Elsevier

Neurologic Clinics

Volume 35, Issue 4, November 2017, Pages 665-694
Neurologic Clinics

Targeted Temperature Management in Brain Injured Patients

https://doi.org/10.1016/j.ncl.2017.06.005Get rights and content

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Key points

  • Evidence from animal models indicates that lowering temperature by a few degrees can produce substantial neuroprotection.

  • In humans, hypothermia has been found to be neuroprotective with an impact on mortality and long-term functional outcome in cardiac arrest and neonatal hypoxic–ischemic encephalopathy.

  • Clinical trials have explored the potential role of maintaining normothermia and treating fever in critically ill patients with brain injury.

Metabolism and heat production

Thermoregulation is one of the most sophisticated functions in the human physiology. Fluctuations in temperature modulate important behavioral and physiologic functions. Healthy humans are able to control temperature tightly. The brain is the most metabolically demanding organ in humans. Although it represents about 2% of the total body weight, it accounts for 20% to 25% of total body glucose and oxygen metabolism and consumption. This high metabolic rate of oxygen consumption (CMRO2) and rate

Thermoregulatory control

In humans, core body temperature (Tc) is more tightly regulated than other important physiologic variables such as heart rate and blood pressure, even during illness. Body temperature is sensed by the transient receptor potential (TRP) ion channels.4, 5 Sensory neurons express thermal TRPs and are activated within different ranges of temperature thresholds.6, 7 The hypothalamus, the dominant thermoregulatory body in humans, receives thermal inputs from the skin, peripheral tissues, core organs,

Thermal perturbations in critically ill patients

Temperature disturbances are frequent in critically ill patients and fever is by far the most prevalent thermal perturbation in patients with a brain injury.14 Hypothermia has been well-defined in the setting of spontaneous or therapeutically induced scenarios.15 Definitions of fever and hyperthermia are more variable, but it is generally agreed that an increase in body Tc above 38°C should be considered fever or hyperthermia.16 Fever is considered a controlled mechanism as opposed to

Mechanisms of action of targeted temperature management

TTM can be used to (a) therapeutically induce hypothermia, (b) maintain normothermia and prevent fever or hyperthermia, and (c) rewarm either spontaneous or therapeutically induced hypothermic patients. The practical rationale of inducing hypothermia or maintaining normothermia is that, therapeutically, it has many potential benefits (Fig. 1).

Abundant evidence from animal models indicates that hypothermia can induce neuroprotection against focal and global ischemia.1 For many years, we thought

Techniques to induce hypothermia in humans

Different levels of target temperature during TTM may be achieved in the ICU: mild (Tc, 35°C–36ºC) or moderate (Tc, 30°C –35°C; Table 2).15 In the intensive care unit (ICU) setting, mild-to-moderate hypothermia (Tc, 30°C–36°C) is most often used because the risk of cardiac arrhythmia increases substantially when temperatures decrease to less than 30°C.27 Deep hypothermia (Tc, <30°C, goal 26°C) is used in the operating room when temporary circulatory arrest is required for complex cardiac or

Side effects of targeted temperature management

The risk for immediate side effects such as shivering, hypovolemia, hypotension, electrolyte disorders, coagulopathy, and hyperglycemia is greatest in the induction phase of hypothermia. The maintenance phase is characterized by increased patient stability with a decrease in the shivering response. The rewarming phase may be characterized by reemergence of the shivering response, electrolyte abnormalities, cardiac arrhythmias, decrease in insulin resistance, loss of cerebral autoregulation, and

Cardiac arrest and hypoxia–ischemia

Cardiac arrest after drowning under hypothermic conditions can be associated with a remarkably good neurologic recovery, even when associated with prolonged periods of hypoxia.90, 91 Since the 1950s, the controlled induction of hypothermia in the operating room has allowed temporary circulatory arrest, facilitating the repair of congenital heart defects and structural vascular lesions. In the early 2000s, two clinical trials showed the robust neuroprotective effects of therapeutic moderate

Refractory status epilepticus

SE carries a high morbidity and mortality.156 Refractory SE (RSE), defined as lack of response or seizure control to second-line conventional therapy, carries a higher mortality and is associated with a lack of response to additional antiseizure medications in 8% to 21% of cases.157 To this end, additional therapies including infusions of anesthetics, sedatives, specialized diets, and hypothermia may be considered as advanced strategies in RSE.158 Biologically, therapeutic hypothermia

Advanced liver failure

Advanced liver failure (ALF) is a critical condition that continues to have a high morbidity and mortality, despite recent advances in supportive intensive care medicine and the use of emergency liver transplantation.165 Cerebral edema and elevated ICP, leading to intracranial hypertension are the leading causes of death in patients with fulminant liver failure. Earlier animal studies suggested that hypothermia produced beneficial cerebral and systemic effects in this setting, preventing the

Severe bacterial meningitis

Increases in ICP are common in patients with meningitis and often occur within 12 hours of admission to the hospital. This time coincides with the increase in the inflammatory response generated by the antibiotic enhancing the inflammatory response, and worsening cerebral edema.171 Recognizing the sequence of these events offers a window of opportunity to attenuate the inflammatory response and treat or prevent secondary neuronal damage. The application of moderate hypothermia in animal models

Maintenance of normothermia and fever prevention

Fever and hyperthermia are prevalent and associated with poorer outcomes in all types of brain injuries.14, 142, 144 Whole brain hyperthermia induces peripheral up-regulation of proinflammatory and antiinflammatory markers (IL-1, IL-6, IL-8, tumor necrosis factor-α, and IL-10), leads to neuronal death, and disrupts the blood–brain barrier.176 In addition, hyperthermia can exaggerate glutamate induced neurotoxicity.177 All of these mechanisms tend to aggravate primary neuronal injury by the

Future approaches

There is no doubt that therapeutic hypothermia is the best neuroprotectant available to date.1 It is also clear from the results of recent pragmatic clinical trials that the heterogeneity of brain injury may be responsible for the lack of translation of the favorable results seen with hypothermia in multiple animal models of brain injury. The major logistical challenge to the application of TTM in patients with a brain injury is how to maintain the temperature goal without having to use

Summary

  • Evidence from animal models indicates that lowering temperature by few degrees can substantially produce neuroprotection against ischemia.

  • TTM can provide neuroprotective effects with a significant impact in both mortality and long-term functional outcome after cardiac arrest and neonatal hypoxic–ischemic encephalopathy.

  • Clinical trials of TTM in TBI, SAH, AIS, meningitis, and SE have failed to demonstrate a significant outcome benefit. Heterogeneity and limitations in these studies, preclude a

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References (190)

  • W.D. Dietrich et al.

    Protection in animal models of brain and spinal cord injury with mild to moderate hypothermia

    J Neurotrauma

    (2009)
  • N.A. Lassen

    Normal average value of cerebral blood flow in younger adults is 50 ml/100 g/min

    J Cereb Blood Flow Metab

    (1985)
  • P.L. Madsen et al.

    Middle cerebral artery blood velocity and cerebral blood flow and O2 uptake during dynamic exercise

    J Appl Physiol (1985)

    (1993)
  • M.C. Almeida et al.

    Pharmacological blockade of the cold receptor TRPM8 attenuates autonomic and behavioral cold defenses and decreases deep body temperature

    J Neurosci

    (2012)
  • D.D. McKemy

    How cold is it? TRPM8 and TRPA1 in the molecular logic of cold sensation

    Mol Pain

    (2005)
  • S. Brauchi et al.

    Clues to understanding cold sensation: thermodynamics and electrophysiological analysis of the cold receptor TRPM8

    Proc Natl Acad Sci U S A

    (2004)
  • A. Moqrich et al.

    Impaired thermosensation in mice lacking TRPV3, a heat and camphor sensor in the skin

    Science

    (2005)
  • A. Kurz et al.

    Desflurane reduces the gain of thermoregulatory arteriovenous shunt vasoconstriction in humans

    Anesthesiology

    (1995)
  • N. Badjatia et al.

    Metabolic benefits of surface counter warming during therapeutic temperature modulation

    Crit Care Med

    (2009)
  • S. Kizilirmak et al.

    Magnesium sulfate stops postanesthetic shivering

    Ann N Y Acad Sci

    (1997)
  • N. Badjatia et al.

    Metabolic impact of shivering during therapeutic temperature modulation: the bedside shivering assessment scale

    Stroke

    (2008)
  • C.M. Lin et al.

    Dantrolene reduces the threshold and gain for shivering

    Anesth Analg

    (2004)
  • M. Lopez et al.

    Rate and gender dependence of the sweating, vasoconstriction, and shivering thresholds in humans

    Anesthesiology

    (1994)
  • F. Rincon et al.

    The epidemiology of spontaneous fever and hypothermia on admission of brain injury patients to intensive care units: a multicenter cohort study

    J Neurosurg

    (2014)
  • M.E. Nunnally et al.

    Targeted temperature management in critical care: a report and recommendations from five professional societies

    Crit Care Med

    (2011)
  • K.H. Polderman et al.

    Therapeutic hypothermia and controlled normothermia in the intensive care unit: practical considerations, side effects, and cooling methods

    Crit Care Med

    (2009)
  • C.B. Saper et al.

    The neurologic basis of fever

    N Engl J Med

    (1994)
  • H.B. Simon

    Hyperthermia

    N Engl J Med

    (1993)
  • J.D. Michenfelder et al.

    Hypothermia: effect on canine brain and whole-body metabolism

    Anesthesiology

    (1968)
  • R. Busto et al.

    Small differences in intraischemic brain temperature critically determine the extent of ischemic neuronal injury

    J Cereb Blood Flow Metab

    (1987)
  • H. Zhao et al.

    General versus specific actions of mild-moderate hypothermia in attenuating cerebral ischemic damage

    J Cereb Blood Flow Metab

    (2007)
  • H. Zhao et al.

    Akt contributes to neuroprotection by hypothermia against cerebral ischemia in rats

    J Neurosci

    (2005)
  • B.J. D'Cruz et al.

    Hypothermic reperfusion after cardiac arrest augments brain-derived neurotrophic factor activation

    J Cereb Blood Flow Metab

    (2002)
  • M.Y. Globus et al.

    Glutamate release and free radical production following brain injury: effects of posttraumatic hypothermia

    J Neurochem

    (1995)
  • P.J. Andrews et al.

    Hypothermia for Intracranial Hypertension after Traumatic Brain Injury

    N Engl J Med

    (2015)
  • M. Schreckinger et al.

    Contemporary management of traumatic intracranial hypertension: is there a role for therapeutic hypothermia?

    Neurocrit Care

    (2009)
  • K.H. Polderman et al.

    Induction of hypothermia in patients with various types of neurologic injury with use of large volumes of ice-cold intravenous fluid

    Crit Care Med

    (2005)
  • S.A. Tisherman

    Salvage techniques in traumatic cardiac arrest: thoracotomy, extracorporeal life support, and therapeutic hypothermia

    Curr Opin Crit Care

    (2013)
  • S.M. Frank et al.

    Multivariate determinants of early postoperative oxygen consumption in elderly patients. Effects of shivering, body temperature, and gender

    Anesthesiology

    (1995)
  • D.G. Klein et al.

    A comparison of pulmonary artery, rectal, and tympanic membrane temperature measurement in the ICU

    Heart Lung

    (1993)
  • C.S. Rumana et al.

    Brain temperature exceeds systemic temperature in head-injured patients

    Crit Care Med

    (1998)
  • C.W. Hoedemaekers et al.

    Comparison of cooling methods to induce and maintain normo- and hypothermia in intensive care unit patients: a prospective intervention study

    Crit Care

    (2007)
  • K.H. Polderman et al.

    Ultrarapid induction of hypothermia using continuous automated peritoneal lavage with ice-cold fluids: final results of the cooling for cardiac arrest or acute ST-elevation myocardial infarction trial

    Crit Care Med

    (2015)
  • N. Deye et al.

    Endovascular versus external targeted temperature management for patients with out-of-hospital cardiac arrest: a randomized, controlled study

    Circulation

    (2015)
  • R.A. Felberg et al.

    Hypothermia after cardiac arrest: feasibility and safety of an external cooling protocol

    Circulation

    (2001)
  • S. Mayer et al.

    Clinical trial of an air-circulating cooling blanket for fever control in critically ill neurologic patients

    Neurology

    (2001)
  • F. Kim et al.

    Pilot study of rapid infusion of 2 L of 4 degrees C normal saline for induction of mild hypothermia in hospitalized, comatose survivors of out-of-hospital cardiac arrest

    Circulation

    (2005)
  • Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest

    N Engl J Med

    (2002)
  • S.A. Bernard et al.

    “Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia.”

    N Engl J Med

    (2002)
  • M. Castren et al.

    Intra-arrest transnasal evaporative cooling: a randomized, prehospital, multicenter study (PRINCE: Pre-ROSC IntraNasal Cooling Effectiveness)

    Circulation

    (2010)
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    Sources of Funding: Dr F. Rincon has received salary support from the Genentech Foundation (Grant # G-29902).

    Disclosures and Conflicts of Interest: Dr F. Rincon is a Consultant for Bard Medical, Inc; and Portola Pharmaceutics.

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