- •
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.
Targeted Temperature Management in Brain Injured Patients
Section snippets
Key points
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
References (190)
- et al.
Induced hypothermia using large volume, ice-cold intravenous fluid in comatose survivors of out-of-hospital cardiac arrest: a preliminary report
Resuscitation
(2003) - et al.
The introduction of an esophageal heat transfer device into a therapeutic hypothermia protocol: a prospective evaluation
Am J Emerg Med
(2016) - et al.
Cerebrovascular reactivity during hypothermia and rewarming
Br J Anaesth
(2007) - et al.
The paracetamol (acetaminophen) in stroke (PAIS) trial: a multicentre, randomised, placebo-controlled, phase III trial
Lancet Neurol
(2009) - et al.
Magnesium sulphate only slightly reduces the shivering threshold in humans
Br J Anaesth
(2005) - et al.
Left ventricular diastolic dysfunction during acute myocardial infarction: effect of mild hypothermia
Resuscitation
(2012) - et al.
The effect of mild therapeutic hypothermia on renal function after cardiopulmonary resuscitation in men
Resuscitation
(2004) - et al.
Hypothermia induces anti-inflammatory cytokines and inhibits nitric oxide and myeloperoxidase-mediated damage in the hearts of endotoxemic rats
Chest
(2004) - et al.
Moderate hypothermia alters interleukin-6 and interleukin-1alpha reactions in ischemic brain in mice
Resuscitation
(2002) - et al.
Effects of mild hypothermia on superoxide anion production, superoxide dismutase expression, and activity following transient focal cerebral ischemia
Neurobiol Dis
(2002)
Protection in animal models of brain and spinal cord injury with mild to moderate hypothermia
J Neurotrauma
Normal average value of cerebral blood flow in younger adults is 50 ml/100 g/min
J Cereb Blood Flow Metab
Middle cerebral artery blood velocity and cerebral blood flow and O2 uptake during dynamic exercise
J Appl Physiol (1985)
Pharmacological blockade of the cold receptor TRPM8 attenuates autonomic and behavioral cold defenses and decreases deep body temperature
J Neurosci
How cold is it? TRPM8 and TRPA1 in the molecular logic of cold sensation
Mol Pain
Clues to understanding cold sensation: thermodynamics and electrophysiological analysis of the cold receptor TRPM8
Proc Natl Acad Sci U S A
Impaired thermosensation in mice lacking TRPV3, a heat and camphor sensor in the skin
Science
Desflurane reduces the gain of thermoregulatory arteriovenous shunt vasoconstriction in humans
Anesthesiology
Metabolic benefits of surface counter warming during therapeutic temperature modulation
Crit Care Med
Magnesium sulfate stops postanesthetic shivering
Ann N Y Acad Sci
Metabolic impact of shivering during therapeutic temperature modulation: the bedside shivering assessment scale
Stroke
Dantrolene reduces the threshold and gain for shivering
Anesth Analg
Rate and gender dependence of the sweating, vasoconstriction, and shivering thresholds in humans
Anesthesiology
The epidemiology of spontaneous fever and hypothermia on admission of brain injury patients to intensive care units: a multicenter cohort study
J Neurosurg
Targeted temperature management in critical care: a report and recommendations from five professional societies
Crit Care Med
Therapeutic hypothermia and controlled normothermia in the intensive care unit: practical considerations, side effects, and cooling methods
Crit Care Med
The neurologic basis of fever
N Engl J Med
Hyperthermia
N Engl J Med
Hypothermia: effect on canine brain and whole-body metabolism
Anesthesiology
Small differences in intraischemic brain temperature critically determine the extent of ischemic neuronal injury
J Cereb Blood Flow Metab
General versus specific actions of mild-moderate hypothermia in attenuating cerebral ischemic damage
J Cereb Blood Flow Metab
Akt contributes to neuroprotection by hypothermia against cerebral ischemia in rats
J Neurosci
Hypothermic reperfusion after cardiac arrest augments brain-derived neurotrophic factor activation
J Cereb Blood Flow Metab
Glutamate release and free radical production following brain injury: effects of posttraumatic hypothermia
J Neurochem
Hypothermia for Intracranial Hypertension after Traumatic Brain Injury
N Engl J Med
Contemporary management of traumatic intracranial hypertension: is there a role for therapeutic hypothermia?
Neurocrit Care
Induction of hypothermia in patients with various types of neurologic injury with use of large volumes of ice-cold intravenous fluid
Crit Care Med
Salvage techniques in traumatic cardiac arrest: thoracotomy, extracorporeal life support, and therapeutic hypothermia
Curr Opin Crit Care
Multivariate determinants of early postoperative oxygen consumption in elderly patients. Effects of shivering, body temperature, and gender
Anesthesiology
A comparison of pulmonary artery, rectal, and tympanic membrane temperature measurement in the ICU
Heart Lung
Brain temperature exceeds systemic temperature in head-injured patients
Crit Care Med
Comparison of cooling methods to induce and maintain normo- and hypothermia in intensive care unit patients: a prospective intervention study
Crit Care
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
Endovascular versus external targeted temperature management for patients with out-of-hospital cardiac arrest: a randomized, controlled study
Circulation
Hypothermia after cardiac arrest: feasibility and safety of an external cooling protocol
Circulation
Clinical trial of an air-circulating cooling blanket for fever control in critically ill neurologic patients
Neurology
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
Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest
N Engl J Med
“Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia.”
N Engl J Med
Intra-arrest transnasal evaporative cooling: a randomized, prehospital, multicenter study (PRINCE: Pre-ROSC IntraNasal Cooling Effectiveness)
Circulation
Cited by (5)
Targeted Temperature Management for Poor Grade Aneurysmal Subarachnoid Hemorrhage: A Pilot Study
2024, World NeurosurgeryManagement of temperature control in post-cardiac arrest care: an expert report
2021, Medicina IntensivaTargeted temperature management in brain edema
2023, Journal of the Korean Medical AssociationMedical Thermology 2017 - A computer-assisted literature survey
2018, Thermology InternationalAcute unconsciousness
2018, Fortschritte der Neurologie Psychiatrie
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.