Targeted temperature management (TTM) after cardiac arrest

Current evidence suggests that normothermia and actively avoiding fever (>37.7 o C) has no significant difference in morbidity or mortality (including QoL and functional outcomes) compared with therapeutic hypothermia (of 33 o C or 36 o C) following CA.

However, current professional organisations continue to recommend TTM of 33-36 o C for at least 24 hours following cardiac arrest.

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.

  PROPOSED BENEFITS FOR THERAPEUTIC HYPOTHERMIA

  • Reduction in cerebral metabolic rate – for every 1 o C a 6-10% drop in CMRO₂
    • Mediated via reduction of fevers, seizures
    • 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

    SYSTEMIC EFFECTS OF THERAPEUTIC HYPOTHERMIA

    • Bradycardia
    • BP changes
      • Stable BP or slight rise with vasoconstriction in mild hypothermia
      • Deep hypothermia may cause hypotension
      • Reduced gut motility
      • Hyperglycaemia
      • May increase serum amylase
      • Reduced number and function of white cells
      • Reduced number and function of platelets
      • Prolonged clotting times
      • Renal dysfunction
      • Diuresis and resulting hypovolemia (via increased venous return, reduced ADH, and increased ANP)
      • Shivering (management of shivering below)
      • 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
      • 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
        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
          • 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)
          • 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’
          • 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
            • 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
              • Issues: a number of substantial differences in treatment arms
              • 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

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

                

                Critical Care

                James Pearlman

                ICU Advanced Trainee BMedSci [UoN], BMed [UoN], MMed(CritCare) [USyd] from a broadacre farm who found himself in a quaternary metropolitan ICU. Always trying to make medical education more interesting and appropriately targeted; pre-hospital and retrieval curious; passionate about equitable access to healthcare; looking forward to a future life in regional Australia. Student of LITFL.

                Chris Nickson

                Chris is an Intensivist and ECMO specialist at the Alfred ICU in Melbourne. He is also a Clinical Adjunct Associate Professor at Monash University. He is a co-founder of the Australia and New Zealand Clinician Educator Network (ANZCEN) and is the Lead for the ANZCEN Clinician Educator Incubator programme. He is on the Board of Directors for the Intensive Care Foundation and is a First Part Examiner for the College of Intensive Care Medicine. He is an internationally recognised Clinician Educator with a passion for helping clinicians learn and for improving the clinical performance of individuals and collectives.

                After finishing his medical degree at the University of Auckland, he continued post-graduate training in New Zealand as well as Australia’s Northern Territory, Perth and Melbourne. He has completed fellowship training in both intensive care medicine and emergency medicine, as well as post-graduate training in biochemistry, clinical toxicology, clinical epidemiology, and health professional education.

                He is actively involved in in using translational simulation to improve patient care and the design of processes and systems at Alfred Health. He coordinates the Alfred ICU’s education and simulation programmes and runs the unit’s education website, INTENSIVE. He created the ‘Critically Ill Airway’ course and teaches on numerous courses around the world. He is one of the founders of the FOAM movement (Free Open-Access Medical education) and is co-creator of litfl.com, the RAGE podcast, the Resuscitology course, and the SMACC conference.

                His one great achievement is being the father of three amazing children.