Pharmacological treatment of hypothermia-induced cardiac dysfunction

Cardiovascular dysfunction is a potentially lethal complication of hypothermia. Due to a knowledge gap, pharmacological interventions are not recommended at core temperatures below 30°C. Yet, further cooling is induced in surgical procedures and survival of accidental hypothermia is reported after rewarming from below 15°C, advocating a need for evidence-based treatment guidelines. In vivo studies proposed a combination of positive inotropic effects through intracellular cAMP-elevation and afterload reduction through arteriole smooth muscle cAMP and/or cGMP-elevation as a favorable strategy to prevent cardiovascular dysfunction in hypothermia. Further development of treatment guidelines demand information about temperature-dependent changes in pharmacological effects of clinically relevant vasodilators.

In our recent papers, we found PDE3- and PDE5-inhibitors were able to inhibit elimination of cGMP and cAMP down to 20°C. As the cellular effects of these drugs can provide increased inotropy and afterload reduction, they show potential in treating cardiovascular dysfunction during hypothermia.

Different in vitro models for studying the temperature-dependent effects of phosphodiesterase-enzymes and transporter proteins were utilized to evaluate how PDE-inhibitors sildenafil, vardenafil, milrinone, amrinone, levosimendan and pentoxifylline affected cellular efflux and enzymatic breakdown of cAMP and cGMP at 37°C-20°C. We also assessed the electrophysiological effects of levosimendan, milrinone and isoprenaline in hiPSC-derived cardiomyocytes. Recordings of cellular action potential waveforms and contraction were recorded from monolayers of cultured cells during cooling to 26°C and after rewarming.


Proarrhythmic changes in human cardiomyocytes during hypothermia by milrinone and isoprenaline, but not levosimendan: an experimental in vitro study (2023)

Moderate but not severe hypothermia increases intracellular cyclic AMP through preserved production and reduced elimination (2023)

Pharmacodynamic properties for inhibition of cAMP- and cGMP elimination by pentoxifylline remain unaltered in vitro during hypothermia (2022)

Treatment of Cardiovascular Dysfunction with PDE3-Inhibitors in Moderate and Severe Hypothermia—Effects on Cellular Elimination of Cyclic Adenosine Monophosphate and Cyclic Guanosine Monophosphate (2022)

Treatment of Cardiovascular Dysfunction With PDE5-Inhibitors – Temperature Dependent Effects on Transport and Metabolism of cAMP and cGMP (2021)


Erik Sveberg Dietrichs (Principal investigator)
Natalia Smaglyukova
Aina Westrheim Ravna
Roy Andre Lyså
Georg Sager
Anders Lund Selli
Ole Martin Fuskevåg