Targeted Temperature Management (TTM)

Introduction

Targeted Temperature Management (TTM), previously termed therapeutic hypothermia, is a neuroprotective strategy used in patients following cardiac arrest and selected hypoxic-ischemic brain injuries. 

Why TTM is Required — Pathophysiological Basis

Post–Cardiac Arrest Brain Injury (PCABI)

Brain injury after cardiac arrest occurs via two major mechanisms:

1. Primary Injury

Occurs during:

• No-flow phase (cardiac arrest)
• Low-flow phase (CPR)

Mechanisms:

• Global cerebral ischemia
• ATP depletion
• Loss of ion gradients
• Cytotoxic edema

2. Secondary Reperfusion Injury

Occurs after ROSC and is the main target of TTM

Mechanisms:

🔹 Excitotoxicity

🔹 Oxidative Stress

🔹 Inflammatory Cascade

🔹 Cerebral Edema

🔹 Mitochondrial Dysfunction

How TTM Provides Neuroprotection

TTM reduces injury via:

Indications of TTM

Primary Indication (Strong Evidence)

Adult Post Cardiac Arrest Patients with ROSC and Coma

Guideline Preferred Candidates:

• Out-of-hospital cardiac arrest (OHCA)
• In-hospital cardiac arrest (IHCA)
• Persistent coma (GCS motor ≤5)
• Both shockable and non-shockable rhythms

Evidence Supporting Use

Landmark Trials

🔹 HACA Trial (2002)

• Demonstrated improved neurological outcomes
• Temperature: 32–34°C

🔹 Bernard Trial (2002)

• Confirmed survival benefit

🔹 TTM Trial (2013)

• Compared 33°C vs 36°C
• Similar outcomes
• Highlighted importance of fever prevention

🔹 TTM2 Trial (2021)

• Compared hypothermia vs strict normothermia
• No mortality difference
• Reinforced fever avoidance as key goal

Current Guideline Recommendations (AHA 2020 / ERC 2021 / ILCOR 2022–24)

👉 Maintain 32–36°C for at least 24 hours
👉 Prevent fever (>37.7°C) for 72 hours

Other Possible Indications (Weaker Evidence)

• Neonatal hypoxic ischemic encephalopathy
• Refractory intracranial hypertension (selected cases)
• Severe traumatic brain injury (investigational)

Contraindications

Absolute

• Active uncontrolled bleeding
• Severe hemodynamic instability refractory to support
• DNR / expected futility

Relative

• Severe sepsis
• Pregnancy
• Coagulopathy
• Pre-existing terminal illness

Target Temperature Selection

👉 Modern guidelines allow any target between 32–36°C
👉 Consistency is more important than exact number

Phases of Targeted Temperature Management

Phase 1 — Induction Phase

Goal: Rapid cooling to target temperature

Methods of Cooling

Surface Cooling Techniques

Includes:

• Cooling blankets
• Gel pad cooling systems
• Ice packs
• Cold saline infusion (limited role now)

Advantages:

• Easy availability
• Non-invasive

Disadvantages:

• Slower cooling
• Temperature fluctuations
• Skin injury risk

Intravascular Cooling

Includes:

• Central venous cooling catheters
• Automated feedback systems

Advantages:

• Precise temperature control
• Faster cooling
• Less shivering variability

Disadvantages:

• Invasive
• Thrombosis risk
• Infection risk

Cooling Rate- 1–2°C per hour, Achieve target within 4–6 hours

Phase 2 — Maintenance Phase

Duration: Minimum 24 hours

Goals:

• Maintain stable target temperature
• Prevent shivering
• Maintain organ perfusion

Phase 3 — Rewarming Phase

Rewarming Rate: 0.15–0.25°C per hour(Max 0.5°C/hr)

Rapid rewarming causes:

• ICP spikes
• Electrolyte shifts
• Vasodilation
• Hemodynamic collapse

Phase 4 — Normothermia / Fever Prevention

Continue:
👉 Maintain <37.7°C for 72 hours

Monitoring During TTM

Core Temperature Monitoring Sites

Preferred sites:

• Esophageal probe
• Bladder probe
• Pulmonary artery catheter (gold standard)
• Rectal probe (least accurate)

Shivering — Major Barrier to TTM

Why Shivering is Harmful

• Increases metabolic rate
• Increases oxygen consumption
• Raises ICP
• Counteracts cooling

Shivering Management Protocol (Stepwise)

Step 1: Non-pharmacologic

• Skin counter-warming
• Adequate analgesia
• Sedation

Step 2: Pharmacologic

Sedatives

• Propofol
• Midazolam

Analgesics

• Fentanyl
• Remifentanil

Anti-shivering drugs

• Magnesium infusion
• Dexmedetomidine
• Buspirone

Step 3: Neuromuscular Blockade

Used when:

• Refractory shivering
• Ventilator dyssynchrony

Common:

• Cisatracurium
• Vecuronium

Systemic Physiological Effects of TTM

Cardiovascular Effects

Early Hypothermia

• Bradycardia (physiologic)
• Increased SVR
• Reduced cardiac output

Severe Hypothermia (<30°C)

• Arrhythmias
• QT prolongation

Respiratory Effects

• Reduced CO₂ production
• ABG interpretation must consider temperature correction

Metabolic Effects

Electrolyte Changes

Glucose

• Insulin resistance
• Hyperglycemia common

Coagulation Effects

• Platelet dysfunction
• Reduced clotting factor activity

Usually mild at 32–36°C

Renal Effects

• Cold diuresis
• Electrolyte wasting

Drug Pharmacokinetics

Hypothermia:

• Reduces hepatic metabolism
• Reduces renal clearance
• Drug accumulation risk

Sedation and Analgesia Strategy

Goal:

• Prevent shivering
• Provide ventilator synchrony
• Avoid over-sedation during neuro-prognostication

Preferred agents:

• Propofol
• Dexmedetomidine
• Short-acting opioids

Hemodynamic Management During TTM

Targets:

• MAP ≥65 mmHg (often higher 70–75 mmHg in PCABI)
• Optimize oxygen delivery
• Avoid hypotension

Preferred vasopressors:

• Norepinephrine
• Vasopressin adjunct

Ventilator Strategy During TTM

Maintain:

• Normoxia (SpO₂ 94–98%)
• Normocapnia (PaCO₂ 35–45 mmHg)

Avoid:

• Hyperoxia → oxidative injury
• Hypocapnia → cerebral vasoconstriction

Complications of TTM

Early Complications

• Arrhythmias
• Coagulopathy
• Electrolyte disturbances
• Insulin resistance

Late Complications

• Infection risk
• Skin injury
• Venous thrombosis
• Drug accumulation

Neuroprognostication During TTM

Guidelines: Delay neuroprognostication until:

• ≥72 hours after ROSC
• After rewarming
• After sedation clearance

Reason:Hypothermia + sedation produce false poor prognostic signs.