Targeted Temperature Management (TTM)

Quick Answer

Critical: Targeted Temperature Management (TTM) is a neuroprotective strategy for comatose survivors of cardiac arrest (GCS motor below 6 post-ROSC). Target temperature 32-36°C for at least 24 hours, followed by slow rewarming (0.25-0.5°C/hour) and strict fever avoidance (below 37.5°C) for 72 hours.

Targeted Temperature Management (TTM) involves controlled regulation of body temperature post-cardiac arrest to reduce secondary brain injury from ischaemia-reperfusion injury [1]. Following the landmark HACA trial (2002) and subsequent TTM trials, current Australian Resuscitation Council (ARC) and ANZCOR guidelines recommend a target temperature of 32-36°C for at least 24 hours in comatose patients post-ROSC [2][3]. The TTM2 trial (2021) demonstrated no superiority of hypothermia (33°C) over normothermia (37°C) with strict fever prevention, shifting practice emphasis toward aggressive fever avoidance [4]. Key elements include: selection of appropriate cooling method (surface or intravascular), shivering management with sedation and paralysis, slow controlled rewarming, and delayed neuroprognostication (≥72 hours post-rewarming).

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ACEM Exam Focus

Primary Exam Relevance

• Physiology: Cerebral autoregulation, oxygen-haemoglobin dissociation curve shift with temperature, metabolic rate reduction (6-10% per 1°C decrease), cellular mechanisms of hypothermic neuroprotection (reduced excitotoxicity, decreased free radical production, stabilised blood-brain barrier)
• Pharmacology: Drug metabolism alterations with hypothermia (reduced hepatic clearance, prolonged half-lives), sedative and neuromuscular blocker pharmacokinetics, anti-shivering medication mechanisms
• Anatomy: Cerebral vascular anatomy, thermoregulatory pathways (hypothalamus, spinal cord, efferent pathways), central venous access sites for intravascular cooling

Fellowship Exam Relevance

• Written SAQ Topics: TTM2 trial interpretation and application, cooling method comparison (surface vs intravascular), shivering management protocols, complications of TTM, rewarming strategies, neuroprognostication timeline post-TTM
• OSCE: Communication stations discussing prognosis with families (key discriminator: appropriate timing of prognostication post-TTM), critical care management stations, post-ROSC resuscitation station with TTM initiation
• Key domains tested: Medical Expert (evidence interpretation, TTM protocols), Communicator (family discussions, prognostication), Scholar (trial evidence synthesis)

High-Yield Exam Points

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Key Points

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Epidemiology

Cardiac Arrest Outcomes and TTM

Evolution of TTM Practice

Australian and New Zealand Context

• Aus-ROC registry data: TTM is standard of care in Australian and New Zealand ICUs for comatose cardiac arrest survivors [10]
• Variation in practice: Some centres target 33°C, others 36°C, with increasing adoption of normothermia (36-37°C) with strict fever avoidance post-TTM2 [13]
• Metro vs regional: TTM initiation may be delayed in regional areas; early cooling during retrieval is encouraged where feasible [13]

Indigenous Health Considerations

Important Note: Aboriginal, Torres Strait Islander, and Maori Considerations:

• Aboriginal and Torres Strait Islander Australians experience cardiac arrest at younger ages (10-15 years earlier) with higher baseline cardiovascular disease burden [15]
• Lower rates of bystander CPR in remote communities may lead to longer no-flow times and more severe hypoxic brain injury [15]
• Remote communities may have delayed access to TTM due to retrieval times - early cooling strategies during transport should be considered [16]
• Family-centred care and extended family involvement in discussions about prognosis and goals of care is essential
• Cultural considerations around death and dying must be respected - involve Aboriginal Health Workers and cultural liaison early
• Language barriers: Use interpreters for complex prognostication discussions
• Maori (NZ): Whanau (family) involvement in decision-making; respect tikanga Maori around death and dying

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Pathophysiology

Mechanisms of Hypoxic-Ischaemic Brain Injury

Cardiac arrest results in immediate cessation of cerebral blood flow, leading to a cascade of cellular injury [17]:

Cardiac Arrest
       ↓
Cessation of Cerebral Blood Flow
       ↓
Oxygen and Glucose Deprivation
       ↓
ATP Depletion (within 2-5 minutes)
       ↓
Failure of Na+/K+-ATPase Pump
       ↓
Cellular Depolarisation → Calcium Influx → Glutamate Release
       ↓
EXCITOTOXICITY
       ↓
Mitochondrial Dysfunction → Free Radical Formation → Apoptosis
       ↓
NEURONAL DEATH

Ischaemia-Reperfusion Injury

Following ROSC, reperfusion paradoxically worsens injury through [18]:

How Hypothermia Protects the Brain

Therapeutic hypothermia provides neuroprotection through multiple mechanisms [19][20]:

1. Metabolic Effects

• Reduces cerebral metabolic rate (CMRO2): 6-10% decrease per 1°C reduction
• Decreases oxygen demand: Reduces ATP consumption
• Slows cellular processes: All enzyme-dependent reactions slow

2. Cellular Protection

3. Blood-Brain Barrier Stabilisation

• Reduced matrix metalloproteinase (MMP) activity
• Decreased vascular permeability
• Less cerebral oedema formation

4. Anti-Inflammatory Effects

• Reduced microglial activation
• Decreased pro-inflammatory cytokine release (IL-1beta, TNF-alpha)
• Attenuated inflammatory cascade

5. Anti-Thrombotic Effects

• Reduced platelet aggregation (but also coagulopathy risk)
• Improved microcirculatory blood flow

Temperature-Dependent Physiological Changes

Oxygen-Haemoglobin Dissociation Curve

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Indications for TTM

ARC/ANZCOR Recommendations (Guideline 14)

Which Patients Qualify?

ROSC Achieved After Cardiac Arrest
              ↓
Assess Level of Consciousness
              ↓
         ┌────────────────────────┬────────────────────────┐
         ↓                        ↓                        ↓
    FOLLOWING COMMANDS       NOT FOLLOWING COMMANDS    UNCERTAIN
    (GCS motor ≥6)           (GCS motor below 6)            (sedation effects)
         ↓                        ↓                        ↓
    No TTM required          TTM INDICATED             Re-assess off sedation
    Observe for deterioration                          If remains comatose → TTM

Selection Criteria in Practice

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Contraindications

Absolute Contraindications

Relative Contraindications

Pre-TTM Assessment Checklist

Before Initiating TTM:
□ Confirm cardiac arrest with ROSC achieved
□ Verify comatose state (GCS motor below 6)
□ Exclude following commands
□ Check for advance care directive/DNR
□ Assess for contraindications
□ Secure airway (intubation)
□ Establish vascular access (central line preferred)
□ Baseline investigations (FBC, coags, electrolytes, lactate)
□ 12-lead ECG (STEMI → cath lab first)
□ Discuss with family regarding TTM plan
□ ICU bed arranged

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Techniques of Temperature Control

Overview of Cooling Methods

Surface Cooling Systems

Conventional Cooling Blankets

• Mechanism: Circulating water through blankets placed above and below patient
• Temperature range: 4-42°C water circulation
• Cooling rate: 0.5-1°C per hour typically
• Advantages: Widely available, non-invasive, low cost
• Disadvantages: Slower cooling, less precise, more shivering

Advanced Surface Cooling (Gel Pad Systems)

Gel Pad Application:

Placement Sites:
• Back pad (under patient)
• Chest pad
• Thigh pads (bilateral)
• Cover ~40% body surface area for optimal cooling
• Avoid direct contact with bony prominences (pressure injury risk)

Intravascular Cooling Devices

Catheter-Based Systems

Catheter Placement:

• Site: Femoral vein (most common), subclavian vein, internal jugular vein
• Size: 8.5-14Fr depending on device
• Technique: Standard central venous access using Seldinger technique
• Confirmation: Fluoroscopy or CXR for positioning

Advantages of Intravascular Cooling:

• Faster cooling (1.5-2°C/hour)
• More precise temperature control (±0.2°C)
• Less shivering (core cooling before peripheral)
• Automated feedback loop
• Predictable rewarming control

Disadvantages:

• Invasive procedure with associated risks
• Central line complications (infection, thrombosis, bleeding)
• Cost
• Not available in all centres

Cold Intravenous Fluids

Pre-Hospital Cooling

Current recommendation: Pre-hospital cooling is NOT strongly recommended; focus on high-quality CPR, rapid transport, and in-hospital TTM initiation [2].

Comparison: Surface vs Intravascular Cooling

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TTM Protocol Implementation

Phase 1: Induction (Cooling to Target)

Target time to reach goal temperature: below 6-8 hours from ROSC (ideally below 4 hours) [24]

Phase 2: Maintenance (At Target Temperature)

Phase 3: Rewarming

Phase 4: Normothermia Maintenance

Temperature Monitoring

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Evidence Base for TTM

Landmark Trials

HACA Trial (2002) [1]

Bernard et al. (2002) [14]

TTM Trial (2013) [3]

TTM2 Trial (2021) [4]

HYPERION Trial (2019) [25]

THAPCA Trials (Paediatric) [22]

Systematic Reviews and Meta-Analyses

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Shivering Management

Why Shivering Matters

Shivering is a major barrier to effective TTM and must be aggressively managed [5][8]:

Shivering Assessment

Bedside Shivering Assessment Scale (BSAS):

Target: BSAS 0-1

Shivering Management Protocol

Step 1: Non-Pharmacological Measures

Step 2: Pharmacological Management (Escalating Approach)

Step 3: Neuromuscular Blockade (Refractory Shivering)

Columbia Anti-Shivering Protocol (Modified)

STEP 1: Non-pharmacological
• Counter-warming (Bair Hugger to extremities)
• Skin counter-warming
          ↓ If BSAS ≥2
STEP 2: First-line pharmacological
• Paracetamol 1g IV
• Magnesium 2-4g IV bolus → 0.5-1g/hr infusion
• Buspirone 30mg NG
          ↓ If BSAS ≥2
STEP 3: Opioid-based
• Meperidine 25-50mg IV (preferred)
  OR Fentanyl infusion
          ↓ If BSAS ≥2
STEP 4: Sedation intensification
• Propofol OR Dexmedetomidine infusion
          ↓ If BSAS ≥2
STEP 5: Neuromuscular blockade
• Cisatracurium infusion
• Ensure adequate sedation
• Train-of-four monitoring

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Complications of TTM

Cardiovascular Complications

Haematological Complications

Important: Coagulation tests (PT, APTT) are performed at 37°C in the lab - they may appear normal despite clinical coagulopathy at 33°C [28].

Infectious Complications

Metabolic Complications

Electrolyte Management During TTM

Drug Metabolism Changes

Drugs requiring dose adjustment:

• Propofol - reduce infusion rate
• Midazolam - significantly prolonged effect
• Fentanyl - accumulation risk
• Neuromuscular blockers - prolonged duration
• Phenytoin - unpredictable levels

Skin Complications (Surface Cooling)

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Rewarming Protocol

Principles of Safe Rewarming

Rewarming Protocol

After ≥24 hours at target temperature:

1. Set rewarming rate: 0.25-0.5°C/hour
   • Most devices have automated rewarming function
   • If passive: Remove active cooling, apply warming blanket at low setting

2. Monitor:
   • Temperature continuously
   • Electrolytes Q2-4 hours (especially K+)
   • Haemodynamics (BP, HR)
   • Glucose Q2-4 hours

3. Target end temperature: 36.5-37°C

4. Duration: 12-16 hours to reach normothermia

5. Post-rewarming:
   • STRICT fever prevention for at least 72 hours post-ROSC
   • Target temperature below 37.5°C
   • Paracetamol, cooling measures if fever develops

Complications of Rapid Rewarming

Post-Rewarming Care

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Monitoring During TTM

Essential Monitoring Parameters

Neurological Monitoring

Documentation

TTM Flowsheet - Hourly Documentation:
□ Core temperature (oesophageal/bladder)
□ Shivering score (BSAS 0-3)
□ Sedation depth (RASS or similar)
□ Vital signs (HR, BP, SpO2)
□ Cooling device settings
□ Interventions (anti-shivering, sedation changes)
□ Skin inspection (if surface cooling)
□ Cooling/rewarming phase

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Special Populations

Paediatric TTM

Pregnancy

Elderly Patients

Patients with Traumatic Brain Injury

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Indigenous Health Considerations

Important Note: Aboriginal, Torres Strait Islander, and Maori Considerations:

Access to TTM Services

Challenges in Remote Communities:

• Delayed EMS response times (over 60 minutes in many remote areas)
• Longer time to ICU admission and TTM initiation
• RFDS retrieval required for most post-arrest patients
• Limited availability of advanced cooling devices
• Telemedicine consultation for initial management guidance

Mitigation Strategies:

• Early activation of retrieval services
• Pre-hospital cooling where feasible (ice packs, cold fluids if appropriate)
• Telemedicine guidance for TTM initiation
• Transfer protocols to nearest ICU with TTM capability

Cultural Considerations in Prognostication

Communication Principles:

• Allow time for extended family/community consultation
• Involve Aboriginal Health Workers and cultural liaison officers
• Respect community decision-making structures
• Understand that prognosis discussions may need to involve elders
• Be patient - decisions may take longer when family is dispersed geographically
• Use interpreters for complex discussions (over 100 Aboriginal languages in Australia)

Specific Cultural Protocols:

• "Sorry Business"
• cultural protocols around death and dying may affect family's responses
• Community grief - the whole community may be affected
• Traditional healers - may wish to be involved alongside Western medicine
• Connection to country - family may want patient returned to traditional lands
• Organ donation - discuss sensitively; beliefs about body integrity vary

Maori Considerations (New Zealand):

• Whanau (family) involvement in all major decisions
• Tikanga Maori - cultural protocols around death and dying
• Karakia (prayers) may be requested
• Cultural liaison officers available in major NZ hospitals
• Tangi (funeral) practices may influence decision-making timing

Health Disparities

• Aboriginal and Torres Strait Islander Australians experience cardiac arrest at younger ages
• Higher rates of underlying cardiovascular disease and risk factors
• May have different goals of care based on cultural beliefs and community role
• Ensure equitable access to post-arrest care including TTM
• Do not make assumptions about prognosis based on ethnicity or location

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Remote and Rural Considerations

Pre-Hospital Cooling in Remote Areas

Retrieval Medicine Considerations

Resource-Limited TTM

RFDS (Royal Flying Doctor Service) Protocols

• Early notification if post-ROSC patient requires TTM
• TTM can be maintained during flight with appropriate equipment
• Temperature monitoring during transport essential
• Handover temperature target and phase to receiving team
• Consider weather and flight time in retrieval planning

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Neuroprognostication After TTM

Timing of Prognostication

Multimodal Prognostic Assessment

False Positive Rate Concerns

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Pitfalls and Pearls

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Viva Practice

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OSCE Scenarios

Station 1: Post-ROSC Management and TTM Initiation

Format: Clinical management station Time: 11 minutes Setting: ED resuscitation bay

Candidate Instructions:

A 62-year-old male has just achieved ROSC after 12 minutes of VF arrest in the ED. He is intubated and sedated. You are the emergency registrar. Initiate post-resuscitation care and discuss TTM with the ICU registrar (examiner).

Examiner Instructions:

• Patient has stable ROSC, BP 85/50 on low-dose noradrenaline
• 12-lead ECG shows ST elevation in V1-V4 (anterior STEMI)
• Patient is comatose, not following commands
• ICU has capacity for admission

Provide information as requested:

• VBG: pH 7.22, lactate 8.5, K+ 4.8
• Temperature: 36.2°C

Expected Actions:

1. Confirm stable ROSC (pulse, ETCO2, arterial waveform)
2. Optimise oxygenation (target SpO2 94-98%, reduce FiO2)
3. Optimise ventilation (confirm ETT position, target normocapnia)
4. Recognise STEMI → activate cath lab
5. Address haemodynamics (MAP target, vasopressors)
6. Identify TTM indication (comatose post-ROSC)
7. Discuss TTM plan with ICU (target temperature, method, monitoring)
8. Communicate priorities: cath lab first, then ICU for TTM

Marking Criteria:

Expected Standard:

• Pass: ≥6/11
• Key discriminators: Recognition of STEMI priority; clear TTM indication and plan

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Station 2: Family Communication - Prognosis After TTM

Format: Communication station Time: 11 minutes Setting: ICU relatives room

Candidate Instructions:

A 55-year-old woman had an OHCA 5 days ago. She completed TTM and rewarming 72 hours ago. Despite stopping sedation, she remains comatose with no motor response. Her husband wants to know "will she wake up?" Discuss prognosis with him (actor).

Actor Brief (Husband):

• Anxious, hopeful, exhausted
• Wants a clear answer about whether his wife will survive
• Has two teenage children at home
• May become emotional or frustrated if answers are vague
• Will ask: "What would you do if it was your wife?"

Examiner Instructions: Observe for:

• Empathetic communication
• Appropriate prognostic information
• Avoidance of false hope or premature certainty
• Explanation of multimodal assessment
• Shared decision-making approach

Provide if asked:

• Clinical exam: Absent pupillary reflexes, absent corneal reflexes, no motor response to pain
• EEG: Highly malignant pattern (burst suppression without reactivity)
• CT brain: Loss of grey-white differentiation globally
• NSE: 95 µg/L (very elevated)

Marking Criteria:

Expected Standard:

• Pass: ≥6/11
• Key discriminators: Balancing honesty with empathy; appropriate timing of prognostic information

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Station 3: TTM Troubleshooting

Format: Clinical management station Time: 11 minutes Setting: ICU bedside

Candidate Instructions:

You are the ICU registrar on call. A nurse calls you about a 48-year-old male who is 18 hours into TTM at 33°C. His temperature has risen to 35.8°C despite the cooling device being set to 33°C. He is also having visible shivering. Manage this situation.

Resources Available:

• Full ICU equipment and drugs
• Surface cooling device (Arctic Sun type)
• Nurse available for assistance

Expected Actions:

1. Review patient (ABCDE approach)
2. Assess shivering (BSAS score)
3. Check cooling device function (pads, water temperature, connections)
4. Initiate anti-shivering protocol:
   • Counter-warming
   • Magnesium, meperidine
   • Increase sedation
   • Consider NMB if refractory
5. Consider infection as cause of temperature rise
6. Escalate cooling (additional ice packs, consider intravascular)
7. Document and communicate plan

Marking Criteria:

Expected Standard:

• Pass: ≥6/11
• Key discriminators: Systematic shivering management; considers multiple causes of temperature rise

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SAQ Practice

Question 1 (6 marks)

Stem: A 60-year-old male is comatose following ROSC from out-of-hospital cardiac arrest with initial VF rhythm. He is intubated and sedated in ICU.

Question: List 6 key components of targeted temperature management (TTM) that should be implemented for this patient.

Model Answer:

• Target temperature 32-36°C for at least 24 hours (1 mark)
• Surface or intravascular cooling method (1 mark)
• Continuous core temperature monitoring (oesophageal or bladder) (1 mark)
• Shivering management with sedation, counter-warming, and NMB if needed (1 mark)
• Controlled rewarming at 0.25-0.5°C per hour (1 mark)
• Strict fever avoidance (below 37.5°C) for at least 72 hours post-ROSC (1 mark)

Examiner Notes:

• Accept: Cold IV fluids as adjunct (not standalone)
• Accept: Electrolyte monitoring/replacement
• Do not accept: Vague answers like "cooling the patient"

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Question 2 (8 marks)

Stem: A patient undergoing TTM at 33°C develops significant shivering despite sedation with propofol and fentanyl.

Question: Outline the stepwise management of refractory shivering during TTM. (8 marks)

Model Answer: Non-pharmacological (2 marks):

• Counter-warming with warm air blanket to hands and feet (1 mark)
• Cover exposed skin, avoid rapid cooling (1 mark)

Pharmacological - first line (3 marks):

• Paracetamol 1g IV (0.5 marks)
• Magnesium sulphate 2-4g IV bolus then infusion (0.5 marks)
• Meperidine (pethidine) 25-50mg IV (1 mark)
• Increase propofol/fentanyl infusion (0.5 marks)
• Consider buspirone 30mg NG (0.5 marks)

Pharmacological - second line (2 marks):

• Dexmedetomidine infusion (1 mark)
• Neuromuscular blockade (cisatracurium) with adequate sedation (1 mark)

Monitoring (1 mark):

• Bedside Shivering Assessment Scale (BSAS) target 0-1 (0.5 marks)
• Train-of-four if NMB used (0.5 marks)

Examiner Notes:

• Must mention counter-warming for full non-pharm marks
• Must mention NMB as escalation option
• Accept reasonable drug alternatives

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Question 3 (6 marks)

Stem: Following the TTM2 trial published in 2021, your ICU is reviewing its TTM protocol.

Question: Describe the key findings of the TTM2 trial and their implications for current practice. (6 marks)

Model Answer: Study design (1 mark):

• Multicentre RCT comparing hypothermia (33°C) vs normothermia (37°C) with early fever treatment in comatose OHCA survivors

Key findings (3 marks):

• No difference in mortality at 6 months (50% vs 48%) (1 mark)
• No difference in neurological outcome (1 mark)
• More arrhythmias in hypothermia group (1 mark)

Implications for practice (2 marks):

• Hypothermia (33°C) is not superior to normothermia with strict fever prevention (1 mark)
• Fever avoidance (below 37.5°C) for 72 hours is the key intervention (1 mark)

Examiner Notes:

• Accept: Discussion of practice variation post-TTM2
• Accept: Reference to ongoing role of temperature management
• Do not accept: Conclusion that TTM is no longer needed

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Question 4 (6 marks)

Stem: A 52-year-old woman completed TTM and rewarming 72 hours ago following OHCA. She remains comatose.

Question: List 6 prognostic markers that would suggest a poor neurological outcome in this patient.

Model Answer: Clinical examination (2 marks):

• Absent pupillary light reflexes at ≥72 hours (1 mark)
• Absent corneal reflexes at ≥72 hours (1 mark)

Electrophysiology (1.5 marks):

• Bilateral absent N20 on SSEPs (1 mark)
• Highly malignant EEG pattern (suppressed, burst-suppression without reactivity) (0.5 marks)

Biomarkers (1 mark):

• Elevated NSE over 60 µg/L at 48-72 hours (1 mark)

Imaging (1.5 marks):

• Diffuse cerebral oedema/loss of grey-white differentiation on CT (0.75 marks)
• Extensive diffusion restriction on MRI (0.75 marks)

Examiner Notes:

• Must specify timing (≥72 hours post-rewarming) for clinical signs
• Accept: Myoclonus status epilepticus
• Accept: Alternative biomarkers (S100B)

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Australian/NZ Guidelines Summary

ARC/ANZCOR Recommendations (Guideline 14)

Key Differences from AHA/ERC Guidelines

Note: Post-TTM2, guidelines are converging toward recommending fever prevention as the key intervention, with the specific temperature target (33°C vs 36°C) being of secondary importance.

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References

Guidelines

1. Hypothermia after Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med. 2002;346(8):549-556. PMID: 11856793

2. Australian Resuscitation Council. ANZCOR Guideline 14 - Post-resuscitation Care. 2023. Available from: https://resus.org.au

3. Nielsen N, Wetterslev J, Cronberg T, et al. Targeted temperature management at 33°C versus 36°C after cardiac arrest. N Engl J Med. 2013;369(23):2197-2206. PMID: 24237006

4. Dankiewicz J, Cronberg T, Lilja G, et al. Hypothermia versus normothermia after out-of-hospital cardiac arrest. N Engl J Med. 2021;384(24):2283-2294. PMID: 34133859

5. Choi HA, Ko SB, Presciutti M, et al. Prevention of shivering during therapeutic temperature modulation: the Columbia anti-shivering protocol. Neurocrit Care. 2011;14(3):389-394. PMID: 21431449

Key Evidence

6. Kim F, Nichol G, Maynard C, et al. Effect of prehospital induction of mild hypothermia on survival and neurological status among adults with cardiac arrest: a randomized clinical trial. JAMA. 2014;311(1):45-52. PMID: 24240712

7. Kirkegaard H, Søreide E, de Haas I, et al. Targeted temperature management for 48 vs 24 hours and neurologic outcome after out-of-hospital cardiac arrest: a randomized clinical trial. JAMA. 2017;318(4):341-350. PMID: 28763548

8. Badjatia N, Strongilis E, Gordon E, et al. Metabolic impact of shivering during therapeutic temperature modulation: the Bedside Shivering Assessment Scale. Stroke. 2008;39(12):3242-3247. PMID: 18927450

9. Sandroni C, D'Arrigo S, Cacciola S, et al. Prediction of poor neurological outcome in comatose survivors of cardiac arrest: a systematic review. Intensive Care Med. 2020;46(10):1803-1851. PMID: 32915254

10. Beck B, Bray J, Cameron P, et al. Regional variation in the characteristics, incidence and outcomes of out-of-hospital cardiac arrest in Australia and New Zealand: results from the Aus-ROC Epistry. Resuscitation. 2018;126:49-57. PMID: 29476883

11. Andersen LW, Holmberg MJ, Berg KM, et al. In-hospital cardiac arrest: a review. JAMA. 2019;321(12):1200-1210. PMID: 30912843

12. Geocadin RG, Callaway CW, Fink EL, et al. Standards for studies of neurological prognostication in comatose survivors of cardiac arrest: a scientific statement from the American Heart Association. Circulation. 2019;140(9):e517-e542. PMID: 31291775

13. Bray JE, Bernard S, Cantwell K, et al. The association between systolic blood pressure on arrival at hospital and outcome in adults surviving from out-of-hospital cardiac arrests of presumed cardiac aetiology. Resuscitation. 2014;85(4):509-515. PMID: 24361673

14. Bernard SA, Gray TW, Buist MD, et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med. 2002;346(8):557-563. PMID: 11856794

Australian-Specific

15. Australian Institute of Health and Welfare. Cardiovascular disease in Aboriginal and Torres Strait Islander people. 2023. Cat. no. CVD 100.

16. Finn JC, Bhanji F, Lockey A, et al. Part 8: Education, implementation, and teams: 2015 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science with Treatment Recommendations. Resuscitation. 2015;95:e203-e224. PMID: 26477705

Pathophysiology

17. Sekhon MS, Ainslie PN, Griesdale DE. Clinical pathophysiology of hypoxic ischemic brain injury after cardiac arrest: a "two-hit" model. Crit Care. 2017;21(1):90. PMID: 28403909

18. Neumar RW. Molecular mechanisms of ischemic neuronal injury. Ann Emerg Med. 2000;36(5):483-506. PMID: 11054204

19. Polderman KH. Mechanisms of action, physiological effects, and complications of hypothermia. Crit Care Med. 2009;37(7 Suppl):S186-S202. PMID: 19535947

20. Yenari MA, Han HS. Neuroprotective mechanisms of hypothermia in brain ischaemia. Nat Rev Neurosci. 2012;13(4):267-278. PMID: 22353781

21. Polderman KH, Herold I. Therapeutic hypothermia and controlled normothermia in the intensive care unit: practical considerations, side effects, and cooling methods. Crit Care Med. 2009;37(3):1101-1120. PMID: 19237924

Paediatric

22. Moler FW, Silverstein FS, Holubkov R, et al. Therapeutic hypothermia after out-of-hospital cardiac arrest in children. N Engl J Med. 2015;372(20):1898-1908. PMID: 25913022

Trials

23. Bernard SA, Smith K, Finn J, et al. Induction of therapeutic hypothermia during out-of-hospital cardiac arrest using a rapid infusion of cold saline: the RINSE trial (Rapid Infusion of Cold Normal Saline). Circulation. 2016;134(11):797-805. PMID: 27562972

24. Perman SM, Ellenberg JH, Grossestreuer AV, et al. Shorter time to target temperature is associated with poor neurologic outcome in post-arrest patients treated with targeted temperature management. Resuscitation. 2015;88:114-119. PMID: 25541429

25. Lascarrou JB, Merdji H, Le Gouge A, et al. Targeted temperature management for cardiac arrest with nonshockable rhythm. N Engl J Med. 2019;381(24):2327-2337. PMID: 31577396

Systematic Reviews

26. Arrich J, Holzer M, Havel C, et al. Hypothermia for neuroprotection in adults after cardiac arrest. Cochrane Database Syst Rev. 2016;2:CD004128. PMID: 26878327

27. Soar J, Berg KM, Andersen LW, et al. Adult advanced life support: 2020 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science with Treatment Recommendations. Resuscitation. 2020;156:A80-A119. PMID: 33099419

Complications

28. Wolberg AS, Meng ZH, Monroe DM 3rd, et al. A systematic evaluation of the effect of temperature on coagulation enzyme activity and platelet function. J Trauma. 2004;56(6):1221-1228. PMID: 15211129

29. Callaway CW, Donnino MW, Fink EL, et al. Part 8: Post-cardiac arrest care: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2015;132(18 Suppl 2):S465-S482. PMID: 26472996

Prognostication

30. Rossetti AO, Rabinstein AA, Engelen J, et al. Electroencephalography predicts poor and good outcomes after cardiac arrest: a two-center study. Crit Care Med. 2017;45(7):e674-e682. PMID: 28410276

31. Stammet P, Collignon O, Hassager C, et al. Neuron-specific enolase as a predictor of death or poor neurological outcome after out-of-hospital cardiac arrest and targeted temperature management at 33°C and 36°C. J Am Coll Cardiol. 2015;65(19):2104-2114. PMID: 25975474

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