Curr Treat Options Cardio Med (2016) 18:30 DOI 10.1007/s11936-016-0454-x

Arrhythmia (D Spragg, Section Editor)

Therapeutic Hypothermia After Cardiac Arrest Sunjeet S. Sidhu, MD Steven P. Schulman, MD John W. McEvoy, MB, BCh, MHS* Address * Johns Hopkins Coronary Care Unit and Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Carnegie 524C, 600 N. Wolfe Street, Baltimore, MD, 21287, USA Email: [email protected]

* Springer Science+Business Media New York 2016

This article is part of the Topical Collection on Arrhythmia Keywords Therapeutic hypothermia I Targeted temperature management I Cardiac arrest I Anoxic encephalopathy

Opinion statement Resuscitated cardiac arrest continues to carry a poor prognosis despite advances in medical care. One such advance, therapeutic hypothermia, is neuroprotective and has been demonstrated to improve clinical outcomes in patients who remain unresponsive despite return of spontaneous circulation after arrhythmogenic cardiac arrest. Two landmark randomized controlled trials, both reported in 2002, led to endorsements by major American and European guidelines for therapeutic hypothermia as a viable treatment option for the prevention of adverse outcomes related to anoxic encephalopathy. Since then, significant research has been conducted to better understand the optimum strategies to maximize the neuroprotective effects of hypothermia. However, dissemination of therapeutic hypothermia guideline recommendations into clinical practice has been slow and incomplete. In this review article, we discuss the historical background and physiologic rationale for therapeutic hypothermia, review the recent literature supporting this intervention, and outline practical considerations.

Introduction Over 326,000 out-of-hospital cardiac arrests were assessed by emergency medical services in the USA in 2014 [1]. It is estimated that approximately 23 % of these present with an initial shockable rhythm (primarily unstable ventricular tachycardia or fibrillation) and 50 % are witnessed. A similar number of patients, 209,000, suffer from in-hospital cardiac arrests on an annual basis in the USA [1]. A major complication of

cardiac arrest, one with significant morbidity for the patient and significant resource expenditure for society, is anoxic encephalopathy. In this context, therapeutic hypothermia is endorsed by major American and European societies for the protection of neurological injury among individuals who are unresponsive after cardiac arrest. Specifically, the 2010 American Heart Association


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(AHA) post cardiac arrest guidelines provide a class I recommendation for induced hypothermia to a goal temperature of between 32 and 34 °C, for 12- to 24-h durations, in patients who are unresponsive after an outof-hospital cardiac arrest due to ventricular fibrillation or unstable ventricular tachycardia [2]. The AHA also provides a class IIb recommendation for the use of induced hypothermia in unresponsive patients after an in-hospital cardiac arrest of any initial rhythm or an outof-hospital cardiac arrest due to pulseless electrical activity or asystole [2]. The European Society of Cardiology provides a similar class I recommendation for patients with an out-of-hospital cardiac arrest [3].

In spite of these guideline recommendations, utilization of therapeutic hypothermia in the USA remains remarkably low, at approximately 2–6 % of post cardiac arrest presentations [4•, 5]. Therefore, implementation strategies are needed to bridge the sizable current gap between evidence and clinical practice in post cardiac arrest patients. In this article, we will detail the historical background and physiologic rationale for therapeutic hypothermia, review major clinical trials and recent literature, and discuss practical considerations (e.g., time to cooling, target temperature, and cooling methods) of relevance to providers administering therapeutic hypothermia.

Historical background The origins of therapeutic hypothermia, more recently referred to as targeted temperature management, date back several millennia to ancient Egypt [6]. Dr. James Currie, in the 1700s, conducted the first systematic experiments to assess the various effects of cooling on the human body. Sir William Osler also experimented with hypothermia as a way to treat typhoid fever with a reported decline in mortality [6]. Dr. Temple Fay is credited for reintroducing therapeutic hypothermia to modern medicine by using it to treat intractable pain and developing one of the earliest cooling blankets. Its use in cardiac arrest arose from initial case reports in the 1930s, describing patients with hypothermia from exposure and cardiac arrest recovering from the “hands of death” [7]. Subsequent studies in the 1950s by Dr. Bigelow and colleagues demonstrated the neuroprotective effects of hypothermia in patients and animal models during cardiac surgery [6, 8–10]. The first trial evaluating hypothermia in cardiac arrest was published in 1958 and reported a 50 versus 14 % survival in perioperative patients treated with hypothermia to 33 °C and normothermia, respectively [11]. This generated enthusiasm that leads to the first published algorithm in 1964, by Dr. Peter Safar, advocating hypothermia initiation within 30 min of return of spontaneous circulation (ROSC) after heart-lung resuscitation [12]. However, this enthusiasm was tempered by reports of bleeding and arrhythmic and septic complications from moderate hypothermia to 28–32 °C [6, 13]. Nonetheless, renewed interest came about after animal model and patient data in severe brain injury showed neuroprotection from mild hypothermia. This work laid the foundations for two landmark trials published in 2002, both demonstrating survival and neurologic benefit from induced hypothermia after an out-ofhospital cardiac arrest [14, 15].

Physiologic effects of induced hypothermia Classically, there are three phases to neurologic injury post cardiac arrest [9, 16]. Initial lack of tissue perfusion results in anaerobic metabolism, energy failure,

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loss of membrane potentials, accumulation of intracellular calcium, and release of excitatory neurotransmitters. Subsequently, after return of ROSC, there is reperfusion injury with production of reactive oxygen species, resulting in direct cellular damage and trigger of pro-apoptotic pathways. Finally, there is a delayed pro-inflammatory state which results in secondary cell injury [9, 16]. During this ischemia-reperfusion period, there are numerous physiologic effects of induced hypothermia. The act of lowering body temperature by 1 °C leads to a 6 to 10 % reduction in cerebral metabolism [8, 9]. This results in decreased free radical production, calcium influx into cells, and mitochondrial injury [9]. Induced hypothermia also results in decreased production and release of excitotoxic amino acids such as glutamate [17]. Cell death is decreased by an inhibitory effect on both intrinsic and extrinsic apoptosis pathways [17]. Furthermore, hypothermia has beneficial effects on cerebral edema and blood-brain barrier integrity [9]. Finally, in the delayed phase of injury, hypothermia acts to dampen the inflammatory response [18]. All of these reduce anoxic brain injury. In contrast to the above salutary effects, there are also some physiologic downsides to therapeutic hypothermia. As all biochemical reactions have some temperature dependence, the potentially negative effects of hypothermia are broad and can be broken into body systems [6]. From a cardiovascular perspective, there is a temperature-dependent decrease in heart rate with an average heart rate of 40–45 beats per min at 32 °C [6]. This is believed to be due to slowing of phase 4 depolarization of the sinus node [19]. Other membrane channels are also affected, causing prolonged action potentials and slowed conduction velocity, which result in prolongation of all intervals [19]. In deep hypothermia, ≤28 °C, there is an increased risk of arrhythmia and decreased effectiveness of arrhythmia therapy, including electrical cardioversion [19]. However, animal studies suggest that mild hypothermia may improve defibrillation success after induced ventricular fibrillation [20, 21]. Osbourne waves are rarely seen in mild hypothermia [6]. In addition, unlike deep hypothermia, patients treated with mild hypothermia will have an increase in cardiac contractility and, hence, only a minor drop in cardiac output due to the bradycardia [6, 19]. Mean arterial pressure will often increase due to peripheral vasoconstriction. However, in some cases, hypotension can occur due to hypovolemia, which may be related to “cold diuresis” rather than a drop in cardiac output [19]. Lastly, in normal volunteers, there is vasodilation of the coronary arteries and increased coronary perfusion pressure although it is unclear if this extends to diseased coronary arteries. Physiologic effects of hypothermia can also be seen in the pulmonary, hematologic, hepatic, and immunologic systems (Table 1). From a pulmonary aspect, there is some improvement seen in the PaO2/FiO2 ratio that persists past the maintenance phase of hypothermia [6]. In addition, because of effects on metabolism, there is a decrease in CO2 production, described further below [6, 19]. Hypothermia-induced increases in metabolism can also result in mild metabolic acidosis; however, this rarely causes the pH to drop below 7.25. Effects on the hematologic system include a reduction in platelet function and quantity (at 35 °C), progressing to a pro-coagulopathic effect at 33 °C [6, 19]. Clinical data suggest a low risk for severe bleeding associated with therapeutic hypothermia; however, these studies excluded patients with active bleeding [14, 15, 19].


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Table 1. Physiologic effects of therapeutic hypothermia System



1. Decreased cerebral metabolism 2. Decreased apoptotic cell death


3. Reduce cerebral edema and preserved blood-brain barrier integrity 1. Sinus bradycardia 2. Prolonged EKG intervals


3. Increased risk for arrhythmia and decreased effectiveness of anti-arrhythmicsa 1. Decreased platelet function


2. Alteration of coagulation cascade 1. Improved oxygenation


2. Decreased CO2 production and lower required minute ventilation 1. Electrolyte abnormalities: hypokalemia, hypomagnesaemia, hypernatremia, hypophosphatemia, and hypocalcemia


2. Cold diuresis (driven by tubular dysfunction and increased atrial natriuretic peptide) 1. Decrease insulin release and sensitivity


2. Increased fatty acid metabolism 1. Ileus from decreased motility

Immunologic Musculoskeletal Pharmacologic

2. Decreased hepatic synthetic function 1. Increased risk for infection 1. Shivering 1. Delayed drug metabolism and clearance

These effects are seen with deep hypothermia, ≤32 °C


Major clinical trials The HACA (Hypothermia after Cardiac Arrest Study Group), published in 2002, reported a significant reduction in mortality at 6 months after therapeutic hypothermia, which was targeted to 32 °C for 24 h, was administered to 137 patients who suffered an out-of-hospital ventricular fibrillation or unstable ventricular tachycardia cardiac arrest, and remained unresponsive after ROSC. The median time from ROSC to initiation of cooling was 105 min. Notable exclusion criteria included tympanic membrane temperature less than 30 °C on admission, comatose state prior to cardiac arrest, responsive to verbal commands prior to initiation of cooling, sustained hypotension, sustained hypoxemia, prior terminal illness, and a pre-existing coagulopathy. The absolute rates of survival and favorable neurologic outcome were 59 and 55 % in the hypothermia versus 45 and 39 % in the standard of care groups, respectively (with resultant hazard ratios [95 % confidence interval] of 1.35 [1.05–1.72] and 1.40 [1.08–1.81] for the control intervention of standard care). The resulting numbers needed to treat for hypothermia to prevent one death and to achieve one favorable neurologic outcome were 7 and 6, respectively [15]. In a separate trial, Bernard et al. also demonstrated a higher likelihood of

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discharge to home or short-term rehabilitation among 43 patients in whom induced hypothermia to 33 °C for 24 h was administered after an out-ofhospital cardiac arrest with an initial rhythm of ventricular fibrillation [14]. The absolute rates of favorable outcomes, defined as discharge to home or rehabilitation, were 49 and 26 % in the hypothermia versus standard of care groups, respectively (with a resultant hazard ratio of 2.65 [1.02–6.88]). The resulting number needed to achieve one good outcome with hypothermia was 4. The difference in mortality did not reach significance. Whether these benefits translate to inpatients or to those with a nonshockable rhythm has not yet been proven in any large randomized trial. Dumas et al. looked at a large observational French registry of 1145 consecutive out-ofhospital cardiac arrests [22••]. Therapeutic hypothermia was induced in 65 and 60 % of patients with shockable and non-shockable rhythms, respectively. Good neurologic outcome was seen in 30 and 16 % of patients with therapeutic hypothermia in the shockable and non-shockable rhythm groups (with resultant hazard ratios of 1.90 [1.18–3.06] and 0.71 [0.37–1.36] when compared to patients without therapeutic hypothermia). This suggested that outcomes were better in patients with shockable rhythms, but failed to show any benefit in patients suffering from a cardiac arrest with a non-shockable rhythm. Kim et al. performed a meta-analysis to answer the same question by looking at a total of 12 nonrandomized studies and 2 randomized studies for a total of 1292 and 44 patients, respectively [23]. The pooled data from the two randomized trials did not show a benefit to hypothermia in persons presenting with nonshockable rhythms, although this was based on a total of 44 patients. However, data from the nonrandomized studies was suggestive of potential benefit, with absolute event rates for in-hospital mortality and good neurologic outcomes of 66 and 21 % in the hypothermia versus 70 and 20 % in the standard of care groups, respectively (with adjusted hazard ratios of 0.84 [0.78–0.92] and 0.95 [0.90–1.01]). More recently, two large randomized trials have enrolled patients with nonshockable rhythms [24••, 25•]. These trials will be discussed in further detail below but were both negative. However, they were designed to assess a different question, namely different hypothermia temperature goals and different target cooling times. These conflicting data highlight the critical need for a large randomized controlled trial to definitely assess the use of therapeutic hypothermia in patients with cardiac arrest with a non-shockable rhythm.

Time to hypothermia Current guidelines do not provide guidance on the optimal time window during which cooling should be initiated (nor the time from initial arrest after which cooling is no longer beneficial). Given the mechanism of ischemiareperfusion injury, it appears logical that the earlier cooling begins after anoxic neurologic injury, the better are the outcomes. This conclusion is echoed by several animal models, which show that earlier post arrest cooling is superior to later cooling in regard to survival and neurologic function [26, 27]. Indeed, intra-arrest cooling has been shown to be superior to cooling at 20 min post arrest in animal models [28]. In humans, the initial trials by HACA and Bernard et al. reported a mean


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Curr Treat Options Cardio Med (2016) 18:30 time to temperature below 34 °C of approximately 3 and 8 h, respectively [14, 15]. However, only one mouse model showed benefit after induced hypothermia initiating 4 h or more after cardiac arrest [29•]. Therefore, there has been interest in pre-hospital cooling for an out-of-hospital cardiac arrest. A metaanalysis conducted by Diao et al. of five trials including 633 patients looked at this question. As expected, the authors found a significant difference in temperature at hospital arrival in the experimental group receiving pre-hospital cooling [30]. However, there was no significant change in survival or neurologic outcomes [30]. Subsequently, Kim et al. conducted a large randomized control trial of 1359 patients randomized to the administration of up to 2 l of normal saline, cooled to 4 °C, by paramedics en route to the emergency room or to standard of care [25•]. The authors reported a difference in arrival temperature as well as a decrease in time to a temperature less than 34 °C by 1 h as compared to control. Despite this, there was no significant change in survival or neurologic outcomes between the groups [25•]. In fact, the group that received pre-hospital chilled normal saline had a lower pH on arrival, higher rates of hypoxia, and more recurrent cardiac arrests [25•]. It is possible that the method of pre-hospital cooling, chilled normal saline, may have caused some of these harmful effects. Yannopoulos et al. looked at a model of induced cardiac arrest in pigs and compared the effects of intra-arrest volume loading with room temperature saline, cold saline, surface cooling, endovascular cooling, and control on coronary perfusion pressure [31]. Pigs that received both room temperature and chilled saline had significantly worse coronary perfusion pressures (12.8 ± 4.78 and 14.6 ± 9.9 mmHg, respectively) when compared to either control, surface cooling, or endovascular cooling during cardiac arrest (20.6 ± 8.2, 20.1 ± 7.8, and 21.3 ± 12.4 mmHg, respectively). Another porcine study by Yu et al. also looked at the effects of intra-arrest chilled saline and compared it to nasopharyngeal cooling [32]. Despite the small numbers, Yu et al. demonstrated an improved coronary perfusion pressure in pigs receiving nasopharyngeal cooling as compared to those with cold saline infusion (23 and 11.8 mmHg, respectively). The authors also demonstrated a significant survival benefit in pigs who received nasopharyngeal cooling. These findings suggest that the negative randomized trial of pre-hospital cooling reported by Kim et al. may be partially related to the method of cooling and that alternative strategies of pre-hospital cooling may need to be studied further. Two studies are currently ongoing, Rapid Infusion of Cold Normal Saline During CPR for Patients With Out-of-hospital Cardiac Arrest (RINSE NCT01173393) and Prehospital Resuscitation Intra Nasal Cooling Effectiveness Survival Study (PRINCESS NCT01400373) [33, 34].

Cooling methods Cooling methods are traditionally thought of as either invasive or non-invasive (e.g., surface). Invasive cooling methods include endovascular cooling catheters, large cavity lavage, transnasal evaporative cooling device, continuous venovenous hemodialysis (CVVH), and even extracorporeal membrane oxygenation (ECMO) [35]. Surface cooling methods range from skin exposure to ice to newer regulated water-circulating cooling pads [35]. Benefits of invasive cooling

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include decreased time achieving to hypothermia, decreased temperature variation, potential for continuous temperature monitoring, and decreased shivering response compared to surface cooling [35]. On the other hand, surface cooling is easier to use, does not require an invasive procedure, and has a decreased delay to initiation. Clinical data comparing different cooling methods are limited to date. Oh et al. conducted a retrospective review of 803 patients presenting to 24 South Korean hospitals [36]. In these patients, surface cooling was significantly associated with increased incidence of adverse effects such as overcooling, rebound hyperthermia, rewarming hypoglycemia, and hypotension. These adverse effects were not seen, however, in the cohort of patients cooled via newer hydrogel pads. Oh et al. also reported that surface cooling was significantly associated with worse neurologic outcome; however, this association did not meet significance after propensity score matching [36]. Deye et al. randomized 400 patients to endovascular cooling or surface cooling with evaporated water or ice packs [37]. Endovascular cooling was associated with shorter time for induction of hypothermia, decreased temperature variability in the maintenance phase, and less nursing workload. Surface cooling, on the other hand, was associated with rebound hyperthermia and rewarming hypoglycemia. Despite these differences, endovascular cooling failed to reach significance in regard to a reduction in the primary outcome, survival without major neurologic damage [37]. This study is criticized as it compared novel endovascular techniques to older methods of surface cooling. Tømte et al. looked at modern techniques for both invasive and surface cooling [38]. They randomized 167 patients to hydrogel pad surface cooling or an endovascular cooling catheter and found no differences in survival or neurologic outcomes [38]. However, a power calculation was not included in this trial, so a lack of difference may be due to a lack of power and not due to true clinical non-inferiority. Therefore, at this time, the optimal method for cooling is still unclear.

Target temperature Another important uncertainty is the optimal target temperature for neuroprotection. One of the criticisms of both the HACA and Bernard trials was that the control group was actually hyperthermic, with a mean temperature greater than 37 °C by 12 h [14, 15]. Given this finding, it was unknown if the beneficial aspect of these trials was from anti-pyrexic temperature control rather than true hypothermia. To answer this question, Nielsen et al. randomized 939 patients to hypothermia at 33 °C as compared to 36 °C [24••]. Despite the significantly different mean temperatures in these groups, there was no difference in survival or good neurologic outcome. This would suggest that 36 °C is an effective target for cooling. However, this study has several biases. The standard of care at these hospitals was already cooling to 32 to 34 °C, which may have introduced an unconscious bias in patient selection [39]. This may have been reflected in a lower than expected enrollment per site. In keeping with selection bias concerns, the outcomes in this trial were numerically worse than previously published outcomes from many of these sites, 50 % survival as compared to 56–63 % [39]. In addition, patients who had CPR for more than 20 min were excluded from the study. Lastly,


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Curr Treat Options Cardio Med (2016) 18:30 the mean time to the target temperature of 33 °C in the intensive hypothermia arm of this study was 8 h. This delayed time to therapeutic hypothermia may have attenuated the potential benefits of achieving lower temperature.

Adjunctive therapies in persons undergoing therapeutic hypothermia Anti-shivering therapies One signal seen in the Nielsen study was the increased number of medications required in patients cooled to 36 °C relative to the lower temperature target of 33 °C [24••]. The body’s main mechanisms for conserving heat are vasoconstriction and shivering. Vasoconstriction typically occurs at a core temperature of 36.5 °C and can reduce heat loss by approximately 25 % [35]. Shivering, in patients with a normal hypothalamic set point, begins at a core temperature approximately 1 °C below the vasoconstriction threshold and peaks at core temperatures near 35 °C [35]. This shivering response decreases significantly at temperatures less than 33.5 °C and ceases completely below 31 °C [35]. Shivering can undermine the protective effects of hypothermia, as sustained shivering can double the metabolic rate, increase the oxygen consumption by 40–100 %, increase the work of breathing, cause tachycardia, and increase intracranial pressure [35]. Shivering has even been linked to an increased risk of cardiovascular events and adverse outcomes in perioperative patients [35]. Given these deleterious effects, control of shivering becomes vitally important. Means of controlling shivering can be separated into non-pharmacologic and pharmacologic methods. Non-pharmacologic methods rely on the fact that cutaneous heat receptors account for approximately 20 % of the shivering response [40]. The contribution of these peripheral temperature receptors result in a 1 °C reduction in shivering threshold with every 4 °C increase in peripheral skin temperature [41]. Therefore, non-pharmacologic methods include passive skin counter warming with blankets on the peripheries or active methods such as radiant heating, forced air warming, or water-circulating garments [40]. In addition to non-pharmacologic methods, there are numerous pharmacologic methods for control of shivering. One medication that is often first line due to its safety profile is IV magnesium sulfate. Magnesium is thought to reduce the shivering threshold [42]. However, in a study of nine healthy volunteers cooled with IV chilled Lactated Ringers, IV magnesium, dosed at 80 mg/kg and then at 2 g/h, had only a very modest effect, reducing the shivering threshold from 36.6 to 36.3 °C [22••]. Anesthetic medications are also commonly used for reduction of shivering. In a review of protocols from 68 ICUs, propofol or midazolam was listed as the analgesic of choice in 28 % of ICUs [43]. Propofol is a potent anti-shivering agent with a dose-dependent linear decrease in shivering threshold [41]. However, propofol administration in patients undergoing hypothermia after a cardiac arrest requires close monitoring of serum concentrations, which can rise by as much as 30 %, as the identification of propofol infusion syndrome is masked in patients after cardiac arrest who have induced hypothermia. Opiates are also commonly used, with fentanyl used as the analgesic of choice in approximately 50 % of ICUs surveyed [43]. Opiates also cause a dose-

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dependent linear reduction in shivering threshold, albeit less so than with propofol [41]. The exception is meperidine which causes a disproportionately greater reduction in shivering threshold. Other medications such as clonidine and dexmedetomidine have also been shown to have effects on the shivering threshold [41]. Furthermore, combination therapy has shown to be either additive (meperidine and dexmedetomidine) or synergistic (meperidine and buspirone) in reducing the shivering threshold. Finally, a neuromuscular blockade is commonly advocated, in over 990 % of ICU protocol according to one survey, for the control of shivering [43]. However, prolonged neuromuscular blockade also has its own challenges, in particular masking seizure activity and critical illness myopathy [43].

Sedation As discussed above, many analgesics are often used for the control of shivering. In addition, in a pig model of neonatal hypoxia, the absence of sedation entirely attenuated the neuroprotective effects of hypothermia, suggesting the benefits of sedation go beyond shivering control [44]. In addition to the medications discussed above, a common drug used in 950 % of surveyed ICUs is midazolam [43]. However, its pharmacokinetic profile does not lend itself well to the post cardiac arrest patient due to active metabolites and altered clearance in hepatic and renal dysfunction [43]. Hypothermia alone can also result in a 5fold increase in plasma concentrations and a 100-fold decrease in the body clearance of midazolam [45]. This of course becomes problematic in terms of assessing for neurologic recovery after long periods of sedation with midazolam.

Other adjunctive therapy considerations Hypothermia after cardiac arrest requires close monitoring of a multitude of other factors. It is important to maintain hemodynamic status after cardiac arrest to prevent a second cerebral hypoperfusion event. For example, patients post arrest may develop distributive shock due to the post-arrest inflammatory state [42]. Because of hypothermia-induced reduction in the inflammatory response, patients are also at increased risk of infection. Based on two studies evaluating a collective of 654 patients, upwards of 60 % of patients admitted to the hospital with an out-of-hospital cardiac arrest will suffer from infection, most commonly pneumonia [46, 47]. Serum glucose most also be monitored closely as hypothermia results in decreased insulin secretion and increased insulin resistance. Potassium homeostasis is also affected directly by hypothermia due to an inward cellular flux of potassium resulting in hypokalemia [42]. Special care must be paid to potassium as well in the rewarming phase as this will result in a reversal of the potassium flux and potentially hyperkalemia. As mentioned earlier, because of the decreased metabolic rate that occurs with hypothermia, there is a significant decrease in CO2 production. Furthermore, the neurologic injury and the use of sedatives and neuromuscular blockade reduce the body’s ability to autoregulate minute ventilation to compensate for this change in CO2 production. Therefore, it often falls to the clinician to


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make ventilator changes in order to prevent hypercapnia or hypocapnia and the associated cerebral vasodilation (associated increased intracranial pressure) or cerebral vasoconstriction (associated recurrent ischemic injury), respectively [19]. This mandates frequent blood gasses; however, it is worth noting that blood gas values are temperature dependent and the laboratory will commonly warm up the sample prior to analysis. The two methods of addressing this issue are referred to as alpha-stat, blood gas management based on analysis at 37 °C, and pH-stat, blood gas management based on actual core body temperature. Strict management based on these two assessment methods can lead to either hyperventilation or hypoventilation, respectively [19]. In a meta-analysis of 16 studies evaluating patients undergoing therapeutic hypothermia during cardiac surgery and cardiopulmonary bypass, the use of alpha-stat was shown to have improved postoperative outcomes and cerebrovascular metabolism in adults, compared to pH-stat. Interestingly, pH-stat was superior in the pediatric population [48]. Another proposed management algorithm is to use information from assays sampled at 37 °C and then to correct PO2, PCO2, and pH by subtracting 5 mmHg/1 °C, subtracting 2 mmHg/1 °C, and adding 0.012 units/1 °C, respectively, for every degree below 37 °C [19]. However, the ideal method remains to be determined, as the optimum CO2 target in this patient population is unclear given that they commonly display altered cerebral autoregulation [19].

Conclusion Despite medical advances, survival to hospital discharge for an out-ofhospital cardiac arrest remains near 10 % with even lower success rates for discharge with good neurologic function [1]. Induced hypothermia has been shown to attenuate ischemia-reperfusion pathways, which has translated into clinical improvement in terms of survival and good neurologic outcomes. Despite two landmark trials showing significant neurological and survival benefit more than a decade ago and endorsements by major American and European societies, dissemination of appropriate therapeutic hypothermia into widespread clinical practice has, thus far, been poor and many outstanding research questions still need to be answered [14, 15]. Future studies—inclusive of assessing non-shockable rhythms, early hypothermia initiation, and optimal method of cooling—are now needed in order to improve our collective ability to optimize neurologic outcomes for survivors of cardiac arrest.

Compliance with Ethical Standards Conflict of Interest Sunjeet S. Sidhu, Steven P. Schulman, and John W. McEvoy each declare no potential conflicts of interest. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.

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References and Recommended Reading Papers of particular interest, published recently, have been highlighted as • Of importance •• Of major importance 1.

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Hypothermia after Cardiac Arrest Study Group, Group TH after CAS. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med. 2002;346(8):549–56. 16. Weisfeldt ML, Becker LB. Resuscitation after cardiac arrest. JAMA. 2002;288(23):3035. 17. Yenari MA, Han HS. Neuroprotective mechanisms of hypothermia in brain ischaemia. Nat Rev Neurosci. 2012;13. 18. La Bisschops L, van der Hoeven JG, Mollnes TE, Hoedemaekers CW. Seventy-two hours of mild hypothermia after cardiac arrest is associated with a lowered inflammatory response during rewarming in a prospective observational study. Crit Care. 2014;18(5):546. 19. Polderman KH. Mechanisms of action, physiological effects, and complications of hypothermia. Crit Care Med. 2009;37(Supplement):S186–202. 20. Boddicker KA, Zhang Y, Zimmerman MB, Davies LR, Kerber RE. Hypothermia improves defibrillation success and resuscitation outcomes from ventricular fibrillation. Circulation. 2005;111(24):3195–201. 21. Rhee BJ, Zhang Y, Boddicker KA, Davies LR, Kerber RE. Effect of hypothermia on transthoracic defibrillation in a swine model. Resuscitation. 2005;65(1):79–85. 22.•• Dumas F, Grimaldi D, Zuber B, et al. Is hypothermia after cardiac arrest effective in both shockable and nonshockable patients?: insights from a large registry. Circulation. 2011;123D8]:877–86. In this study, Dumas et al. retrospectively reviewed 1145 consecutive patients with non-traumatic out-of-hospital cardiac arrest admitted to a tertiary care center in Paris after return of spontaneous circulation. This study, similar to the landmark trials by Bernard and HACA, showed an associated between therapeutic hypothermia in patients with a VF/AVT arrest and good neurologic outcome. This study, however, did not demonstrate any association in patients with a PEA/asystole arrest. This observational study is important as it is one of the limited analyses examining patients with a non-shockable rhythm and highlights the need for more directed study of these patients. 23. Kim Y-M, Yim H-W, Jeong S-H, Lou KM, Callaway CW. Does therapeutic hypothermia benefit adult cardiac arrest patients presenting with non-shockable initial rhythms?: a systematic review and meta-analysis of randomized and non-randomized studies. Resuscitation. 2012;83(2):188–96. 24.•• 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;369D23]:2197–206. In this study, Nielsen et al. attempted to answer a question left unanswered by the landmark trials by Bernard et al. and HACA, namely, is therapeutic hypothermia itself protective or is it the


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control of hyperthermia. Therefore, Nielsen et al. randomized 939 patients to 33 or 36 °C. There was no difference seen in the primary outcome of all-cause mortality. This study highlights the as-of-yet unanswered question of optimal temperature for hypothermia or targeted-temperature management protocols. 25.• 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. JAMA. 2014;311D1]:45. Based on animal data discussed above, time to cooling is critically important; however, in the landmark trials by Bernard and HACA, the time to hypothermia was 8 and 3 h, respectively. In this study, Kim et al. looked at early cooling by randomizing 1359 patients to pre-hospital cooling as compared to standard of care. No difference was seen in survival to discharge or neurologic outcome at discharge; however, as described above, this can be related to the method of cooling. This study again highlights the need for continued research in the area of therapeutic hypothermia. 26. Nozari A. Critical time window for intra-arrest cooling with cold saline flush in a dog model of cardiopulmonary resuscitation. Circulation. 2006;113(23):2690–6. 27. Kuboyama K, Safar P, Radovsky A, Tisherman SA, Stezoski SW, Alexander H. Delay in cooling negates the beneficial effect of mild resuscitative cerebral hypothermia after cardiac arrest in dogs: a prospective, randomized study. Crit Care Med. 1993;21(9):1348–58. 28. Abella BS. Intra-arrest cooling improves outcomes in a murine cardiac arrest model. Circulation. 2004;109(22):2786–91. 29.• Che D, Li L, Kopil CM, Liu Z, Guo W, Neumar RW. Impact of therapeutic hypothermia onset and duration on survival, neurologic function, and neurodegeneration after cardiac arrest. Crit Care Med. 2011;39D6]:1423–3. Covers important practical considerations on how to achieve hypothermia. 30. 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(8):1021–8. 31. Yannopoulos D, Zviman M, Castro V, et al. Intracardiopulmonary resuscitation hypothermia with and without volume loading in an ischemic model of cardiac arrest. Circulation. 2009;120(14):1426–35. 32. Yu T, Barbut D, Ristagno G, et al. Survival and neurological outcomes after nasopharyngeal cooling or peripheral vein cold saline infusion initiated during cardiopulmonary resuscitation in a porcine model of prolonged cardiac arrest. Crit Care Med. 2010;38(3):916–21. 33. Rapid infusion of cold normal saline during CPR for patients with out-of-hospital cardiac arrest. Full text view. [Internet]. [cited 2015 Nov 9].

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Therapeutic Hypothermia After Cardiac Arrest.

Resuscitated cardiac arrest continues to carry a poor prognosis despite advances in medical care. One such advance, therapeutic hypothermia, is neurop...
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