Therapeutic hypothermia after cardiac arrest


  • Targeted temperature management (TTM) refers to strict temperature control following cardiac arrest
  • Current evidence suggests TTM after cardiac arrest (CA) improves neurologically intact survival, though the mechanism is uncertain
  • Prior to TTM, the term ‘therapeutic hypothermia’ was used — this was superseded by TTM due to concerns that hypothermia was not a necessary component of therapy and this has been reinforced following the recent publication of the TTM trial
  • Protocols vary from center to center, and with some now targeting T36C in preference to T33C in the wake of the TTM trial


Phases of cerebral blood flow (CBF) after cardiac arrest

  1. multifocal no-reflow (phase I)
  2. global hyperaemia  (phase II), due to CPR
  3. delayed hypoperfusion (phase III) in the first 24 hours after return of spontaneous circulation (ROSC), may result in cerebral ischaemia as cerebral metabolic rate may not decrease (or may increase if fever)
  4. normal or increased CBF (phase IV)


  • Non- survivors had a higher CBF than survivors (P<0.01), with peak CBF occurring 18 to 30 hours following CA (Xenon-133 labelling studies)
  • Cerebral autoregulation is often lost after CA, and in those with preserved autoregulation there is typically a “rightward shift”, with autoregulation lost below MAPs of 80 to 120 mm Hg
  • Intra-cranial hypertension > 25 mm Hg is associated with death or severe disability following CA
  • Hypocapnia is associated with poor neurological outcome after CA in observational studies

The mechanisms for TTM is controversial, these are non-mutually exclusive possibilities:

  • avoidance of hyperthermia (decreased metabolic demand and fever-related tissue injury)
  • reduction in metabolic demand (through prevention of fever, seizure control, cooling, sedation and neuromuscular blockade)
  • improved overall care (focusing the coordinated efforts of an expert team with close monitoring and prioritisation of therapies on a critically ill patient)
  • reduction in ischemic-reperfusion injury (including effects on excitotoxicty, neuroinflammation, apoptosis, free radical production, seizure activity, blood-brain barrier disruption, blood vessel leakage and cerebral thermopooling)


Inclusion and exclusion criteria vary between institutions

The following are suggested inclusion criteria based on the T33C targeted protocol at my institution:

  • Post cardiac arrest (any cause)
  • ROSC < 30 mins from team arrival
  • Time < 6 hours from ROSC
  • Patient is comatose
  • MAP >= 65mmHg

Exclusions may include:

  • Advanced directive stipulating DNR (absolute)
  • Traumatic arrest
  • Active bleeding (including intracranial)
  • Pregnancy, recent major surgery, severe sepsis


There are 3 phases to TTM targeting T33C: Induction, Maintenance and Rewarming

  • Induction
    — Aim to reduce the core body temperature to T33C (other protocols aim for between 32-34°C (90-93°F))
    – within 6 hours
  • Maintenance
    — Maintain core body temperature for 24 hours (other protocols 12-36 hours)
  • Rewarming
    — Either controlled or passive rewarming to normothermia 37°C (98.6°F)
    — 0.25°C per hour (others target 0.5C per hour)
    – over 8-12 hours
    — avoid hyperthermia
    — can adjust rate if necessitated by hemodynamic instability

After the TTM trial protocols may change, some of the changes may include:

  • similar protocols are likely to be used but targeting an initial temperature of 36C
  • Many patients will actually be cooler than this initially, I expect that passive rewarming to 36°C will be allowed in the range from T33°C to T36°C
  • Patients cooler than T33°C may be actively rewarmed to this target at no more than 0.5C/hour


My institution uses

  • IV cold saline 2-3 mL/kg stat
  • cooling vest and cooling machine
  • sedation and paralysis

Pros and cons of different methods

After TTM, if a T36C is targeted then boluses of cold saline are unlikely to be required, or lower volumes will be used



  • bradycardia
  • hypotension
  • decreased cardiac output (matched by reduced metabolic demand)
  • AF is common
  • severe dysrhythmias are more common below 30°C (86°F)
  • Other ECG changes in hypothermia include prolongation of the PR, QRS and QT intervals, as well as Osborn waves (or J-waves)

Laboratory tests

  • Potassium and magnesium levels fall (should be corrected)
  • low WBC, high PT/APPT and LFTs (do not require treatment)
  • 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.


  • Drug metabolism is generally slowed, leading to increased half-life, and hence drug accumulation.


  • T<36C may not confer additional benefits over TTM aiming for T36C
  • cold diuresis and hypovolemia
  • coagulopathy and platelet dysfunction
    — no observed difference in adverse bleeding events following TTM
    — even in those who underwent PCI or thrombolysis in the immediate post-arrest period
    — in patients with intracerebral bleeding, TTM has not been shown to increase morbidity or mortality
    ->  Aspirin, thrombolysis and other anticoagulation methods should therefore be used if indicated
  • Shivering occurs at a core temperature of ~ 35.5°C (96°F) and may be counterproductive to induction of cooling
    — Treatment includes adequate sedation, followed by muscle paralysis if needed
  • Rectal temperatures lag behind true core temperature
    — Use nasopharyngeal or esophageal temperature probes



  • Targeted Temperature Management (TTM) is an inexpensive, noninvasive therapy that offers hope of benefit for a condition with potentially devastating consequences
  •  Following the publication of two randomised controlled trials in 2002, by the Bernard et al and the HACA group — and despite their inherent flaws — the use of therapeutic hypothermia protocols targeting T32-34C became widespread
  • T36C is likely to become widely used as the target following the TTM trial (Nielsen et al, 2013), which found no difference between targets of T33C and T36C

Bernard, et al (2002) found an Absolute Risk Reduction (ARR) for death or severe disability of 23%, number needed to treat (NNT) was 4.5

  • small pseudo-randomised (alternate days) trial without allocation concealment; n =77
  • cooled to T33 for 12h versus standard care
  • no record of baseline neurological status prior to the event
  • no record of GCS on arrival in ED
  • good outcome: home or rehab facility at discharge (rather than a structured assessment)
  • positive outcome of trial would have been lost if 1 patient in good outcome group had a bad outcome

The Hypothermia After Cardiac Arrest (HACA) Group (2002) found an ARR for unfavourable neurological outcome of 24%, and NNT of 4

  • MCRCT,  n =273
  • 24 hours cooling versus usual care
  • primary outcome: favorable neurologic outcome within six months after cardiac arrest (used grading system)
  • no active temperature control — usual care group were not actually normothermic, they tended to be hyperthermic
  • trial stopped early
  • only 8% of screened ED patients were included

The Cochrane Database’s systematic review in 2009

  • suggested that for a hospital using conventional cooling methods with a baseline event rate of 20%, the NNT for a good neurologic outcome would be ~ 10
  • based on moderate level evidence

However, the TTM trial by Nielsen et al (2013) found no difference between targeted temperature management at T33C versus T36C following ROSC

  • MCRCT, stratified according to site, no allocation concealment, 36 ICUs in Europe and Australia
  • modified intention-to-treat analysis
  • n= 939 (T33C: 473 vs T36C: 466 patients in the primary analysis)
    — inclusion criteria: Age ≥18y, OOHCA of presumed cardiac cause, sustained ROSC for 20 minutes, GCS <8 after sustained ROSC
    — exclusion criteria: . pregnancy, known bleeding diathesis (other than medically induced coagulopathy, e.g. warfarin), suspected or confirmed acute intracranial bleeding or acute stroke, unwitnessed cardiac arrest with initial rhythm asystole, known limitations in therapy and Do Not Resuscitate-order, known disease making 180 days survival unlikely, known pre-arrest Cerebral Performance Category 3 or 4, >4 hours from ROSC to screening, SBP <80 mm Hg in spite of fluid loading/vasopressor and/or inotropic medication/intra aortic balloon pump, temperature on admission <30°C
  • Intervention: TTM at T33C: cooled my various means to target <6hours, maintained T33C for 36h, then rewarmed at 0.25C per hour; fever actively managed until at least 72 hours after cardiac arrest.
  • Comparison: TTM at T36C (otherwise similar treatment to the intervention group)
  • Outcomes:
    — Primary: mortality at 180 days
    — Secondary:  composite of poor neurologic function or death, defined as a Cerebral Performance Category (CPC) of 3 to 5 and a score of 4 to 6 on the modified Rankin scale, at or around 180 days
  • Results:
    — no difference in mortality: 50% of the T33C (235 of 473 patients) had died, as compared with 48% of the patients in the 36°C group (225 of 466 patients) (hazard ratio with a T33°C, 1.06; 95%CI 0.89-1.28; P=0.51)
    — no difference in neurological outcomes: 54% of the T33C group versus 52% of the 36C group died or had poor neurologic function according to the CPC (RR, 1.02; 95% CI 0.88 to 1.16; P=0.78). Using the modified Rankin scale, the comparable rate was 52% in both groups (RR 1.01; 95% CI 0.89 to 1.14; P=0.87).
    — shorter duration of mechanical ventilation in the T36C group: T33C = 0.83 versus T33C = 0.76 median days receiving mechanical ventilation/days in ICU (P=0.006)
    — serious adverse effects were common and marginally higher (with borderline significance) in the T33C group (93%) compared with the T36C (90%) (RR 1.03; 95% CI 1.00 to 1.08; P=0.09)
    — higher rates of hypokalemia in T33C group (19%) than the T36C group (13%)  P=0.02)
    — no differences found in subgroup analyses: age > 65 years, presence of initial shockable rhythm, time from cardiac arrest to ROSC >25 min, and presence of shock at admission
    — no differences in shivering
    — during the first 7 days of hospitalization, life-sustaining therapy was withdrawn in 247 patients (132 in the 33°C group and 115 in the 36°C group)
  • Commentary and criticisms
    — this study is a methodological masterpiece!
    — unlike Bernard 2002 and HACA 2002, not just VT/VF OOHCA were included (~80% were VF/VT)
    — a useful standardised protocol for neurological prognostication and treatment withdrawal was used
    — the study was powered to detect a RRR of 20% or an ARR of ~11%, thus the study was not powered to detect a smaller treatment effect (this may be more realistic due to the lower ‘separation effect’ between T33C and T36C)
    — less than 50% of T33C patients had reached target at 6 hours, but there was good separation between T33C and T36C groups
    — Baseline balance: higher rates of previous MI and IHD in the T33C group, but no difference in the rates of interventions for these conditions
    — the true patient-orientated outcome that matters is neurologically intact survival, the authors didn’t use this as the primary outcome because mortality is a ‘harder endpoint’ and less subject to bias
    — staff caring for the patients could not be blinded; however the doctors who perform neurological prognostication and data interpretation for the study were
    — TTM differs to the Bernard 2002 and HACA 2002 trials: larger MCRCT with excellent methodology, not limited to VT/VF, control group still received TTM (but at T36C)
    — patients in TTM had short times to CPR (e.g. ~1 minute), could T33C be more beneficial in patients with more anoxic injury?
    — is prognostication of the T33C group at 72h too soon, could ‘late wakers’ have been missed?
  • Bottom line: No difference found between targeted temperature management with a target of T36C compared to T33C

Controversies and uncertainties remain regarding

  • patient selection
  • optimum target temperature
  • timing of initiation of cooling
  • duration of therapy
  • rate of rewarming
  • the impact of fever in the control groups of the Bernard et al ,2002 and HAC 2002 studies
  • in versus out-of-hospital
  • VT/VF versus non-VT/VF

References and Links


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
  • 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.
  • 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]

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Chris is an Intensivist and ECMO specialist at the Alfred ICU in Melbourne. He is also the Innovation Lead for the Australian Centre for Health Innovation at Alfred Health and 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, the RAGE podcast, the Resuscitology course, and the SMACC conference.

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

On Twitter, he is @precordialthump.

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