For This Reason, Caution Must Be Exercised with Regard to Determining Prognosis in the Setting of Therapeutic Hypothermia
Clinical Efficacy
Hypothermia After Cardiac Arrest Study Group (HACA) Trial (NEJM, 2002) [MEDLINE]
Therapeutic Hypothermia (32-34°C) Improved Neurologic Outcome After Cardiac Arrest Due to Ventricular Fibrillation
Trial of Therapeutic Hypothermia in Comatose Survivors of Out-of-Hospital Cardiac Arrest (NEJM, 2002) [MEDLINE]
Therapeutic Hypothermia (33°C) Improved Neurologic Outcome After Cardiac Arrest
Hypothermia was Associated with a lower cardiac index, higher systemic vascular resistance, and hyperglycemia
TTM Trial of Therapeutic Hypothermia (33°C versus 36°C) After Out-of-Hospital Cardiac Arrest (NEJM, 2013) [MEDLINE]
Hypothermia to 33°C Did Not Confer a Benefit, as Compared with Hypothermia to 36°C
Pre-Hospital Mild Hypothermia After Cardiac Arrest (JAMA, 2014) [MEDLINE]: pre-hospital cooling reduced core temperature by hospital arrival and reduced the time to reach a temperature of 34°C, but it did not improve survival or neurological outcome
Pre-Hospital Mild Hypothermia After Cardiac Arrest (J Am Heart Assoc, 2015) [MEDLINE]
Pre-Hospital Hypothermia Did Not Improve Neurological Outcome or 1‐year Mortality Rate
Systematic Review of Pre-Hospital Versus In-Hospital Therapeutic Hypothermia After Out-of-Hospital Cardiac Arrest (Cochrane Database Syst Rev, 2016) [MEDLINE]
No Convincing Evidence to Delineate Beneficial or Harmful Effects of Pre-Hospital Induction of Cooling, as Compared to In-Hospital Induction of Cooling (Based on Low Quality Data)
Systematic Review of Therapeutic Hypothermia After Cardiac Arrest (Cochrane Database Syst Rev, 2016) [MEDLINE]
Therapeutic Hypothermia Improves Neurologic Outcome After Cardiac Arrest (Based on Moderate Quality Evidence)
Insufficient Evidence to Demonstrate the Effects of Therapeutic Hypothermia with In-Hospital Cardiac Arrest, Asystole, Non-Cardiac Causes of Arrest
Observational Study of the Effect of Therapeutic Hypothermia on Survival After In-Hospital Cardiac Arrest (JAMA, 2016) [MEDLINE]
After In-Hospital Cardiac Arrest, Therapeutic Hypothermia Decreased Survival to Hospital Discharge and Decreased Likelihood of Favorable Neurologic Outcome
Temperature Data was Only Available for 23.9% of Hypothermia Group and 16.3% of Non-Hypothermia Group
Median Lowest Temperature in Hypothermia Group: 33.1 C (Interquartile Range: 32.3-35.7 C)
Approximately 20.9% of Patients were Below the Recommended Nadir of 32 C in the Hypothermia Group
Median Lowest Temperature in Non-Hypothermia Group: 36.3 (Interquartile Range: 35.6-36.8 C)
Randomized Trial is Warranted to Confirm These Findings
French Open Label, Randomized HYPERION Trial of Targeted Temperature Management Following In-Hospital Cardiac Arrest with a Non-Shockable Rhythm (NEJM, 2019) [MEDLINE]: n = 584 (25 ICU’s)
Among Patients with Coma Who Had Been Resuscitated from Cardiac Arrest with a Non-Shockable Rhythm, Moderate Therapeutic Hypothermia at 33°C for 24 hrs Led to a Higher Percentage of Patients Who Survived with a Favorable Neurologic Outcome at Day 90 than was Observed with Targeted Normothermia
TTM-2 Randomized Open-Label Trial (with Blinded Outcomes) of Therapeutic Hypothermia Following Adult Out-of-Hospital Cardiac Arrest (NEJM, 2021) [MEDLINE]: n = 1,850
6-Month Mortality Rate was Not Statistically Significantly Different Between the Therapeutic Hypothermia Group (33°C) and the Normothermia Group (with Early Treatment of Fever for Body Temperature ≥37.8°C) (Relative Risk with Hypothermia 1.04; 95% CI: 0.94 to 1.14; P = 0.37)
In the Hypothermia Group, 55% Had Moderately Severe Disability or Worse (Modified Rankin Scale Score ≥4), as Compared to 55% in the Normothermia Group (Relative Risk with Hypothermia 1.00; 95% CI: 0.92 to 1.09)
Arrhythmia Resulting in Hemodynamic Compromise was More Common in the Hypothermia Group, as Compared to the Normothermia Group (24% vs 17%, P<0.001) -Incidence of Other Adverse Events Did Not Differ Significantly Between the Groups
Canadian Single-Center CAPITAL CHILL Randomized Trial of Therapeutic Hypothermia (31°C vs 34°C) in Comatose Survivors of Out-of-Hospital Cardiac Arrest (JAMA, 2021) [MEDLINE]: n = 367
In Comatose Survivors of Out-of-Hospital cardiac Arrest, a Target Temperature of 31°C Did Not Significantly Decrease the Mortality Rate or Poor Neurologic Outcome at 180 Days, as Compared with a Target Temperature of 34°C
Study May Have Been Underpowered to Detect a Clinically Important Difference
Post-Hoc Analysis of HYPERION Trial of Targeted Temperature Management Following In-Hospital Cardiac Arrest with a Non-Shockable Rhythm (Chest, 2022) [MEDLINE]
As Compared with Targeted Normothermia for 48 hrs, Therapeutic Hypothermia at 33°C for 24 hrs was Associated with a Higher Percentage of Patients Who were Alive with Good Neurologic Outcomes at Day 90 (16.4% vs 5.8%; P = 0.03)
Day 90 Mortality was Not Significantly Different Between the Groups (68.5% vs 76.7%; P = 0.24)
By Mixed Multivariate Analysis Adjusted by Cardiac Arrest Hospital Prognosis Score and Circulatory Shock Status, Therapeutic Hypothermia was Associated Significantly with Good Day 90 Neurologic Outcomes (Odds Ratio 2.40; 95% CI: 1.17-13.03; P = 0.03)
Post-Hoc Analysis of TTM-2 Trial for Adult Out-of-Hospital Cardiac Arrest (Crit Care, 2022) [MEDLINE]
Therapeutic Hypothermia to 33°C Following Out-of-Hospital Cardiac Arrest, as Compared to Normothermia, was Not Associated with a Higher Mortality Rate in Patients Stratified According to Vasopressor Support on Admission
Recommendations (2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care) [MEDLINE]
Therapeutic Hypothermia is Recommended (Between 32-36°C) for At Least 24 hrs for Comatose Adult Patients with Return of Spontaneous Circulation After Cardiac Arrest (Including In-Hospital Cardiac Arrest)
The temperature sensitivity of the brain after cardiac arrest may persist as long as the brain dysfunction (coma) is present: consequently, the upper limit time duration for temperature management is unknown
Similar recommendation was provided from the 2015 Recommendations from the International Liaison Committee on Resuscitation (ILCOR)
Pre-Hospital Hypothermia with Rapid Infusion of Cold Intravenous Fluids is Not Recommended: no evidence supporting clinical benefit
Cochrane Database Systematic Review (Cochrane Database Syst Rev, 2009) [MEDLINE]: therapeutic hypothermia may be effective in reducing death and unfavourable outcomes for traumatic head injured patients, but significant benefit was found only in the low quality trials -> therapeutic hypothermia is not recommended in traumatic brain injury
Systematic Review (CJEM, 2010) [MEDLINE]: prophylactic mild-to-moderate therapeutic hypothermia (32-34°C) in traumatic brain injury (Glasgow coma scale score < or = 8) decreased mortality and improved rates of good neurologic recovery
Maximal benefit occurred with cooling continued for at least 72 hours and/or until stable normalization of intracranial pressure for at least 24 hrs
National Acute Brain Injury Study: Hypothermia II Trial (Lancet, 2011) [MEDLINE]: therapeutic hypothermia to 33°C or 35°C (in patients enrolled within 2.5 hrs of injury) had no clinical benefit in terms of Glasgow outcome scale score at 6 mo
Greater benefit from therapeutic hypothermia was observed in patients undergoing surgical removal of hematomas, as compared with those with diffuse axonal/brain injury
Systematic Review of Therapeutic Hypothermia in Traumatic Brain Injury (Brain Injury, 2012) [MEDLINE]: therapeutic hypothermia decreased intracranial pressure
Recommendations (Guidelines for the Management of Severe Traumatic Brain Injury, 2007) [MEDLINE]
Prophylactic Therapeutic Hypothermia is Not Associated with Decreased Mortality in Traumatic Brain Injury (When Compared to Normothermic Controls) (Level III Recommendation)
However, When Maintained for >48 hrs, Mortality May Be Decreased
Prophylactic Therapeutic Hypothermia is Associated with Significantly Higher GCS Scores (When Compared to Normothermic Controls)
Recommendations
Therapeutic Hypothermia Has Unclear Clinical Benefit in TBI: however, may be considered in patients with refractory elevations in intracranial pressure (despite other therapies)
Contraindications
General Comments
Pregnancy and Hemodynamic Instability are Not Considered Specific Contraindications to Therapeutic Hypothermia
Active Non-Compressible Hemorrhage: although temperature management to 36°C or below in this population may still be attempted
Systematic Review and Meta-Analysis of the Impact of Therapeutic Hypothermia on the Risk of Hemorrhage (Medicine, 2015) [MEDLINE]
Therapeutic Hypothermia was Not Associated with an Increased Risk of Hemorrhage, Despite Increased Risk of Thrombocytopenia and Increased Transfusion Requirements
However, Prolonged Duration of Cooling May Be Associated with an Increased Risk of Hemorrhage
Advanced Directive Stating No Desire for Aggressive Care
Physiology
Physiologic Effects of Therapeutic Hypothermia
Cardiovascular
Decreaased Heart Rate
Decreased Infarct Size with Cardiac Arrest or Acute Myocardial Infarction
Increased Myocardial Salvage: with use of therapeutic hypothermia before revascularization in STEMI
Increased Systemic Vascular Resistance (SVR)
Neurologic
Decreased Cerebral Oxygen Demand
Decreased Formation of Reactive Oxygen Species in Brain
Direct Cellular Effects on Brain
Technique
Arctic Sun Device
Endovascular Cooling Catheters: more accurate and reliable at maintaining target temperature than other methods
Zoll Icy Catheter: combines a triple-lumen central venous catheter with an endovascular cooling catheter
Gaymar Medi-Therm II
Surface Cooling with Cooling Blankets/Ice Packs
Transnasal Evaporation: novel method which may be used during cardiac arrest
Adverse Effects/Complications During Cooling
Cardiovascular Adverse Effects
Arrhythmias
Physiology
Due to Hypothermia-Associated Slowed Cardiac Conduction
Ventricular Arrhythmias (May Occur at Body Temperature <30°C)
Decreased Cardiac Output
Physiology
Hypothermia Impairs Cardiac Contraction and Prolongs the Subphases of the Cardiac Cycle to Varying Degrees (Arctic Med Res, 1991) [MEDLINE]
Diagnosis
Single-Center Study of Cardiac Output Measurement (Using Doppler Echocardiography vs Thermodilution Cardiac Output Via Swan-Ganz Catheter) During Therapeutic Hypothermia for Out-of-Hospital Cardiac Arrest (Ther Hypothermia Temp Manag, 2021) [MEDLINE]: n = 141
Average Cardiac Output was 5.28 ± 1.94 L/min Measured by Thermodilution and 4.06 ± 1.49 L/min Measured by Doppler with a Mean Bias of 1.22 L/min (Limits of Agreements -1.92 to 4.36 L/min)
Correlation Between Methods was Moderate (R2 = 0.36)
Using Thermodilution as the Gold Standard, Positive Predictive Value of a Low Cardiac Output Measurement (<3.5 L/min) by Doppler was 33% and the Negative Predictive Value was 92%
In ventilated Out-of-Hospital Cardiac Arrest Patients, the Two Methods Correlated Moderately and There was a Consistent Underestimation of Doppler Cardiac Output
Absolute Doppler Cardiac Output Values Should Be Interpreted with Caution
However, Doppler Can Be Used to Exclude Low Cardiac Output with High Accuracy
Therapeutic Hypothermia at 33°C Did Not Negatively Affect the Correlation or Bias of Cardiac Output Measurements
Peripheral Vasoconstriction
Physiology
Initial Cooling Shunts Blood Toward the Core, Resulting in a Subsequent “Cold Diuresis” (See Below)
Systematic Review and Meta-Analysis of the Impact of Therapeutic Hypothermia on the Risk of Hemorrhage (Medicine, 2015) [MEDLINE]
Therapeutic Hypothermia was Not Associated with an Increased Risk of Hemorrhage, Despite Increased Risk of Thrombocytopenia and Increased Transfusion Requirements
However, Prolonged Duration of Cooling May Be Associated with an Increased Risk of Hemorrhage
Physiology
Impairment of Both Clotting Factor and Platelet Function Below 35°C
Serum potassium levels during prolonged hypothermia. Intensive Care Med. 1983;9(5):275-7 [MEDLINE]
Mild therapeutic hypothermia in cardiogenic shock syndrome. Crit Care Med. 2012 Jun;40(6):1715-23. doi: 10.1097/CCM.0b013e318246b820 [MEDLINE]
Therapeutic Hypothermia and the Risk of Hemorrhage: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Medicine (Baltimore). 2015 Nov;94(47):e2152. doi: 10.1097/MD.0000000000002152 [MEDLINE]
Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med 2002;346:557–63 [MEDLINE]
Hypothermia after Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med 2002;346: 549–56 [MEDLINE]
Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. Hypothermia after Cardiac Arrest Study Group. N Engl J Med. 2002;346(8):549 [MEDLINE]
Therapeutic hypothermia after cardiac arrest. N Engl J Med 2002;346:612 [MEDLINE]
From evidence to clinical practice: Effective implementation of therapeutic hypothermia to improve patient outcome after cardiac arrest. Crit Care Med 2006;34:1865 [MEDLINE]
Induced hypothermia and fever control for prevention and treatment of neurological injuries. Lancet 2008;371:1955 [MEDLINE]
Early goal-directed hemodynamic optimization combined with therapeutic hypothermia in comatose survivors of out-of-hospital cardiac arrest. Resuscitation. 2009;80:418-424 [MEDLINE]
Outcome, timing and adverse events in therapeutic hypothermia after out-of-hospital cardiac arrest. Acta Anaesthesiol Scand. 2009;53(7):926 [MEDLINE]
Targeted temperature management for comatose survivors of cardiac arrest. N Engl J Med. 2010 Sep 23;363(13):1256-64. doi: 10.1056/NEJMct1002402 [MEDLINE]
TTM Trial. Targeted temperature management at 33°C versus 36°C after cardiac arrest. N Engl J Med. 2013 Dec 5;369(23):2197-206. doi: 10.1056/NEJMoa1310519. Epub 2013 Nov 17 [MEDLINE]
Temperature management and modern post-cardiac arrest care. N Engl J Med. 2013;369:2262–2263 [MEDLINE]
Effect of prehospital induction of mild hypothermia on survival and neurological status among adults with cardiac arrest: a randomized clinical trial. JAMA. 2014 Jan 1;311(1):45-52. doi: 10.1001/jama.2013.282173 [MEDLINE]
Effect of prehospital induction of mild hypothermia on 3-month neurological status and 1-year survival among adults with cardiac arrest: long-term follow-up of a randomized, clinical trial. J Am Heart Assoc. 2015 Mar 11;4(3):e001693. doi: 10.1161/JAHA.114.001693 [MEDLINE]
Cardiac arrest and therapeutic hypothermia. Trends Cardiovasc Med. 2015 Oct 22. pii: S1050-1738(15)00240-6. doi: 10.1016/j.tcm.2015.10.002 [MEDLINE]
Pre-hospital versus in-hospital initiation of cooling for survival and neuroprotection after out-of-hospital cardiac arrest. Cochrane Database Syst Rev. 2016 Mar 15;3:CD010570 [MEDLINE]
Hypothermia for neuroprotection in adults after cardiopulmonary resuscitation. Cochrane Database Syst Rev. 2016 Feb 15;2:CD004128. doi: 10.1002/14651858.CD004128.pub4 [MEDLINE]
Association between therapeutic hypothermia and long-term quality of life in survivors of cardiac arrest: A systematic review. Resuscitation. 2016 Jun;103:54-9. doi: 10.1016/j.resuscitation.2016.03.024. Epub 2016 Apr 7 [MEDLINE]
Association Between Therapeutic Hypothermia and Survival After In-Hospital Cardiac Arrest. JAMA. 2016 Oct 4;316(13):1375-1382. doi: 10.1001/jama.2016.14380 [MEDLINE]
HYPERION Trial. Targeted Temperature Management for Cardiac Arrest With Nonshockable Rhythm. N Engl J Med. 2019 Dec 12;381(24):2327-2337. doi: 10.1056/NEJMoa1906661 [MEDLINE]
TTM2 Trial. Hypothermia versus Normothermia after Out-of-Hospital Cardiac Arrest. N Engl J Med. 2021 Jun 17;384(24):2283-2294. doi: 10.1056/NEJMoa2100591 [MEDLINE]
Effect of Moderate vs Mild Therapeutic Hypothermia on Mortality and Neurologic Outcomes in Comatose Survivors of Out-of-Hospital Cardiac Arrest: The CAPITAL CHILL Randomized Clinical Trial. JAMA. 2021 Oct 19;326(15):1494-1503. doi: 10.1001/jama.2021.15703 [MEDLINE]
Targeted Temperature Management After In-Hospital Cardiac Arrest: An Ancillary Analysis of Targeted Temperature Management for Cardiac Arrest With Nonshockable Rhythm Trial Data. Chest. 2022 Aug;162(2):356-366. doi: 10.1016/j.chest.2022.02.056 [MEDLINE]
Influence of temperature management at 33 °C versus normothermia on survival in patients with vasopressor support after out-of-hospital cardiac arrest: a post hoc analysis of the TTM-2 trial. Crit Care. 2022 Jul 31;26(1):231. doi: 10.1186/s13054-022-04107-9 [MEDLINE]
Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2013 Mar;44(3):870-947. doi: 10.1161/STR.0b013e318284056a. Epub 2013 Jan 31 [MEDLINE]
Lack of effect of induction of hypothermia after acute brain injury. N Engl J Med 2001;344:556 [MEDLINE]
Induced hypothermia and fever control for prevention and treatment of neurological injuries. Lancet 2008;371:1955 [MEDLINE]
Hypothermia for traumatic head injury. Cochrane Database of Systematic Reviews 2009, Issue 2. Art. No.: CD001048. DOI: 10.1002/ 14651858.CD001048.pub4 [MEDLINE]
Prophylactic hypothermia for traumatic brain injury: a quantitative systematic review. CJEM 2010; 12:355-364 [MEDLINE]
Very early hypothermia induction in patients with severe brain injury (the National Acute Brain Injury Study: Hypothermia II): a randomised trial. Lancet Neurol 2011; 10:131-139 [MEDLINE]
Therapeutic hypothermia for the management of intracranial hypertension in severe traumatic brain injury: a systematic review. Brain Inj 2012; 26:899-908 [MEDLINE]
Therapeutic hypothermia for acute brain injuries. Scand J Trauma Resusc Emerg Med. 2015 Jun 5;23:42. doi: 10.1186/s13049-015-0121-3 [MEDLINE]
Adverse Effects
Cardiac function in hypothermia. Arctic Med Res. 1991;50 Suppl 6:63-6 [MEDLINE]
Comparing Doppler Echocardiography and Thermodilution for Cardiac Output Measurements in a Contemporary Cohort of Comatose Cardiac Arrest Patients Undergoing Targeted Temperature Management. Ther Hypothermia Temp Manag. 2021 Aug 20. doi: 10.1089/ther.2021.0008 [MEDLINE]
