Cardiovascular Effects of Epinephrine During Experimental Hypothermia (32°C) With Spontaneous Circulation in an Intact Porcine Model

Abstract

Aims: Rewarming from accidental hypothermia and therapeutic temperature management could be complicated by cardiac dysfunction. Although pharmacologic support is often applied when rewarming these patients, updated treatment recommendations are lacking. There is an underlying deficiency of clinical and experimental data to support such interventions and this prevents the development of clinical guidelines. Accordingly, we explored the clinical effects of epinephrine during hypothermic conditions.Materials and methods: Anesthetized pigs were immersion cooled to 32°C. Predetermined variables were compared at temperature/time-point baseline, after receiving 30 ng/kg/min and 90 ng/kg/min epinephrine infusions: (1) before and during hypothermia at 32°C, and after rewarming to 38°C (n = 7) and (2) a time-matched (5 h) normothermic control group (n = 5).Results: At 32°C, both stroke volume and cardiac output were elevated after 30 ng/kg/min administration, while systemic vascular resistance was reduced after 90 ng/kg/min. Epinephrine infusion did not alter blood flow in observed organs, except small intestine flow, and global O2 extraction rate was significantly reduced in response to 90 ng/kg/min infusion. Electrocardiographic measurements were unaffected by epinephrine infusion.Conclusion: Administration of both 30 ng/kg/min and 90 ng/kg/min at 32°C had a positive inotropic effect and reduced afterload. We found no evidence of increased pro-arrhythmic activity after epinephrine infusion in hypothermic pigs. Our experiment therefore suggests that β₁-receptor stimulation with epinephrine could be a favorable strategy for providing cardiovascular support in hypothermic patients, at core temperatures >32°C.

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

“…β-receptor stimulation through administration of isoprenaline, has earlier been suggested to lack inotropic effects during hypothermia when administered to rats [ 37 , 38 ]. However, recent studies have shown that β1-stimulus by epinephrine has positive inotropic effects on pigs cooled down to 32 °C [ 6 ], which corresponds with the findings in the present study. A case report from 2015 also indicates that isoprenaline had beneficial effect in treatment of VF in an accidental hypothermia patient [ 39 ].…”

“…Thus, treatment guidelines for accidental hypothermia recommend withholding any drug administration until a core temperature of at least 30 °C is reached [ 2 ]. However, recent studies have shown that phosphodiesterase 3 (PDE3)-inhibitors and β-receptor stimulators have the potential to alleviate HCD in vivo [ 6 – 8 ], and that the cellular mechanisms of these drugs remain intact at temperatures down to 20 °C [ 9 , 10 ].…”

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

“…Well-known β-receptor agonists, such as epinephrine and isoproterenol, increase cAMP levels through the adenylyl cyclase (AC) pathway. Studies in a rat model of severe hypothermia suggest that these drugs increase SVR without simultaneous positive inotropic effect ( Dietrichs, Sager and Tveita, 2016 ) but species-dependent differences exist ( Mohyuddin et al, 2021 ). More promisingly, in vivo studies performed in rat models, have demonstrated that PDE3 inhibitors, such as milrinone and levosimendan, have positive effects on stroke volume and cardiac output, almost restoring these parameters to baseline levels during rewarming ( Detrichstrichs et al, 2014a; Dettrichstrichs et al, 2014b ).…”