Cooling after out-of-hospital cardiac arrest: The TTM2 trial

• Incredible follow-up! 72% of participants had face-to-face follow-up with structured mRS assessment in 94% of participants. Binary assessment of functional status performed in 98% of participants. Very few missing data on mortality (<1%).
• Variability in clinical practice was minimized by utilizing protocolized care with minimal protocol deviation related to temperature management.
• Shivering was aggressively controlled in the study with a standardized protocol.

Limitations

• Only ~20% of the subjects enrolled in the study were female.
• 56% of screened patients were not randomized into the trial due to various reasons
• This study did not explore the effect of no temperature management on patient outcomes. It would have been nice to see a third group in this study that evaluated the effect of no temperature control. Based on previous studies, the working hypothesis is that avoiding fever is the name of the game with therapeutic hypothermia. In the past, the overwhelming data behind targeted temperature management, made it “unethical” to include a pure control group. Perhaps in light of this data, no temperature control versus fever prevention should be the next study conducted.
• The external validity of this study is questionable with >90% of subjects having bystander-witnessed arrest and ~80% having bystander CPR. Nearly three-quarters of patients had an initial rhythm that was a shockable rhythm. The proportion of STEMI patients was also quite large. Most of the places where we (the authors) work, do not see this cohort of patients.
• Surface cooling was used more frequently than intravascular devices (70% vs. 30%), and almost half of the normothermia group also received some cooling. This is also slightly questionable as more often than not, we (the authors) are inserting intravascular cooling devices to manage temperature, as opposed to using surface cooling devices.
• In-hospital cardiac arrests were excluded from the study.
• Unwitnessed asystole patients were also excluded from the study; however, these patients have very poor prognosis in general. Achieving ROSC in this group is a challenge in and of itself.
• It is unclear why the authors did not randomize patients who had noncardiac causes of cardiac arrest. Since we perform targeted temperature management to preserve brain function, does the brain know why the blood isn’t flowing?
• 130 protocol deviations in 126 participants (63 in each group); 6.7% of the study population
  • 8 randomized despite not fulfilling eligibility criteria
  • 10 participants did not have intervention started due to cerebral hemorrhage or brain death
  • 7 participants’ interventions were stopped before 6 hours and palliative care was started
  • 3 protocol deviations in temperature management
  • 29 early awakening
  • 11 missing EEGs
  • 62 participants had deviations from the protocol for neuroprognostication

Discussion

Compared to the early hypothermia studies, the TTM2 trial contains a larger sample size and is generally better designed to minimize bias. Josh Farkas (@pulmcrit) aptly refers to the study as a “methodological fortress”. It showed that OHCA patients who were randomized to receive lower targeted temperature did not have better mortality and functional outcome and suffered from increased iatrogenic harm (specifically arrhythmias) compared to patients who were kept normothermic. The authors propose some possible reasons for arrhythmias causing hemodynamic instability: electrolyte disturbances, fluid status, and temperature effect on cardiac myocytes. They also note that of 53 patients that were rewarmed in the hypothermia group, 17 (32%) were due to hemodynamic compromise and 12 (23%) were due to bradycardia.

The supplementary materials in the paper also list the various unexpected serious adverse events, ranging from leg ischemia, cardiac tamponade, major stroke, tension pneumothorax, tracheal injury during intubation, and many others. In fact, patients in the hypothermia group had more than twice as many unexpected complications than patients in the normothermia group (3.7% vs. 1.4%). Is “therapeutic hypothermia” really therapeutic with all of these complications?

Based on the results of this trial, is it time to change clinical practice and completely forget about “therapeutic hypothermia”? Given the results of highly-powered studies like the TTM and TTM2 trials, hypothermia is becoming less and less useful as a means to prevent further neurologic injury. While it seems clear that targeted temperature management to 33C does not improve outcomes compared to normothermia, it is hard to ignore the skewed patient population included in this study (~90% witnessed arrest, ~80% bystander CPR, ~80% male, ~72% shockable). These demographics are also consistently found in the 2013 TTM trial. Despite this, we may be seeing a shift to temperature control at normothermic ranges and prevention of fevers.

Author’s Conclusion

“Patients with coma after out-of-hospital cardiac arrest who were treated with hypothermia did not have a lower incidence of death at 6 months than those who were treated with normothermia.”

Our Conclusion

Protocolized care that focuses on achieving hypothermia (32C-33C) is not supported by current evidence and may confer risk without clear benefit. Active temperature management targeting normothermia and avoiding fever makes more logical sense; however, further studies need to be conducted to actually determine if targeted temperature management (at normothermic temperatures) actually has any benefit.