The Effect of Targeted Temperature Management on the Metabolome Following Out-of-Hospital Cardiac Arrest

Abstract

Targeted temperature management (TTM) may moderate the injury from out-of-hospital cardiac arrest. Slowing the metabolism has been a suggested effect. Nevertheless, studies have found higher lactate levels in patients cooled to 33°C compared with 36°C even days from TTM cessation. Larger studies have not been performed on the TTM's effect on the metabolome. Accordingly, to explore the effect of TTM, we used ultra-performance liquid–mass spectrometry in a substudy of 146 patients randomized in the TTM trial to either 33°C or 36°C for 24 hours and quantified 60 circulating metabolites at the time of hospital arrival (T₀) and 48 hours later (T₄₈). From T₀ to T_48, profound changes to the metabolome were observed: tricarboxylic acid (TCA) cycle metabolites, amino acids, uric acid, and carnitine species all decreased. TTM significantly modified these changes in nine metabolites (Benjamini–Hochberg corrected false discovery rate <0.05): branched amino acids valine and leucine levels dropped more in the 33°C arm (change [95% confidence interval]: −60.9 μM [−70.8 to −50.9] vs. −36.0 μM [−45.8 to −26.3] and −35.5 μM [−43.1 to −27.8] vs. −21.2 μM [−28.7 to −13.6], respectively), whereas the TCA metabolites including malic acid and 2-oxoglutaric acid remained higher for the first 48 hours (−7.7 μM [−9.7 to −5.7] vs. −10.4 μM [−12.4 to −8.4] and −3 μM [−4.3 to −1.7] vs. −3.7 μM [−5 to −2.3]). Prostaglandin E2 only dropped in the TTM 36°C group. The results show that TTM affects the metabolism hours after normothermia have been reached.

Clinical Trial Number: NCT01020916