Targeted temperature management (TTM) after cardiac arrest

PEARLS

OVERVIEW

• Targeted temperature management (TTM) refers to strict temperature control following Cardiac Arrest (CA)
• There is evidence that suggests TTM following CA may improve neurologically intact survival with a number of proposed mechanisms
• Prior to TTM, the term ‘therapeutic hypothermia’ was used, however recent evidence (TTM2 trial June 2021) demonstrated that hypothermia does not lead to improved mortality or morbidity
• The results from the TTM2 trial are not necessarily generalisable to:
  • people under 18 years of age,
  • pregnant women,
  • non-cardiac causes of arrest,
  • IHCA.
• Professional guidelines from the ERC and ANZCOR continue to recommend therapeutic hypothermia of between 33-36^oC for 24 hours, and normothermia for at least 72 hours after ROSC with In-Hospital Cardiac Arrests (IHCA) and Out-of-Hospital Cardiac Arrests (OHCA) (guidelines were updated pre-TTM2 results, 2016 for ARC and 2021 for ERC)

PROPOSED BENEFITS FOR THERAPEUTIC HYPOTHERMIA

• Reduction in cerebral metabolic rate – for every 1^oC a 6-10% drop in CMRO₂
  • Mediated via reduction of fevers, seizures
• Reduce ischaemic-reperfusion injury by:
  • Interruption of apoptotic pathways – calpain-mediated proteolysis and mitochondrial dysfunction
  • Decreasing harmful excitatory processes mediated via intracellular calcium accumulation, and release of glutamate and glycine
  • Reduction of neuroinflammation
  • Reduction of free radical production
  • Reduction in vascular permeability, blood-brain barrier disruption and oedema formation
  • Reduction of areas of hyperthermia within injured brain tissue (a self-aggravating cycle)
  • Possible reduction of post-CA coagulation activation and formulation of microthrombi
  • Down-regulation of the release of and imbalance of local vasoactive mediators such as endothelin, thromboxane A2 and prostaglandin I2
• May improve brain glucose metabolism
• May cause upregulation of cold shock proteins which may be protective from ischaemia
• Result in improved overall care (focusing the coordinated efforts of an expert team with close monitoring and prioritisation of therapies on a critically ill patient)

SYSTEMIC EFFECTS OF THERAPEUTIC HYPOTHERMIA

CARDIOVASCULAR

• Bradycardia
• BP changes
  • Stable BP or slight rise with vasoconstriction in mild hypothermia
  • Deep hypothermia may cause hypotension
• Reduced cardiac output (matched by reduced metabolic demand)
• Reduced cardiac metabolic rate
• Mild hypothermia (35°C) may result in coronary artery vasodilation, and can also induce vasoconstriction in atherosclerotic coronary arteries
• AF is common
• Severe dysrhythmias are more common below 30°C (86°F), and less common at 33°C
• Other ECG changes in hypothermia include prolongation of the PR, QRS and QT intervals, as well as Osborn waves (or J-waves)

GASTROINTESTINAL

• Reduced gut motility
• Hyperglycaemia
• May increase serum amylase

HAEMATOLOGICAL

• Reduced number and function of white cells
• Reduced number and function of platelets
• Prolonged clotting times

RENAL

• Renal dysfunction
• Diuresis and resulting hypovolemia (via increased venous return, reduced ADH, and increased ANP)

MUSCULOSKELETAL

• Shivering (management of shivering below)

METABOLIC

• Global reduction in metabolic rate, at 32°C up to 50-60% reduction
• Hypokalaemia
• Hypomagnesaemia
• Hypophosphataemia
• Hyperglycaemia and insulin resistance
• Drug metabolism is slowed leading to increased half-life and therefore risk of drug accumulation

LABORATORY TESTS

• Potassium and magnesium levels fall (should be corrected)
• low WBC, high PT/APPT and LFTs (do not require treatment)
• Elevated amylase
• Elevated LFTs
• Increased glycerol, FFAs, ketones, lactate
• Increased cortisol, noradrenaline and adrenaline
• Blood gas analysis may show low pH and HCO3- and high pCO2 and pO2 — these values may or may not be temperature adjusted, depending on your blood-gas analyser

SUGGESTED TTM PROTOCOL
Based off TTM2

• TTM NOT indicated if:
  • Patients who wake up and obey commands after ROSC; or
  • those who had a witnessed in-hospital arrest with immediate CPR and ROSC within 5 mins
• All patients should have a bladder temperature probe (a PAC thermister is the gold standard)
• Target normothermia (temp <37.7°C) for 72 hours after ROSC
• If the patient has an initial temperature 30-32.9°C, actively rewarm the patient to 33°C
• If the patient has a temperature of 33-34.9°C cover with a warm blanket and allow for passive warming until the core temperature reaches 35°C
• Patients should be sedated for at least 40 hours while undertaking TTM, however, patients should be attempted to be extubated at the earliest possible time if neurologically appropriate (of course they must meet other extubation criteria according to your local protocols) throughout this intervention period
• All patients should have paracetamol charted regularly unless contraindicated
• If the temperature reaches 37.7°C and is continuing to climb, commence cooling strategies
  1. Completely expose the patient
  2. Lower the ambient temperature
  3. If failing to achieve normothermia, use an active cooling device such as:
     • An endovascular cooling device with a closed-loop system
     • A surface cooling device with a closed-loop system
     • IV cold fluids (4°C) for the initial commencement of cooling should a device not be in situ. Crystalloids up to a maximum volume of 30mL/kg^-1 or up to 2 litres.

MANAGEMENT OF SHIVERING

• Shivering occurs at a core temperature of ~35.5°C (96°F) and may be counterproductive to the induction of cooling
• TIER 1 THERAPY: BEFORE IT STARTS
  1. Paracetamol 1g Q6H regularly
  2. Target magnesium level >0.8mmol/L
  3. Consider buspirone 30mg Q8H via NGT if available
• TIER 2 THERAPY: IF SHIVERING STARTS
  1. Wrap hands and feet with warm towels
  2. Dexmedetomidine or clonidine infusion (never both) and/or
  3. Propofol infusion if dexmedetomidine infusion is contraindicated — e.g. bradycardia, and/or
  4. Remifentanil infusion and/or
  5. Ketamine infusion
  6. Target magnesium level 1.2-1.6mmol/L
• TIER 3 THERAPY: IF ALL ELSE FAILS
  1. Fentanyl boluses (avoid the infusion where able)
  2. Muscle relaxant as a last resort

PROFESSIONAL ORGANISATION RECOMMENDATIONS

Note that the recommendations were last updated prior to the publication of TTM2

• European Resuscitation Council (ERC) – Updated March 2021
  • TTM: constant temperature of 32-36°C for ≽ 24 hours; then prevent fever for at least 72 hours
  • Recommended for adult IHCA and OHCA patients who have a GCS <8 after ROSC
• American Heart Association (AHA) – Reviewed October 2020, last updated 2015.
  • TTM: constant temperature of 32-36°C for ≥ 24 hours; then prevent fever in the following 24 hours to 48 hours post-ROSC.
  • Recommended for adult IHCA and OHCA patients who are comatose (i.e. lack of meaningful response to verbal commands)
• Australian and New Zealand Committee on Resuscitation (ANZCOR) – Updated January 2016
  • TTM: constant temperature of 32-36°C for at least 24 hours; then prevention and treatment of fever in the post TTM period without signifying how long for
  • Recommended for adults with OHCA with initial shockable rhythm who ‘remain unresponsive post-ROSC
  • Suggested for adults with OHCA with non-shockable rhythms, and adults with IHCA with any rhythm, who ‘remain unresponsive’ post-ROSC
  • Extends this broadly to non-cardiac causes by stating, ‘these patients may also benefit from TTM’

Paediatrics

• ANZCOR Guidelines for Paediatrics – Updated November 2021
  • TTM: Active control of temperature to maintain central temperature of ≤37.5°C
  • For infants and children who remain comatose following ROSC from OHCA or IHCA
• ILCOR CoSTR – Updated April 2021
  • Suggest either: TTM 32-34°C OR 36-37.5°C for comatose paediatric patients who achieve ROSC for both OHCA and IHCA

EVIDENCE

• HACA trial (2002): mRCT, n = 273 of OHCA patients (VF or VT), 24 hours of cooling to 32-34°C vs usual care; demonstrated favourable neurological outcome. (The Bottom Line Review)
  • Issues: 8% of screened patients included, the control group became hyperthermic
• TTM trial (2013): MCRCT, n = 939 of OHCA patients presumed cardiac origin, 36 hours of cooling to 33°C vs 36°C with 72 hours of normothermia post-ROSC; demonstrated no benefit between arms. (The Bottom Line Review)
• HYPERION trial (2019): MCRCT, n = 584 of OHCA and IHCA patients (non-shockable rhythm), 24 hours of 33°C then normothermia for 24 hours vs normothermia for 48 hours; demonstrated significantly improved neurological outcomes in the treatment arm. (The Bottom Line Review)
  • Issues: a number of substantial differences in treatment arms
• TTM2 trial (2021): MCRCT, n = 1861 of OHCA patients, 33°C for 28 hours then rewarmed until 40 hours then normothermia to 72 hours vs normothermia 36.5-37.7°C for 72 hours post-ROSC; demonstrated no significant difference both morbidity (functional and QoL) and mortality. (The Bottom Line Review)

Paediatric

• ILCOR Paediatric Life Support Task Force Systematic Review and Meta-analysis (2019): 12 studies included, 2 RCTs and including 2060 patients. Inconclusive evidence to either support or refute the use of TTM at 32-34°C for comatose children who achieve ROSC.
  • Of note, this systematic review and meta-analysis helped to inform the ILCOR Consensus on Science with Treatment Recommendations (CoSTR)

References and Links

LITFL

• Reports of the death of therapeutic hypothermia are greatly exaggerated (2013)
• All in a lather over TTM (2013)
• CCC — ABG changes in Cardiac Arrest and CPR
• CCC — Arterial Blood Gas in Hypothermia
• CCC — Prognosis after cardiac arrest
• CCC — Post-cardiac arrest syndrome

Journal articles

• Arrich J, Holzer M, Herkner H, Müllner M. Hypothermia for neuroprotection in adults after cardiopulmonary resuscitation. Cochrane Database of Systematic Reviews 2009. PMID: 19821320
• Bernard SA, Gray TW, Buist MD et al. Treatment of comatose survivors of out-of -hospital cardiac arrest with induced hypothermia. N Eng J Med 2002;346:557-63 PMID: 11856794 [Free Full Text]
• Bernard SA, Smith K, Cameron P, et al. Induction of therapeutic hypothermia by paramedics after resuscitation from out-of-hospital ventricular fibrillation cardiac arrest, a randomized controlled trial. Circ. 2010; 122:737-42. PMID: 20679551
• Buick JE, Wallner C, Aickin R, Meaney PA, de Caen A, Maconochie I, Skrifvars MB, Welsford M; International Liaison Committee on Resuscitation Pediatric Life Support Task Force. Paediatric targeted temperature management post cardiac arrest: A systematic review and meta-analysis. Resuscitation. 2019 Jun;139:65-75. doi: 10.1016/j.resuscitation.2019.03.038. Epub 2019 Apr 2. PMID: 30951842.
• Dankiewicz J, Cronberg T, Lilja G, Nielsen N, et al; TTM2 Trial Investigators. Hypothermia versus Normothermia after Out-of-Hospital Cardiac Arrest. N Engl J Med. 2021 Jun 17;384(24):2283-2294. doi: 10.1056/NEJMoa2100591. PMID: 34133859. [Free Full Text]
• Hypothermia after cardiac arrest (HACA) study group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Eng J Med 2002;346:549-56. PMID: 11856793 [Free Full Text]
• Nielsen N, Friberg H, Gluud C, Herlitz J, Wetterslev J. Hypothermia after cardiac arrest should be further evaluated–a systematic review of randomised trials with meta-analysis and trial sequential analysis. Int J Cardiol. 2011 Sep 15;151(3):333-41. doi: 10.1016/j.ijcard.2010.06.008. Epub 2010 Jul 1. Review. PubMed PMID: 20591514.
• Nolan JP, Sandroni C, Böttiger BW, Cariou A, Cronberg T, Friberg H, Genbrugge C, Haywood K, Lilja G, Moulaert VRM, Nikolaou N, Olasveengen TM, Skrifvars MB, Taccone F, Soar J. European Resuscitation Council and European Society of Intensive Care Medicine guidelines 2021: post-resuscitation care. Intensive Care Med. 2021 Apr;47(4):369-421. doi: 10.1007/s00134-021-06368-4. Epub 2021 Mar 25. PMID: 33765189; PMCID: PMC7993077. [Free Full Text]
• Polderman KH. Mechanisms of action, physiological effects, and complications of hypothermia. Crit Care Med 2009; 37[S]: S186-S202. PMID: 19535947
• Sandroni C, Cavallaro F, Antonelli M. Therapeutic hypothermia: is it effective for non-VF/VT cardiac arrest? Crit Care. 2013 Mar 19;17(2):215. [Epub ahead of print] PubMed PMID: 23510394; PubMed Central PMCID: PMC3672513. [Free Full Text]
• Wassink G, Davidson JO, Lear CA, Juul SE, Northington F, Bennet L, Gunn AJ. A working model for hypothermic neuroprotection. J Physiol. 2018 Dec;596(23):5641-5654. doi: 10.1113/JP274928. Epub 2018 May 24. PMID: 29660115; PMCID: PMC6265568. [Free Full Text]

 FOAM and web resources

• Kim, A; Flower, O. Resuscitation After Cardiac Arrest – NeuroResus. Retrieved 26 April 2022, from https://neuroresus.com/lessons/resuscitation-after-cardiac-arrest/.
• Center for Resuscitation Science
• EMCrit — Induced Hypothermia after Cardiac Arrest Lecture
• ICN — SMACC: Macken – Targeted Temperature Management After Out of Hospital Cardiac Arrest (2013)
• ICN — 67. NIELSEN on Therapeutic Hypothermia after Cardiac Arrest (2013)
• Bradford, C. (2022). TTM2 – The Bottom Line. Retrieved 26 April 2022, from https://www.thebottomline.org.uk/summaries/icm/ttm2/.
• Chambler, D. (2014). HACA – The Bottom Line. Retrieved 26 April 2022, from https://www.thebottomline.org.uk/summaries/icm/haca/.
• Chambler, D. (2014). TTM – The Bottom Line. Retrieved 26 April 2022, from https://www.thebottomline.org.uk/summaries/icm/ttm/.
• Olusanya, S. (2019). HYPERION – The Bottom Line. Retrieved 26 April 2022, from https://www.thebottomline.org.uk/summaries/hyperion/.

Books

• Bersten, A. and Soni, N., 2014. Oh’s Intensive Care Manual. 7th ed. Elsevier.

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