Therapeutic hypothermia

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Cafer Zorkun, M.D., Ph.D. [2]; Priyamvada Singh, M.B.B.S. [3]; Ogheneochuko Ajari, MB.BS, MS [4]


Brain temperature during the first 24 hours after resuscitation from cardiac arrest has a significant effect on survival and neurological recovery. Fever (Tmax) during the first 48 hours is associated with a decreased chance of good neurological recovery (OR 2.26 [1.24, 4.12] for each 1°C over 37°C).[1] Cooling to 32-34°C for 24 hours decreases chance of death (OR 0.74 [0.58, 0.95]) and increases chance of good neurological recovery (OR 1.40 [1.08,1.81]).[2] Cooling to 32-34°C for 12 hours increases chance of good neurological recovery (OR 2.65 [1.02, 6.88]).[3]

Mechanism of Effects

  • Hypothermia activates the sympathetic nervous system causing vasoconstriction and shivering.
  • Shivering increases O2 consumption by 40-100%.
  • Sedatives, opiates, and neuromuscular blockers can counteract these responses and enhance the effectiveness of active cooling.
  • However, initiating paralysis in a patient who is already hypothermic should be avoided as it can result in a precipitous drop in core body temperature.
  • Elderly patients will cool more quickly than younger or obese patients. [4]
  • Hypothermia shifts the oxyhemoglobin curve to the left and may result in decreased O2 delivery.
  • However, the metabolic rate is also lowered, decreasing O2 consumption / CO2 production, cardiac output and cerebral blood flow.
  • Ventilator settings may need to be adjusted due to decreased CO2 production, using temperature corrected blood gases. [5]
  • Hypothermia initially causes sinus tachycardia, then bradycardia. With temp <30º C there is an increased risk for arrhythmias. With temp <28º C there is an increased risk for ventricular fibrillation. The severely hypothermic myocardium (<30°C) is less responsive to defibrillation and medications. Therefore it is extremely important to keep temp >30ºC.
  • Hypothermia can induce coagulopathy which is treatable with platelets and FFP.
  • Hypothermia-induced diuresis is to be expected and should be treated aggressively with fluid and electrolyte repletion. Magnesium, phosphorus and potassium should be monitored closely and maintained in the normal (because it will rebound to very high) range.
  • Decreased insulin secretion and sensitivity leads to hyperglycemia, which should be treated aggressively.
  • Re-warming too rapidly can cause vasodilation, hypotension, and rapid electrolyte shifts.

Eligibility Criteria for Post-Cardiac Arrest Therapeutic Hypothermia

Clinical practice guidelines by the American Heart Association state[6]

  • "We recommend TTM as opposed to no TTM for adults with OHCA with an initial shockable rhythm who remain unresponsive after ROSC (strong recommendation, low-quality evidence).
  • "We suggest TTM as opposed to no TTM for adults with OHCA with an initial nonshockable rhythm who remain unresponsive after ROSC (weak recommendation, very-low-quality evidence).
  • "We suggest TTM as opposed to no TTM for adults with IHCA with any initial rhythm who remain unresponsive after ROSC (weak recommendation, very-low-quality evidence)."

Clinical practice guidelines by the European Resuscitation Council and American Heart Association state[7]

  • "We recommend TTM as opposed to no TTM for adults with out-of-hospital cardiac arrest (OHCA) with an initial shockable rhythm who remain unresponsive after ROSC."
  • “We suggest targeted temperature management as opposed to no targeted temperature management for adults with OHCA with an initial nonshockable rhythm (weak recommendation, very low-quality evidence) who remain unresponsive after ROSC.”
  • "We suggest TTM as opposed to no TTM for adults with in-hospital cardiac arrest (IHCA) with any initial rhythm who remain unresponsive after ROSC."
  • "We recommend selecting and maintaining a constant target temperature between 32◦ C and 36◦ C for those patients in whom temperature control is used." "We suggest that if TTM is used, duration should be at least 24 hours."

Other Indications

Therapeutic hypothermia is an active area of research. Many trials are underway to see its possible benefits in conditions other than post-cardiac arrests like:

  • Traumatic brain injury: Benefits are seen in patients with elevated intra cranial pressure [8][9] and those treated with long-term hypothermia. However, studies on pediatrics population found an increase in rates of pulmonary hypertension and seizures in pediatric patients treated with therapeutic hypothermia.
  • Traumatic spinal cord injury

Therapeutic Goals

Therapeutic hypothermia is practiced in many tertiary hospitals. The treatment goals followed in most of them are:

  • Goal temperature- 32-34 degree celsius
  • Active cooling for 24 hours.
  • Rapid achievement of cooling temperature (within 3-4 hours) although one abstract reported no difference in outcomes based on a delay of more or less than 2 hours[12].
  • Rewarming
    • Slow rewarming (may take 8-10 hours) is preferred over rapid rewarming as the latter may cause dilatation of the vessel and result in hypotension.
    • It can be achieved by discontinuation of methods used for cooling like cooling blankets, ice and drugs.
    • Continuous blood pressure monitoring should be done to avoid the development of hypotension.
    • It should be started 24 hours after the time of initiation of cooling.
    • Slow rewarming @ 0.3-0.5ºC/hr
    • Target rewarming temperature 36°C


For contraindications[7]:

  • Meets eligibility criteria for Post-Cardiac Arrest Care Pathway
  • Comatose at enrollment with a Glasgow Coma Motor Score <6 pre-sedation (i.e., patient doesn’t follow commands)
  • No other obvious reasons for coma
  • No uncontrolled bleeding
  • Hemodynamically stable with no evidence of:
  • Uncontrollable dysrhythmias
  • Severe cardiogenic shock
  • Refractory hypotension (MAP <60 mm Hg) despite preload optimization and use of vasoactive medications
  • No existing, multi-organ dysfunction syndrome, severe sepsis, or comorbidities with minimal chance of meaningful survival independent of neurological status

The following have been proposed, but the origin of these statements is not known:

  • Prolonged arrest time (> 60 minutes)
  • Thrombocytopenia or other coagulopathies (hypothermia may impair the clotting factors)
  • Pregnancy (Therapeutic hypothermia can potentially be performed on pregnant female in consultation with OB/Gyn)
  • Major surgery within 14 days (it may increase risk of infections and bleeding in this group of patients)
  • Sepsis and other systemic infections (decreased immune function due to hypothermia)
  • Coma from other causes like drug intoxication
  • Patients who have signed a 'Do not resuscitate' (DNR)

Cooling Techniques

Surface Cooling with Ice Packs

  • Head, neck, axilla, and groin are preferred sites (these areas have good heat exchange)
  • Advantage - Inexpensive
  • Disadvantages
    • Difficulties in achieving and maintaining rapid rates of cooling
    • Variable and unpredictable rates of cooling

Blankets or Surface Heat-Exchange Device and Ice

  • During cooling phases blankets, the cooling device's (heat-exchange pads) and ice packs are applied. Ice packs are removed once target temperature is achieved. The temperature is maintained with blanket or heat exchange pads.
  • Disadvantages
    • Difficulties in achieving and maintaining rapid rates of cooling
    • Variable and unpredictable rates of cooling

Surface Cooling Helmet

  • The helmet has a solution of aqueous glycerol that helps in achieving hypothermia.
  • Disadvantage - Slow, unpredictable attainment of target temperature

Transnasal evaporative cooling

Devices available: Rhinochill.

Advantages: rapid pre-hospital cooling, operates independently of power supply

The PRINCE trial showed decreased time to target temperature compared to control; however, the study was not adequately powered to assess neurologic outcomes and overall survival[13].

Catheter Based Internal Cooling Methods / Endovascular Heat-Exchange Catheters

  • Devices available: Celsius Control System and Cool Line System
  • Placed in femoral vein
  • Advantages
    • Both endovascular cooling and rewarming are faster
    • Good at maintaining target temperature
    • Low rates of complications
    • Minimization of shivering
    • Decreased need for chemical paralysis

Infusion of Cold Fluids

  • Achieved by infusion of normal saline or lactated Ringer solution
  • Advantage - rapid cooling
  • Disadvantage - rate of cooling is unpredictable
  • No increased risks of pulmonary edema, cardiac arrhythmias or other major complications were found.[14][15]

Arctic Sun medical device

The Arctic Sun Temperature Management System is a non-invasive Targeted Temperature Management System medical device used to modulate patient temperature with precision by circulating chilled water in pads directly adhered to the patient's skin. Using varying water temperatures and a sophisticated computer algorithm, a patient's body temperature can be controlled within 0.2°C. The Arctic Sun Temperature Management System is produced by Medivance, Inc. of Louisville, Colorado.

The Arctic Sun has been explained as dry water immersion. It is a non-invasive precision temperature management system that is often used to induce hypothermia in comatose patients that have suffered from Sudden Cardiac Arrest (SCA) and patients at risk for ischemic brain damage. The unique thing about the Arctic Sun is the gel pads, which stick to a patient’s body using an adhesive called hydrogel—a substance that adheres to the skin without removing hair follicles. The gel pads cover only a portion of a patient’s body and subsequently leave most of the body free for augmenting medical procedures. The device operates under negative pressure and circulates water through these pads at a temperature between 4–42 °C (39–108 °F). Water is pulled through the pads, which minimizes the risk of leakage. By controlling the temperature of the water running through the gel pads, the Arctic Sun’s adjusts a patient’s temperature. Arctic Sun can also rewarm patients. Controlled rewarming has been cited in the literature as beneficial in preventing reperfusion injury. Because of the Arctic Sun’s noninvasive nature, treatment can be delivered without the host of adverse events associated with invasive procedures such as cooling catheters.[16]

A fomer complaint levied against the Arctic Sun relates to the risk of skin injury. a study published in 2007 found that the Arctic Sun was, "highly effective in lowering patients’ temperature rapidly without inducing skin irritations.[17]. Further, when comparing MDR's registed by Medivance vs the cooling catheters and conventional cooling blankets and wraps, one will find far fewere incidence of patient injury.

Invasive cooling catheter companies have claimed that catheters can lower body temperature at a faster rate, which is relevant because most of the clinical data suggests that the sooner cooling initiates the better a patient’s outcome. However, there exists a 75 minute delay on average between admittance and catheter insertion. Even with a physician readily available to place the cooling catheter, the operating instructions underline the importance of the device set up with takes a minimum of 25 minutes. When objectively evaluating the published data the average cooling rate for cooling catheters is 1.12°C. Treatment with the Arctic Sun can be administered within 10 minutes by unsupervised nursing professionals.

Historically, clinicians reported that catheters cool at a quicker rate, however, a 2011 study published in the Society of Critical Care Medicine where 167 patients treated either with the Arctic Sun or the Alsius Coolgard Cather showed the following:

There was no significant difference in survival with good neurologic function, either to hospital discharge or at follow-up. Time from cardiac arrest to achieving mild therapeutic hypothermia was equal with both devices (surface, 273 min, core, 270 min).”

  • Cooling was initiated immediately in the emergency department on hospital arrival with ice packs around groin, armpits and neck and infusion of up to 3 L of refrigerated saline
  • All patients were “deeply sedated”
  • No device-specific patient injuries were observed; skin injuries with the Arctic Sun or DVT with Coolgard
  • No differences in shivering: “
  • Article quote: ”Skin temperature is known to influence thermoregulatory control, and it previously has been speculated that core cooling could result in less shivering.

However, this could not be confirmed in the present study, because there was no difference in the rate of shivering in surface-cooled or core-cooled patients.”

  • No differences were observed in Lengths of ICU stay, durations of respirator dependency, rates of MTH discontinuation, and post cooling

Conclusions: “Surface and core cooling of out-of hospital cardiac arrest patients following the same established postresuscitation treatment protocol resulted in similar survival to hospital discharge and comparable neurologic function at follow-up.”[18]

In a case attracting much media attention in May 2008, the Arctic Sun was used to induce hypothermia in a 59 year old woman in West Virginia who had suffered 3 cardiac arrests within a 24 hour period. For more than 17 hours the woman had no measurable brain waves, according to her doctors, and her heart had been stopped for a prolonged period of time. The family decided to take her off life support. Shortly after being disconnected from the ventilator, the woman surprisingly recovered, regaining consciousness, motor function, and speech.[19][20]


Delaying coronary intervention till after neurologic recovery is not harmful according to the COACT trial[21]

Barriers to usage

Although clinical practice guidelines[6] do not list contraindications, the CRICS-TRIGGERSEP randomized controlled trial[22] listed inclusion criteria:

  • No-flow time (from collapse to initiation of cardiopulmonary resuscitation [CPR]) of more than 10 minutes
  • Low-flow time (from initiation of CPR to return of spontaneous circulation) of more than 60 minutes
  • Major hemodynamic instability (continuous epinephrine or norepinephrine infusion >1 μg per kilogram of body weight per minute)
  • Time from cardiac arrest to screening of more than 300 minutes
  • Moribund condition
  • Child–Pugh class C cirrhosis of the liver (severe hepatic dysfunction)
  • Pregnancy or breast-feeding
  • Decision by the next of kin for the patient not to participate

Targeted Temperature Management may be underused[23][24][25][26]:

Evidence of effectiveness

Clinical practice guidelines summarize management for adults[6][27] and children[28].

A systematic review by the Cochrane Collaboration suggests benefit.[29] A second systematic review[30] and the more recent CRICS-TRIGGERSEP randomized controlled trial[22] focusing on survivors of non-shockable rhythms suggests benefit.

A systematic review of pre-hospital TTM found no improvement in neurological survival[31]

A more recent, living systematic review suggests benefit for in-hospital TTM[32].

See also


  1. Zeiner A, Holzer M, Sterz F, et al. Hyperthermia after cardiac arrest is associated with an unfavorable neurologic outcome. Arch Intern Med. Sep 10 2001;161(16):2007-2012.
  2. Hypothermia after Cardiac Arrest Study G. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest.[see comment][erratum appears in N Engl J Med 2002 May 30;346(22):1756]. New England Journal of Medicine. Feb 21 2002;346(8): 549-556.
  3. Bernard SA, Gray TW, Buist MD, et al. Treatment of comatose survivors of out-ofhospital cardiac arrest with induced hypothermia.[see comment]. New England Journal of Medicine. Feb 21 2002;346(8):557-563.
  4. Sunde K, Pytte M, Jacobsen D, Mangschau A, Jensen LP, Smedsrud C, et al. Implementation of a standardised treatment protocol for post resuscitation care after out-of-hospital cardiac arrest. Resuscitation 2007;73:29-39
  5. Kim F, Olsufka M, Longstreth WT Jr, Maynard C, Carlbom D, Deem S, et al. Pilot randomized clinical trial of prehospital induction of mild hypothermia in out-of-hospital cardiac arrest patients with a rapid infusion of 4 degrees C normal saline. Circulation 2007;115:3064-70
  6. 6.0 6.1 6.2 Donnino MW, Andersen LW, Berg KM, Reynolds JC, Nolan JP, Morley PT; et al. (2015). "Temperature Management After Cardiac Arrest: An Advisory Statement by the Advanced Life Support Task Force of the International Liaison Committee on Resuscitation and the American Heart Association Emergency Cardiovascular Care Committee and the Council on Cardiopulmonary, Critical Care, Perioperative and Resuscitation". Circulation. 132 (25): 2448–56. doi:10.1161/CIR.0000000000000313. PMID 26434495.
  7. 7.0 7.1 Soar J, Callaway CW, Aibiki M, Böttiger BW, Brooks SC, Deakin CD; et al. (2015). "Part 4: Advanced life support: 2015 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science with Treatment Recommendations". Resuscitation. 95: e71–120. doi:10.1016/j.resuscitation.2015.07.042. PMID 26477429.
  8. Booth CM, Boone RH, Tomlinson G, Detsky AS (2004). "Is this patient dead, vegetative, or severely neurologically impaired? Assessing outcome for comatose survivors of cardiac arrest". JAMA. 291 (7): 870–9. doi:10.1001/jama.291.7.870. PMID 14970067. Review in: ACP J Club. 2004 Sep-Oct;141(2):49
  9. Jiang JY, Xu W, Li WP, Gao GY, Bao YH, Liang YM; et al. (2006). "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 (6): 771–6. doi:10.1038/sj.jcbfm.9600253. PMID 16306933.
  10. Kammersgaard LP, Rasmussen BH, Jørgensen HS, Reith J, Weber U, Olsen TS (2000). "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 (9): 2251–6. PMID 10978060.
  11. 11.0 11.1 Nolan JP, Deakin CD, Soar J, Böttiger BW, Smith G, European Resuscitation Council (2005). "European Resuscitation Council guidelines for resuscitation 2005. Section 4. Adult advanced life support". Resuscitation. 67 Suppl 1: S39–86. doi:10.1016/j.resuscitation.2005.10.009. PMID 16321716.
  12. Chaaban, Said; Kallail, K James; Parry, Colin; Gosnell, Dawn; Donaldson, Melissa; Youngman, Darrell (2013). "Early Vs Late Initiation of Induced Hypothermia: Is There Any Benefit?". Chest. 144 (4): 360A. doi:10.1378/chest.1702869. ISSN 0012-3692.
  13. Castrén M, Nordberg P, Svensson L, Taccone F, Vincent JL, Desruelles D; et al. (2010). "Intra-arrest transnasal evaporative cooling: a randomized, prehospital, multicenter study (PRINCE: Pre-ROSC IntraNasal Cooling Effectiveness)". Circulation. 122 (7): 729–36. doi:10.1161/CIRCULATIONAHA.109.931691. PMID 20679548.
  14. Kim F, Olsufka M, Longstreth WT, Maynard C, Carlbom D, Deem S; et al. (2007). "Pilot randomized clinical trial of prehospital induction of mild hypothermia in out-of-hospital cardiac arrest patients with a rapid infusion of 4 degrees C normal saline". Circulation. 115 (24): 3064–70. doi:10.1161/CIRCULATIONAHA.106.655480. PMID 17548731.
  15. Bernard S, Buist M, Monteiro O, Smith K (2003). "Induced hypothermia using large volume, ice-cold intravenous fluid in comatose survivors of out-of-hospital cardiac arrest: a preliminary report". Resuscitation. 56 (1): 9–13. PMID 12505732.
  17. Haugk, Moritz et al. “Feasibility and efficacy of new non-invasive cooling device in post resuscitation intensive care medicine.” Resuscitation (2007 75, 76-81.
  18. Crit Care Med Vol 39 No 3
  19. Stone, Gigi, Tracey Marx, Stephanie Dahle (24 May 2008). "Doctor Calls Near-Death Experience a 'Miracle': Hospital Took Velma Thomas off Life Support – Then She Woke Up". Retrieved 27 June 2009.
  20. Pettit, Zack (20 May 2008). "Son making funeral plans gets call that mom's alive: New apparatus helped stave off brain injury". Charleston Daily Mail. Retrieved 27 June 2009.
  21. Lemkes JS, Janssens GN, van der Hoeven NW, Jewbali LSD, Dubois EA, Meuwissen M; et al. (2019). "Coronary Angiography after Cardiac Arrest without ST-Segment Elevation". N Engl J Med. 380 (15): 1397–1407. doi:10.1056/NEJMoa1816897. PMID 30883057. Review in: Ann Intern Med. 2019 Jul 16;171(2):JC4
  22. 22.0 22.1 Lascarrou JB, Merdji H, Le Gouge A, Colin G, Grillet G, Girardie P; et al. (2019). "Targeted Temperature Management for Cardiac Arrest with Nonshockable Rhythm". N Engl J Med. 381 (24): 2327–2337. doi:10.1056/NEJMoa1906661. PMID 31577396.
  23. Bradley SM, Liu W, McNally B, Vellano K, Henry TD, Mooney MR; et al. (2018). "Temporal Trends in the Use of Therapeutic Hypothermia for Out-of-Hospital Cardiac Arrest". JAMA Netw Open. 1 (7): e184511. doi:10.1001/jamanetworkopen.2018.4511. PMC 6324404. PMID 30646357.
  24. 24.0 24.1 Khera R, Humbert A, Leroux B, Nichol G, Kudenchuk P, Scales D; et al. (2018). "Hospital Variation in the Utilization and Implementation of Targeted Temperature Management in Out-of-Hospital Cardiac Arrest". Circ Cardiovasc Qual Outcomes. 11 (11): e004829. doi:10.1161/CIRCOUTCOMES.118.004829. PMID 30571336.
  25. Brooks SC, Morrison LJ (2008). "Implementation of therapeutic hypothermia guidelines for post-cardiac arrest syndrome at a glacial pace: seeking guidance from the knowledge translation literature". Resuscitation. 77 (3): 286–92. doi:10.1016/j.resuscitation.2008.01.017. PMID 18329157.
  26. Boyce R, Bures K, Czamanski J, Mitchell M (2012). "Adherence to therapeutic hypothermia guidelines for out-of-hospital cardiac arrest". Aust Crit Care. 25 (3): 170–7. doi:10.1016/j.aucc.2012.02.006. PMID 22459557.
  27. ECC Committee, Subcommittees and Task Forces of the American Heart Association (2005). "2005 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care". Circulation. 112 (24 Suppl): IV1–203. doi:10.1161/CIRCULATIONAHA.105.166550. PMID 16314375.
  28. Duff JP, Topjian AA, Berg MD, Chan M, Haskell SE, Joyner BL; et al. (2020). "2019 American Heart Association Focused Update on Pediatric Advanced Life Support: An Update to the American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care". Pediatrics. 145 (1). doi:10.1542/peds.2019-1361. PMID 31727859.
  29. Arrich J, Holzer M, Havel C, Müllner M, Herkner H (2012). "Hypothermia for neuroprotection in adults after cardiopulmonary resuscitation". Cochrane Database Syst Rev. 9: CD004128. doi:10.1002/14651858.CD004128.pub3. PMID 22972067.
  30. Kim YM, Yim HW, Jeong SH, Klem ML, Callaway CW (2012). "Does therapeutic hypothermia benefit adult cardiac arrest patients presenting with non-shockable initial rhythms?: A systematic review and meta-analysis of randomized and non-randomized studies". Resuscitation. 83 (2): 188–96. doi:10.1016/j.resuscitation.2011.07.031. PMID 21835145.
  31. Szarpak L, Filipiak KJ, Mosteller L, Jaguszewski M, Smereka J, Ruetzler K; et al. (2020). "Survival, neurological and safety outcomes after out of hospital cardiac arrests treated by using prehospital therapeutic hypothermia: A systematic review and meta-analysis". Am J Emerg Med. doi:10.1016/j.ajem.2020.02.019. PMID 32088060 Check |pmid= value (help).
  32. GitHub Contributors. Cardiac arrest survivors treated with therapeutic hypothermia: a living systematic review. GitHub. Available at Accessed February 25, 2020

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