Is targeted temperature management (TTM) still indicated in adults with hypoxic-ischemic encephalopathy (HIE)?

Targeted Temperature Management in Adult HIE: Current Recommendations

Yes, targeted temperature management (TTM) remains indicated for adults with hypoxic-ischemic encephalopathy following cardiac arrest who remain comatose after return of spontaneous circulation (ROSC), with a target temperature maintained between 32°C and 36°C for at least 24 hours. 1, 2

Strength of Recommendation by Cardiac Arrest Type

Out-of-Hospital Cardiac Arrest (OHCA) with Shockable Rhythm

• Strong recommendation to use TTM for adults with OHCA and initial shockable rhythm (VF/pVT) who remain unresponsive after ROSC 1, 2
• This represents the highest level of evidence and strongest indication for TTM 1

Out-of-Hospital Cardiac Arrest with Non-Shockable Rhythm

• Weak recommendation to use TTM for adults with OHCA and initial non-shockable rhythm who remain unresponsive after ROSC 1
• Evidence quality is very low, but potential benefits outweigh minimal risks 1

In-Hospital Cardiac Arrest (IHCA)

• Weak recommendation to use TTM for adults with IHCA of any initial rhythm who remain unresponsive after ROSC 1
• Based on very-low-quality evidence from observational studies showing no clear benefit (OR 0.9,95% CI 0.65-1.23), but given high mortality and limited treatment options, TTM is still suggested 1

Target Temperature Selection

Select and maintain a constant target temperature between 32°C and 36°C (strong recommendation, moderate-quality evidence) 1

Key Evidence on Temperature Targets

• The landmark TTM trial (939 patients) compared 33°C versus 36°C and found no significant difference in mortality (HR 1.06,95% CI 0.89-1.28) or neurologic outcome at 6 months (RR 1.02,95% CI 0.88-1.16) 1
• This means both 33°C and 36°C are acceptable targets—the critical factor is maintaining a constant temperature within this range 1
• Whether specific subpopulations benefit from lower (32-34°C) versus higher (36°C) temperatures remains unknown 1

Duration of TTM

Maintain TTM for at least 24 hours after achieving target temperature 1, 3

• The two largest RCTs used 24-28 hours at target temperature 1, 3
• No evidence supports extending beyond 24 hours—observational data show no difference between 24 versus 72 hours of hypothermia 1, 3
• After the initial 24-hour TTM period, continue strict fever prevention until 72 hours after ROSC, maintaining temperature <37.5°C 3, 2

Rewarming Protocol

• Rewarm gradually at approximately 0.25-0.5°C per hour to avoid rebound hyperthermia and secondary brain injury 3
• Prevent fever aggressively during and after rewarming, as hyperthermia is associated with worse outcomes 2

Rationale for Continued Use Despite Mixed Evidence

The 2015 International Consensus guidelines emphasize several critical points:

• Mortality after cardiac arrest is extremely high and treatment options are severely limited 1
• TTM is the only post-ROSC intervention that has been found to improve survival with good neurologic outcome 1
• The potential for increased survival with good neurologic outcome outweighs the minimal risks and costs of TTM 1
• Even though evidence quality is low to moderate, the strong recommendation reflects the lack of alternatives and potential benefit 1

Common Pitfalls and Caveats

Temperature Control Precision

• Avoid temperature fluctuations—maintain a constant target temperature throughout the 24-hour period 1, 3
• The TTM trial achieved 91.67% time within 1°C of target (median 95.83%) 4

Drug Dosing Considerations

• TTM significantly alters pharmacokinetics of cytochrome P450-metabolized drugs, with effects lasting 4-5 days post-treatment 5
• Monitor sedative and analgesic levels closely, as hypothermia increases drug concentrations during cooling and rewarming phases 5

Prognostication Timing

• Delay neurologic prognostication until after rewarming and allow adequate time for sedation clearance, as TTM modifies clinical assessments 1
• Use multiple modalities (EEG, somatosensory evoked potentials, biomarkers, neuroimaging) rather than single predictors 1

Contraindications

• TTM is not recommended for patients who are awake and following commands after ROSC 1, 2
• The indication is specifically for those who remain comatose/unresponsive after ROSC 1, 2

Knowledge Gaps

• No high-quality evidence exists for optimal temperature targets tailored to individual patients based on injury severity 1
• The benefit in non-shockable rhythms and IHCA remains uncertain due to very-low-quality evidence 1
• More detailed neurocognitive evaluations are needed to determine granular outcome differences 1