Pharmacological Approaches To Management Of Hypothermia-Induced Cardiac Dysfunction

Abstract

We performed randomized, controlled experimental studies in an intact rat model and in isolated rat cardiomyocytes with the following aims:

Paper I: To investigate the effects of epinephrine during hypothermia and after rewarming and determine hypothermia-induced effects on in vivo and in vitro cardiac β-receptor sensitivity.

Paper II: To describe hemodynamic responses to the phosphodiesterase 3 (PDE3) inhibitor milrinone when compared to saline infusion during rewarming from deep, stable hypothermia (15°C).

Paper III: To describe hemodynamic response and phosphorylation of cardiac troponin I (cTnI) during rewarming from deep, stable hypothermia with use of the calcium sensitizer and PDE3 inhibitor levosimendan, compared to animals given placebo.

Main results and conclusions: β-receptor sensitivity is increased in hypothermia (15°C) compared to normothermia (37°C) (paper I), but administering epinephrine at 15°C had adverse effects, expressed with increased afterload and negative inotropy. Cardiac dysfunction during rewarming from stable hypothermia is however ameliorated by PDE3 inhibition alone (paper I) and combined with calcium sensitizing (paper III). PDE3 inhibition through levosimendan possesses the ability to increase cTnI phosphorylation after rewarming from stable hypothermia (paper III). Treatment of hypothermia-induced cardiac dysfunction is therefore better achieved through intracellular strategies like PDE3 inhibition and calcium sensitizing than β-receptor stimulation.