Out-of-hospital cardiac arrest (OHCA) affects over 300,000 people annually and remains a major public health issue. Survival and recovery after cardiac arrest (CA) largely depend on restoring circulation and minimising brain injury from ischaemia and reperfusion following return of spontaneous circulation (ROSC). Early trials showed benefits of therapeutic hypothermia (TH) at 32–34 °C in OHCA patients with shockable rhythms, prompting guidelines to evolve towardtargeted temperature management (TTM), ranging from hypothermia (32–36 °C), normothermia (37 °C), to fever prevention (<37.5 °C). TTM with hypothermia is referred to as TTM-HT, while normothermia or fever prevention is termed TTM-NT. Although temperature control and pyrexia prevention can reduce brain injury, inconsistent trial results and variations in patient profiles, cooling methods, and protocols have led to confusion about optimal temperature targets. This uncertainty, compounded by physician biases and technical challenges, may contribute to inconsistent use of temperature control in post-CA care.
CA leads to cerebral ischaemia and neuronal damage, which is worsened by reperfusion injury after ROSC. Post-CA hyperthermia is linked to higher mortality. Hypothermia helps protect the brain by lowering metabolism, reducing excitotoxicity, and limiting oxidative stress, suggesting that patients with more severe brain injury may benefit from deeper cooling. However, uncertainties remain about the optimal use of TTM-HT, including the ideal temperature, the actual benefit in critically ill patients, and whether aggressive cooling helps specific groups or poses unnecessary risks.
Early studies like the HACA trial and Bernard et al. demonstrated improved neurological outcomes, and in HACA, reduced mortality, with cooling to 32–34 °C after OHCA due to shockable rhythms. These results led to strong recommendations for TH. However, later large-scale trials such as TTM1 and TTM2 found no survival benefit when comparing 33 °C to higher temperature targets (36 °C or ≤37.8 °C), which led to decreased enthusiasm for aggressive cooling.
Unlike early studies, TTM and TTM2 were rigorously designed with standardised neuroprognostication and strict temperature control in both arms. Yet, these trials enrolled patients with more favourable arrest characteristics, such as high rates of witnessed arrest, bystander CPR, and shockable rhythms which may limit generalisability to broader, more critically ill populations. In contrast, the HYPERION trial showed neurological benefit with hypothermia in patients with nonshockable rhythms and in-hospital arrests, despite no mortality difference.
While recent trials suggest no clear survival advantage of deeper hypothermia across all OHCA patients, earlier and real-world data imply that TTM-HT may still benefit patients with more severe neurological injury. The effectiveness of TTM-HT may thus depend on patient selection, arrest severity, and early initiation, highlighting a need for individualised approaches rather than a one-size-fits-all strategy.
Hesitation to start TTM-HT stems from uncertainty about its benefits and concerns over complications, influenced by varied patient factors, epinephrine use, rewarming times, and physician or institutional biases. Because neurological survival depends on rapid restoration of circulation and early injury mitigation, clinicians must decide quickly between TTM-NT and TTM-HT despite limited and non-generalisable trial data. This often leads to delayed or omitted temperature management, with real-world practice leaning toward a uniform approach that may neglect patient-specific needs and contribute to worse outcomes. Since the TTM2 trial, use of active cooling has declined, resulting in higher patient temperatures, more fevers, and increased mortality.
The recommended approach is to start guideline-based TTM-NT promptly, then escalate to TTM-HT when indicated by neurological injury severity, assessed through clinical exams, neuroimaging, EEG, and biomarkers. At centres with appropriate resources, a personalised, multidisciplinary strategy should guide temperature targets and care goals through shared decision-making.
A practical approach, supported by the HYPERION trial, is to use TTM-HT in patients showing severe anoxic-ischaemic brain injury, especially in those with nonshockable rhythms, unwitnessed arrests, and prolonged CPR/ROSC times (20–30 minutes). For patients with moderate injury, an intermediate temperature target of 34–36 °C may be appropriate. Patients with milder injury are best managed with normothermia and TTM-NT, as the benefit of deeper cooling appears limited for them.
While this stratified temperature approach aligns with clinical logic and some evidence, definitive proof is lacking, especially since large trials like TTM and TTM2 enrolled mainly less severe cases and found no clear interaction between risk profiles and temperature targets. Current American and European guidelines reflect this uncertainty by recommending a broad temperature range of 32–37.5 °C without tailoring targets to arrest characteristics.
Implementing TTM broadly faces challenges, especially in resource-limited settings lacking trained staff, specialised equipment, or protocols. Early withdrawal of life-sustaining therapy (WLST) remains a major cause of post-CA death, often premature and potentially preventable, underscoring the need for patience and standardised neuroprognostication per guidelines.
TTM-HT carries risks such as electrolyte imbalances, bradyarrhythmias, bleeding, and haemodynamic instability, which must be balanced against potential neurological benefits. Optimal care involves multidisciplinary coordination among intensivists, cardiologists, and other specialists, adherence to rewarming protocols, vigilant monitoring, and ongoing family communication to align treatment with patient values and realistic expectations.
As postresuscitation science evolves, future research should focus on timing, patient-specific arrest characteristics, neurological risk stratification, and cooling techniques to guide treatment decisions more precisely. Several ongoing trials (ICECAP, STEPCARE, PRINCESS 2) are investigating these critical questions. Ultimately, personalised, neuro-targeted temperature management is the next key step in improving outcomes for cardiac arrest survivors.
Source: JACC
Image Credit: iStock
References:
Mark JD, Lopez JL, Wahood W et al. (2025) Personalizing Temperature Targets After Cardiac Arrest: Our Neurologically Driven Approach. JACC.
