Abstract
Hypothermia is widely accepted as the gold-standard method by which the body can protect the brain. Therapeutic cooling—or targeted temperature management (TTM)—is increasingly being used to prevent secondary brain injury in patients admitted to the emergency department and intensive care unit. Rapid cooling to 33 °C for 24 h is considered the standard of care for minimizing neurological injury after cardiac arrest, mild-to-moderate hypothermia (33–35 °C) can be used as an effective component of multimodal therapy for patients with elevated intracranial pressure, and advanced cooling technology can control fever in patients who have experienced trauma, haemorrhagic stroke, or other forms of severe brain injury. However, the practical application of therapeutic hypothermia is not trivial, and the treatment carries risks. Development of clinical management protocols that focus on detection and control of shivering and minimize the risk of other potential complications of TTM will be essential to maximize the benefits of this emerging therapeutic modality. This Review provides an overview of the potential neuroprotective mechanisms of hypothermia, practical considerations for the application of TTM, and disease-specific evidence for the use of this therapy in patients with acute brain injuries.
Key Points
-
Targeted temperature management (TTM) is the most powerful mechanism of neuroprotection currently available
-
Hypothermia is proven to have clinically beneficial effects in preventing secondary brain injury in patients who have experienced cardiac arrest, and in neonates with hypoxic–ischaemic injuries
-
Cooling is an effective mechanism to reduce intracranial pressure in patients who do not respond to standard medications
-
Shivering is a common and potentially damaging adverse effect of TTM that needs to be controlled
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Bigelow, W. G., Lindsay, W. K. & Greenwood, W. F. Hypothermia; its possible role in cardiac surgery: an investigation of factors governing survival in dogs at low body temperatures. Ann. Surg. 132, 849–866 (1950).
Rosomoff, H. L. & Holaday, D. A. Cerebral blood flow and cerebral oxygen consumption during hypothermia. Am. J. Physiol. 179, 85–88 (1954).
Benson, D. W., Williams, G. R. Jr, Spencer, F. C. & Yates, A. J. The use of hypothermia after cardiac arrest. Anesth. Analg. 38, 423–428 (1959).
Williams, G. R. Jr & Spencer, F. C. The clinical use of hypothermia following cardiac arrest. Ann. Surg. 148, 462–468 (1958).
Young, R. S., Zalneraitis, E. L. & Dooling, E. C. Neurological outcome in cold water drowning. JAMA 244, 1233–1235 (1980).
Polderman, K. H. Induced hypothermia and fever control for prevention and treatment of neurological injuries. Lancet 371, 1955–1969 (2008).
Bernard, S. A. et al. Treatment of comatose survivors of outofhospital cardiac arrest with induced hypothermia. N. Engl. J. Med. 346, 557–563 (2002).
The Hypothermia after Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N. Engl. J. Med. 346, 549–556 (2002).
Steen, P. A., Newberg, L., Milde, J. H. & Michenfelder, J. D. Hypothermia and barbiturates: individual and combined effects on canine cerebral oxygen consumption. Anesthesiology 58, 527–532 (1983).
Baker, A. J. et al. Hypothermia prevents ischemia-induced increases in hippocampal glycine concentrations in rabbits. Stroke 22, 666–673 (1991).
Feng, J. F. et al. Effect of therapeutic mild hypothermia on the genomics of the hippocampus after moderate traumatic brain injury in rats. Neurosurgery 67, 730–742 (2010).
Truettner, J. S., Alonso, O. F., Bramlett, H. M. & Dietrich, W. D. Therapeutic hypothermia alters microRNA responses to traumatic brain injury in rats. J. Cereb. Blood Flow Metab. 31, 1897–1907 (2011).
Kil, H. Y., Zhang, J. & Piantadosi, C. A. Brain temperature alters hydroxyl radical production during cerebral ischemia/reperfusion in rats. J. Cereb. Blood Flow Metab. 16, 100–106 (1996).
Olsen, T. S., Weber, U. J. & Kammersgaard, L. P. Therapeutic hypothermia for acute stroke. Lancet Neurol. 2, 410–416 (2003).
van der Worp, H. B., Sena, E. S., Donnan, G. A., Howells, D. W. & Macleod, M. R. Hypothermia in animal models of acute ischaemic stroke: a systematic review and meta-analysis. Brain 130, 3063–3074 (2007).
Karibe, H., Zarow, G. J., Graham, S. H. & Weinstein, P. R. 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. J. Cereb. Blood Flow Metab. 14, 620–627 (1994).
Eguchi, Y., Yamashita, K., Iwamoto, T. & Ito, H. Effects of brain temperature on calmodulin and microtubule-associated protein 2 immunoreactivity in the gerbil hippocampus following transient forebrain ischemia. J. Neurotrauma 14, 109–118 (1997).
Xu, L., Yenari, M. A., Steinberg, G. K. & Giffard, R. G. Mild hypothermia reduces apoptosis of mouse neurons in vitro early in the cascade. J. Cereb. Blood Flow Metab. 22, 21–28 (2002).
Lotocki, G. et al. Alterations in blood-brain barrier permeability to large and small molecules and leukocyte accumulation after traumatic brain injury: effects of post-traumatic hypothermia. J. Neurotrauma 26, 1123–1134 (2009).
Wartenberg, K. E., Schmidt, J. M. & Mayer, S. A. Multimodality monitoring in neurocritical care. Crit. Care Clin. 23, 507–538 (2007).
Jiang, J., Yu, M. & Zhu, C. Effect of long-term mild hypothermia therapy in patients with severe traumatic brain injury: 1 year follow-up review of 87 cases. J. Neurosurg. 93, 546–549 (2000).
Clifton, G. L. et al. Lack of effect of induction of hypothermia after acute brain injury. N. Engl. J. Med. 344, 556–563 (2001).
Qiu, W. et al. Effects of therapeutic mild hypothermia on patients with severe traumatic brain injury after craniotomy. J. Crit. Care 22, 229–235 (2007).
Shiozaki, T. et al. Effect of mild hypothermia on uncontrollable intracranial hypertension after severe head injury. J. Neurosurg. 79, 363–368 (1993).
Tokutomi, T. et al. Optimal temperature for the management of severe traumatic brain injury: effect of hypothermia on intracranial pressure, systemic and intracranial hemodynamics, and metabolism. Neurosurgery 52, 102–111 (2003).
Sahuquillo, J. et al. Intravascular cooling for rapid induction of moderate hypothermia in severely head-injured patients: results of a multicenter study (IntraCool). Intensive Care Med. 35, 890–898 (2009).
Schreckinger, M. & Marion, D. W. Contemporary management of traumatic intracranial hypertension: is there a role for therapeutic hypothermia? Neurocrit. Care 11, 427–436 (2009).
Kliegel, A. et al. Cold simple intravenous infusions preceding special endovascular cooling for faster induction of mild hypothermia after cardiac arrest-a feasibility study. Resuscitation 64, 347–351 (2005).
Mayer, S. A. et al. Clinical trial of a novel surface cooling system for fever control in neurocritical care patients. Crit. Care Med. 32, 2508–2515 (2004).
De Georgia, M. A. et al. Cooling for Acute Ischemic Brain Damage (COOL AID): a feasibility trial of endovascular cooling. Neurology 63, 312–317 (2004).
Badjatia, N. et al. Achieving normothermia in patients with febrile subarachnoid hemorrhage: feasibility and safety of a novel intravascular cooling catheter. Neurocrit. Care 1, 145–156 (2004).
Hoedemaekers, C. W., Ezzahti, M., Gerritsen, A. & van der Hoeven, J. G. Comparison of cooling methods to induce and maintain normo- and hypothermia in intensive care unit patients: a prospective intervention study. Crit. Care 11, R91 (2007).
Moran, J. L. et al. Tympanic temperature measurements: are they reliable in the critically ill? A clinical study of measures of agreement. Crit. Care Med. 35, 155–164 (2007).
Rajek, A. et al. Core cooling by central venous infusion of ice-cold (4 °C and 20 °C) fluid: isolation of core and peripheral thermal compartments. Anesthesiology 93, 629–637 (2000).
Bernard, S., Buist, M., Monteiro, O. & Smith, K. Induced hypothermia using large volume, ice-cold intravenous fluid in comatose survivors of outofhospital cardiac arrest: a preliminary report. Resuscitation 56, 9–13 (2003).
Polderman, K. H., Rijnsburger, E. R., Peerdeman, S. M. & Girbes, A. R. Induction of hypothermia in patients with various types of neurologic injury with use of large volumes of ice-cold intravenous fluid. Crit. Care Med. 33, 2744–2751 (2005).
Oddo, M. et al. Effect of shivering on brain tissue oxygenation during induced normothermia in patients with severe brain injury. Neurocrit. Care 12, 10–16 (2010).
Jiang, J. Y. et al. Effect of long-term mild hypothermia or short-term mild hypothermia on outcome of patients with severe traumatic brain injury. J. Cereb. Blood Flow Metab. 26, 771–776 (2006).
Linares, G. & Mayer, S. A. Hypothermia for the treatment of ischemic and hemorrhagic stroke. Crit. Care Med. 37, S243–249 (2009).
Clifton, G. L. Hypothermia in patients with brain injury: the way forward? Lancet Neurol. 10, 406–407 (2011).
Polderman, K. H. & Herold, I. Therapeutic hypothermia and controlled normothermia in the intensive care unit: practical considerations, side effects, and cooling methods. Crit. Care Med. 37, 1101–1120 (2009).
Badjatia, N. Fever control in the neuro-ICU: why, who, and when? Curr. Opin. Crit. Care 15, 79–82 (2009).
Sessler, D. I. Defeating normal thermoregulatory defenses: induction of therapeutic hypothermia. Stroke 40, e614–e621 (2009).
Badjatia, N. Hyperthermia and fever control in brain injury. Crit. Care Med. 37, S250–S257 (2009).
Badjatia, N. et al. Metabolic impact of shivering during therapeutic temperature modulation: the Bedside Shivering Assessment Scale. Stroke 39, 3242–3247 (2008).
Badjatia, N. et al. Metabolic benefits of surface counter warming during therapeutic temperature modulation. Crit. Care Med. 37, 1893–1897 (2009).
Choi, H. A. et al. Prevention of shivering during therapeutic temperature modulation: The Columbia Anti-Shivering Protocol. Neurocrit. Care 14, 389–394 (2011).
Zweifler, R. M., Voorhees, M. E., Mahmood, M. A. & Parnell, M. Magnesium sulfate increases the rate of hypothermia via surface cooling and improves comfort. Stroke 35, 2331–2334 (2004).
Mokhtarani, M. et al. Buspirone and meperidine synergistically reduce the shivering threshold. Anesth. Analg. 93, 1233–1239 (2001).
Kasner, S. E. et al. Acetaminophen for altering body temperature in acute stroke: a randomized clinical trial. Stroke 33, 130–134 (2002).
Lennon, R. L., Hosking, M. P., Conover, M. A. & Perkins, W. J. Evaluation of a forced-air system for warming hypothermic postoperative patients. Anesth. Analg. 70, 424–427 (1990).
Doufas, A. G. et al. Dexmedetomidine and meperidine additively reduce the shivering threshold in humans. Stroke 34, 1218–1223 (2003).
Matsukawa, T. et al. Propofol linearly reduces the vasoconstriction and shivering thresholds. Anesthesiology 82, 1169–1180 (1995).
Kurz, A. et al. Midazolam minimally impairs thermoregulatory control. Anesth. Analg. 81, 393–398 (1995).
Polderman, K. H., Peerdeman, S. M. & Girbes, A. R. Hypophosphatemia and hypomagnesemia induced by cooling in patients with severe head injury. J. Neurosurg. 94, 697–705 (2001).
Polderman, K. H. Application of therapeutic hypothermia in the intensive care unit. Opportunities and pitfalls of a promising treatment modality—Part 2: Practical aspects and side effects. Intensive Care Med. 30, 757–769 (2004).
Polderman, K. H. Mechanisms of action, physiological effects, and complications of hypothermia. Crit. Care Med. 37, S186–202 (2009).
Bacher, A. Effects of body temperature on blood gases. Intensive Care Med. 31, 24–27 (2005).
Lay, C. & Badjatia, N. Therapeutic hypothermia after cardiac arrest. Curr. Atheroscler. Rep. 12, 336–342 (2010).
Knight, D. R. & Horvath, S. M. Urinary responses to cold temperature during water immersion. Am. J. Physiol. 248, R560–566 (1985).
Zeiner, A. et al. The effect of mild therapeutic hypothermia on renal function after cardiopulmonary resuscitation in men. Resuscitation 60, 253–261 (2004).
Bergman, R. et al. Haemodynamic consequences of mild therapeutic hypothermia after cardiac arrest. Eur. J. Anaesthesiol. 27, 383–387 (2010).
Hemmen, T. M. et al. Intravenous thrombolysis plus hypothermia for acute treatment of ischemic stroke (ICTuSL): final results. Stroke 41, 2265–2270 (2010).
Seule, M. A., Muroi, C., Mink, S., Yonekawa, Y. & Keller, E. Therapeutic hypothermia in patients with aneurysmal subarachnoid hemorrhage, refractory intracranial hypertension, or cerebral vasospasm. Neurosurgery 64, 86–92 (2009).
Todd, M. M., Hindman, B. J., Clarke, W. R. & Torner, J. C. Mild intraoperative hypothermia during surgery for intracranial aneurysm. N. Engl. J. Med. 352, 135–145 (2005).
Schefold, J. C., Storm, C., Joerres, A. & Hasper, D. Mild therapeutic hypothermia after cardiac arrest and the risk of bleeding in patients with acute myocardial infarction. Int. J. Cardiol. 132, 387–391 (2009).
Nolan, J. P. et al. Therapeutic hypothermia after cardiac arrest: an advisory statement by the advanced life support task force of the International Liaison Committee on Resuscitation. Circulation 108, 118–121 (2003).
Lundbye, J. B. et al. Therapeutic hypothermia is associated with improved neurologic outcome and survival in cardiac arrest survivors of non-shockable rhythms. Resuscitation http://dx.doi.org/10.1016/j.resuscitation.2011.08.005.
Testori, C. et al. Mild therapeutic hypothermia is associated with favourable outcome in patients after cardiac arrest with non-shockable rhythms. Resuscitation 82, 1162–1167 (2011).
Storm, C., Nee, J., Roser, M., Jorres, A. & Hasper, D. Mild hypothermia treatment in patients resuscitated from non-shockable cardiac arrest. Emerg. Med. J. 29, 100–103 (2011).
Bernard, S. A. et al. Induction of prehospital therapeutic hypothermia after resuscitation from nonventricular fibrillation cardiac arrest. Crit. Care Med. http://dx.doi.org/10.1097/CCM.0b013e3182377038.
Azzopardi, D. V. et al. Moderate hypothermia to treat perinatal asphyxial encephalopathy. N. Engl. J. Med. 361, 1349–1358 (2009).
Gluckman, P. D. et al. Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomised trial. Lancet 365, 663–670 (2005).
Shankaran, S. et al. Whole-body hypothermia for neonates with hypoxic–ischemic encephalopathy. N. Engl. J. Med. 353, 1574–1584 (2005).
Edwards, A. D. et al. Neurological outcomes at 18 months of age after moderate hypothermia for perinatal hypoxic ischaemic encephalopathy: synthesis and meta-analysis of trial data. BMJ 340, c363 (2010).
Jacobs, S., Hunt, R., Tarnow-Mordi, W., Inder, T. & Davis, P. Cooling for newborns with hypoxic ischaemic encephalopathy. Cochrane Database of Systematic Reviews, Issue 2. Art. No.: CD003311 http://dx.doi.org/10.1002/14651858.CD001048.pub4.
Perlman, J. M. et al. Part 11: Neonatal resuscitation: 2010 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations. Circulation 122, S516–538 (2010).
Qiu, W. S. et al. Therapeutic effect of mild hypothermia on severe traumatic head injury. Chin. J. Traumatol. 8, 27–32 (2005).
Sydenham, E., Roberts, I. & Alderson, P. Hypothermia for traumatic head injury. Cochrane Database of Systematic Reviews, Issue 2. Art. No.: CD001048 http://dx.doi.org/10.1002/14651858.CD001048.pub4.
Polderman, K. H., Tjong Tjin Joe, R., Peerdeman, S. M., Vandertop, W. P. & Girbes, A. R. Effects of therapeutic hypothermia on intracranial pressure and outcome in patients with severe head injury. Intensive Care Med. 28, 1563–1573 (2002).
Marion, D. W. et al. Treatment of traumatic brain injury with moderate hypothermia. N. Engl. J. Med. 336, 540–546 (1997).
Clifton, G. L. et al. Very early hypothermia induction in patients with severe brain injury (the National Acute Brain Injury Study: Hypothermia II): a randomised trial. Lancet Neurol. 10, 131–139 (2011).
Hutchison, J. S. et al. Hypothermia therapy after traumatic brain injury in children. N. Engl. J. Med. 358, 2447–2456 (2008).
Andrews, P. J. et al. European society of intensive care medicine study of therapeutic hypothermia (32–35 °C) for intracranial pressure reduction after traumatic brain injury (the Eurotherm3235Trial). Trials 12, 8 (2011).
Cappuccino, A. et al. The use of systemic hypothermia for the treatment of an acute cervical spinal cord injury in a professional football player. Spine (Phila. Pa 1976) 35, E57–62 (2010).
Levi, A. D. et al. Clinical outcomes using modest intravascular hypothermia after acute cervical spinal cord injury. Neurosurgery 66, 670–677 (2010).
Levi, A. D. et al. Clinical application of modest hypothermia after spinal cord injury. J. Neurotrauma 26, 407–415 (2009).
Stroke Therapy Academic Industry Roundtable II (STAIR-II). Recommendations for clinical trial evaluation of acute stroke therapies. Stroke 32, 1598–1606 (2001).
O'Collins, V. E. et al. 1,026 experimental treatments in acute stroke. Ann. Neurol. 59, 467–477 (2006).
Kollmar, R. et al. Neuroprotective effect of delayed moderate hypothermia after focal cerebral ischemia: an MRI study. Stroke 33, 1899–1904 (2002).
Maier, C. M., Sun, G. H., Kunis, D., Yenari, M. A. & Steinberg, G. K. Delayed induction and long-term effects of mild hypothermia in a focal model of transient cerebral ischemia: neurological outcome and infarct size. J. Neurosurg. 94, 90–96 (2001).
Markarian, G. Z., Lee, J. H., Stein, D. J. & Hong, S. C. Mild hypothermia: therapeutic window after experimental cerebral ischemia. Neurosurgery 38, 542–550 (1996).
Ohta, H., Terao, Y., Shintani, Y. & Kiyota, Y. Therapeutic time window of post-ischemic mild hypothermia and the gene expression associated with the neuroprotection in rat focal cerebral ischemia. Neurosci. Res. 57, 424–433 (2007).
Guluma, K. Z., Hemmen, T. M., Olsen, S. E., Rapp, K. S. & Lyden, P. D. A trial of therapeutic hypothermia via endovascular approach in awake patients with acute ischemic stroke: methodology. Acad. Emerg. Med. 13, 820–827 (2006).
Kammersgaard, L. P. et al. Feasibility and safety of inducing modest hypothermia in awake patients with acute stroke through surface cooling: A case–control study: the Copenhagen Stroke Study. Stroke 31, 2251–2256 (2000).
Guluma, K. Z. et al. Effect of endovascular hypothermia on acute ischemic edema: morphometric analysis of the ICTuS trial. Neurocrit. Care 8, 42–47 (2008).
Martin-Schild, S. et al. Combined neuroprotective modalities coupled with thrombolysis in acute ischemic stroke: a pilot study of caffeinol and mild hypothermia. J. Stroke Cerebrovasc. Dis. 18, 86–96 (2009).
Howell, D. A., Posnikoff, J. & Stratford, J. G. Prolonged hypothermia in treatment of massive cerebral haemorrhage; a preliminary report. Can. Med. Assoc. J. 75, 388–394 (1956).
Venkatasubramanian, C. et al. Natural history of perihematomal edema after intracerebral hemorrhage measured by serial magnetic resonance imaging. Stroke 42, 73–80 (2011).
Kollmar, R. et al. Hypothermia reduces perihemorrhagic edema after intracerebral hemorrhage. Stroke 41, 1684–1689 (2010).
Anei, R., Sakai, H., Iihara, K. & Nagata, I. Effectiveness of brain hypothermia treatment in patients with severe subarachnoid hemorrhage: comparisons at a single facility. Neurol. Med. Chir. (Tokyo) 50, 879–883 (2010).
Gasser, S., Khan, N., Yonekawa, Y., Imhof, H. G. & Keller, E. Long-term hypothermia in patients with severe brain edema after poor-grade subarachnoid hemorrhage: feasibility and intensive care complications. J. Neurosurg. Anesthesiol. 15, 240–248 (2003).
Nakamura, T., Tatara, N., Morisaki, K., Kawakita, K. & Nagao, S. Cerebral oxygen metabolism monitoring under hypothermia for severe subarachnoid hemorrhage: report of eight cases. Acta Neurol. Scand. 106, 314–318 (2002).
Nagao, S. et al. Protective effect of mild hypothermia on symptomatic vasospasm: a preliminary report. Acta Neurochir Suppl. 76, 547–550 (2000).
Hindman, B. J. et al. Mild hypothermia as a protective therapy during intracranial aneurysm surgery: a randomized prospective pilot trial. Neurosurgery 44, 23–32 (1999).
Anderson, S. W. et al. Effects of intraoperative hypothermia on neuropsychological outcomes after intracranial aneurysm surgery. Ann. Neurol. 60, 518–527 (2006).
Dmello, D., Cruz-Flores, S. & Matuschak, G. M. Moderate hypothermia with intracranial pressure monitoring as a therapeutic paradigm for the management of acute liver failure: a systematic review. Intensive Care Med. 36, 210–213 (2010).
Jalan, R. et al. Moderate hypothermia prevents cerebral hyperemia and increase in intracranial pressure in patients undergoing liver transplantation for acute liver failure. Transplantation 75, 2034–2039 (2003).
Stravitz, R. T. et al. Intensive care of patients with acute liver failure: recommendations of the U.S. Acute Liver Failure Study Group. Crit. Care Med. 35, 2498–2508 (2007).
Author information
Authors and Affiliations
Contributions
H. A. Choi researched data for and wrote the article. N. Badjatia provided substantial contribution to discussion of the content and to review and/or editing of the manuscript before submission. S. A. Mayer provided substantial contribution to discussion of the content, and writing, review and editing of the manuscript before submission.
Corresponding author
Ethics declarations
Competing interests
S. A. Mayer has received consulting fees from Medivance/CR Bard. N. Badjatia has received grant and research support from Cumberland Pharmaceuticals, Medivance/CR Bard and Philips. H. A. Choi declares no competing interests.
Rights and permissions
About this article
Cite this article
Choi, H., Badjatia, N. & Mayer, S. Hypothermia for acute brain injury—mechanisms and practical aspects. Nat Rev Neurol 8, 214–222 (2012). https://doi.org/10.1038/nrneurol.2012.21
Published:
Issue Date:
DOI: https://doi.org/10.1038/nrneurol.2012.21
This article is cited by
-
Mild Hypothermia Protects Brain Injury After Intracerebral Hemorrhage in Mice Via Enhancing the Nrdp1/MyD88 Signaling Pathway
Neurotoxicity Research (2022)
-
Targeted Temperature Management at 36 °C Shows Therapeutic Effectiveness via Alteration of Microglial Activation and Polarization After Ischemic Stroke
Translational Stroke Research (2022)
-
Effects of local hypothermia–rewarming on physiology, metabolism and inflammation of acutely injured human spinal cord
Scientific Reports (2020)
-
Therapeutic Hypothermia in Acute Ischemic Stroke—a Systematic Review and Meta-Analysis
Current Neurology and Neuroscience Reports (2020)
-
The Medical Management of Cerebral Edema: Past, Present, and Future Therapies
Neurotherapeutics (2019)