The TTM Trial was just published today in the NEJM (Nielsen et al. Targeted Temperature Management at 33°C versus 36°C after Cardiac Arrest NEJM 2013;epub Nov 17, 2013)
For my take and the take of Jon Rittenberger, come to the 2nd TTM Post
but even more important is to hear from the primary author himself: Niklas Nielsen on the TTM Trial
International multicenter RCT
Inclusion criteria: Age >= 18 years, out-of-hospital cardiac arrest of presumed cardiac cause, unconsciousness (Glasgow Coma Score <8) after sustained return of spontaneous circulation (ROSC) (20 minutes of circulation).
Exclusion criteria: Conscious patients, pregnancy , out-of-hospital cardiac arrest of presumed non-cardiac cause, cardiac arrest after arrival in hospital, known bleeding diathesis, suspected or confirmed acute intracranial bleeding, suspected or confirmed acute stroke, temperature on admission <30°C, unwitnessed asystole, persistent cardiogenic shock, known limitations in therapy, known disease making 180 day survival unlikely, known pre-arrest cerebral performance category 3 or 4, >240 minutes from ROSC to randomisation.
Primary outcome: Survival to end of trial (at least 180 days).
Secondary outcomes: Composite outcomes of all-cause mortality and poor neurological function (Cerebral Performance Category (CPC) 3 and 4 and modified Rankin Scale (mRS) 4 and 5) at 180 days. All – cause mortality and CPC and mR S at 180 – days. Adverse events: Bleeding, pneumonia, sepsis, electrolyte disorders, hyperglycaemia, hypoglycaemia, cardiac arrhythmia, renal replacement therapy.
Tertiary outcomes: Complete neurological recovery. Best neurological outcome during trial perio d. Quality of life according to SF – 36. Biomarkers at 24, 48 and 72 hours
Intervention: The core body temperature will be set as quickly as possible at the predefined target temperature, according to intervention allocation, with 4°C intravenous solutions, 43 ice – packs 8, 44 and commercially available cooling devices 45 at the discretion of the treating physician . The target core temperature is then maintained for 24 h. After the maintenance period core temperature is gradually raised to normothermia of 37°C during 8 hours with a rewarming rate of 0.5°C/hour in both groups. Body temperature is then maintained at normothermia 37 ±0.5°C until 72 hours from sustained ROSC in both treatment groups, as long as the patient is in the ICU, using pharmacological treatment and temperature management systems when applicable
See all of the nitty-gritty in the appendix
rewarmed at 0.5 C/hr and then induced normothermia (37.5 C) for 36 hrs post arrest
Nonblinded to temp allocation, but neuro assessment was blinded
fluids icepacks surface and intravasc cooling– 1/4 intravasc and rest surface
900 pts give 90% power to detect 20% difference
80% shockable, 12% asystole
Table S2 – SOFA-C Scores in the first 72 hours
*SOFA denotes Sequential Organ Failure Assessment, SOFA-C denotes the cardiovascular subcomponent of the SOFA score. SOFA-C=0 No need for inotrope or vasopressor, mean arterial pressure (MAP) > 70mmHg, SOFA-C =1 MAP < 70mmHg, SOFA-C=2 any dose of dobutamine or dopamine <5 ìg/kg/minute, SOFA-C=3 dopamine 5-15 ìg/kg/minute or epinephrine or nor-epinephrine <0.1 ìg/kg/minute, SOFA-C=4 dopamine >15 ìg/kg/minute or epinephrine or nor-epinephrine >0.1 ìg/kg/minute.
Neuroprognostication from the TTM Trial
Excerpted from Life in the Fast Lane CCC
The TTM trial (Nielsen et al, 2013) used a standardised protocol for neurological prognostication to guide decisions regarding treatment withdrawal following targeted temperature management post-cardiac arrest:
- All patients in the trial were actively treated until a minimum 72 hours after the intervention period, i.e. after rewarming, when neurological evaluation was done on patients not regaining consciousness.
Exceptions from this rule were
- (1) patients with myoclonus status in the first 24 hours after admission and a bilateral absence of N20-peak on median nerve somatosensory evoked potentials (SSEP)
- (2) patients who became brain dead due to cerebral herniation, and
- (3) because of ethical reasons described below.
At that time-point, limitations in and withdrawal of therapy could be instituted by the treating physicians. The neurological evaluation was based on:
- clinical neurological examination (including Glasgow Coma Scale (GCS), pupillary and corneal reflexes)
- SSEP and electroencephalogram (EEG)
- Biomarkers for brain damage were not used for operational prognostication
Findings allowing for discontinuation of active intensive care:
- Brain death due to cerebral herniation
- Severe myoclonus status in the first 24 hours after admission and a bilateral absence of N20-peak on median nerve SSEP
- Minimum 72 hours after the intervention period: persisting coma with a Glasgow Motor Score 1-2 and bilateral absence of N20-peak on median nerve SSEP.
- Minimum 72 hours after the end of the intervention period: persisting coma with a Glasgow Motor Score 1-2 and a treatment refractory status epilepticus (see TTM trial supplement for definition)
Patients with Glasgow Motor Score 1-2 at 72 hours or later who had retained N20-peak on the SSEP, or patients in hospitals where SSEP was not available were:
- re-examined daily
- the limitations/withdrawal of intensive care considered if GCS-Motor did not improve and metabolic and pharmacological affection was ruled out
Active treatment could be withdrawn prior to 72 hours after the intervention period for ethical reasons
- for instance: previously unknown information about disseminated end-stage cancer or refractory shock with end-stage multiorgan failure
- However assumptions of a poor neurological function were not allowed be the sole reason for withdrawal of active treatment prior to 72 h after the intervention period (exception: brain death and early myoclonus status including a negative SSEP)
Should we change right now?
In the coming months, you may see induced hypothermia protocols changing to induced normothermia protocols. Read the study and tell me what you think in the comments. This article just published in Resuscitation adds additional credence to the concept of: fever=bad.(23153649)
And here is an excellent rebuttal from Kees Polderman on the ditching of 33 (Polderman Kees H. and Varon Joseph. Therapeutic Hypothermia and Temperature Management. June 2015, 5(2): 73-76. doi:10.1089/ther.2014.0031. )