Targeted hypothermia vs. targeted normothermia after out-of-hospital cardiac arrest, a randomised clinical trial

The TTM1 trial (NCT01020916) [1] was a multicenter, multinational, outcome
assessor-blinded,
parallel group, randomised clinical trial comparing two strict target
temperature regimens of
33°C and 36°C in adult patients, who had sustained return of spontaneous
circulation and were
unconscious after out-of-hospital cardiac arrest, when admitted to hospital.
The trial did not
demonstrate any difference in survival until end of trial (Hazard Ratio with a
point estimate
in favour of 36°C of 1.06 (95% confidence interval 0.89-1.28; P=0.51)) or
neurologic function at
six months after the arrest, measured with the Cerebral Performance Category
(CPC) and the
modified Rankin Scale (mRS).

We designed the study to test the hypothesis that post-ischaemic hypothermia,
when compared to
normothermia and early treatment of fever, decreases mortality and improves
neurologic function
in unconscious adults after out-of-hospital cardiac arrest. This hypothesis
will be assessed by
studying the primary and secondary endpoints at 180 days after cardiac arrest.

The planned study is a international, multicenter, parallel group,
non-commercial, randomised,
superiority trial in which a target temperature of 33°C after cardiac arrest
will be compared to
normothermia with early treatment of fever (37.8°C)

The intervention period will commence at the time of randomisation. Rapid
cooling in the
hypothermia group will be achieved by means of cold fluids and state-of-the-art
cooling devices
(intravascular/body-surface/nasal/oesophageal). A closed loop system will be
used to maintain
the target temperature. In the normothermia arm the aim will be early treatment
of fever
(37.8°C) using pharmacological measures and physical cooling when needed. For
patients
who develop a temperature of 37.8°C (trigger), a device will be used and set at
37.5°C. All
patients will be sedated, mechanically ventilated and haemodynamically
supported throughout
the intervention period of 40 hours. After 28 hours the patients in the
hypothermia group will
be rewarmed during 12 hours.

Standard therapy for patients in coma after cardiopulmonary resuscitation is 24
hours hypothermia, but the most effective target temprature is at the moment
uncertain. Known adverse effects of hypothermia treatment are with infection,
coagulopathy, electrolyte disorders and arrhythmia. To enable treatment with
hypothermia the patient has to be sedated thoroughly which also has risks. The
burden and risk of patients in this study is comparable to the burden of the
standard treatment with hypothermia. Additional test needed for this study are
serum sampling for neuron specific enolase levels and two return visits to the
hospital for follow-up tests.