You are the nurse caring for an adult patient admitted to the ICU. He was resuscitated from a cardiac arrest in the ED 20 minutes ago after presenting with chest pain. His vital signs are currently stable, but the patient does not have a meaningful response to verbal commands.1 The resident physician suggests starting targeted temperature management (TTM) for neuroprotection, and a conversation begins about the relative risks and benefits of the various target temperatures.
This article provides nurses with the latest TTM evidence empowering them to discuss the 33°C (91.4°F) versus 36°C (96.8°F) question. This article weighs the pros and cons of target temperatures as it examines the evidence surrounding TTM and applies it to clinical scenarios.
Evidence supporting TTM
TTM is an evidence-based therapy for patients who have experienced a cardiac arrest and who are unresponsive, or comatose, without purposeful movements or the ability to follow simple verbal commands.1 TTM has been associated with improved neurologic outcomes after cardiac arrest, and national and international guidelines currently reinforce the use of TTM in patients who experience neurologic injury after cardiac arrest.1-6
Comatose survivors of cardiac arrest have a high risk of death and poor neurologic function. TTM provides neuroprotection for a hypoxic-ischemic brain injury sustained during cardiac arrest to improve survival with good neurologic function.7 The American Heart Association's (AHA) 2015 Cardiopulmonary Resuscitation (CPR) Guidelines state that any comatose patient who achieves return of spontaneous circulation (ROSC) after cardiac arrest should have TTM and be maintained at a constant temperature between 32°C and 36°C for at least 24 hours.1 Although the AHA strengthened its recommendation for the use of temperature management, the guidelines still allow for provider preference when choosing a temperature. So, why is there a range of target temperatures to choose from?
In 2002, two randomized controlled trials were published showing that patients who experienced a cardiac arrest and were cooled to a target temperature of 32°C to 34°C had better survival with good neurologic recovery than patients who were not in the intervention arm.2,3 In these studies, neurologic outcome was evaluated in addition to survival. This is important because neurologic recovery is a more patient-centered outcome and a more desired result of therapy than simply survival. The Cerebral Performance Category (CPC) is commonly used to define neurologic function after cardiac arrest. A “good” neurologic outcome is defined by a CPC score of 1 (no or mild disability; for example, the patient is able to lead a normal life with mild deficits) or 2 (moderate disability; for example, the patient can independently perform activities of daily life and work part-time in a sheltered environment). The CPC is used to differentiate “good” neurologic outcomes from “poor” neurologic outcomes described by CPC categories 3 (severe disability), 4 (persistent vegetative state), or 5 (brain death).8,9 Based on the significant benefit for patients shown in these two trials, the therapy of “mild hypothermia” became the standard of practice.
In 2013, another randomized controlled trial was published showing that neurologic outcomes were the same whether patients were cooled to target temperatures of 33°C or 36°C, regardless of the initial rhythm during the arrest.4 After this publication, many hospitals worldwide quickly adopted the new findings by targeting 36°C, and the therapy became known as TTM.10,11 The current evidence appears to support two temperatures for patients after cardiac arrest, and practice is known to be variable. So which is the better target temperature?
In debate format, this article will now explore the arguments for each of the two most popular temperatures—33°C and 36°C—chosen as the optimal temperature for a TTM protocol.
The case for 33°C
A solid body of evidence supports the use of 33°C as the optimal target temperature. Both of the 2002 landmark studies used 33°C as the target temperature.2,3 The near twofold increase in survival with good neurologic recovery observed in these two studies was groundbreaking with respect to postcardiac arrest care. Researchers had found a protocol that would achieve better neurologic recovery—defined as a CPC of 1 or 2—for patients who experienced an out-of-hospital cardiac arrest, a group of patients that previously had dismal outcomes.
After the publication of the landmark trials of 2002, early adopters applied TTM internationally to patients who had experienced a cardiac arrest, resulting in a body of real-world literature that further supported the findings of the initial trials.12,13 One particular study by Oddo and colleagues found that in a before-and-after study, implementation of TTM to 33°C resulted in 55.6% of patients with out-of-hospital ventricular fibrillation (VF) cardiac arrest surviving with good neurologic recovery, compared with 25.6% of the historical cohort that was treated with standard therapy (no TTM).12 In a review of studies that addressed the efficacy of TTM in clinical environments, Sagalyn and colleagues found that in six studies including a total of 1,004 patients, the application of TTM achieved a higher rate of good neurologic recovery compared with standard therapy (OR 2.5, 95% CI: 1.9-3.4).13
Though initial studies specifically targeted the utility of therapeutic hypothermia in patients who initially present with shockable rhythms, such as VF or pulseless ventricular tachycardia, the evidence supports translating this therapy to patients with all initial rhythms. In the first randomized controlled trial to test the utility of hypothermia (33°C) in patients with cardiac arrest and nonshockable rhythms (pulseless electrical activity and asystole), Lascarrou and colleagues found that 10.2% of patients receiving TTM targeted to 33°C survived with a good neurologic recovery versus 5.7% of patients receiving targeted normothermia at 37°C (P = .04).5 Some observational studies have also found that patients with nonshockable initial rhythms receive benefit from therapy with therapeutic hypothermia to temperatures between 32°C and 34°C.14-16
Given the early randomized controlled trials and the wealth of observational data over the years, multiple studies have shown that 33°C does impart benefit to neurologic recovery for comatose survivors of cardiac arrest. This firmly placed temperature management as a mainstay of therapy within the guideline recommendations for postcardiac arrest care.1 The argument in favor of 33°C is based on the large number of patients treated with the therapy with relatively few adverse events. Since healthcare professionals are unable to measure the extent of hypoxic-ischemic brain injury after cardiac arrest, why reduce the dose of therapy by using a warmer target temperature? Afterall, clinicians have only one chance to impart neurologic protection to this patient population. Is it fact or misperception that makes clinicians opt for warmer temperatures for patients after cardiac arrest?
The case for 36°C
The evidence for targeting a goal core temperature of 36°C is strongly based on the findings of the TTM Trial that 36°C is just as safe and just as effective as 33°C.4
The concept of using 36°C as an alternative target for TTM was introduced in November 2013 with the publication of the TTM Trial.4 Nielsen and his colleagues across Europe randomized 950 patients who had out-of-hospital cardiac arrests to be cooled to either 33°C or 36°C. They highlighted that in the 2002 Mild Therapeutic Hypothermia to Improve the Neurologic Outcome after Cardiac Arrest (HACA) Trial many patients in the standard treatment (normothermia) group developed fevers, so it was unclear whether the outcome benefits were due to the hypothermia (33°C) or to the prevention of fever.2 The TTM Trial was designed to prevent fever in both groups and isolate the effects of the temperature.
The colossal finding from this study was that there was no difference in survival or neurologic outcomes between patients maintained at 33°C and those maintained at 36°C. Further, the patients' outcomes were similar to the outcomes achieved in the hypothermia group in the 2002 trial.4 This randomized controlled trial provides evidence that 36°C is a valid choice as a target temperature in patients eligible for TTM, with equivalent outcomes to the target of 33°C.
So why consider targeting 36°C instead of 33°C? The major line of reasoning is that it can provide neurologic and survival benefits while avoiding some of the adverse reactions that occur during hypothermia. In the TTM Trial, patients maintained at 36°C experienced significantly less hypokalemia. Hypothermia drives potassium from the blood into cells, and the reverse happens when a patient is rewarmed. Hypo- and hyperkalemia can both contribute to dysrhythmias, so fewer electrolyte shifts may be safer for some patients at risk for dysrhythmias.
Using a target temperature of 36°C may allow patients with cardiac arrest to receive TTM who may otherwise have been disqualified from the therapy, such as patients with major bleeding. Although randomized controlled trials indicate no difference in rates of bleeding between temperatures, patients with bleeding or known coagulopathy were not included in several of the major studies.4 Clinicians may hesitate to initiate TTM in patients who are bleeding. An observational study reveals less bleeding at a warmer target temperature, indicating that a target of 36°C may be a safer choice in this patient population.17
Another adverse reaction of hypothermia is bradycardia. In most patients receiving TTM, the bradycardia is not considered severe. However, a warmer target temperature of 36°C could be a safer target for any patient for whom bradycardia poses independent risk factors, such as patients who have a prolonged corrected QT (QTc) interval. Prolongation of the QTc interval places a patient at risk for torsades de pointes, a lethal ventricular dysrhythmia. Both hypokalemia and bradycardia can further prolong the QTc and increase the risk of torsades de pointes, making 33°C potentially unsafe for this patient population.
Another potential population for whom clinicians may consider targeting a goal temperature of 36°C are those with profound hemodynamic instability, such as refractory septic shock requiring multiple vasopressors. To date, no definitive data support that patients with profound hemodynamic shock fare better at 36°, but patients with this degree of instability may concern clinicians as they discuss temperature selection opting to avoid possible temperature fluctuation and fluid shifts that may be more detrimental to an already unstable patient.
The introduction of 36°C as an option for TTM has opened the door to neuroprotection benefit for patients with cardiac arrest who may otherwise not have received TTM. Patients who are candidates for TTM therapy after cardiac arrest from a neurologic standpoint but have other characteristics such as bleeding, bradycardia, or dysrhythmias that may have excluded them may receive TTM more safely at 36°C, increasing their chances of a good neurologic recovery (as defined by a CPC score of 1 or 2).
Misperceptions of the 33°C vs. 36°C debate
There are several misunderstandings related to both target temperatures. Many of the misperceptions surrounding 33°C focus on adverse reactions. For example, concern exists that patients may encounter fatal dysrhythmias at such a cold temperature. This, in fact, is not true. Studies have shown no difference in the occurrence of malignant dysrhythmia between the two temperatures, and that concerning dysrhythmias only become prevalent when the myocardium is lower than temperatures recommended for TTM.2-5,18 Bleeding risk is sometimes cited as a concern for dropping the core temperature to 33°C, but in the patients included in the TTM Trial there was no difference in bleeding risk between the two temperatures. Further, most of the bleeding risk associated with TTM is minimal and not fatal, such as bleeding from line insertion sites.4
Another misperception is that 36°C will be easier to maintain than 33°C, but this is simply not true.19 The evidence shows that 36°C is safe, but that does not mean it is any less intense of a protocol. For example, clinicians sometimes claim they do not need a device or drugs to maintain 36°C as long as no fever occurs. The TTM Trial does not support this claim; the 36°C group received active temperature management, not only fever prevention. Both temperature groups in the trial received active temperature management at their target temperature for 24 hours, followed by gradual controlled rewarming and then normothermia below 37.5°C for 72 hours.4 Targeting 36°C does not make the protocol faster or reduce length of stay when compared with a target of 33°C.
Additionally, targeting 36°C does not reduce the amount of shivering. Shivering, even microshivering—which may be difficult to detect without specialized monitoring—can have a detrimental impact on brain oxygenation and should be avoided.20,21 In the TTM Trial, there was no difference in the percentage of patients who experienced shivering: 30% of patients at 33°C versus 34% of patients at 36°C shivered, which was not a significant difference.4 Patients may in fact need more aggressive shivering management at 36°C because the average shiver threshold has been identified between 34°C and 36°C, mean 35.5°C.22 Patients at 36°C might be more prone to shiver, while patients at 33°C are at the lower end of the shiver threshold so assessment and treatment of shivering remain essential.23 Data from Australia underscore the importance of adequate sedation when targeting a temperature of 36°C: after changing the target temperature from 33°C to 36°C, they found patients spending less time within their target temperature range and higher rates of fever.11 Fever contributes to worse neurologic outcomes so these trends make it clear that if 36°C is the target, it is crucial to manage the temperature closely.24
Another misperception is that a target temperature of 36°C will require fewer sedatives for the patient. Again, the TTM Trial does not support that. Both temperature groups in the trial received the same pharmacologic protocol, which included mandatory sedation for 36 hours during cooling and rewarming. The amount of sedatives used was not reported, so there is no evidence that targeting 36°C does or does not require fewer sedatives. The trial data showed no difference between groups in the number of days that sedation affected neurologic evaluation.4
Finally, the notion that clinicians can conduct ongoing neuroprognostication earlier if the patient is at 36°C instead of at 33°C is an error. A patient on any TTM protocol, no matter the target temperature, should be sedated and may be receiving neuromuscular blockade. The state of the science indicates that patients cannot undergo valid accurate neuroprognostication until 72 hours after arrival at normothermia and some might suggest even later given the observation that many patients have delayed awakening.1,25,26
The most dangerous misperception of the 33°C versus 36°C debate would be not using TTM at all or replacing it with passive temperature strategies. The introduction of 36°C as a target temperature brought with it a statistically significant decrease in the use of active cooling methods for patients with cardiac arrest in the US, possibly reflecting the misperception that 36°C is not active TTM.27 Active temperature management remains the key in giving patients a better chance for a good neurologic outcome after cardiac arrest.
As you evaluate the patients in the two following clinical scenarios, decide if the patient needs TTM, and if so, would they benefit most from a target temperature of 33°C or 36°C.
Case study #1. A 56-year-old man found unresponsive at home was just admitted to the ICU. Upon EMS arrival he was in pulseless electrical activity with agonal respirations. EMS initiated CPR and intubated the patient in the field. In the ED, the patient received 20 minutes of CPR and four rounds of epinephrine. ROSC was achieved with an irregular wide complex rhythm that was defibrillated to sinus rhythm. Now in the ICU, the patient has a Glasgow Coma Scale score of 4 and is not following simple verbal commands. His initial temperature is 31.5°C.
Considering the evidence-based guidelines, which of the three options below would you choose, and why?
- Option 1–Do not initiate TTM.
- Option 2–Initiate TTM at 33°C.
- Option 3–Initiate TTM at 36°C.
Option 1–Do not initiate TTM. This would not be an evidence-based choice. The patient has ROSC, but is lacking meaningful response to verbal commands, so to comply with the 2015 AHA Guidelines, TTM should be implemented. Also, new evidence in patients presenting with nonshockable initial rhythms indicates TTM is beneficial.5
Option 2–Initiate TTM at 33°C. This would be a good option, as current evidence supports the use of 33°C for patients presenting with nonshockable rhythms.5 Also, the patient is already at 31.5°C, making it more efficient to get him to 33°C than 36°C. This patient doesn't have any contraindications to 33°C; for example, his QTc interval is not prolonged and he has no reported bleeding issues, so remaining at 33°C is a good option.
Option 3–Initiate TTM at 36°C. This could be a more difficult target temperature to choose because clinicians would technically have to rewarm the patient to “cool” them. Guidelines suggest rewarming at a rate of 0.25-0.5°C per hour to avoid electrolyte shifts and cerebral edema, so it would take 9 to 18 hours before the patient safely reaches target temperature.1,6 The patient would be going through the shiver zone of 34°C to 36°C so there may be a need for more sedation and paralytics to control shivering. Although this target temperature choice would be suboptimal, it is still better than not cooling at all.
Case study #2. A 42-year-old man is receiving a nitroglycerin infusion in the ICU. He has construction gear with him and says he was at work when he began experiencing chest pain. He becomes diaphoretic, clammy, and disoriented. The ECG shows acute ST-elevation myocardial infarction. The patient stops talking and a rhythm of VF shows on the monitor. You begin CPR and defibrillate. After 10 minutes of advanced cardiac life support including 2 mg of epinephrine, the patient achieves ROSC. He is unresponsive and the ECG now shows bradycardia with prolonged QTc. His initial temperature is 35°C.
Considering the evidence-based guidelines, which of the three options below would you choose, and why?
- Option 1–Do not initiate TTM.
- Option 2–Initiate TTM at 33°C.
- Option 3–Initiate TTM at 36°C.
Option 1–Do not initiate TTM. Patients with in-hospital cardiac arrest are included in the recommendations to receive TTM if they are unresponsive after ROSC.1 The evidence for this patient population is of lower quality, but the pathophysiology of a hypoxic-ischemic brain injury would be the same no matter the location of the cardiac arrest.1
Option 2–Initiate TTM at 33°C. This would be a higher-risk option than Option 3. Bradycardia with a prolonged QTc puts the patient at risk for torsades de pointes and cooling to 33°C could potentially worsen the bradycardia. Keep in mind that 33°C has a higher incidence of hypokalemia, which also puts the patient at greater risk for dysrhythmias.
Option 3–Initiate TTM at 36°C. This is the optimal choice because of the risks outlined in Option 2. Evidence shows that 36°C provides equivalent outcomes to 33°C for patients such as this one whose arrest has a presumed cardiac cause.4 Just remember, because the patient presented at 35°C it is important to increase the patient's temperature by only 0.25°C to 0.5°C per hour until 36°C is reached. This slow controlled rewarm helps prevent cerebral edema and electrolyte shifts.
In summary, there are many things to consider when selecting 33°C or 36°C as a target temperature after cardiac arrest. There are numerous misperceptions surrounding both temperatures. Although some patients may be better managed at one temperature over the other, evidence supports both temperatures as safe and effective therapy for patients.
While there is variation in practice when choosing a target temperature of 33°C or 36°C for patients after cardiac arrest, patients should receive TTM, and TTM requires active temperature management using a cooling device and tight temperature control. A target temperature of 33°C or 36°C should be chosen and maintained for at least 24 hours.1 Patients at either temperature could shiver or have seizures. Use a shivering protocol with medications to prevent and treat shivering and microshivering while ensuring that shivering is assessed frequently and treated aggressively during TTM.20 It is also important to evaluate and treat seizure at either temperature, as this could also be detrimental to recovery. Meticulous nursing care, including skin care (especially under surface cooling devices), positioning, and infection prevention, is important no matter the target temperature.
After maintaining a goal temperature of 33°C or 36°C for 24 hours, the patient should be slowly rewarmed to normothermia.1 When normothermia is achieved, it should be maintained and fever prevented for 72 hours after ROSC.1,4,6 Fever after cardiac arrest has been shown to have adverse neurologic outcomes.24 Last, neuroprognostication should occur no earlier than 72 hours after returning to normothermia.1 This time frame could be even longer if sedation or neuromuscular blocking agents could confound the neurologic exam.
The questions about optimal temperature for TTM continue to be investigated. Future studies are planned to further elucidate the appropriate temperature, the best way to deliver therapy, the optimal duration of therapy, and how to best rewarm. Research continues to focus on advancing the therapies in postcardiac arrest care to ensure improved outcomes from this devastating event.
Critical care nurses are instrumental in executing TTM therapy effectively. Regardless of target temperature chosen, the keys to success are tight temperature control, the use of a shivering protocol, a slow controlled rewarm, and fever prevention. Clinicians have one chance to protect the brain after cardiac arrest, so evidence-based practices must be followed to achieve optimal patient outcomes.
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