{{Short description|Medical procedure}} {{About|deliberately induced cooling|the adverse condition of hypothermia|Hypothermia}} {{Infobox interventions | | Name = Targeted temperature management | Image = | Caption = | Specialty = Critical care medicine | ICD10 = {{ICD10PCS|6A4|6/A/4}} | ICD9 = | OPS301 = {{OPS301|8-607}} | Synonyms = Therapeutic hypothermia | HCPCSlevel2 = | MeshID=C18.452.394.750|| }}
'''Targeted temperature management''' ('''TTM'''), previously known as '''therapeutic hypothermia''' or '''protective hypothermia''', is an active treatment that tries to achieve and maintain a specific body temperature in a person for a specific duration of time in an effort to improve health outcomes during recovery after a period of stopped blood flow to the brain.<ref name=Peb2010>{{cite journal|last1=Peberdy|first1=MA|last2=Callaway|first2=CW|last3=Neumar|first3=RW|last4=Geocadin|first4=RG|last5=Zimmerman|first5=JL|last6=Donnino|first6=M|last7=Gabrielli|first7=A|last8=Silvers|first8=SM|last9=Zaritsky|first9=AL|last10=Merchant|first10=R|last11=Vanden Hoek|first11=TL|last12=Kronick|first12=SL|last13=American Heart|first13=Association|title=Part 9: post-cardiac arrest care: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care.|journal=Circulation|date=2 November 2010|volume=122|issue=18 Suppl 3|pages=S768–786|pmid=20956225|doi=10.1161/CIRCULATIONAHA.110.971002|doi-access=free}}</ref> This is done in an attempt to reduce the risk of tissue injury following lack of blood flow.<ref name=Bernard2002>{{cite journal|last=Bernard|first=Stephen A.|author2=Gray, Timothy W. |author3=Buist, Michael D. |author4=Jones, Bruce M. |author5=Silvester, William |author6=Gutteridge, Geoff |author7= Smith, Karen |title=Treatment of Comatose Survivors of Out-of-Hospital Cardiac Arrest with Induced Hypothermia|journal=New England Journal of Medicine|date=21 February 2002|volume=346|issue=8|pages=557–563|doi=10.1056/NEJMoa003289|pmid=11856794|doi-access=free}}</ref> Periods of poor blood flow may be due to cardiac arrest or the blockage of an artery by a clot as in the case of a stroke.<ref>{{cite web | url=http://www.hopkinsmedicine.org/healthlibrary/test_procedures/cardiovascular/therapeutic_hypothermia_after_cardiac_arrest_135,393 | title=Therapeutic Hypothermia After Cardiac Arrest | publisher=Johns Hopkins Medicine Health Library | access-date=October 22, 2017}}</ref>
Targeted temperature management improves survival and brain function following resuscitation from cardiac arrest.<ref name=":0">{{Cite journal |last1=Arrich |first1=Jasmin |last2=Schütz |first2=Nikola |last3=Oppenauer |first3=Julia |last4=Vendt |first4=Janne |last5=Holzer |first5=Michael |last6=Havel |first6=Christof |last7=Herkner |first7=Harald |date=2023-05-22 |title=Hypothermia for neuroprotection in adults after cardiac arrest |url= |journal=The Cochrane Database of Systematic Reviews |volume=5 |issue=5 |article-number=CD004128 |doi=10.1002/14651858.CD004128.pub5 |issn=1469-493X |pmc=10202224 |pmid=37217440 }}</ref> Evidence supports its use following certain types of cardiac arrest in which an individual does not regain consciousness.<ref name=Peb2010/> The target temperature is often between 32 and 34 °C.<ref name=":0" /> Targeted temperature management following traumatic brain injury is of unclear benefit.<ref>{{Cite journal|last1=Lewis|first1=Sharon R.|last2=Evans|first2=David Jw|last3=Butler|first3=Andrew R.|last4=Schofield-Robinson|first4=Oliver J.|last5=Alderson|first5=Phil|date=September 21, 2017|title=Hypothermia for traumatic brain injury|journal=The Cochrane Database of Systematic Reviews|volume=2017|issue=9 |article-number=CD001048|doi=10.1002/14651858.CD001048.pub5|issn=1469-493X|pmc=6483736|pmid=28933514}}</ref> While associated with some complications, these are generally mild.<ref name=Xiao2013>{{cite journal |doi=10.1136/emermed-2012-201120 |title=Safety profile and outcome of mild therapeutic hypothermia in patients following cardiac arrest: Systematic review and meta-analysis |year=2012 |last1=Xiao |first1=G. |last2=Guo |first2=Q. |last3=Shu |first3=M. |last4=Xie |first4=X. |last5=Deng |first5=J. |last6=Zhu |first6=Y. |last7=Wan |first7=C. |s2cid=23723711 |journal=Emergency Medicine Journal |volume=30 |issue=2 |pages=91–100 |pmid=22660549}}</ref>
Targeted temperature management is thought to prevent brain injury by several methods, including decreasing the brain's oxygen demand, reducing the production of neurotransmitters like glutamate, as well as reducing free radicals that might damage the brain. Body temperature may be lowered by many means, including cooling blankets, cooling helmets, cooling catheters, ice packs and ice water lavage. {{TOC limit|3}}
==Medical uses== Targeted temperature management may be used in the following conditions:
===Cardiac arrest=== The 2013 ILCOR and 2010 American Heart Association guidelines support the use of cooling following resuscitation from cardiac arrest.<ref name="Peb2010"/><ref name="ILCOR2013">{{cite web |author1=Ian Jacobs |date=Dec 17, 2013 |title=Targeted temperature management following cardiac arrest An update |url=http://www.ilcor.org/data/TTM-ILCOR-update-Dec-2013.pdf |access-date=14 November 2014 |website=ilcor.org}}</ref> These recommendations were largely based on two trials from 2002 which showed improved survival and brain function when cooled to {{convert|32-34|C|F}} after cardiac arrest.<ref name=Bernard2002/><ref name="HACA 2002">{{cite journal |vauthors=Holzer M |collaboration=The Hypothermia after Cardiac Arrest Study Group |title=Mild Therapeutic Hypothermia to Improve the Neurologic Outcome after Cardiac Arrest|journal=New England Journal of Medicine|date=21 February 2002|volume=346|issue=8|pages=549–556|doi=10.1056/NEJMoa012689|pmid=11856793|doi-access=free}}</ref>
However, more recent research suggests that there is no benefit to cooling to {{convert|33|C|F}} when compared with less aggressive cooling only to a near-normal temperature of {{convert|36|C|F}}; it appears cooling is effective because it prevents fever, a common complication seen after cardiac arrest.<ref>{{cite journal|last1=Vargas|first1=M|last2=Servillo|first2=G|last3=Sutherasan|first3=Y|last4=Rodríguez-González|first4=R|last5=Brunetti|first5=I|last6=Pelosi|first6=P|title=Effects of in-hospital low targeted temperature after out of hospital cardiac arrest: A systematic review with meta-analysis of randomized clinical trials.|journal=Resuscitation|date=June 2015|volume=91|pages=8–18|pmid=25796995|doi=10.1016/j.resuscitation.2015.02.038|hdl=20.500.11940/8397|hdl-access=free}}</ref> There is no difference in long term quality of life following mild compared to more severe cooling.<ref>{{cite journal|last1=Patel|first1=JK|last2=Parikh|first2=PB|title=Association between therapeutic hypothermia and long-term quality of life in survivors of cardiac arrest: A systematic review.|journal=Resuscitation|date=7 April 2016|volume=103|pages=54–59|pmid=27060536|doi=10.1016/j.resuscitation.2016.03.024}}</ref>
In children, following cardiac arrest, cooling does not appear useful as of 2018.<ref>{{cite journal |last1=Scholefield |first1=BR |last2=Silverstein |first2=FS |last3=Telford |first3=R |last4=Holubkov |first4=R |last5=Slomine |first5=BS |last6=Meert |first6=KL |last7=Christensen |first7=JR |last8=Nadkarni |first8=VM |last9=Dean |first9=JM |last10=Moler |first10=FW |title=Therapeutic hypothermia after paediatric cardiac arrest: Pooled randomized controlled trials. |journal=Resuscitation |date=3 October 2018 |volume=133 |pages=101–107 |doi=10.1016/j.resuscitation.2018.09.011 |pmid=30291883|pmc=6361524 }}</ref>
A recent Cochrane Review summarized available evidence on the topic and found that targeted temperature management around 33 °C may increase the chance to prevent brain damage after cardiac arrest by 40%.<ref>{{cite journal |last1=Arrich |first1=Jasmin |last2=Schütz |first2=Nikola |last3=Oppenauer |first3=Julia |last4=Vendt |first4=Janne |last5=Holzer |first5=Michael |last6=Havel |first6=Christof |last7=Herkner |first7=Harald |title=Hypothermia for neuroprotection in adults after cardiac arrest |journal=Cochrane Database of Systematic Reviews |date=22 May 2023 |volume=2023 |issue=6 |article-number=CD004128 |doi=10.1002/14651858.CD004128.pub5 |pmid=37217440 |pmc=10202224 |language=en}}</ref>
===Neonatal encephalopathy=== Hypothermia therapy for neonatal encephalopathy has been proven to improve outcomes for newborn infants affected by perinatal hypoxia-ischemia, hypoxic ischemic encephalopathy or birth asphyxia. A 2013 Cochrane review found that it is useful in full term babies with encephalopathy.<ref>{{cite journal|last1=Jacobs|first1=SE|last2=Berg|first2=M|last3=Hunt|first3=R|last4=Tarnow-Mordi|first4=WO|last5=Inder|first5=TE|last6=Davis|first6=PG|title=Cooling for newborns with hypoxic ischaemic encephalopathy|journal=The Cochrane Database of Systematic Reviews|date=31 January 2013|volume=1|issue=1|article-number=CD003311|pmid=23440789|doi=10.1002/14651858.CD003311.pub3|pmc=7003568}}</ref> Whole body or selective head cooling to {{convert|33|-|34|C|F}}, begun within six hours of birth and continued for 72 hours, reduces mortality and reduces cerebral palsy and neurological deficits in survivors.{{citation needed|date=July 2017}}
===Open heart surgery=== Targeted temperature management is used during open-heart surgery because it decreases the metabolic needs of the brain, heart, and other organs, reducing the risk of damage to them. The patient is given medication to prevent shivering. The body is then cooled to {{convert|25|–|32|C|F}}. The heart is stopped and an external heart-lung pump maintains circulation to the patient's body. The heart is cooled further and is maintained at a temperature below {{convert|15|°C|°F|abbr=on}} for the duration of the surgery. This very cold temperature helps the heart muscle to tolerate its lack of blood supply during the surgery.<ref>{{cite journal |last1=Gocoł |first1=Radosław |last2=Hudziak |first2=Damian |last3=Bis |first3=Jarosław |last4=Mendrala |first4=Konrad |last5=Morkisz |first5=Łukasz |last6=Podsiadło |first6=Paweł |last7=Kosiński |first7=Sylweriusz |last8=Piątek |first8=Jacek |last9=Darocha |first9=Tomasz |title=The Role of Deep Hypothermia in Cardiac Surgery |journal=International Journal of Environmental Research and Public Health |date=January 2021 |volume=18 |issue=13 |page=7061 |doi=10.3390/ijerph18137061 |pmid=34280995 |pmc=8297075 |doi-access=free }}</ref><ref name="openstax">{{cite book |last1=Betts |first1=J. Gordon |title=Anatomy and Physiology |chapter=1.4 Requirements for Human Life |date=25 April 2013 |publisher=Openstax |isbn=978-1-947172-04-3 |url=https://openstax.org/books/anatomy-and-physiology/pages/1-4-requirements-for-human-life |access-date=14 May 2023 |language=en}}</ref>
==Adverse effects== Possible complications may include: infection, bleeding, dysrhythmias and high blood sugar.<ref name=PostCare2010/> One review found an increased risk of pneumonia and sepsis but not the overall risk of infection.<ref>{{cite journal |doi=10.1097/CCM.0b013e3182a276e8 |title=Therapeutic Hypothermia and the Risk of Infection |year=2013 |last1=Geurts |first1=Marjolein |last2=MacLeod |first2=Malcolm R. |last3=Kollmar |first3=Rainer |last4=Kremer |first4=Philip H. C. |last5=Van Der Worp |first5=H. Bart |s2cid=26412547 |journal=Critical Care Medicine |pages=231–242 |volume=42 |issue=2 |pmid=23989182}}</ref> Another review found a trend towards increased bleeding but no increase in severe bleeding.<ref>{{cite journal|last1=Stockmann|first1=H|last2=Krannich|first2=A|last3=Schroeder|first3=T|last4=Storm|first4=C|title=Therapeutic temperature management after cardiac arrest and the risk of bleeding: Systematic review and meta-analysis.|journal=Resuscitation|date=November 2014|volume=85|issue=11|pages=1494–1503|pmid=25132475|doi=10.1016/j.resuscitation.2014.07.018}}</ref> Hypothermia induces a "cold diuresis" which can lead to electrolyte abnormalities – specifically hypokalemia, hypomagnesaemia, and hypophosphatemia, as well as hypovolemia.<ref>{{cite journal |vauthors=Polderman KH, Peerdeman SM, Girbes AR | s2cid = 25834720 | date = May 2001 | title = Hypophosphatemia and hypomagnesemia induced by cooling in patients with severe head injury | journal = J Neurosurg | volume = 94 | issue = 5| pages = 697–705 | doi=10.3171/jns.2001.94.5.0697| pmid = 11354399 }}</ref>
==Mechanism== The earliest rationale for the effects of hypothermia as a neuroprotectant focused on the slowing of cellular metabolism resulting from a drop in body temperature. For every one degree Celsius drop in body temperature, cellular metabolism slows by 5–7%.<ref name="Kam">{{cite journal |doi=10.1161/01.STR.0000019910.90280.F1 |title=Admission Body Temperature Predicts Long-Term Mortality After Acute Stroke: The Copenhagen Stroke Study |year=2002 |last1=Kammersgaard |first1=L.P. |last2=Jørgensen |first2=H.S. |last3=Rungby |first3=J.A. |last4=Reith |first4=J. |last5=Nakayama |first5=H. |last6=Weber |first6=U.J. |last7=Houth |first7=J. |last8=Olsen |first8=T.S. |journal=Stroke |volume=33 |issue=7 |pages=1759–1762 |pmid=12105348|doi-access=free }}</ref> Accordingly, most early hypotheses suggested that hypothermia reduces the harmful effects of ischemia by decreasing the body's need for oxygen.<ref name="main"/> The initial emphasis on cellular metabolism explains why the early studies almost exclusively focused on the application of deep hypothermia, as these researchers believed that the therapeutic effects of hypothermia correlated directly with the extent of temperature decline.<ref>{{cite journal |doi=10.1016/S0140-6736(08)60837-5 |pmid=18539227 |title=Induced hypothermia and fever control for prevention and treatment of neurological injuries |year=2008 |last1=Polderman |first1=Kees H |s2cid=8691457 |journal=The Lancet |volume=371 |issue=9628 |pages=1955–1969}}</ref>
In the special case of infants with perinatal asphyxia, it appears that apoptosis is a prominent cause of cell death and that hypothermia therapy for neonatal encephalopathy interrupts the apoptotic pathway. In general, cell death is not directly caused by oxygen deprivation, but occurs indirectly as a result of the cascade of subsequent events. Cells need oxygen to create ATP, a molecule used by cells to store energy, and cells need ATP to regulate intracellular ion levels. ATP is used to fuel both the importation of ions necessary for cellular function and the removal of ions that are harmful to cellular function. Without oxygen, cells cannot manufacture the necessary ATP to regulate ion levels and thus cannot prevent the intracellular environment from approaching the ion concentration of the outside environment. It is not oxygen deprivation itself that precipitates cell death, but rather without oxygen the cell can not make the ATP it needs to regulate ion concentrations and maintain homeostasis.<ref name="main"/>
Notably, even a small drop in temperature encourages cell membrane stability during periods of oxygen deprivation. For this reason, a drop in body temperature helps prevent an influx of unwanted ions during an ischemic insult. By making the cell membrane more impermeable, hypothermia helps prevent the cascade of reactions set off by oxygen deprivation. Even moderate dips in temperature strengthen the cellular membrane, helping to minimize any disruption to the cellular environment. It is by moderating the disruption of homeostasis caused by a blockage of blood flow that many now postulate, results in hypothermia's ability to minimize the trauma resultant from ischemic injuries.<ref name="main"/>
Targeted temperature management may also help to reduce reperfusion injury, damage caused by oxidative stress when the blood supply is restored to a tissue after a period of ischemia. Various inflammatory immune responses occur during reperfusion. These inflammatory responses cause increased intracranial pressure, which leads to cell injury and in some situations, cell death. Hypothermia has been shown to help moderate intracranial pressure and therefore to minimize the harmful effects of a patient's inflammatory immune responses during reperfusion. The oxidation that occurs during reperfusion also increases free radical production. Since hypothermia reduces both intracranial pressure and free radical production, this might be yet another mechanism of action for hypothermia's therapeutic effect.<ref name="main"/> Overt activation of N-methyl-D-aspartate (NMDA) receptors following brain injuries can lead to calcium entry which triggers neuronal death via the mechanisms of excitotoxicity.<ref>{{Cite journal|last1=Lau|first1=Anthony|last2=Tymianski|first2=Michael|s2cid=12421120|date=2010-07-01|title=Glutamate receptors, neurotoxicity and neurodegeneration|journal=Pflügers Archiv: European Journal of Physiology|volume=460|issue=2|pages=525–542|doi=10.1007/s00424-010-0809-1|pmid=20229265}}</ref>
==Methods== There are a number of methods through which hypothermia is induced.<ref name=PostCare2010>{{cite journal|last1=Peberdy|first1=MA|last2=Callaway|first2=CW|last3=Neumar|first3=RW|last4=Geocadin|first4=RG|last5=Zimmerman|first5=JL|last6=Donnino|first6=M|last7=Gabrielli|first7=A|last8=Silvers|first8=SM|last9=Zaritsky|first9=AL|last10=Merchant|first10=R|last11=Vanden Hoek|first11=TL|last12=Kronick|first12=SL|last13=American Heart|first13=Association|title=Part 9: post-cardiac arrest care: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care.|journal=Circulation|date=2 November 2010|volume=122|issue=18 Suppl 3|pages=S768–786|pmid=20956225|doi=10.1161/CIRCULATIONAHA.110.971002|doi-access=free}}</ref> These include: cooling catheters, cooling blankets, and application of ice applied around the body among others.<ref name=PostCare2010/><ref name=Fer2013/> As of 2013 it is unclear if one method is any better than the others.<ref name=Fer2013/> While cool intravenous fluid may be given to start the process, further methods are required to keep the person cold.<ref name=PostCare2010/>
Core body temperature must be measured (either via the esophagus, rectum, bladder in those who are producing urine, or within the pulmonary artery) to guide cooling.<ref name=PostCare2010/> A temperature below {{convert|30|C|F|abbr=on}} should be avoided, as adverse events increase significantly.<ref name=Fer2013/> The person should be kept at the goal temperature plus or minus half a degree Celsius for 24 hours.<ref name=Fer2013/> Rewarming should be done slowly with suggested speeds of {{convert|0.1|to|0.5|C-change}} per hour.<ref name=Fer2013/>
Targeted temperature management should be started as soon as possible.<ref>{{cite journal |pmid=21878875 |year=2011 |last1=Taccone |first1=FS |last2=Donadello |first2=K |last3=Beumier |first3=M |last4=Scolletta |first4=S |title=When, where and how to initiate hypothermia after adult cardiac arrest |volume=77 |issue=9 |pages=927–933 |journal=Minerva Anestesiologica}}</ref> The goal temperature should be reached before 8 hours.<ref name=Fer2013>{{cite journal|last1=Ferreira Da Silva|first1=IR|last2=Frontera|first2=JA|title=Targeted temperature management in survivors of cardiac arrest.|journal=Cardiology Clinics|date=November 2013|volume=31|issue=4|pages=637–655, ix|pmid=24188226|doi=10.1016/j.ccl.2013.07.010}}</ref> Targeted temperature management remains partially effective even when initiated as long as 6 hours after collapse.<ref name="Chill">{{cite journal |pmid=15931934 |url=http://www.modernmedicine.com/modern-medicine/news/big-chill-improving-odds-after-cardiac-arrest |title=The big chill: Improving the odds after cardiac arrest |year=2005 |last1=Calver |first1=P |last2=Braungardt |first2=T |last3=Kupchik |first3=N |last4=Jensen |first4=A |last5=Cutler |first5=C |volume=68 |issue=5 |pages=58–62; quiz 63 |journal=RN}}</ref>
Prior to the induction of targeted temperature management, pharmacological agents to control shivering must be administered. When body temperature drops below a certain threshold—typically around {{convert|36|C}}—people may begin to shiver.<ref name=Sessler/> It appears that regardless of the technique used to induce hypothermia, people begin to shiver when temperature drops below this threshold.<ref name=Sessler/> Drugs commonly used to prevent and treat shivering in targeted temperature management include acetaminophen, buspirone, opioids including pethidine (meperidine), dexmedetomidine, fentanyl, and/or propofol.<ref>{{Cite journal|title = Prevention of Shivering During Therapeutic Temperature Modulation: The Columbia Anti-Shivering Protocol|journal = Neurocritical Care|date = 2011-01-06|issn = 1541-6933|pages = 389–394|volume = 14|issue = 3|doi = 10.1007/s12028-010-9474-7|pmid = 21210305|first1 = H. Alex|last1 = Choi|first2 = Sang-Bae|last2 = Ko|first3 = Mary|last3 = Presciutti|first4 = Luis|last4 = Fernandez|first5 = Amanda M.|last5 = Carpenter|first6 = Christine|last6 = Lesch|first7 = Emily|last7 = Gilmore|first8 = Rishi|last8 = Malhotra|author9-link=Stephan A. Mayer|first9 = Stephan A.|last9 = Mayer|s2cid = 21272649}}</ref> If shivering is unable to be controlled with these drugs, patients are often placed under general anesthesia and/or are given paralytic medication like vecuronium. People should be rewarmed slowly and steadily in order to avoid harmful spikes in intracranial pressure.<ref name="Chill"/>
===Cooling catheters=== Cooling catheters are inserted into a femoral vein. Cooled saline solution is circulated through either a metal coated tube or a balloon in the catheter. The saline cools the person's whole body by lowering the temperature of a person's blood. Catheters reduce temperature at rates ranging from {{convert|1.5|to|2|C-change}} per hour. Through the use of the control unit, catheters can bring body temperature to within {{convert|0.1|C-change}} of the target level. Furthermore, catheters can raise temperature at a steady rate, which helps to avoid harmful rises in intracranial pressure. A number of studies have demonstrated that targeted temperature management via catheter is safe and effective.<ref name="DiringerMichael">{{cite journal |doi=10.1097/01.CCM.0000108868.97433.3F |title=Treatment of fever in the neurologic intensive care unit with a catheter-based heat exchange system |year=2004 |last1=Diringer |first1=Michael N. |journal=Critical Care Medicine |volume=32 |issue=2 |pages=559–564 |pmid=14758179 |author2=Neurocritical Care Fever Reduction Trial Group|s2cid=85796 }}</ref><ref name="HinzJose">{{cite journal |doi=10.1097/ANA.0b013e318032a208 |title=Effectiveness of an Intravascular Cooling Method Compared with a Conventional Cooling Technique in Neurologic Patients |year=2007 |last1=Hinz |first1=Jos?? |last2=Rosmus |first2=Martin |last3=Popov |first3=Aron |last4=Moerer |first4=Onnen |last5=Frerichs |first5=Inez |last6=Quintel |first6=Michael |s2cid=34579955 |journal=Journal of Neurosurgical Anesthesiology |volume=19 |issue=2 |pages=130–135 |pmid=17414000}}</ref><ref name="KellerEmanuela">{{cite journal |pmid=12728304 |year=2003 |last1=Keller |first1=E |last2=Imhof |first2=HG |last3=Gasser |first3=S |last4=Terzic |first4=A |last5=Yonekawa |first5=Y |s2cid=19971940 |title=Endovascular cooling with heat exchange catheters: A new method to induce and maintain hypothermia |volume=29 |issue=6 |pages=939–943 |doi=10.1007/s00134-003-1685-3 |journal=Intensive Care Medicine|url=https://www.zora.uzh.ch/id/eprint/192121/1/Manuskript_Keller_et_al.pdf }}</ref><ref>{{cite journal |doi=10.1161/01.STR.0000227265.52763.16 |title=Efficacy and Safety of Endovascular Cooling After Cardiac Arrest: Cohort Study and Bayesian Approach |year=2006 |last1=Holzer |first1=M. |last2=Müllner |first2=M. |last3=Sterz |first3=F. |last4=Robak |first4=O. |last5=Kliegel |first5=A. |last6=Losert |first6=H. |last7=Sodeck |first7=G. |last8=Uray |first8=T. |last9=Zeiner |first9=A. |last10=Laggner |first10=A. N. |journal=Stroke |volume=37 |issue=7 |pages=1792–7 |pmid=16763179|doi-access=free }}</ref><ref>{{cite journal |doi=10.1186/cc5956 |title=Efficacy of and tolerance to mild induced hypothermia after out-of-hospital cardiac arrest using an endovascular cooling system |year=2007 |last1=Pichon |first1=Nicolas |last2=Amiel |first2=Jean |last3=François |first3=Bruno |last4=Dugard |first4=Anthony |last5=Etchecopar |first5=Caroline |last6=Vignon |first6=Philippe |journal=Critical Care |volume=11 |issue=3 |pages=R71 |pmid=17598898 |pmc=2206437 |doi-access=free }}</ref>
Adverse events associated with this invasive technique include bleeding, infection, vascular puncture, and deep vein thrombosis (DVT).<ref name="ddt">{{cite journal |doi=10.1161/hs0901.095394 |title=Feasibility and Safety of Moderate Hypothermia After Massive Hemispheric Infarction |year=2001 |last1=Schwab |first1=S. |last2=Georgiadis |first2=D. |last3=Berrouschot |first3=J. |last4=Schellinger |first4=P. D. |last5=Graffagnino |first5=C. |last6=Mayer |first6=S. A. |journal=Stroke |volume=32 |issue=9 |pages=2033–2035 |pmid=11546893|doi-access=free }}</ref> Infection caused by cooling catheters is particularly harmful, as resuscitated people are highly vulnerable to the complications associated with infections.<ref name="haugk">{{cite journal |doi=10.1016/j.resuscitation.2007.03.001 |title=Feasibility and efficacy of a new non-invasive surface cooling device in post-resuscitation intensive care medicine |year=2007 |last1=Haugk |first1=Moritz |last2=Sterz |first2=Fritz |last3=Grassberger |first3=Martin |last4=Uray |first4=Thomas |last5=Kliegel |first5=Andreas |last6=Janata |first6=Andreas |last7=Richling |first7=Nina |last8=Herkner |first8=Harald |last9=Laggner |first9=Anton N. |journal=Resuscitation |volume=75 |pages=76–81 |pmid=17462808 |issue=1 }}</ref> Bleeding represents a significant danger, due to a decreased clotting threshold caused by hypothermia. The risk of deep vein thrombosis may be the most pressing medical complication.{{citation needed|date=June 2020}}
Deep vein thrombosis can be characterized as a medical event whereby a blood clot forms in a deep vein, usually the femoral vein. This condition may become potentially fatal if the clot travels to the lungs and causes a pulmonary embolism. Another potential problem with cooling catheters is the potential to block access to the femoral vein, which is a site normally used for a variety of other medical procedures, including angiography of the venous system and the right side of the heart. However, most cooling catheters are triple lumen catheters, and the majority of people post-arrest will require central venous access. Unlike non-invasive methods which can be administered by nurses, the insertion of cooling catheters must be performed by a physician fully trained and familiar with the procedure. The time delay between identifying a person who might benefit from the procedure and the arrival of an interventional radiologist or other physician to perform the insertion may minimize some of the benefit of invasive methods' more rapid cooling.{{citation needed|date=January 2014}}
===Transnasal evaporative cooling=== Transnasal evaporative cooling is a method of inducing the hypothermia process and provides a means of continuous cooling of a person throughout the early stages of targeted temperature management and during movement throughout the hospital environment. This technique uses two cannulae, inserted into a person's nasal cavity, to deliver a spray of coolant mist that evaporates directly underneath the brain and base of the skull. As blood passes through the cooling area, it reduces the temperature throughout the rest of the body.{{citation needed|date=January 2014}}
The method is compact enough to be used at the point of cardiac arrest, during ambulance transport, or within the hospital proper. It is intended to reduce rapidly the person's temperature to below {{convert|34|C|F}} while targeting the brain as the first area of cooling. Research into the device has shown cooling rates of {{convert|2.6|C-change}} per hour in the brain (measured through infrared tympanic measurement) and {{convert|1.6|C-change}} per hour for core body temperature reduction.<ref name="Missingor">{{cite journal |doi=10.1161/CIRCULATIONAHA.109.931691 |title=Intra-Arrest Transnasal Evaporative Cooling: A Randomized, Prehospital, Multicenter Study (PRINCE: Pre-ROSC IntraNasal Cooling Effectiveness) |year=2010 |last1=Castren |first1=M. |last2=Nordberg |first2=P. |last3=Svensson |first3=L. |last4=Taccone |first4=F. |last5=Vincent |first5=J.-L. |last6=Desruelles |first6=D. |last7=Eichwede |first7=F. |last8=Mols |first8=P. |last9=Schwab |first9=T. |last10=Vergnion |first10=M. |last11=Storm |first11=C. |last12=Pesenti |first12=A. |last13=Pachl |first13=J. |last14=Guérisse |first14=F. |last15=Elste |first15=T. |last16=Roessler |first16=M. |last17=Fritz |first17=H. |last18=Durnez |first18=P. |last19=Busch |first19=H.-J. |last20=Inderbitzen |first20=B. |last21=Barbut |first21=D. |journal=Circulation |volume=122 |issue=7 |pages=729–736 |pmid=20679548|doi-access=free }}</ref><ref>{{cite journal |doi=10.1016/j.resuscitation.2010.04.027 |title=Safety and feasibility of nasopharyngeal evaporative cooling in the emergency department setting in survivors of cardiac arrest |year=2010 |last1=Busch |first1=H.-J. |last2=Eichwede |first2=F. |last3=Födisch |first3=M. |last4=Taccone |first4=F.S. |last5=Wöbker |first5=G. |last6=Schwab |first6=T. |last7=Hopf |first7=H.-B. |last8=Tonner |first8=P. |last9=Hachimi-Idrissi |first9=S. |last10=Martens |first10=P. |last11=Fritz |first11=H. |last12=Bode |first12=Ch. |last13=Vincent |first13=J.-L. |last14=Inderbitzen |first14=B. |last15=Barbut |first15=D. |last16=Sterz |first16=F. |last17=Janata |first17=A. |journal=Resuscitation |volume=81 |issue=8 |pages=943–949 |pmid=20627524|url=https://dipot.ulb.ac.be/dspace/bitstream/2013/140497/1/Elsevier_123684.pdf }}</ref>
===Water blankets=== With these technologies, cold water circulates through a blanket, or torso wraparound vest and leg wraps. To lower temperature with optimal speed, 70% of a person's surface area should be covered with water blankets. The treatment represents the most well studied means of controlling body temperature. Water blankets lower a person's temperature exclusively by cooling a person's skin and accordingly require no invasive procedures.{{citation needed|date=January 2014}}
Water blankets possess several undesirable qualities. They are susceptible to leaking, which may represent an electrical hazard since they are operated in close proximity to electrically powered medical equipment.<ref name="holden">{{cite journal |pmid=16767013 |year=2006 |last1=Holden |first1=M |last2=Makic |first2=MB |s2cid=32000169 |title=Clinically induced hypothermia: Why chill your patient? |volume=17 |issue=2 |pages=125–132 |journal=AACN Advanced Critical Care |doi=10.1097/00044067-200604000-00007}}</ref> The Food and Drug Administration also has reported several cases of external cooling blankets causing significant burns to the skin of person. Other problems with external cooling include overshoot of temperature (20% of people will have overshoot), slower induction time versus internal cooling, increased compensatory response, decreased patient access, and discontinuation of cooling for invasive procedures such as the cardiac catheterization.<ref name="Clumpner">{{cite journal |pmid=18839889 |year=2008 |last1=Clumpner |first1=M |last2=Mobley |first2=J |title=Raising the dead. Prehospital hypothermia for cardiac arrest victims may improve neurological outcome and survival to discharge |volume=37 |issue=9 |pages=52–60 |journal=EMS Magazine}}</ref>
If therapy with water blankets is given along with two litres of cold intravenous saline, people can be cooled to {{convert|33|C}} in 65 minutes.{{Citation needed|date=October 2010}} Most machines now come with core temperature probes. When inserted into the rectum, the core body temperature is monitored and feedback to the machine allows changes in the water blanket to achieve the desired set temperature. In the past some of the models of cooling machines have produced an overshoot in the target temperature and cooled people to levels below {{convert|32|C}}, resulting in increased adverse events. They have also rewarmed patients at too fast a rate, leading to spikes in intracranial pressure. Some of the new models have more software that attempt to prevent this overshoot by utilizing warmer water when the target temperature is close and preventing any overshoot.{{cn|date=November 2024}} Some of the new machines now also have 3 rates of cooling and warming; a rewarming rate with one of these machines allows a patient to be rewarmed at a very slow rate of just {{convert|0.17|C-change}} an hour in the "automatic mode", allowing rewarming from {{convert|33|C}} to {{convert|37|C}} over 24 hours.{{cn|date=November 2024}}
===Cool caps=== There are a number of non-invasive head cooling caps and helmets designed to target cooling at the brain.<ref>{{cite journal |pmid=23171713 |pmc=4781040 |year=2012 |last1=Harris |first1=B |last2=Andrews |first2=PJ |last3=Murray |first3=GD |last4=Forbes |first4=J |last5=Moseley |first5=O |title=Systematic review of head cooling in adults after traumatic brain injury and stroke |volume=16 |issue=45 |pages=1–175 |doi=10.3310/hta16450 |journal=Health Technology Assessment}}</ref> A hypothermia cap is typically made of a synthetic material such as neoprene, silicone, or polyurethane and filled with a cooling agent such as ice or gel which is either cooled to a very cold temperature, {{convert|-25|to|-30|C|F}}, before application or continuously cooled by an auxiliary control unit. Their most notable uses are in preventing or reducing alopecia in chemotherapy,<ref>{{cite journal |doi=10.3109/0284186X.2012.658966 |title=Scalp cooling for hair preservation and associated characteristics in 1411 chemotherapy patients – Results of the Dutch Scalp Cooling Registry |year=2012 |last1=Van Den Hurk |first1=Corina J. |last2=Peerbooms |first2=Mijke |last3=Van De Poll-Franse |first3=Lonneke V. |last4=Nortier |first4=Johan W. |last5=Coebergh |first5=Jan Willem W. |last6=Breed |first6=Wim P. |s2cid=26709009 |journal=Acta Oncologica |volume=51 |issue=4 |pages=497–504 |pmid=22304489|hdl=1887/98452 |hdl-access=free }}</ref> and for preventing cerebral palsy in babies born with hypoxic ischemic encephalopathy.<ref>{{cite journal |last1=Jacobs |first1=Susan E |last2=Berg |first2=Marie |last3=Hunt |first3=Rod |last4=Tarnow-Mordi |first4=William O |last5=Inder |first5=Terrie E |last6=Davis |first6=Peter G |title=Cooling for newborns with hypoxic ischaemic encephalopathy |journal=Cochrane Database of Systematic Reviews |date=31 January 2013 |volume=2013 |issue=1 |article-number=CD003311 |doi=10.1002/14651858.CD003311.pub3 |pmid=23440789 |pmc=7003568 }}</ref> In the continuously cooled iteration, coolant is cooled with the aid of a compressor and pumped through the cooling cap. Circulation is regulated by means of valves and temperature sensors in the cap. If the temperature deviates or if other errors are detected, an alarm system is activated. The frozen iteration involves continuous application of caps filled with Crylon gel cooled to {{convert|-30|C}} to the scalp before, during and after intravenous chemotherapy. As the caps warm on the head, multiple cooled caps must be kept on hand and applied every 20 to 30 minutes.
==History== Hypothermia has been applied therapeutically since antiquity. The Greek physician Hippocrates, the namesake of the Hippocratic Oath, advocated the packing of wounded soldiers in snow and ice.<ref name="main">{{cite journal |doi=10.1007/s00134-003-2152-x |title=Application of therapeutic hypothermia in the ICU: Opportunities and pitfalls of a promising treatment modality. Part 1: Indications and evidence |year=2004 |last1=Polderman |first1=Kees H. |s2cid=5733761 |journal=Intensive Care Medicine |volume=30 |issue=4 |pages=556–575 |pmid=14767591}}</ref> Napoleonic surgeon Baron Dominique Jean Larrey recorded that officers who were kept closer to the fire survived less often than the minimally pampered infantrymen.<ref name="main"/> In modern times, the first medical article concerning hypothermia was published in 1945.<ref name="main"/><!-- Deleted image removed: thumb|left|Baron Dominque Larrey --> This study focused on the effects of hypothermia on patients with severe head injury. In the 1950s, hypothermia received its first medical application, being used in intracerebral aneurysm surgery to create a bloodless field.<ref name="main"/> Most of the early research focused on the applications of deep hypothermia, defined as a body temperature of {{convert|20|-|25|C|F}}. Such an extreme drop in body temperature brings with it a whole host of side effects, which made the use of deep hypothermia impractical in most clinical situations.
This period also saw sporadic investigation of more mild forms of hypothermia, with mild hypothermia being defined as a body temperature of {{convert|32|-|34|C|F}}. In the 1950s, Doctor Rosomoff demonstrated in dogs the positive effects of mild hypothermia after brain ischemia and traumatic brain injury.<ref name="main"/> In the 1980s further animal studies indicated the ability of mild hypothermia to act as a general neuroprotectant following a blockage of blood flow to the brain. This animal data was supported by two landmark human studies that were published simultaneously in 2002 by the New England Journal of Medicine.<ref name=tws06oct8878>{{cite news | author = Ron Winslow | title = How Ice Can Save Your Life | newspaper = Wall Street Journal | date = 6 October 2009 | url = https://www.wsj.com/articles/SB10001424052748703298004574455011023363866 | access-date = 6 October 2009 }}</ref> Both studies, one occurring in Europe and the other in Australia, demonstrated the positive effects of mild hypothermia applied following cardiac arrest.<ref name="HACA 2002"/> Responding to this research, in 2003 the American Heart Association (AHA) and the International Liaison Committee on Resuscitation (ILCOR) endorsed the use of targeted temperature management following cardiac arrest.<ref>{{cite journal |doi=10.1161/01.CIR.0000079019.02601.90 |title=Therapeutic Hypothermia After Cardiac Arrest: An Advisory Statement by the Advanced Life Support Task Force of the International Liaison Committee on Resuscitation |year=2003 |last1=Nolan |first1=J.P. |journal=Circulation |volume=108 |pages=118–121 |pmid=12847056 |last2=Morley |first2=PT |last3=Vanden Hoek |first3=TL |last4=Hickey |first4=RW |last5=Kloeck |first5=WG |last6=Billi |first6=J |last7=Böttiger |first7=BW |last8=Morley |first8=PT |last9=Nolan |first9=JP |last10=Okada |first10=K |last11=Reyes |first11=C |last12=Shuster |first12=M |last13=Steen |first13=PA |last14=Weil |first14=MH |last15=Wenzel |first15=V |last16=Hickey |first16=RW |last17=Carli |first17=P |last18=Vanden Hoek |first18=TL |last19=Atkins |first19=D |author20=International Liaison Committee on Resuscitation |issue=1|doi-access= }}</ref> Currently, a growing percentage of hospitals around the world incorporate the AHA/ILCOR guidelines and include hypothermic therapies in their standard package of care for patients with cardiac arrest.<ref name=tws06oct8878/> Some researchers go so far as to contend that hypothermia represents a better neuroprotectant following a blockage of blood to the brain than any known drug.<ref name="Sessler">Sessler, Daniel. "[https://books.google.com/books?id=lpETxii5bjQC&q=Thermoregulation+and+Heat+Balance&pg=PA406 Thermoregulation and Heat Balance]." Therapeutic Hypothermia. Ed. Mayer, Stephen and Sessler, Daniel. Marcel Decker: New York, 2005. '''406'''</ref> Over this same period a particularly successful research effort showed that hypothermia is a highly effective treatment when applied to newborn infants following birth asphyxia. Meta-analysis of a number of large randomised controlled trials showed that hypothermia for 72 hours started within 6 hours of birth significantly increased the chance of survival without brain damage.<ref>{{cite journal |doi=10.1136/bmj.c363 |title=Neurological outcomes at 18 months of age after moderate hypothermia for perinatal hypoxic ischaemic encephalopathy: Synthesis and meta-analysis of trial data |year=2010 |last1=Edwards |first1=A D. |last2=Brocklehurst |first2=P. |last3=Gunn |first3=A. J |last4=Halliday |first4=H. |last5=Juszczak |first5=E. |last6=Levene |first6=M. |last7=Strohm |first7=B. |last8=Thoresen |first8=M. |last9=Whitelaw |first9=A. |last10=Azzopardi |first10=D. |journal=BMJ |volume=340 |pages=c363 |pmid=20144981 |pmc=2819259}}</ref>
==Research== TTM has been studied in several use scenarios where it has not usually been found to be helpful, or is still under investigation, despite theoretical grounds for its usefulness.<ref name="pmid19535947">{{cite journal | author=Polderman KH | title=Mechanisms of action, physiological effects, and complications of hypothermia | journal=Critical Care Medicine | volume=37 | issue=7 Suppl | pages=S186–202 | year=2009 | doi = 10.1097/CCM.0b013e3181aa5241 | pmid=19535947| s2cid=6494903 }}</ref>
===Stroke=== There is currently no evidence supporting targeted temperature management use in humans for stroke and clinical trials have not been completed.<ref name="emed">{{EMedicine|article|812407|Targeted Temperature Management (Therapeutic Hypothermia)}}</ref> Most of the data concerning hypothermia's effectiveness in treating stroke is limited to animal studies. These studies have focused primarily on ischemic stroke as opposed to hemorrhagic stroke, as hypothermia is associated with a lower clotting threshold. In these animal studies, hypothermia was represented an effective neuroprotectant.<ref>{{cite journal |pmid=11486115 |year=2001 |last1=Krieger |first1=DW |last2=De Georgia |first2=MA |last3=Abou-Chebl |first3=A |last4=Andrefsky |first4=JC |last5=Sila |first5=CA |last6=Katzan |first6=IL |last7=Mayberg |first7=MR |last8=Furlan |first8=AJ |title=Cooling for acute ischemic brain damage (cool aid): An open pilot study of induced hypothermia in acute ischemic stroke |volume=32 |issue=8 |pages=1847–1854 |journal=Stroke |doi=10.1161/01.STR.32.8.1847|doi-access=free }}</ref> The use of hypothermia to control intracranial pressure (ICP) after an ischemic stroke was found to be both safe and practical.<ref>{{cite journal |id={{INIST|1604537}} |doi=10.1161/01.STR.29.12.2461 |title=Moderate Hypothermia in the Treatment of Patients with Severe Middle Cerebral Artery Infarction |year=1998 |last1=Schwab |first1=S. |last2=Schwarz |first2=S. |last3=Spranger |first3=M. |last4=Keller |first4=E. |last5=Bertram |first5=M. |last6=Hacke |first6=W. |journal=Stroke |volume=29 |issue=12 |pages=2461–2466 |pmid=9836751|doi-access=free }}</ref>
===Traumatic brain or spinal cord injury=== Animal studies have shown the benefit of targeted temperature management in traumatic central nervous system (CNS) injuries. Clinical trials have shown mixed results with regards to the optimal temperature and delay of cooling. Achieving therapeutic temperatures of {{convert|33|C|F|abbr=on}} is thought to prevent secondary neurological injuries after severe CNS trauma.<ref name="Journal of Special Operations Medicine">{{cite journal |first1=Jess |last1=Arcure |first2=Eric E |last2=Harrison |title=Review Article of the Use of Early Hypothermia in the Treatment of Traumatic Brain Injuries |journal=Journal of Special Operations Medicine |date=Summer 2009 |volume=10 |issue=3 |pages=22–25 |doi=10.55460/6EAQ-Z4AP |pmid=19739473 |s2cid=12292935 |url=http://www.socom.mil/JSOMDocs/2009322Arcure.pdf}}</ref> A systematic review of randomised controlled trials in traumatic brain injury (TBI) suggests there is no evidence that hypothermia is beneficial.<ref>{{cite journal |last1=Lewis |first1=Sharon R |last2=Evans |first2=David JW |last3=Butler |first3=Andrew R |last4=Schofield-Robinson |first4=Oliver J |last5=Alderson |first5=Phil |title=Hypothermia for traumatic brain injury |journal=Cochrane Database of Systematic Reviews |date=21 September 2017 |volume=2017 |issue=9 |article-number=CD001048 |doi=10.1002/14651858.CD001048.pub5 |pmid=28933514 |pmc=6483736 }}</ref>
===Cardiac arrest=== A clinical trial in cardiac arrest patients showed that hypothermia improved neurological outcome and reduced mortality.<ref name="HACA 2002" /> A retrospective study of the use of hypothermia for cardiac arrest patients showed favorable neurological outcome and survival.<ref name="pmid21864480">{{cite journal | vauthors=Lundbye JB, Rai M, Kluger J | title=Therapeutic hypothermia is associated with improved neurologic outcome and survival in cardiac arrest survivors of non-shockable rhythms | journal=Resuscitation | volume=83 | issue=2 | pages=202–207 | year=2012 | doi = 10.1016/j.resuscitation.2011.08.005 | pmid=21864480}}</ref> Osborn waves on electrocardiogram (ECG) are frequent during TTM after cardiac arrest, particularly in patients treated with 33 °C.<ref name=":1">{{Cite journal |last1=Hadziselimovic |first1=Edina |last2=Thomsen |first2=Jakob Hartvig |last3=Kjaergaard |first3=Jesper |last4=Køber |first4=Lars |last5=Graff |first5=Claus |last6=Pehrson |first6=Steen |last7=Nielsen |first7=Niklas |last8=Erlinge |first8=David |last9=Frydland |first9=Martin |last10=Wiberg |first10=Sebastian |last11=Hassager |first11=Christian |date=July 2018 |title=Osborn waves following out-of-hospital cardiac arrest—Effect of level of temperature management and risk of arrhythmia and death |journal=Resuscitation |volume=128 |pages=119–125 |doi=10.1016/j.resuscitation.2018.04.037 |pmid=29723608 |s2cid=19236851 |issn=0300-9572}}</ref> Osborn waves are not associated with increased risk of ventricular arrhythmia, and may be considered a benign physiological phenomenon, associated with lower mortality in univariable analyses.<ref name=":1" />
===Neurosurgery=== As of 2015 hypothermia had shown no improvements in neurological outcomes or in mortality in neurosurgery.<ref>{{cite journal | pmid = 25626888 | doi=10.1002/14651858.CD006638.pub3 | volume=1 | title=Cooling for cerebral protection during brain surgery | year=2015 | journal=Cochrane Database Syst Rev | article-number=CD006638 |vauthors=Galvin IM, Levy R, Boyd JG, Day AG, Wallace MC | issue=1 | doi-access=free | pmc=10692402 }}</ref>
=== Naegleriasis === TTM has been used in some cases of naegleriasis.<ref>{{Cite web |date=23 April 2015 |title=''Naegleria fowleri'' — Primary Amebic Meningoencephalitis (PAM) — Amebic Encephalitis |url=https://www.cdc.gov/parasites/naegleria/treatment.html |url-status=live |archive-url=https://web.archive.org/web/20150214042623/http://www.cdc.gov/parasites/naegleria/treatment.html |archive-date=14 February 2015 |access-date=17 January 2016}}</ref>
==See also== * Deep hypothermic circulatory arrest
==References== {{reflist}}
==External links== {{sister project links}} * {{usurped|1=[https://web.archive.org/web/20110723145840/http://hypothermic.net/AboutASHM/ The American Society of Hypothermic Medicine]}} * [http://www.liebertpub.com/products/product.aspx?pid=380 Therapeutic Hypothermia and Temperature Management]
==Sources== {{Free-content attribution| | title = Anatomy and Physiology | author = J. Gordon Betts ''et al'' | publisher = [https://openstax.org/ Openstax] | source= <!-- The source of the work if not from the publisher or the author --> | documentURL = https://openstax.org/details/books/anatomy-and-physiology | License statement URL = <!-- The URL of the license statement of the work if not included within the document --> | license = CC BY 4.0 |howto = }} {{Authority control}}
{{DEFAULTSORT:Therapeutic Hypothermia}} Category:Medical treatments Category:Cryobiology Category:Neonatology