure.
Little can be done to counter an inherent resistance to change, but it should be emphasized that TH does not require any new skills for paramedics. Follow-up studies should ensure any implementation is smooth and all personnel are adjusted. Uncomfortable personnel lead to poor healthcare.
Implementing TH: One Agency's Experience
Many of the limiting factors discussed here have different impacts for each EMS agency. The concern about lack of evidence and uncertainty about adverse effects are issues everyone has to analyze for themselves; however, both ILCOR and the AHA have recommended the use of TH. Concerns about cost, induction methodology, resources and personal barriers are specific to individual agencies. The two more universal limiting factors are the concerns about time and the continuum of care. Urban agencies with shorter transport distances must consider the induction methodology most feasible for their agency. EMS must also drive their accepting medical centers to implement TH before they can implement it themselves.16
The method embraced by Austin-Travis County EMS was similar to one used by Wake County EMS in North Carolina. After deciding to implement TH, service leaders discussed with all of the area's receiving hospitals their willingness to be involved in continuing the cooling of patients post-ROSC. These discussions occurred in face-to-face meetings and in a conference designed to demonstrate the benefits of centers' involvement in TH.19 Leaders brought in experts to speak. After presenting their data, Austin-Travis County EMS reassessed each of the hospitals to determine their buy-in. The agency then explained that if a receiving hospital was not going to continue TH, ATCEMS would no longer take their patients to that hospital, and would instead transport farther to a center that could continue the treatment. The service then started training its paramedics and provided each hospital with a "drop-dead" date by which it would be implementing and participating hospitals would have to show they could continue the TH treatment.20 In addition, to be designated as Resuscitation Centers of Excellence, the hospitals must be able to provide 24/7 revascularization, implantable cardioverter defibrillators, and outcome data back to the EMS agency. Wishing to compete for these patients, eight medical centers within the city met ATCEMS' deadline and were designated as Resuscitation Centers of Excellence.20
To prevent delays in transportation, Austin-Travis County EMS requires TH to be initiated en route to the hospital. If that is not possible, there is to be no delay in transportation to one of the eight designated centers. The cooling method used is both passive and active. Passive cooling includes application of chemical cold packs to major pulse points (neck, armpits, groin). Active cooling includes administration of chilled 0.9% sodium chloride (normal saline) solution via IV or IO. The saline is kept at 2-3 degrees, and 30 ml/Kg is administered to a maximum of 2 liters.20
Therapeutic hypothermia has been associated with improved survival and decreased neurological impairment in cardiac arrest patients. It is a beneficial treatment that should be implemented as early in patient care as possible--thus within the EMS system. However, if continued care cannot be guaranteed at receiving hospitals, TH cannot be started by EMS.
Despite recommendations by ILCOR and the AHA, several factors inhibit implementation of TH in medical centers and EMS agencies. Still, EMS agencies can drive the implementation of TH by pressuring hospitals and creating a sense of competition between them for lucrative cardiac arrest patients. Once the process starts, implementation spreads throughout the service region. Austin-Travis County EMS provides an example of using this strategy to drive local hospitals to adopt TH protocols.
1. Neira JA. Post-Resuscitation Care: Induced Hypothermia to Whom, How, and When? World Congress of Cardiology, 2008.
2. Clumpner M, Mobley J. Raising the dead: Prehospital hypothermia for cardiac arrest patients may improve neurological outcome and survival to discharge. EMS 37(9): 52-60, Sep 2008.
3. American Heart Association. Cooling therapy for cardiac arrest survivors is as cost-effective as accepted treatments for other conditions. www.newsroom.heart.org.
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11. NAEMSP. Induced therapeutic hypothermia in resuscitated cardiac arrest patients. Preh Emerg Care 12: 393-394, 2008.
12. Neumar RW, et al. Post cardiac arrest syndrome: Epidemiology, pathophysiology, treatment, and prognostication. Circ 118(23): 2,452-83, Dec 2, 2008.
13. Fisher GC. Hypothermia after cardiac arrest: Feasible but is it therapeutic? Anaesthesia 63: 885-886, 2008.
14. Cady C, Andrews S. Prehospital resuscitated cardiac arrest patients: Role for induced hypothermia. Preh Emerg Care 13: 402-405, 2009.
15. NAEMSP. Prehospital management of acute myocardial infarction. Preh Emerg Care 12: 393-394, 2008.
16. Hayes J. If I Die… I Want to Be in Austin, TX. Lecture, Texas EMS Conference, Nov. 23, 2009.
17. Merchant RM, et al. Cost-effectiveness of therapeutic hypothermia after cardiac arrest. Circ 2(5): 421-428, Aug 4, 2009.
18. McQuillan K. Inducing hypothermia after cardiac arrest. Crit Care Nurs 29: 75-78, Aug 4, 2009.
19. Hayes J. Personal correspondence, Dec 2009.
20. Hayes J. Personal correspondence, May 2010.
Pedram M. Rahmanian is a BBA and premedicine freshman at the University of Texas' Red McCombs School of Business. He is an International Baccalaureate graduate of Westwood High in Austin, where he earned his NREMT-B certification. He is a member of Longhorn Student EMS and UT Events EMS, as well as a volunteer at University Medical Center Brackenridge.