The TTM1 and TTM2 studies, published in The New England Journal of Medicine, explored the efficacy of different temperature management strategies in unconscious survivors of out-of-hospital cardiac arrest. TTM1 compared targeted temperatures of 33°C and 36°C, finding no significant difference in mortality or neurological outcomes. TTM2 examined hypothermia (33°C) versus normothermia with early fever control, similarly concluding that hypothermia provided no survival benefit. Despite these results, critiques have emerged regarding the interpretation and implementation of targeted temperature management (TTM) in clinical practice. This article analyzes the methodology, outcomes, and implications of both studies, addressing concerns raised by clinicians and offering insights into how TTM might still play a critical role in post-arrest care.
Targeted temperature management (TTM) has long been a cornerstone of post-cardiac arrest care. Early studies suggested that induced hypothermia could improve neurological outcomes by reducing cerebral metabolic demand and limiting ischemic injury. However, the optimal target temperature and its actual efficacy have remained subjects of debate. The TTM1 and TTM2 trials, conducted by international research teams, sought to clarify these uncertainties. While their findings challenge earlier assumptions, they have also sparked controversy over their interpretation and the subsequent shift in clinical practice.
The TTM1 Study: Comparing 33°C and 36°C
Study Design and Methods
The TTM1 trial, led by Niklas Nielsen, was a randomized controlled trial (RCT) involving 950 unconscious adults who experienced out-of-hospital cardiac arrest. Patients were randomly assigned to either 33°C or 36°C target temperature groups. The study aimed to determine whether a more aggressive cooling strategy (33°C) conferred any survival or neurological benefit compared to a slightly less hypothermic target (36°C).
Primary outcomes included all-cause mortality, while secondary outcomes assessed neurological function using the Cerebral Performance Category (CPC) and modified Rankin scale at 180 days.
Key Findings
The results revealed no significant difference in mortality between the two groups:
- Mortality Rates: 50% in the 33°C group vs. 48% in the 36°C group (P=0.51).
- Neurological Outcomes: Comparable across both groups, with no significant differences in CPC or modified Rankin scores.
Implications
The study concluded that targeting a temperature of 33°C did not offer a survival or functional advantage over 36°C. This finding challenged earlier recommendations favoring aggressive hypothermia and suggested that preventing fever, rather than inducing deep hypothermia, might be sufficient.
The TTM2 Study: Hypothermia vs. Normothermia
Study Design and Methods
The TTM2 trial, conducted by Josef Dankiewicz and colleagues, expanded the scope by comparing hypothermia at 33°C with targeted normothermia (maintaining body temperature below 37.8°C). A total of 1900 patients were enrolled, and outcomes were assessed at six months.
Primary outcomes focused on all-cause mortality, while secondary outcomes evaluated functional status using the modified Rankin scale. The study also recorded adverse events, including pneumonia, sepsis, and arrhythmias.
Key Findings
TTM2 found no significant difference in mortality or neurological outcomes between the groups:
- Mortality: 50% in the hypothermia group vs. 48% in the normothermia group (P=0.37).
- Functional Outcomes: Similar rates of disability (55% in both groups).
- Adverse Events: Arrhythmias were more common in the hypothermia group, but other complications were comparable.
Implications
The study concluded that hypothermia did not improve outcomes compared to normothermia with fever control. This reinforced the notion that active cooling may not be necessary if fever is adequately managed.
Critique and Controversies
Interpretation Challenges
An editorial by Laurie J. Morrison and Brent Thoma raised concerns about how the findings of these trials were interpreted and applied in clinical settings. Surveys indicated that many clinicians relaxed or abandoned TTM protocols, possibly misinterpreting the results as evidence that TTM is ineffective. Morrison and Thoma emphasized that both trials demonstrated an impressive 50% survival rate at six months—a significant improvement over historical outcomes (~25%)—suggesting that TTM remains a vital component of care, albeit with less emphasis on aggressive hypothermia.
Methodological Considerations
Critics have pointed out potential limitations in both studies:
- Patient Selection: Both trials focused on patients with out-of-hospital cardiac arrest of presumed cardiac cause, potentially limiting generalizability to other populations.
- Temperature Control: The normothermia group in TTM2 still received active temperature management, which may have confounded results.
- Blinding: TTM2 was open-label, although outcome assessments were blinded, which may introduce some bias.
Clinical Implications
Despite the lack of a clear survival benefit from deep hypothermia, TTM still plays a crucial role in preventing fever, which is known to worsen outcomes. The challenge lies in balancing effective temperature control without overreliance on aggressive cooling.
Conclusion
The TTM1 and TTM2 trials provide valuable insights into the nuanced role of targeted temperature management in post-cardiac arrest care. While neither study found a significant benefit from hypothermia at 33°C, they underscored the importance of preventing fever. Moving forward, clinicians should focus on individualized temperature management strategies, emphasizing fever control and considering patient-specific factors. Future research may further refine these approaches, ensuring optimal outcomes for cardiac arrest survivors.
Randomized Controlled Trial N Engl J Med, 2013 Dec, Niklas Nielsen, Jørn Wetterslev, Tobias Cronberg
Targeted temperature management at 33°C versus 36°C after cardiac arrest
Randomized Controlled Trial, Engl J Med, 2021 Jun, Josef Dankiewicz, Tobias Cronberg, Gisela Lilja
Hypothermia versus Normothermia after Out-of-Hospital Cardiac Arrest
Editorial N Engl J Med, 2021 Jun 17, Laurie J Morrison, Brent Thoma
Translating Targeted Temperature Management Trials into Postarrest Care + Journal
Review Article, Originally Published 16 August 2023, Sarah M. Perman, MD, MSCE, FAHA, Vice Chair