Highlights
- Targeted hypothermia at 33°C does not improve functional outcomes or societal participation at 24 months compared to targeted normothermia with early fever management.
- Cognitive outcomes, measured by MoCA and SDMT, showed no significant difference between the two temperature strategies in the long term.
- The majority of functional recovery occurs within the first six months post-arrest, followed by a general plateau in the overall population.
- Despite the population-level plateau, significant intraindividual variability exists, with some patients continuing to improve or decline up to two years later.
The Evolution of Temperature Management in Post-Cardiac Arrest Care
For nearly two decades, targeted temperature management (TTM) has been a cornerstone of post-cardiac arrest care. Following two landmark trials in 2002, clinical guidelines pivoted toward the use of induced hypothermia (32°C to 34°C) to mitigate the effects of post-cardiac arrest syndrome and improve neurological recovery. However, the physiological rationale—reducing cerebral metabolic rate and limiting reperfusion injury—has been increasingly scrutinized as subsequent larger trials failed to replicate early successes.
The original TTM trial (2013) suggested no difference between 33°C and 36°C. More recently, the TTM2 trial (2021) compared 33°C to targeted normothermia (keeping temperature below 37.8°C) and found no benefit at six months. Critics of these findings argued that six months might be too short a window to capture the full spectrum of neurological recovery or the potential long-term benefits of early neuroprotection. The 2-year follow-up of the TTM2 trial, recently published in JAMA Neurology, provides the definitive long-term data needed to address these concerns.
Methodology of the TTM2 Long-Term Follow-Up
The TTM2 trial was an international, multicenter, randomized clinical trial involving 61 hospitals across 14 countries. It included 1,861 adults who experienced out-of-hospital cardiac arrest (OHCA) of presumed cardiac or unknown cause and remained comatose upon hospital admission. Participants were randomized 1:1 to either targeted hypothermia at 33°C for 24 hours or targeted normothermia, where fever (≥37.8°C) was aggressively managed with cooling devices if necessary.
The primary focus of this long-term follow-up was functional outcome and societal participation at 24 months, as measured by the Glasgow Outcome Scale-Extended (GOSE). Secondary outcomes focused on cognitive functioning, utilizing the Montreal Cognitive Assessment (MoCA) for global cognition and the Symbol Digit Modalities Test (SDMT) for processing speed and executive function. The researchers also sought to map recovery trajectories by comparing outcomes at 1, 6, and 24 months post-randomization.
Of the initial survivors, 835 participants were available for the 24-month assessment. While there was some attrition (20% nonparticipation at 24 months), the study remains one of the largest and most robust longitudinal analyses of cardiac arrest survivors ever conducted.
Key Findings: Stability in Outcomes Between 6 and 24 Months
Functional Outcomes and Societal Participation
The analysis revealed that at 24 months, there was no statistically significant difference between the hypothermia and normothermia groups regarding functional outcomes. The odds ratio (OR) for a better GOSE score in the hypothermia group was 0.97 (95% CI, 0.72-1.30), indicating that lowering the body temperature to 33°C did not improve the likelihood of returning to previous levels of social or professional activity.
The GOSE scores demonstrated that most survivors achieved a high level of independence. However, the data also highlighted that the functional status of patients at six months is highly predictive of their status at two years. The significant improvements observed between one month and six months (P < .001) were not mirrored in the period between six and 24 months (P = .10), suggesting a functional plateau for the majority of survivors.
Cognitive Performance
Cognitive impairment is a major concern for OHCA survivors, often affecting memory, attention, and executive function. In the TTM2 follow-up, cognitive scores were remarkably similar between the two treatment arms. The mean difference for the MoCA was a negligible -0.02 (95% CI, -0.67 to 0.63), and for the SDMT, it was -0.09 (95% CI, -0.33 to 0.16). These results reinforce the conclusion that the depth of temperature control in the acute phase does not alter the long-term cognitive trajectory of survivors.
Analyzing Recovery Trajectories and Individual Variability
Perhaps the most clinically insightful aspect of the study is the exploration of recovery trajectories. While the population-level data suggest a plateau after six months, the intraindividual data tell a more nuanced story. The researchers observed both significant improvements and declines in individual patients between six and 24 months.
These fluctuations exceeded the thresholds for “minimal important differences,” suggesting that for a subset of patients, recovery is a dynamic process that continues long after the initial injury. This variability may be attributed to several factors, including the quality of post-discharge rehabilitation, secondary health complications, or the psychological impact of surviving a life-threatening event. For clinicians, this underscores the necessity of long-term monitoring and personalized rehabilitation programs, as some patients may still achieve meaningful gains well into their second year of recovery.
Expert Commentary: Shifting the Focus from Temperature to Rehabilitation
The TTM2 2-year follow-up effectively closes the door on the debate over 33°C versus normothermia for unselected OHCA patients. The lack of long-term benefit, coupled with the potential side effects of deep hypothermia—such as increased risk of arrhythmias, sepsis, and the need for prolonged sedation—suggests that targeted normothermia should be the standard of care.
However, it is vital not to interpret these results as a sign that “temperature doesn’t matter.” The normothermia arm of the TTM2 trial involved strict fever prevention, which is likely a key component of neuroprotection. The study suggests that preventing the secondary insult of hyperthermia is the critical intervention, rather than the induction of hypothermia itself.
Furthermore, the data regarding recovery trajectories suggest that the medical community should shift its focus from the acute cooling phase to the long-term rehabilitative phase. If the neurological damage is largely determined by the time of hospital arrival and the subsequent management of fever and oxygenation, then the greatest opportunity for improving “societal participation” may lie in multidisciplinary neuro-rehabilitation and psychological support during the first year of survival.
Study Limitations and Considerations
The study authors acknowledge several limitations. While the 24-month follow-up is extensive, there was a 20% nonparticipation rate, which could introduce bias if those who did not participate had significantly different outcomes. Additionally, the study primarily included patients with witnessed arrests and shockable rhythms, meaning the results might not be fully generalizable to patients with prolonged untreated downtime or non-shockable rhythms, who generally have a poorer prognosis.
Finally, while the GOSE and MoCA are validated tools, they may not capture subtle neurocognitive deficits or specific quality-of-life nuances that are important to patients and their families. Future research should perhaps focus on more sensitive biomarkers of brain injury or more granular assessments of emotional and social well-being.
Conclusion
The TTM2 2-year follow-up provides high-quality evidence that targeted hypothermia at 33°C offers no long-term functional or cognitive advantage over targeted normothermia for OHCA survivors. These findings support a shift in clinical practice toward maintaining normothermia and preventing fever, while emphasizing that the first six months are the most critical period for functional recovery. However, the observed individual variability in recovery trajectories serves as a reminder that post-cardiac arrest care is a long-term commitment, requiring ongoing assessment and support far beyond the intensive care unit.
Funding and Trial Registration
The TTM2 trial was supported by grants from the Swedish Research Council, the Swedish Heart-Lung Foundation, and various regional health authorities in Sweden and participating countries. The trial is registered at ClinicalTrials.gov (NCT02908308).
References
- Hultgren M, Blennow Nordström E, Ullén S, et al. Long-Term Outcomes and Recovery Trajectories in Out-of-Hospital Cardiac Arrest: A 2-Year Follow-Up of the Randomized Clinical TTM2 Trial. JAMA Neurol. Published online February 16, 2026. doi:10.1001/jamaneurol.2025.5614
- 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.
- 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.
- Nolan JP, Sandroni P, Bottiger BW, et al. European Resuscitation Council and European Society of Intensive Care Medicine guidelines for post-resuscitation care 2021. Intensive Care Med. 2021;47(4):369-421.
