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Targeted Temperature Management in Survivors of Cardiac Arrest

      Keywords

      Key points

      • Evidence supports mild therapeutic hypothermia (MTH) as the fifth link of the life chain, with significant decrease in mortality and improvement of neurologic outcomes in cardiac arrest (CA) survivors throughout the last decade.
      • Cardiologist and intensivists must be acquainted with the indications and technique because MTH is the only proven neuroprotective therapy for CA survivors.
      • Future research will help define current questions, such as the optimal timing, target temperature, and duration of MTH.

      Introduction

      Cardiac arrest (CA) is one of the most challenging situations in medicine because it involves not only reinstituting meaningful cardiac activity, but also minimizing secondary neurologic injuries. It is a major public health issue worldwide and a considerable amount of resources are spent in research yearly to understand better pathophysiological mechanisms, as well as therapies, to reduce secondary injuries in survivors. It is estimated that the global incidence of out-of-hospital CA is 82 to 189 cases per 100,000 inhabitants in industrialized countries.
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      Incidence of out-of-hospital cardiac arrest.
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      Part 5: adult basic life support: 2010 international consensus on cardiopulmonary resuscitation and emergency cardiovascular care science with treatment recommendations.
      Data from studies conducted before the widespread use of mild therapeutic hypothermia (MTH) show that only 5% to 20% of CA survivors were discharged from the hospital with good neurologic outcomes.
      Randomized clinical study of thiopental loading in comatose survivors of cardiac arrest. Brain Resuscitation Clinical Trial I Study Group.
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      Long term outcome after out-of-hospital cardiac arrest with physician staffed emergency medical services: the Utstein style applied to a midsized urban/suburban area.
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      Out-of-hospital cardiac arrests: an 8-year New York City experience.
      Of all the numerous randomized controlled trials (RCTs) that tested therapies to improve neurologic outcome after CA, the only ones with positive reproducible results were studies using MTH.
      • Frontera J.A.
      Clinical trials in cardiac arrest and subarachnoid hemorrhage: lessons from the past and ideas for the future.
      This article focuses on MTH as the main strategy for post-CA care.

      Rationale for the use of MTH after CA

      Hypoxic-ischemic brain injury is a well-known consequence of CA. Brain injury and cardiovascular instability are the major determinants of survival after CA.
      • Laver S.
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      • Turner D.
      • et al.
      Mode of death after admission to an intensive care unit following cardiac arrest.
      It is estimated that the cost of care during the first 6 months after a CA for a patient severely disabled or in a vegetative state can be as high as $300,000.
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      • Becker L.B.
      • Abella B.S.
      • et al.
      Cost-effectiveness of therapeutic hypothermia after cardiac arrest.

      Historical perspective

      The use of hypothermia for clinical purposes has been suggested for thousands of years. Hippocrates advocated the packing of wounded soldiers in snow and ice in 400 BC.
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      • Zhang J.
      • Muehlschlegel S.
      Therapeutic hypothermia for acute neurological injuries.
      Baron Dominique Jean Larrey, surgeon-in-chief of the Napoleonic armies, observed that the wounded soldiers lying closer to the campfire died sooner than those in more remote, colder areas did.
      • Kochanek P.M.
      Bakken lecture: the brain, the heart, and therapeutic hypothermia.
      Clinical interest in hypothermia was revived in the 1930s and 1940s with observations and case reports describing successful resuscitation of drowning victims who were hypothermic.
      • Polderman K.H.
      Application of therapeutic hypothermia in the ICU: opportunities and pitfalls of a promising treatment modality. Part 1: indications and evidence.
      Subsequently, scientific reports of its use after CA
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      The use of hypothermia after cardiac arrest.
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      Lightning stroke. Report of a case with recovery after cardiac massage and prolonged artificial respiration.
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      • Spencer F.C.
      The clinical use of hypothermia following cardiac arrest.
      and in patients with traumatic brain injury
      • Fay T.
      Early experiences with local and generalized refrigeration of the human brain.
      were published in the 1950s and 1960s.
      In 1964, the legendary anesthesiologist and intensivist Peter Safar
      • Safar P.
      Community-wide cardiopulmonary resuscitation.
      recommended in his historic “first ABCs of resuscitation” that hypothermia be used in patients who remain comatose after successful restoration of spontaneous circulation.
      At that time, no consensus was reached about the ideal duration and goal temperature, or the ideal candidates for induced hypothermia. Due to adverse effects observed at very low temperatures, and difficulty efficiently and safely inducing and maintaining hypothermia, interest in this treatment modality declined precipitously. Approximately 30 years later, laboratory studies using animal models demonstrated the benefit of mild hypothermia after CA.
      • Leonov Y.
      • Sterz F.
      • Safar P.
      • et al.
      Mild cerebral hypothermia during and after cardiac arrest improves neurologic outcome in dogs.
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      • Tisherman S.
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      Mild hypothermic cardiopulmonary resuscitation improves outcome after prolonged cardiac arrest in dogs.
      These were followed by several pilot trials of MTH in humans showing improved neurologic function compared with historic controls, as well as safety and feasibility.
      • Bernard S.A.
      • Jones B.M.
      • Horne M.K.
      Clinical trial of induced hypothermia in comatose survivors of out-of-hospital cardiac arrest.
      • Nagao K.
      • Hayashi N.
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      • et al.
      Cardiopulmonary cerebral resuscitation using emergency cardiopulmonary bypass, coronary reperfusion therapy and mild hypothermia in patients with cardiac arrest outside the hospital.
      • Yanagawa Y.
      • Ishihara S.
      • Norio H.
      • et al.
      Preliminary clinical outcome study of mild resuscitative hypothermia after out-of-hospital cardiopulmonary arrest.
      Those studies set the foundation for the seminal RCTs,
      • Hypothermia After Cardiac Arrest Study Group
      Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest.
      • Bernard S.A.
      • Gray T.W.
      • Buist M.D.
      • et al.
      Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia.
      which ushered in a new era in the post-CA care, culminating in 2003 with a statement from the International Liaison Committee on Resuscitation that “unconscious adult patients with spontaneous circulation after out-of-hospital CA should be cooled to 32°C to 34°C for 12 to 24 hours when the initial rhythm was ventricular fibrillation.”
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      • et al.
      Therapeutic hypothermia after cardiac arrest: an advisory statement by the advanced life support task force of the International Liaison Committee on Resuscitation.
      In 2005, induced hypothermia was included in the American Heart Association chain of survival.
      • ECC Committee, Subcommittees and Task Forces of the American Heart Association
      2005 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care.

      Pathophysiology of Brain Injury in CA

      The brain receives approximately 25% of the cardiac output and is a strict aerobic organ with very high demand for glucose and very limited energy storage. Thus, it is extremely vulnerable to ischemic insults. Studies using animal models demonstrated that after 10 minutes of induced brain ischemia brain concentrations of glucose, glycogen, adenosine triphosphate, and phosphocreatine are virtually nonexistent.
      • Wagner S.R.
      • Lanier W.L.
      Metabolism of glucose, glycogen, and high-energy phosphates during complete cerebral ischemia. A comparison of normoglycemic, chronically hyperglycemic diabetic, and acutely hyperglycemic nondiabetic rats.
      This is usually followed by loss of transmembrane electrochemical gradients and consequent failure of synaptic transmission,
      • Hoesch R.E.
      • Koenig M.A.
      • Geocadin R.G.
      Coma after global ischemic brain injury: pathophysiology and emerging therapies.
      release of glutamate leading to excitotoxic cell death,
      • Redmond J.M.
      • Gillinov A.M.
      • Zehr K.J.
      • et al.
      Glutamate excitotoxicity: a mechanism of neurologic injury associated with hypothermic circulatory arrest.
      neuronal necrosis, and apoptosis.
      • Nolan J.P.
      • Neumar R.W.
      • Adrie C.
      • et al.
      Post-cardiac arrest syndrome: epidemiology, pathophysiology, treatment, and prognostication: a scientific statement from the International Liaison Committee on Resuscitation; the American Heart Association Emergency Cardiovascular Care Committee; the Council on Cardiovascular Surgery and Anesthesia; the Council on Cardiopulmonary, Perioperative, and Critical Care; the Council on Clinical Cardiology; the Council on Stroke (Part II).
      Although the restoration of brain perfusion will reestablish energy stores, further injuries can ensue in a process known as reperfusion injury. Some of the studied mechanisms of reperfusion injury include lipid peroxidation, generation of oxygen reactive species, continued glutamate neurotoxicity, activation of calcium-dependent systems, and neuronal damage mediated by inflammatory cells.
      • Hammer M.D.
      • Krieger D.W.
      Hypothermia for acute ischemic stroke: not just another neuroprotectant.
      Box 1 summarizes some of the known mechanisms of neuronal injury associated with CA.
      Mechanisms of anoxic-ischemic brain injury

        Immediate

      • 1.
        Cellular energy depletion, with anaerobic metabolism
      • 2.
        Collapse of transmembrane sodium and potassium gradients
      • 3.
        Failure of synaptic transmission, axonal conduction, and action potential firing
      • 4.
        Intracellular acidosis
      • 5.
        Hypercalcemia
      • 6.
        Glutamate release, with neuronal hyperexcitability
      • 7.
        Activation of intracellular enzymatic systems (protein kinase C and B, calcium/calmodulin-dependent protein kinase II, mitogen-activated protein kinases, phospholipase A2, C and D).
      • 8.
        Mitochondrial dysfunction
      • 9.
        Reperfusion, with generation of reactive oxygen species and lipid peroxidation
      • 10.
        Elevated production of nitric oxide and peroxynitrite
      • 11.
        Blood-brain barrier dysfunction
      • 12.
        Loss of cerebral autoregulation

        Delayed

      • 1.
        Release of proinflammatory mediators (eg, tumor necrosis factor-α and interleukin-1)
      • 2.
        Inflammatory cells recruitment
      • 3.
        Complement activation
      • 4.
        Caspase activation with apoptosis
      • 5.
        Coagulation activation

      Protective Effects Associated with MTH

      Since the 1950s, animal studies have shown that induced hypothermia can decrease the cerebral blood flow and cerebral metabolic rate of oxygen consumption as much as 6% to 7% for each 1°C reduction in brain temperature.
      • Alzaga A.G.
      • Cerdan M.
      • Varon J.
      Therapeutic hypothermia.
      • Rosomoff H.L.
      • Holaday D.A.
      Cerebral blood flow and cerebral oxygen consumption during hypothermia.
      Recent studies using transcranial Doppler ultrasonography showed a significant decrease in the mean velocities of flow of the middle cerebral artery during MTH, but no changes in jugular venous oxygen saturation, showing a preserved metabolic coupling without further ischemia.
      • Bisschops L.L.
      • Hoedemaekers C.W.
      • Simons K.S.
      • et al.
      Preserved metabolic coupling and cerebrovascular reactivity during mild hypothermia after cardiac arrest.
      • Bisschops L.L.
      • van der Hoeven J.G.
      • Hoedemaekers C.W.
      Effects of prolonged mild hypothermia on cerebral blood flow after cardiac arrest.
      Additionally, MTH inhibits the release of glutamate and dopamine
      • Hachimi-Idrissi S.
      • Van Hemelrijck A.
      • Michotte A.
      • et al.
      Postischemic mild hypothermia reduces neurotransmitter release and astroglial cell proliferation during reperfusion after asphyxial cardiac arrest in rats.
      and induces the release of brain-derived neurotrophic factor,
      • D'Cruz B.J.
      • Fertig K.C.
      • Filiano A.J.
      • et al.
      Hypothermic reperfusion after cardiac arrest augments brain-derived neurotrophic factor activation.
      which further inhibits glutamate. A decrease in oxidative stress, free radical generation,
      • Lei B.
      • Cai H.
      • Xu Q.
      • et al.
      Effect of moderate hypothermia on lipid peroxidation in canine brain tissue after cardiac arrest and resuscitation.
      • Maier C.M.
      • Sun G.H.
      • Cheng D.
      • et al.
      Effects of mild hypothermia on superoxide anion production, superoxide dismutase expression, and activity following transient focal cerebral ischemia.
      and cell-death secondary to apoptosis has also been observed.
      • Eberspacher E.
      • Werner C.
      • Engelhard K.
      • et al.
      Long-term effects of hypothermia on neuronal cell death and the concentration of apoptotic proteins after incomplete cerebral ischemia and reperfusion in rats.
      Hypothermia suppresses the inflammatory cascade triggered after CA
      • Aibiki M.
      • Maekawa S.
      • Ogura S.
      • et al.
      Effect of moderate hypothermia on systemic and internal jugular plasma IL-6 levels after traumatic brain injury in humans.
      • Kimura A.
      • Sakurada S.
      • Ohkuni H.
      • et al.
      Moderate hypothermia delays proinflammatory cytokine production of human peripheral blood mononuclear cells.
      • Webster C.M.
      • Kelly S.
      • Koike M.A.
      • et al.
      Inflammation and NFkappaB activation is decreased by hypothermia following global cerebral ischemia.
      and reduces early hyperemia, delayed hypoperfusion, blood-brain barrier disruption and cerebral edema.
      • Karibe H.
      • Zarow G.J.
      • Graham S.H.
      • et al.
      Mild intraischemic hypothermia reduces postischemic hyperperfusion, delayed postischemic hypoperfusion, blood-brain barrier disruption, brain edema, and neuronal damage volume after temporary focal cerebral ischemia in rats.
      • Jurkovich G.J.
      • Pitt R.M.
      • Curreri P.W.
      • et al.
      Hypothermia prevents increased capillary permeability following ischemia-reperfusion injury.
      Box 2 summarizes the protective mechanisms of MTH.
      Protective mechanism of therapeutic hypothermia

        Early

      • 1.
        Decrease of cerebral metabolism
      • 2.
        Decrease in mitochondrial injury and dysfunction
      • 3.
        Improve ion pump function, decrease intracellular influx of calcium
      • 4.
        Improve cell membrane leakage, decrease intracellular acidosis
      • 5.
        Decrease production of reactive oxygen species
      • 6.
        Decrease formation of cytotoxic edema

        Late

      • 1.
        Decrease of local production of endothelin and thromboxane A2, increase generation of prostaglandins
      • 2.
        Improve tolerance for ischemia
      • 3.
        Decrease neuroinflammation
      • 4.
        Decrease apoptosis
      • 5.
        Decrease cerebral thermo-pooling
      • 6.
        Decrease vascular permeability
      • 7.
        Activation of protective genes
      • 8.
        Suppression of cortical spreading depression
      • 9.
        Suppression of seizure activity
      • 10.
        Decrease coagulation activation and formation of microthrombi

      Hypothermia After CA with Initial Shockable Rhythm

      Two landmark studies, published simultaneously in 2002, reported significant improvement of neurologic outcomes using MTH in patients with out-of-hospital CA with ventricular tachycardia or ventricular fibrillation (VT/VF) as the initial arrest rhythm.
      The Hypothermia After Cardiac Arrest (HACA) trial was a multicenter European RCT that enrolled 275 survivors of out-of-hospital CA with the initial rhythm of unstable VT or VF.
      • Hypothermia After Cardiac Arrest Study Group
      Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest.
      Subjects were randomly assigned to MTH, with a goal temperature of 32° to 34°C for 24 hours using cold air as the cooling method (TheraKool, Kinetic Concepts, Wareham, United Kingdom) versus standard treatment with normothermia. The goal was to reach the target temperature (measured with a bladder probe) within 4 hours after the return of spontaneous circulation (ROSC) and, if necessary, ice packs were used as an adjunct method. After 24 hours at the goal temperature, subjects were passively rewarmed, which was expected to occur over a period of 8 hours. Fifty-five percent of the subjects in the MTH group had a favorable neurologic recovery after 6 months (Cerebral Performance Category score 1 and 2, or ability to work with minor deficit and full independent activities of daily living). This was in contrast to 39% of subjects in the control group (risk ratio for a favorable outcome with hypothermia, 1.40; 95% CI, 1.08–1.81) with an absolute risk reduction of 16% and a number needed to treat to achieve a positive neurologic outcome of six. Additionally, a significant reduction in the rate of death at 6 months in the MTH group was observed (risk ratio for death, 0.74; 95% CI, 0.58–0.95), with an absolute risk reduction of 14% and number needed to treat to avoid one death of seven.
      Simultaneously, an Australian trial conducted by Bernard and colleagues
      • Bernard S.A.
      • Gray T.W.
      • Buist M.D.
      • et al.
      Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia.
      enrolled 77 survivors of out-of-hospital CA with an initial rhythm of unstable VT/VF. Subjects enrolled on odd-numbered days received MTH, with a goal temperature of 33°C, for 12 hours, using ice packs as the cooling method. Subjects enrolled on even-numbered days received standard treatment with normothermia. Cooling was started by rescue personnel at the scene of the CA using cold packs (CoolCare, Cheltenham, Victoria, Australia). This was continued in the hospital using ice packs. Body temperature monitoring was performed with a pulmonary artery catheter. After 12 hours, subjects were actively rewarmed for the next 6 hours by external warming with a heated-air blanket, with continued sedation and neuromuscular blockade to suppress shivering. Twenty-one of the 43 subjects (49%) who were treated with MTH survived and had a favorable neurologic recovery (defined as discharged home or to a rehabilitation center) at hospital discharge, compared with 9 of the 34 subjects (26%) treated with normothermia (P = .05). The number needed to treat to obtain a favorable neurologic recovery was four. The odds ratio for a good outcome in the hypothermia group compared with the normothermia group, after adjustment by logistic regression for age and time from collapse to ROSC, was 5.25 (95% CI, 1.47 to 18.76; P = .011). Though mortality was reduced in the hypothermia group compared with the normothermia group (51% vs 68%), this did not reach statistical significance, likely due to the small sample size in this study.

      Hypothermia After CA with Initial Nonshockable Rhythm

      In contrast to the studies with VT/VF as the initial rhythm, there are no large RCTs to evaluate the efficacy of MTH in subjects with CA and nonshockable rhythms. Although it would be logical to deduce that the brain injury mechanism could be the same, it is not clear whether other factors influence outcome. Patients with pulseless electric activity or asystole (PEA/asystole) arrest are usually sicker at baseline, and asphyxia and circulatory shock often result in bradycardia or hypotension, or both, before progressing to pulseless CA, during which time additional brain injury may be incurred. Studies from the era before hypothermia showed that subjects with CA and nonshockable rhythms have worse prognosis when compared with VT/VF arrest,
      • Meaney P.A.
      • Nadkarni V.M.
      • Kern K.B.
      • et al.
      Rhythms and outcomes of adult in-hospital cardiac arrest.
      • Nadkarni V.M.
      • Larkin G.L.
      • Peberdy M.A.
      • et al.
      First documented rhythm and clinical outcome from in-hospital cardiac arrest among children and adults.
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      Medical futility in asystolic out-of-hospital cardiac arrest.
      • Vayrynen T.
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      • Maatta T.
      • et al.
      Who survives from out-of-hospital pulseless electrical activity?.
      with the exception of children
      • Nadkarni V.M.
      • Larkin G.L.
      • Peberdy M.A.
      • et al.
      First documented rhythm and clinical outcome from in-hospital cardiac arrest among children and adults.
      and subjects with out-of-hospital witnessed CA secondary to a cardiac cause.
      • Stratton S.J.
      • Niemann J.T.
      Outcome from out-of-hospital cardiac arrest caused by nonventricular arrhythmias: contribution of successful resuscitation to overall survivorship supports the current practice of initiating out-of-hospital ACLS.
      • Niemann J.T.
      • Stratton S.J.
      • Cruz B.
      • et al.
      Outcome of out-of-hospital postcountershock asystole and pulseless electrical activity versus primary asystole and pulseless electrical activity.
      Some nonrandomized, retrospective and prospective analyses of MTH in nonshockable rhythms have been published. Of these, three studies of out-of-hospital nonshockable rhythm CA found some possible improvement of neurologic outcomes with MTH,
      • Lundbye J.B.
      • Rai M.
      • Ramu B.
      • et al.
      Therapeutic hypothermia is associated with improved neurologic outcome and survival in cardiac arrest survivors of non-shockable rhythms.
      • Testori C.
      • Sterz F.
      • Behringer W.
      • et al.
      Mild therapeutic hypothermia is associated with favourable outcome in patients after cardiac arrest with non-shockable rhythms.
      • Soga T.
      • Nagao K.
      • Sawano H.
      • et al.
      Neurological benefit of therapeutic hypothermia following return of spontaneous circulation for out-of-hospital non-shockable cardiac arrest.
      although one of these showed only a trend for better prognosis but without statistical significance.
      • Soga T.
      • Nagao K.
      • Sawano H.
      • et al.
      Neurological benefit of therapeutic hypothermia following return of spontaneous circulation for out-of-hospital non-shockable cardiac arrest.
      Another two studies found no benefit of using MTH for out-of-hospital nonshockable rhythm CA.
      • 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.
      • Storm C.
      • Nee J.
      • Roser M.
      • et al.
      Mild hypothermia treatment in patients resuscitated from non-shockable cardiac arrest.
      The only retrospective study that analyzed in-hospital nonshockable rhythm CA found no benefit for MTH.
      • Kory P.
      • Fukunaga M.
      • Mathew J.P.
      • et al.
      Outcomes of mild therapeutic hypothermia after in-hospital cardiac arrest.
      A meta-analysis including studies before 2010 that tested MTH in nonshockable rhythm CA survivors found that MTH is associated with reduced in-hospital mortality, but no significant neurologic benefit could be found.
      • Kim Y.M.
      • Yim H.W.
      • Jeong S.H.
      • et al.
      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.
      Currently, two trials are recruiting subjects to study MTH in nonshockable rhythm CA in-hospital (NCT00886184) and out-of-hospital (NCT00391469). Until further data are available, MTH does not seem to confer any survival or neurologic benefit to CA survivors who present with a nonshockable rhythm.

      Application of MTH

      Indications

      MTH is currently indicated for patients who survive CA with VT/VF as the initial rhythm and who are not able to follow commands after being adequately resuscitated. Its use is strongly supported by the American Heart Association guidelines,
      • Field J.M.
      • Hazinski M.F.
      • Sayre M.R.
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      Part 1: executive summary: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care.
      the European Resuscitation Council guidelines,
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      • Soar J.
      • Zideman D.A.
      • et al.
      European Resuscitation Council Guidelines for Resuscitation 2010 Section 1. Executive summary.
      and the International Liaison Committee on Resuscitation guidelines.
      • Hazinski M.F.
      • Nolan J.P.
      • Billi J.E.
      • et al.
      Part 1: executive summary: 2010 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations.
      Some centers also use MTH in patients with PEA/asystole as the initial rhythm, although evidence for this practice is limited (see previous discussion). The current data support the use of out-of-hospital CA, although it would be reasonable to treat someone with a witnessed CA secondary to a cardiac cause with VT/VF as the rhythm in the inpatient setting. In addition, the largest trial (HACA) did not include subjects who were resuscitated for more than 60 minutes, which seems a reasonable cutoff, unless the cause for the CA was near-drowning in cold water. Recently, the analysis of a large registry of CA care, including several hospitals in the United States, showed that, compared with patients at hospitals in the quartile with the shortest median resuscitation attempts in nonsurvivors (16 min; interquartile range [IQR] 15–17), those at hospitals in the quartile with the longest attempts (25 min; IQR 25–28) had a higher likelihood of ROSC (P<.0001) and survival to discharge (P<.021).
      • Goldberger Z.D.
      • Chan P.S.
      • Berg R.A.
      • et al.
      Duration of resuscitation efforts and survival after in-hospital cardiac arrest: an observational study.

      Induction

      Regardless of the method used to induce MTH, it is extremely important to expedite the process because delays in initiation seem to diminish or even abrogate its beneficial effects in animal models.
      • Colbourne F.
      • Corbett D.
      Delayed postischemic hypothermia: a six month survival study using behavioral and histological assessments of neuroprotection.
      • Kuboyama K.
      • Safar P.
      • Radovsky A.
      • et al.
      Delay in cooling negates the beneficial effect of mild resuscitative cerebral hypothermia after cardiac arrest in dogs: a prospective, randomized study.
      It is suggested that goal core temperature (32°–34°C) should be reached as soon as possible and no more than 8 hours after ROSC. The goal is to reach mild hypothermia because severe cardiac complications are usually encountered with temperatures lower than 30°C.
      Several cooling methods, including ice packs and infusion of cold saline, as well as devices (intravascular cooling catheters, nasal cooling, helmets, surface cooling), were tested in small trials. The methods are usually divided in surface cooling (eg, cooling pads, ice packs) or core cooling (eg, intravascular cooling catheters, cold saline infusion). Table 1 summarizes the most commonly used methods, with their advantages and disadvantages. To date, there is no evidence to determine the most effective method. A retrospective nonrandomized study with 167 subjects compared surface cooling (using cooling pads) with core cooling (using an intravascular cooling catheter) and found no difference in survival or neurologic outcome between groups.
      • Tomte O.
      • Draegni T.
      • Mangschau A.
      • et al.
      A comparison of intravascular and surface cooling techniques in comatose cardiac arrest survivors.
      These findings were corroborated by another retrospective study.
      • Gillies M.A.
      • Pratt R.
      • Whiteley C.
      • et al.
      Therapeutic hypothermia after cardiac arrest: a retrospective comparison of surface and endovascular cooling techniques.
      Evidence does suggest, however, that devices with hydrogel cooling pads are much more effective than conventional cooling blankets.
      • Heard K.J.
      • Peberdy M.A.
      • Sayre M.R.
      • et al.
      A randomized controlled trial comparing the Arctic Sun to standard cooling for induction of hypothermia after cardiac arrest.
      • Mayer S.A.
      • Kowalski R.G.
      • Presciutti M.
      • et al.
      Clinical trial of a novel surface cooling system for fever control in neurocritical care patients.
      Finally, pressure bag infusion of 30 to 40 ml/kg of cold saline or Ringer lactate solution (4°C) can decrease the core body temperature by roughly 1°C per liter of fluid infused.
      • Kim F.
      • Olsufka M.
      • Longstreth Jr., W.T.
      • et al.
      Pilot randomized clinical trial of prehospital induction of mild hypothermia in out-of-hospital cardiac arrest patients with a rapid infusion of 4 degrees C normal saline.
      • Kliegel A.
      • Losert H.
      • Sterz F.
      • et al.
      Cold simple intravenous infusions preceding special endovascular cooling for faster induction of mild hypothermia after cardiac arrest–a feasibility study.
      • Polderman K.H.
      • Rijnsburger E.R.
      • Peerdeman S.M.
      • et al.
      Induction of hypothermia in patients with various types of neurologic injury with use of large volumes of ice-cold intravenous fluid.
      Some investigators defend that a combination of core cooling with cold saline infusion with surface cooling might be very effective, possibly with less shivering during induction, although this hypothesis has not been tested in trials to date.
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      • Herold I.
      Therapeutic hypothermia and controlled normothermia in the intensive care unit: practical considerations, side effects, and cooling methods.
      Table 1Most commonly adopted cooling methods
      MethodComments
      Core cooling
       Infusion of cold fluidsUsually bolus of 30 ml/kg of normal saline solution at 4°C

      Very rapid method and inexpensive, but no control over temperature goals

      Should not be used as maintenance, but as an induction adjuvant (even in the prehospital setting)

      Studies have shown this volume is well tolerated
       Intravascular cooling cathetersProvides quick induction (1.5°–4.5°C) and highly reliable maintenance and rewarming

      Requires invasive procedure with risk of infection, hemorrhage, and venous thrombosis

      Anecdotal evidence suggests less shivering than surface cooling
      Surface cooling
       Ice packsEasy, inexpensive, can provide fairly rapid induction

      No control over temperature goals and overshoot is common

      Should not be used as maintenance, but may be used an induction adjuvant (even in the prehospital setting)

      Risk of severe skin lesions
       Water-circulating cooling blanketsLess expensive than other methods, reusable, but inferior to cooling pads or intravascular catheters
      • Mayer S.A.
      • Kowalski R.G.
      • Presciutti M.
      • et al.
      Clinical trial of a novel surface cooling system for fever control in neurocritical care patients.


      Risk of skin lesions
       Cooling padsMost effective are hydrogel-coated water circulating pads

      Easy to apply, less labor intensive, with fairly fast induction (1.5°–2.0°C) and reliable maintenance and rewarming

      Risk of skin lesions, particularly with prolonged use at a low water temperature

      Cooling pads are reasonably expensive, but avoid risks associated with invasive procedures
      The Neurocritical Care Society Emergency Neurologic Life Support (NCS ENLS) suggests a goal temperature of 32° to 34°C, with the concomitant use of cold saline infusion (4°C, 40 ml/kg intravenous bolus) and a surface or core cooling method for MTH induction.
      • Rittenberger J.C.
      • Polderman K.H.
      • Smith W.S.
      • et al.
      Emergency neurological life support: resuscitation following cardiac arrest.

      Maintenance

      After core temperature goal is reached, it should be maintained with minimal fluctuations (±0.5°C) for 24 hours. Although one of the main positive RCTs used 12 hours for the maintenance phase, most centers currently adopt 24 hours.
      • Rittenberger J.C.
      • Polderman K.H.
      • Smith W.S.
      • et al.
      Emergency neurological life support: resuscitation following cardiac arrest.
      A recent small, pilot, randomized trial with 36 subjects suggests that MTH with a target of 32°C may yield better protection than cooling at 34°C, resulting in better short-term and long-term outcomes.
      • Lopez-de-Sa E.
      • Rey J.R.
      • Armada E.
      • et al.
      Hypothermia in comatose survivors from out-of-hospital cardiac arrest: pilot trial comparing 2 levels of target temperature.
      Table 2 summarizes tests commonly ordered during MTH.
      Table 2Tests performed during MTH
      TypeFrequencyComments
      Complete blood count, international normalized ratio, activated partial thromboplastin time, fibrinogenEvery 12 hWatch for DIC, hemolysis, platelet dysfunction
      Serum electrolytes (sodium, potassium, phosphorus, magnesium, calcium) and renal functionEvery 8 hIntracellular electrolyte shifts can occur during induction and extracellular shifts during rewarming

      Monitor for hypokalemia during induction and rebound hyperkalemia during rewarming

      Replete potassium <3.5 mg/dL

      Watch for ATN
      Arterial blood gasesEvery 12 hOxygen and carbon dioxide can be overestimated and pH underestimated if not corrected to actual body temperature
      GlucoseEvery 6 hInsulin resistance commonly seen
      Amylase, lipase, liver functionEvery 12 hElevation of liver and pancreatic enzymes can occur during MTH, but usually do not represent cell injury
      LactateEvery 8 hMild lactic academia can be seen in MTH
      Chest radiographDailyObserve for infections and volume overload
      EEGContinuousPatients should be monitored continuously to detect nonconvulsive status epilepticus
      Blood culturesEvery 48 hSome investigators suggest screening cultures to detect occult bacteremia (MTH induces mild leukopenia and fever cannot be detected)
      Abbreviations: ATN, acute tubular necrosis; DIC, disseminated intravascular coagulation.

      Rewarming

      The rewarming phase should be as slow and controlled as possible. Animal experiments and human clinical observations suggest that rapid rewarming might lead to loss of many of the benefits and neuroprotective effects of MTH.
      • Alam H.B.
      • Rhee P.
      • Honma K.
      • et al.
      Does the rate of rewarming from profound hypothermic arrest influence the outcome in a swine model of lethal hemorrhage?.
      • Bissonnette B.
      • Holtby H.M.
      • Davis A.J.
      • et al.
      Cerebral hyperthermia in children after cardiopulmonary bypass.
      • Hildebrand F.
      • van Griensven M.
      • Giannoudis P.
      • et al.
      Effects of hypothermia and re-warming on the inflammatory response in a murine multiple hit model of trauma.
      • Kawahara F.
      • Kadoi Y.
      • Saito S.
      • et al.
      Slow rewarming improves jugular venous oxygen saturation during rewarming.
      • Maxwell W.L.
      • Watson A.
      • Queen R.
      • et al.
      Slow, medium, or fast re-warming following post-traumatic hypothermia therapy? An ultrastructural perspective.
      Significant decreases in jugular venous oxygen saturation have been reported during rapid rewarming,
      • Kawahara F.
      • Kadoi Y.
      • Saito S.
      • et al.
      Slow rewarming improves jugular venous oxygen saturation during rewarming.
      as well as isolated brain hyperthermia (with normal core temperature),
      • Bissonnette B.
      • Holtby H.M.
      • Davis A.J.
      • et al.
      Cerebral hyperthermia in children after cardiopulmonary bypass.
      increases in interleukin 6, and activation of the complement cascade.
      • Bisschops L.L.
      • Hoedemaekers C.W.
      • Mollnes T.E.
      • et al.
      Rewarming after hypothermia after cardiac arrest shifts the inflammatory balance.
      Rebound cerebral edema and further brain injury are the most feared consequences of rewarming too rapidly.
      Some investigators suggest a rewarming rate of 0.2° to 0.5°C per hour in patients after CA and an even slower rate of 0.1° to 0.2°C per hour in patients with primary neurologic conditions, such as traumatic brain injury or stroke.
      • Polderman K.H.
      Mechanisms of action, physiological effects, and complications of hypothermia.
      Many cooling devices have feedback mechanisms that permit rewarming at specific speeds. When the target temperature of 36° to 37°C is reached, the cooling device should lock the patient at this normothermic goal for the next 24 to 48 hours because rebound hyperthermia is common, and can be extremely detrimental to the brain.
      • Zeiner A.
      • Holzer M.
      • Sterz F.
      • et al.
      Hyperthermia after cardiac arrest is associated with an unfavorable neurologic outcome.
      A slower rewarming period can also minimize electrolyte shifts and resistance to insulin changes, normally observed during this phase.

      Temperature Monitoring

      Monitoring core body temperature during MTH is essential. Noninvasive measurements, such as axillary, oral, tympanic, and temporal temperature, were tested in small studies and are completely unreliable.
      • Polderman K.H.
      • Herold I.
      Therapeutic hypothermia and controlled normothermia in the intensive care unit: practical considerations, side effects, and cooling methods.
      • Erickson R.S.
      • Kirklin S.K.
      Comparison of ear-based, bladder, oral, and axillary methods for core temperature measurement.
      • Robinson J.
      • Charlton J.
      • Seal R.
      • et al.
      Oesophageal, rectal, axillary, tympanic and pulmonary artery temperatures during cardiac surgery.
      According to the NCS ENLS, the preferred route of monitoring temperature in approximate order of preference would be endovascular, esophageal, and bladder or rectal.
      • Rittenberger J.C.
      • Polderman K.H.
      • Smith W.S.
      • et al.
      Emergency neurological life support: resuscitation following cardiac arrest.
      Intracranial monitoring devices, such as intracranial pressure or brain tissue oxygenation monitors, can offer an exquisite opportunity for reliable brain temperature monitoring, although the device should not be primarily placed for temperature monitoring. Worth mentioning, bladder temperatures in anuric patients might differ considerably from brain temperatures.
      • Akata T.
      • Setoguchi H.
      • Shirozu K.
      • et al.
      Reliability of temperatures measured at standard monitoring sites as an index of brain temperature during deep hypothermic cardiopulmonary bypass conducted for thoracic aortic reconstruction.
      In the context of anuria, an esophageal, intravascular, or rectal temperature probe is preferred.

      Commonly encountered problems during MTH

      Table 3 discusses commonly encountered clinical complications during MTH.
      Table 3Most commonly observed physiologic changes and complications during MTH
      Physiologic Changes and Complications by SystemsComments
      Cardiovascular
       1. HypovolemiaNormally secondary to cold diuresis during induction
       2. Heart ratePatients usually develop bradycardia, but matched with decreased body metabolism

      Malignant bradycardia and decreased stroke volumes normally only seen with temperature <30°C (patients should be rewarmed because atropine is usually ineffective)

      Care with use of dexmedetomidine
       3. EKG changesIncrease in PR, QT, and QRS intervals

      Arrhythmias normally seen in temperature <30°C (atrial fibrillation and ventricular arrhythmias)

      Rewarming is the most effective treatment in this situation

      Osborn waves normally noted only in cases of severe accidental hypothermia
      Renal and electrolytesIntracellular electrolyte shifts can occur during induction and extracellular shifts during rewarming

      Rapid induction and slow rewarming usually minimize changes

      ATN only observed in case of accidental hypothermia with temperature <28°C
      EndocrineInsulin resistance with hyperglycemia commonly seen

      Goal is normally serum glucose of 140–180 mg/dL

      Insulin requirements may increase during induction and maintenance phases and decrease during rewarming

      Insulin drips are the preferred therapy
      InfectionsMTH can increase the chances of developing infections, particularly pulmonary infections due to decreased airway ciliary clearance

      Some investigators suggest surveillance blood culture every 48 h, to detect occult bacteremia (MTH induces mild leukopenia and fever cannot be detected)

      Decrease in the temperature used by cooling device to maintain a constant body temperature can be an indirect sign of fever
      Blood and coagulationMTH can induce mild leukopenia, as well as mild coagulation cascade and platelet dysfunction, but without significant clinical impact

      DIC is mostly commonly observed in accidental hypothermia
      Thermoregulation:Shivering markedly increases brain and body metabolism, mitigating most of the protective effects of MTH

      Rapid induction can minimize shivering, and the shivering response is blunted with temperature <34°C (see Box 3)
      Gastrointestinal
       1. MotilityPatients can develop ileus and delayed gastric emptying

      Effective bowel regimen should be prophylactically prescribed
       2. Pancreas and liverLiver metabolism is markedly decreased and mild increases in liver function enzymes can be observed, but usually of no significance

      Amylase and lipase can also be mildly elevated, but without representing cell injury

      Pancreatitis has been described in patients with severe accidental hypothermia
       3. Drug metabolismDue to liver function decrease, drug metabolism is usually compromised and half-lives of drugs primarily cleared by the enzymatic system may be prolonged
      NutritionPatients should be fed during MTH, but metabolic requirements should be corrected to body temperature
      SkinPatients are in high risk for bedsores, due to skin vasoconstriction, immobilization and immune suppression

      Careful observation should be exerted in patients wearing cooling pads
      Respiratory and blood gasesOxygen and carbon dioxide can be overestimated and pH underestimated if blood gas analyses are not corrected to actual body temperature, due to gas solubilization

      Patients in MTH tend to have low actual PCO2, due to decreased metabolism

      It is controversial whether pH and PCO2 values management should be guided by corrected arterial blood gases (alpha-stat vs pH-stat theories)

      The authors believe that a combination of corrected arterial blood gases aiming for PCO2 levels mildly lower than normal (around 35 mm Hg) could avoid cerebral ischemia secondary to extremely low PCO2 or hyperemia (with increased intracranial pressure) due to high actual PCO2 levels
      NeurologicNeurologic examination can be extremely blunted during MTH and obscured after rewarming due to decreased drug metabolism

      Patients should be monitored with continuous EEG because nonconvulsive status epilepticus is not rare following anoxic brain injury
      Abbreviations: ATN, acute tubular necrosis; DIC, disseminated intravascular coagulation.

      Shivering

      One of the most problematic challenges when inducing MTH is the triggering of the human body’s thermoregulatory defenses. Shivering and vasoconstriction are physiologic reactions to a decrease in the core body temperature to values lower than the physiologic range. With any minimal decrease of the skin temperature, vasoconstriction ensues. If the core body temperature drops below 35.5, shivering with vigorous muscle contractions to generate heat occurs.
      • Sessler D.I.
      Defeating normal thermoregulatory defenses: induction of therapeutic hypothermia.
      Shivering not only decreases the effectiveness of MTH, but can also be harmful because it activates a catecholaminergic response with consequent hypertension, tachycardia, and severe hemodynamic stress. Shivering is associated with increased oxygen consumption and metabolic rate, excess work of breathing, and increased myocardial oxygen consumption.
      • Polderman K.H.
      • Herold I.
      Therapeutic hypothermia and controlled normothermia in the intensive care unit: practical considerations, side effects, and cooling methods.
      • Polderman K.H.
      Mechanisms of action, physiological effects, and complications of hypothermia.
      In the surgical literature, shivering is strongly associated with cardiac events,
      • De Witte J.
      • Sessler D.I.
      Perioperative shivering: physiology and pharmacology.
      • Frank S.M.
      • Beattie C.
      • Christopherson R.
      • et al.
      Unintentional hypothermia is associated with postoperative myocardial ischemia. The Perioperative Ischemia Randomized Anesthesia Trial Study Group.
      • Frank S.M.
      • Fleisher L.A.
      • Breslow M.J.
      • et al.
      Perioperative maintenance of normothermia reduces the incidence of morbid cardiac events. A randomized clinical trial.
      • Leslie K.
      • Sessler D.I.
      Perioperative hypothermia in the high-risk surgical patient.
      and animal models of MTH have shown that shivering can negate its neuroprotective effects.
      • Thoresen M.
      • Satas S.
      • Loberg E.M.
      • et al.
      Twenty-four hours of mild hypothermia in unsedated newborn pigs starting after a severe global hypoxic-ischemic insult is not neuroprotective.
      • Tooley J.R.
      • Satas S.
      • Porter H.
      • et al.
      Head cooling with mild systemic hypothermia in anesthetized piglets is neuroprotective.
      In a study with neurocritical subjects with traumatic brain injury, shivering was associated with significant lowering of brain tissue oxygenation levels,
      • Oddo M.
      • Frangos S.
      • Maloney-Wilensky E.
      • et al.
      Effect of shivering on brain tissue oxygenation during induced normothermia in patients with severe brain injury.
      indicated ischemia and metabolic distress. The Bedside Shivering Assessment Scale (BSAS) is a simple and reliable tool for evaluating the metabolic stress of shivering. It was validated in a study in which it was compared with indirect calorimetry.
      • Badjatia N.
      • Strongilis E.
      • Gordon E.
      • et al.
      Metabolic impact of shivering during therapeutic temperature modulation: the bedside shivering assessment scale.
      Box 3 describes the BSAS.
      The BSAS
      Tabled 1
      ScoreDescription
      0None: no shivering noted on palpation of the masseter, neck, or chest wall
      1Mild: shivering localized to the neck and/or thorax only
      2Moderate: shivering involves gross movement of the upper extremities (in addition to neck and thorax)
      3Severe: shivering involves gross movements of the trunk and upper and lower extremities
      Most of the autonomic response to a lowering of the core body temperature is derived from hypothalamic centers; however, it is estimated that skin temperature contributes about 20% to control of vasoconstriction and shivering.
      • Sessler D.I.
      Defeating normal thermoregulatory defenses: induction of therapeutic hypothermia.
      All candidates for MTH will be intubated and on mechanical ventilation, so blunting the physiologic responses of the central nervous system to hypothermia with sedation is a natural choice. Propofol is one of the preferred drugs because of its short half-life. Other options include opiates, such as fentanyl infusions or meperidine. The authors typically use meperidine for shivering only in conjunction with continuous electroencephalogram (EEG) monitoring because it has a substantial risk of lowering the seizure threshold. Recently, α2-receptor agonists (dexmedetomidine and clonidine) have received some interest as options for shivering control. Several other drugs with different mechanisms of action have been studied, such as buspirone, nefopam, doxapram, ketanserin, physostigmine, tramadol, ondansetron, and dantrolene, but with mixed results.
      • Sessler D.I.
      Defeating normal thermoregulatory defenses: induction of therapeutic hypothermia.
      Magnesium sulfate was shown to lower the shivering threshold in some studies.
      • Maxwell W.L.
      • Watson A.
      • Queen R.
      • et al.
      Slow, medium, or fast re-warming following post-traumatic hypothermia therapy? An ultrastructural perspective.
      • Badjatia N.
      • Kowalski R.G.
      • Schmidt J.M.
      • et al.
      Predictors and clinical implications of shivering during therapeutic normothermia.
      • Wadhwa A.
      • Sengupta P.
      • Durrani J.
      • et al.
      Magnesium sulphate only slightly reduces the shivering threshold in humans.
      • Zweifler R.M.
      • Voorhees M.E.
      • Mahmood M.A.
      • et al.
      Magnesium sulfate increases the rate of hypothermia via surface cooling and improves comfort.
      Small bolus doses of muscle paralyzers can be used in severe shivering, but repeated or continuous use should be discouraged owing to the risk of development of neuromuscular complications.
      Nonpharmacologic approaches can be extremely helpful to combat shivering. Counterwarming of the skin was shown to be feasible and effective in some studies
      • Badjatia N.
      • Strongilis E.
      • Prescutti M.
      • et al.
      Metabolic benefits of surface counter warming during therapeutic temperature modulation.
      • Kimberger O.
      • Ali S.Z.
      • Markstaller M.
      • et al.
      Meperidine and skin surface warming additively reduce the shivering threshold: a volunteer study.
      • van Zanten A.R.
      • Polderman K.H.
      Blowing hot and cold? Skin counter warming to prevent shivering during therapeutic cooling.
      because each 4°C increase in mean skin temperature reduces the thresholds for vasoconstriction and shivering by 1°C and 50% of thermal comfort is determined by skin temperature.
      • Sessler D.I.
      Defeating normal thermoregulatory defenses: induction of therapeutic hypothermia.
      • Frank S.M.
      • Raja S.N.
      • Bulcao C.F.
      • et al.
      Relative contribution of core and cutaneous temperatures to thermal comfort and autonomic responses in humans.
      Though skin counterwarming may seem paradoxic, such skin rewarming typically does not affect core body temperature when advanced cooling devices are used.
      • Polderman K.H.
      • Herold I.
      Therapeutic hypothermia and controlled normothermia in the intensive care unit: practical considerations, side effects, and cooling methods.
      • Sessler D.I.
      Defeating normal thermoregulatory defenses: induction of therapeutic hypothermia.
      Finally, fast induction to goal core temperature might also decrease the incidence of shivering because the shivering response often ceases completely at temperatures below 33.5°C.
      • Fay T.
      Early experiences with local and generalized refrigeration of the human brain.
      • Polderman K.H.
      • Herold I.
      Therapeutic hypothermia and controlled normothermia in the intensive care unit: practical considerations, side effects, and cooling methods.
      • Taniguchi Y.
      • Lenhardt R.
      • Sessler D.I.
      • et al.
      The effect of altering skin-surface cooling speeds on vasoconstriction and shivering thresholds.
      Table 4 summarizes the most commonly used drugs and techniques to suppress shivering.
      Table 4Most commonly used strategies to combat shivering
      Therapy (Frequently Adopted Sequence)Comments
      Fast induction of hypothermiaShivering tends to be minimized after temperature <35°C is reached
      CounterwarmingFairly effective and safe

      Use of air-warmed blanket

      Some hand and feet warming devices have been found to cause thermal burns
      BuspironeUsual dose 30–60 mg po every 8 h

      Might take 24 h to start acting

      Contraindicated in cases of severe renal or liver dysfunction

      Not useful in patients with ileus related to MTH
      Magnesium sulfateBolus 2–4 g, intravenous, with goal of serum magnesium >2

      Continuous drips of 12–16 g/24 h can be used

      Caution in patients with renal dysfunction

      Safe in pregnant patients
      MeperidineBolus of 10–25 mg, intravenous, every 2–3 h

      Not very sedating

      Seizures can be observed especially in patients with renal dysfunction
      FentanylBolus of 50–100 μg and drip 25–100 μg/h

      Watch for hypotension
      DexmedetomidineContinuous infusion at 0.1–1.4 μg/kg/min

      May cause hypotension and bradycardia

      Clonidine is another option with alpha-2 agonism
      PropofolBolus of 30–50 mg, maintenance drip 20–200 μg/kg/min

      Watch for hypotension, bradycardia, hypertriglyceridemia, propofol infusion syndrome
      BenzodiazepinesSometimes preferred in patients with hemodynamic instability or seizures
      Muscle paralyzersVery effective, but reserved as last option, due to neuromuscular complications related to prolonged use

      Bolus administration might decrease incidence of adverse effects

      Use compromises neurologic examination evaluation

      Associated Cardiologic Conditions

      Cardiac conditions are the leading primary cause for out-of-hospital CA in the general population; therefore, those patients frequently need further aggressive cardiac care after recovery of spontaneous circulation. Multiple small studies have reported the feasibility and safety of using MTH in patients with cardiogenic shock
      • Hovdenes J.
      • Laake J.H.
      • Aaberge L.
      • et al.
      Therapeutic hypothermia after out-of-hospital cardiac arrest: experiences with patients treated with percutaneous coronary intervention and cardiogenic shock.
      • Oddo M.
      • Schaller M.D.
      • Feihl F.
      • et al.
      From evidence to clinical practice: effective implementation of therapeutic hypothermia to improve patient outcome after cardiac arrest.
      • Skulec R.
      • Kovarnik T.
      • Dostalova G.
      • et al.
      Induction of mild hypothermia in cardiac arrest survivors presenting with cardiogenic shock syndrome.
      and the application of MTH in combination with emergent percutaneous coronary intervention (PCI),
      • Batista L.M.
      • Lima F.O.
      • Januzzi Jr., J.L.
      • et al.
      Feasibility and safety of combined percutaneous coronary intervention and therapeutic hypothermia following cardiac arrest.
      • Kandzari D.E.
      • Chu A.
      • Brodie B.R.
      • et al.
      Feasibility of endovascular cooling as an adjunct to primary percutaneous coronary intervention (results of the LOWTEMP pilot study).
      • Knafelj R.
      • Radsel P.
      • Ploj T.
      • et al.
      Primary percutaneous coronary intervention and mild induced hypothermia in comatose survivors of ventricular fibrillation with ST-elevation acute myocardial infarction.
      • Ly H.Q.
      • Denault A.
      • Dupuis J.
      • et al.
      A pilot study: the Noninvasive Surface Cooling Thermoregulatory System for Mild Hypothermia Induction in Acute Myocardial Infarction (the NICAMI Study).
      • Maze R.
      • Le May M.R.
      • Hibbert B.
      • et al.
      The impact of therapeutic hypothermia as adjunctive therapy in a regional primary PCI program.
      • Nielsen N.
      • Hovdenes J.
      • Nilsson F.
      • et al.
      Outcome, timing and adverse events in therapeutic hypothermia after out-of-hospital cardiac arrest.
      • Sunde K.
      • Pytte M.
      • Jacobsen D.
      • et al.
      Implementation of a standardised treatment protocol for post resuscitation care after out-of-hospital cardiac arrest.
      • Wolfrum S.
      • Pierau C.
      • Radke P.W.
      • et al.
      Mild therapeutic hypothermia in patients after out-of-hospital cardiac arrest due to acute ST-segment elevation myocardial infarction undergoing immediate percutaneous coronary intervention.
      as well as the adjunct use of fibrinolytic therapy.
      • Voipio V.
      • Kuisma M.
      • Alaspaa A.
      • et al.
      Thrombolytic treatment of acute myocardial infarction after out-of-hospital cardiac arrest.
      • Weston C.F.
      • Avery P.
      Thrombolysis following pre-hospital cardiopulmonary resuscitation.
      One multicenter randomized study, Cooling as an Adjunctive Therapy to Percutaneous Intervention in Patients with Acute Myocardial Infarction (COOL-MI), with subjects with acute myocardial ischemia (but no CA) showed that is safe and feasible to perform endovascular core cooling in conjunction with PCI.

      Prognostication

      The advent of MTH in CA helped improved the neurologic prognosis in survivors, but also created the uncertainty on how to prognosticate outcome in patients who do not follow commands after rewarming. Several studies have tested neurologic examination findings, MRI with diffusion-weighted imaging, somatosensory-evoked potentials (SSEP), EEG, and neuron-specific enolase (NSE) with some interesting results. No definitive guidelines currently exist on how to interpret the test results, but most of the studies have shown that the previous data derived from CA survivors who did not receive MTH do not fully apply to those who receive MTH. The current guidelines of the American Academy of Neurology for prognostication after CA
      • Wijdicks E.F.
      • Hijdra A.
      • Young G.B.
      • et al.
      Practice parameter: prediction of outcome in comatose survivors after cardiopulmonary resuscitation (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology.
      (without MTH) are heavily based on the seminal paper of Levy and colleagues
      • Levy D.E.
      • Caronna J.J.
      • Singer B.H.
      • et al.
      Predicting outcome from hypoxic-ischemic coma.
      in the early 1980s, which relied on neurologic examination 72 hours after CA. Some current studies with subjects who received MTH showed that the neurologic examination is not a totally reliable tool in this setting. The current experience in most specialized centers indicate that, in addition to the neurologic examination, MRI, EEG, SSEP, and NSE might be interpreted together, with no test alone being more accurate than the others. Moreover, most specialists believe that a longer observation time (at least >72 h but probably >5–7 days) is needed to prognosticate more accurately because some patients can have a remarkable recovery later in the course and elderly patients may take longer to metabolize drugs with central nervous system action because of decreased liver function secondary to hypothermia. One clear problem with the existing literature regarding outcomes after CA with MTH is that most studies are retrospective, unblinded, and confounded by withdrawal of life-sustaining therapy. A rigorous, prospective, and blinded approach to understanding predictors of outcome is needed. Table 5 summarizes the most relevant evidence on prognostication after CA and MTH.
      Table 5Relevant current evidence on prognostication after CA in patients treated with MTH
      Data from Refs.
      • Al Thenayan E.
      • Savard M.
      • Sharpe M.
      • et al.
      Predictors of poor neurologic outcome after induced mild hypothermia following cardiac arrest.
      • Cronberg T.
      • Rundgren M.
      • Westhall E.
      • et al.
      Neuron-specific enolase correlates with other prognostic markers after cardiac arrest.
      • Rossetti A.O.
      • Oddo M.
      • Logroscino G.
      • et al.
      Prognostication after cardiac arrest and hypothermia: a prospective study.
      • Rossetti A.O.
      • Urbano L.A.
      • Delodder F.
      • et al.
      Prognostic value of continuous EEG monitoring during therapeutic hypothermia after cardiac arrest.
      • Rossetti A.O.
      • Oddo M.
      • Liaudet L.
      • et al.
      Predictors of awakening from postanoxic status epilepticus after therapeutic hypothermia.
      • Bouwes A.
      • Binnekade J.M.
      • Kuiper M.A.
      • et al.
      Prognosis of coma after therapeutic hypothermia: a prospective cohort study.
      • Leithner C.
      • Ploner C.J.
      • Hasper D.
      • et al.
      Does hypothermia influence the predictive value of bilateral absent N20 after cardiac arrest?.
      • Oksanen T.
      • Tiainen M.
      • Skrifvars M.B.
      • et al.
      Predictive power of serum NSE and OHCA score regarding 6-month neurologic outcome after out-of-hospital ventricular fibrillation and therapeutic hypothermia.
      • Fugate J.E.
      • Wijdicks E.F.
      • Mandrekar J.
      • et al.
      Predictors of neurologic outcome in hypothermia after cardiac arrest.
      • Steffen I.G.
      • Hasper D.
      • Ploner C.J.
      • et al.
      Mild therapeutic hypothermia alters neuron specific enolase as an outcome predictor after resuscitation: 97 prospective hypothermia patients compared to 133 historical non-hypothermia patients.
      • Wijman C.A.
      • Mlynash M.
      • Caulfield A.F.
      • et al.
      Prognostic value of brain diffusion-weighted imaging after cardiac arrest.
      • Rossetti A.O.
      • Carrera E.
      • Oddo M.
      Early EEG correlates of neuronal injury after brain anoxia.
      • Fugate J.E.
      • Wijdicks E.F.
      • White R.D.
      • et al.
      Does therapeutic hypothermia affect time to awakening in cardiac arrest survivors?.
      • Crepeau A.Z.
      • Rabinstein A.A.
      • Fugate J.E.
      • et al.
      Continuous EEG in therapeutic hypothermia after cardiac arrest: prognostic and clinical value.
      .
      StudyInvestigatorsConclusion
      Retrospective chart review of 37 consecutive adults treated with MTHAl Thenayan et al,
      • Al Thenayan E.
      • Savard M.
      • Sharpe M.
      • et al.
      Predictors of poor neurologic outcome after induced mild hypothermia following cardiac arrest.
      2008
      A motor response better than extension by day 3 was not prognostically reliable after therapeutic induced mild hypothermia for comatose cardiac arrest survivors

      None of the patients who lost pupillary or corneal reflexes on day 3 or developed myoclonic status epilepticus recovered awareness
      Prospective, observational study with 111 subjects treated with MTHCronberg et al,
      • Cronberg T.
      • Rundgren M.
      • Westhall E.
      • et al.
      Neuron-specific enolase correlates with other prognostic markers after cardiac arrest.
      2011
      All 17 subjects with NSE levels >33 ng/l failed to recover consciousness

      In the >33 ng/l NSE group, all 10 studied with MRI had extensive brain injury on diffusion-weighted images, 12/16 lacked cortical responses on SSEP, and all 6 who underwent autopsy had extensive severe histologic damage
      Prospective study with 111 subjects treated with MTHRossetti et al,
      • Rossetti A.O.
      • Oddo M.
      • Logroscino G.
      • et al.
      Prognostication after cardiac arrest and hypothermia: a prospective study.
      2010
      Three clinical variables, assessed within 72 h after CA, showed higher false-positive mortality predictions in MTH compared with the AAN guidelines: incomplete brainstem reflexes recovery (4% vs 0%), myoclonus (7% vs 0%), and absent motor response to pain (24% vs 0%)

      Unreactive EEG background was incompatible with good long-term neurologic recovery and strongly associated with in-hospital mortality

      The presence of at least 2 independent predictors out of 4 (incomplete brainstem reflexes, myoclonus, unreactive EEG, and absent cortical SSEP) accurately predicted poor long-term neurologic recovery (positive predictive value = 1.00); EEG reactivity significantly improved the prognostication
      Prospective study with 34 subjects treated with MTHRossetti et al,
      • Rossetti A.O.
      • Urbano L.A.
      • Delodder F.
      • et al.
      Prognostic value of continuous EEG monitoring during therapeutic hypothermia after cardiac arrest.
      2010
      Continuous EEG monitoring showing a nonreactive or discontinuous background during MTH is strongly associated with unfavorable outcome in subjects with coma after CA
      Retrospective study with 6 subjects with PSE treated with MTHRossetti et al,
      • Rossetti A.O.
      • Oddo M.
      • Liaudet L.
      • et al.
      Predictors of awakening from postanoxic status epilepticus after therapeutic hypothermia.
      2009
      Subjects with PSE and preserved brainstem reactions, SSEP and EEG reactivity may have a favorable outcome if their condition is treated as status epilepticus

      Subjects with nonconvulsive PSE showed a better prognosis than subjects with myoclonic PSE (P = .042)
      Multicenter prospective cohort study with 391 subjects treated with MTHBouwes et al,
      • Bouwes A.
      • Binnekade J.M.
      • Kuiper M.A.
      • et al.
      Prognosis of coma after therapeutic hypothermia: a prospective cohort study.
      2012
      53% had a poor outcome

      Absent pupillary light responses (FPR 1; 95% CI, 0–7) or absent corneal reflexes (FPR 4; 95% CI, 1–13) 72 h after CPR, and absent SSEPs during hypothermia (FPR 3; 95% CI, 1–7) and after rewarming (FPR 0; 95% CI, 0–18) were reliable predictors

      Motor scores 72 h after CPR (FPR 10; 95% CI, 6–16) and NSE levels were not reliable predictors
      Retrospective study with 185 subjects treated with MTHLeithner et al,
      • Leithner C.
      • Ploner C.J.
      • Hasper D.
      • et al.
      Does hypothermia influence the predictive value of bilateral absent N20 after cardiac arrest?.
      2010
      Of 36 subjects with bilateral absent SSEP N20 responses, 35 (97%) had poor outcome

      One subject had prolonged high amplitude peripheral SSEP, but bilaterally absent N20 3 d after CA and regained consciousness with normal cognitive functions and reproducible N20 responses

      One subject had minimally detectable N20 at day 3 and recovered consciousness and normal N20 responses on follow-up
      Prospective study with 90 subjects treated with MTHOksanen et al,
      • Oksanen T.
      • Tiainen M.
      • Skrifvars M.B.
      • et al.
      Predictive power of serum NSE and OHCA score regarding 6-month neurologic outcome after out-of-hospital ventricular fibrillation and therapeutic hypothermia.
      2009
      In multiple logistic regression analysis, age, NSE at 48 h, and increase in NSE levels were predictors of poor outcome

      Cut-off points with 100% specificity in predicting poor outcome were 33 microg/l for NSE at 48 h and a change of 6.4 microg/l from baseline NSE at 24–48 h
      Prospective study with 192 subjects (103 hypothermic, 89 nonhypothermic)Fugate et al,
      • Fugate J.E.
      • Wijdicks E.F.
      • Mandrekar J.
      • et al.
      Predictors of neurologic outcome in hypothermia after cardiac arrest.
      2010
      The absence of pupillary light responses, corneal reflexes, and an extensor or absent motor response at day 3 after CA remained accurate predictors of poor outcome after therapeutic hypothermia (P<.0001 for all)

      Myoclonic status epilepticus was invariably associated with death (P = .0002)

      Malignant EEG patterns and global cerebral edema on head computed tomography were associated with death in both hypothermic and normothermic subjects (P<.001)

      NSE >33 ng/ml levels measured 1–3 d after CA remained associated with poor outcome (P = .017), but had a false-positive rate of 29.3%
      Prospective study with 97 subjects who received MTH compared with 133 maintained in normothermiaSteffen et al,
      • Steffen I.G.
      • Hasper D.
      • Ploner C.J.
      • et al.
      Mild therapeutic hypothermia alters neuron specific enolase as an outcome predictor after resuscitation: 97 prospective hypothermia patients compared to 133 historical non-hypothermia patients.
      2010
      NSE serum levels were significantly lower under MTH compared with normothermia in univariate analysis

      Recommended cutoff levels for NSE 72 h after ROSC (>33 ng/l) do not reliably predict poor neurologic outcome in CA subjects treated with MTH
      Prospective study with 83 subjects treated with MTHWijman et al,
      • Wijman C.A.
      • Mlynash M.
      • Caulfield A.F.
      • et al.
      Prognostic value of brain diffusion-weighted imaging after cardiac arrest.
      2009
      Based on MRI: the percentage of brain volume less than an ADC
      Measures the magnitude of diffusion of water molecules within cerebral tissue; areas with cytotoxic brain injury are darker on an ADC map compared to healthy tissue.
      cutoff of 650–700 × 10(-6) mm2/s best differentiated between survivors and subjects who died or remained vegetative

      The percentage of brain volume less than ADC 400 to 450 × 10(-6) mm2/s best distinguished between survivors with good vs impaired neurologic outcome at 6 mo

      Quantitative DWI at this threshold resulted in a 38% absolute increase in sensitivity for predicting poor outcome compared with the neurologic examination while maintaining 100% specificity
      Prospective study with 61 subjects treated with MTHRossetti et al,
      • Rossetti A.O.
      • Carrera E.
      • Oddo M.
      Early EEG correlates of neuronal injury after brain anoxia.
      2012
      Serum NSE and EEG findings were strongly correlated (Spearman rho = 0.45; P<.001)

      Median NSE peak values were higher in subjects with unreactive EEG background (P<.001) and discontinuous patterns (P = .001)

      All subjects with nonreactive EEG died

      5 survivors (3 with good outcome) had NSE levels >33 μg/L
      Retrospectively analysis of 227 subjects (128 subjects received MTH)Fugate et al,
      • Fugate J.E.
      • Wijdicks E.F.
      • White R.D.
      • et al.
      Does therapeutic hypothermia affect time to awakening in cardiac arrest survivors?.
      2011
      Median day of awakening was day 2 for both groups and most (91% hypothermic and 79% nonhypothermic) awakened within 3 d
      Retrospective study with 54 subjects treated with MTHCrepeau et al,
      • Crepeau A.Z.
      • Rabinstein A.A.
      • Fugate J.E.
      • et al.
      Continuous EEG in therapeutic hypothermia after cardiac arrest: prognostic and clinical value.
      2013
      EEG features correlating with poor outcome included seizures, nonreactive background, and epileptiform discharges
      Abbreviations: AAN, American Academy of Neurology; ADC, Apparent Diffusion Coefficient; FPR, false-positive ratio; N20, response recorded at 20 ms during SSEP; PSE, postanoxic status epilepticus.
      a Measures the magnitude of diffusion of water molecules within cerebral tissue; areas with cytotoxic brain injury are darker on an ADC map compared to healthy tissue.

      Current outcome trends after CA in the hypothermia era

      Recent large population studies in the United States showed a consistent trend of decreased mortality after CA in the last decade,
      Randomized clinical study of thiopental loading in comatose survivors of cardiac arrest. Brain Resuscitation Clinical Trial I Study Group.
      • Fugate J.E.
      • Brinjikji W.
      • Mandrekar J.N.
      • et al.
      Post-cardiac arrest mortality is declining: a study of the US National Inpatient Sample 2001 to 2009.
      • Girotra S.
      • Nallamothu B.K.
      • Spertus J.A.
      • et al.
      Trends in survival after in-hospital cardiac arrest.
      • Nichol G.
      • Thomas E.
      • Callaway C.W.
      • et al.
      Regional variation in out-of-hospital cardiac arrest incidence and outcome.
      which can be partially attributed to the more widespread use of MTH. Girotra and colleagues
      • Girotra S.
      • Nallamothu B.K.
      • Spertus J.A.
      • et al.
      Trends in survival after in-hospital cardiac arrest.
      analyzed all adults who had an in-hospital CA between 2000 and 2009 at 374 hospitals in the Get with the Guidelines-Resuscitation registry. They reported that risk-adjusted rates of survival to discharge increased from 13.7% in 2000 to 22.3% in 2009 (P<.001), and that rates of clinically significant neurologic disability among survivors decreased over time, with a risk-adjusted rate of 32.9% in 2000 and 28.1% in 2009 (P = .02). Worth mentioning, this study also included subjects with an initial rhythm of PEA/asystole and the exact percentage of subjects who received MTH is not known. The same trend for improved mortality after the implementation of MTH was observed in Dutch, Japanese, and Finnish studies.
      • Reinikainen M.
      • Oksanen T.
      • Leppanen P.
      • et al.
      Mortality in out-of-hospital cardiac arrest patients has decreased in the era of therapeutic hypothermia.
      • van der Wal G.
      • Brinkman S.
      • Bisschops L.L.
      • et al.
      Influence of mild therapeutic hypothermia after cardiac arrest on hospital mortality.
      • Tagami T.
      • Hirata K.
      • Takeshige T.
      • et al.
      Implementation of the fifth link of the chain of survival concept for out-of-hospital cardiac arrest.
      Some studies also indicated an increased use of MTH in the United States and Europe throughout the last decade.
      • Heffner A.C.
      • Pearson D.A.
      • Nussbaum M.L.
      • et al.
      Regionalization of post-cardiac arrest care: implementation of a cardiac resuscitation center.
      • Jena A.B.
      • Romley J.A.
      • Newton-Cheh C.
      • et al.
      Therapeutic hypothermia for cardiac arrest: real-world utilization trends and hospital mortality.
      • Lick C.J.
      • Aufderheide T.P.
      • Niskanen R.A.
      • et al.
      Take Heart America: a comprehensive, community-wide, systems-based approach to the treatment of cardiac arrest.
      • Oksanen T.
      • Pettilä V.
      • Hynynen M.
      • et al.
      Therapeutic hypothermia after cardiac arrest: implementation and outcome in Finnish intensive care units.
      • Patil S.
      • Bhayani S.
      • Denton J.M.
      • et al.
      Therapeutic hypothermia for out-of-hospital cardiac arrest: implementation in a district general hospital emergency department.
      Some investigators defend that CA survivors should be transferred to CA centers
      • Stub D.
      • Bernard S.
      • Smith K.
      • et al.
      Do we need cardiac arrest centres in Australia?.
      for higher level of care, with some studies showing that it is feasible and might help improve outcomes.
      • Heffner A.C.
      • Pearson D.A.
      • Nussbaum M.L.
      • et al.
      Regionalization of post-cardiac arrest care: implementation of a cardiac resuscitation center.
      • Lick C.J.
      • Aufderheide T.P.
      • Niskanen R.A.
      • et al.
      Take Heart America: a comprehensive, community-wide, systems-based approach to the treatment of cardiac arrest.
      • Stub D.
      • Bernard S.
      • Smith K.
      • et al.
      Do we need cardiac arrest centres in Australia?.
      • Kajino K.
      • Iwami T.
      • Daya M.
      • et al.
      Impact of transport to critical care medical centers on outcomes after out-of-hospital cardiac arrest.
      • Mooney M.R.
      • Unger B.T.
      • Boland L.L.
      • et al.
      Therapeutic hypothermia after out-of-hospital cardiac arrest: evaluation of a regional system to increase access to cooling.
      • Roberts B.W.
      • Kilgannon J.H.
      • Mitchell J.A.
      • et al.
      Emergency department inter-hospital transfer for post-cardiac arrest care: initial experience with implementation of a regional cardiac resuscitation center in the United States.
      • Stub D.
      • Smith K.
      • Bray J.E.
      • et al.
      Hospital characteristics are associated with patient outcomes following out-of-hospital cardiac arrest.

      Hyperthermia

      Fever after surviving a CA is deleterious and has been shown to impair brain recovery. The exact cause is not fully understood, but evidence shows that activation of inflammatory cytokines occurs after CA, resembling the systemic inflammation seen in septic patients.
      • Sunde K.
      • Pytte M.
      • Jacobsen D.
      • et al.
      Implementation of a standardised treatment protocol for post resuscitation care after out-of-hospital cardiac arrest.
      • Wolfrum S.
      • Pierau C.
      • Radke P.W.
      • et al.
      Mild therapeutic hypothermia in patients after out-of-hospital cardiac arrest due to acute ST-segment elevation myocardial infarction undergoing immediate percutaneous coronary intervention.
      Small studies and case series have disclosed that there is a strong association between poor survival outcomes and a body temperature greater than 37.8°C.
      • Hazinski M.F.
      • Nolan J.P.
      • Billi J.E.
      • et al.
      Part 1: executive summary: 2010 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations.
      • Voipio V.
      • Kuisma M.
      • Alaspaa A.
      • et al.
      Thrombolytic treatment of acute myocardial infarction after out-of-hospital cardiac arrest.
      • Weston C.F.
      • Avery P.
      Thrombolysis following pre-hospital cardiopulmonary resuscitation.
      • Wijdicks E.F.
      • Hijdra A.
      • Young G.B.
      • et al.
      Practice parameter: prediction of outcome in comatose survivors after cardiopulmonary resuscitation (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology.
      Moreover, fever is directly associated with worse prognosis in stroke and neurocritical patients.
      • Levy D.E.
      • Caronna J.J.
      • Singer B.H.
      • et al.
      Predicting outcome from hypoxic-ischemic coma.
      • Fugate J.E.
      • Brinjikji W.
      • Mandrekar J.N.
      • et al.
      Post-cardiac arrest mortality is declining: a study of the US National Inpatient Sample 2001 to 2009.
      • Girotra S.
      • Nallamothu B.K.
      • Spertus J.A.
      • et al.
      Trends in survival after in-hospital cardiac arrest.
      • Nichol G.
      • Thomas E.
      • Callaway C.W.
      • et al.
      Regional variation in out-of-hospital cardiac arrest incidence and outcome.
      • Reinikainen M.
      • Oksanen T.
      • Leppanen P.
      • et al.
      Mortality in out-of-hospital cardiac arrest patients has decreased in the era of therapeutic hypothermia.
      • van der Wal G.
      • Brinkman S.
      • Bisschops L.L.
      • et al.
      Influence of mild therapeutic hypothermia after cardiac arrest on hospital mortality.
      To date, no RCT has evaluated induced normothermia versus conventional temperature management with the use of antipyretics in CA survivors. The authors suggest an intensive control, aiming for a core body temperature around 37°C, for at least the first 48 hours after completion of a standard MTH protocol for VF/VT CA.

      Future perspectives and ongoing trials

      MTH after CA is still new and, in the near future, some questions still must be answered, such as the optimal goal temperature, duration of MTH, optimal device for MTH, and better ways of prognosticating outcome for these patients. Trials evaluating intra-arrest MTH (NCT00886184) and out-of-hospital initiation of MTH with cold saline (NCT00391469), as well as for in-hospital arrests (NCT00886184), are currently recruiting subjects. Moreover, a trial that will compare surface cooling to core cooling (NCT00827957) and another that will compare MTH at 36°C versus 33°C (NCT01020916) will try to resolve some of the current questions.

      Summary

      A growing body of evidence supports MTH as the fifth link of the life chain, with significant decrease in mortality and improvement of neurologic outcomes in CA survivors throughout the last decade. The cardiologist and the intensivist must be acquainted with the indications and technique because MTH is, so far, the only proven neuroprotective therapy for CA survivors. Future research will help better define current questions, such as the optimal timing, target temperature, and duration of MTH.

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