Thread by @JohannesGrand

**Fever-prevention and Temperature Control after Cardiac Arrest**

Tomorrow, an important intervention from #BOXtrial will be presented by my supervisor prof @CHassager from @cardiac_group:
Device-based prevention of fever 🌡️ (after 24 hours of #TTM). This requires a tweetorial

Targeted temperature management (therapeutic hypothermia, now temperature control) has been the cornerstone of neuroprotection in patients resuscitated but comatose after #OHCA for the past 20 years

The exact mechanism of action is unknown.
Experimental data suggest that low temperature decreases the cerebral metabolic rate, and consequently reduces the release of excitatory aminoacids and free radicals.

Several case reports have also showed, that #hypothermia BEFORE cardiac arrest can protect the brain. Ie.: doi.org/10.1007/BF0170…

In the 1900's research into this matter intensified. Hypothermia was used during open heart surgery with great effect, and mild hypothermia applied after a cardiac arrest mitigated brain damage in dogs. doi.org/10.1161/01.STR…

The first published randomised trial was the HACA trial in 2002 https://10.0.4.32/NEJMoa012689

29 patients after OHCA with ventricular fibrillation randomised to 32–34°C for 24 h) or standard therapy. Trial stopped after 273 patients because of slow recruitment.

Mortality at 6 months was 41% in the hypothermia group and 55% in the group that did not receive targeted tempterature management (risk ratio 0·74, 95% CI 0·58–0·95)

The second trial, by Bernard et al. supported these findings. It was a quasirandomised trial of 77 patients treated temperature at 32–34°C for 12 h. https://10.1056/NEJMoa003289
In-hospital mortality was 51% in the hypothermia group and 68% in control group

Based on this evidence, treatment with targeted temperature management entered the guidelines as standard therapy for OHCA due to ventricular fibrillation.

"There's always a but" with reference to @drjohnm
And a big but indeed:
During the 2010s cooling was studies intensively. Almost all trials, couldn't find positiv effects of cooling.
Rapid cooling, prehospital cooling, longer duration of cooling, intra-arrest cooling, negative

2013: Enter the #TTM-trial. HTTPS://10.1056/NEJMoa1310519
939 patients resuscitated after OHCA were randomly assigned to 33°C or 36°C for 24 h. Prevention of fever for the first 72 h was attempted in both groups (this is important. Remember this)

Mortality at 6 months did not differ between the groups (hazard ratio [HR] 1·06, 95% CI 0·89–1·28. Furthermore, there were no indications of any difference between groups in neurological function.

Guidelines changed and several centers changed to 36 degrees TTM. Since this temperature is close to normal, the question arised:
Do hypothermia after cardiac arrest really benefit patients?

To answer this question, the #TTM2 trial was published in 2021.
1850 randomly allocated to either:
1. 24 h at 33°C, followed by controlled rewarming, or
2. No temperature controle (normothermia) with fever-prevention (body temperature, ≥37.8°C)

At 6 months, 465 of 925 patients (50%) in the hypothermia group had died, compared with 446 of 925 (48%) in the normothermia group (relative risk with hypothermia, 1.04; 95% confidence interval [CI], 0.94 to 1.14; P = 0.37).

Newest guidelines from @ERC_resus and @ESICM • HTTPS://10.1007/s00134-022-06620-5 does not recommend for or against temperature control at 32-36 °C or early cooling after cardiac arrest.

However, they recommen in patients who remain comatose after cardiac arrest, continuous monitoring of core temperature and actively preventing fever (defined as a temperature > 37.7 °C) for at least 72 h.

Now back to the study at hand.

We randomly assigned comatose patients resuscitated after OHCA the either:
1. TTM at 36°C for 24 hours + 12 h device-based temperature controle of 37°C, or
2. TTM at 36°C for 24 hours + 48 device-based temperature controle of 37°C.

The primary outcome was a composite of death
from any cause or hospital discharge with a Cerebral Performance Category of 3 or 4 (range, 1 to 5, with higher scores indicating more severe disability; a category of 3 or 4 indicates severe cerebral disability or coma) within 90 days

It have been an absolute priviligie to be part of #boxtrial.
Thanks to my supervisors @jek_kj @CHassager and colleagues/friends:
@JakobHartvig @scwib @joyland2704 @BorregaardBritt @BCNyholm @JosiassenJakob

Study results will be presented at this years #ReSS22 late breaking session sunday 2:15 PM (GMT-5)