Synergistic Effects of Moderate Therapeutic Hypothermia and Levosimendan on Cardiac Function and Survival After Asphyxia-Induced Cardiac Arrest in Rats

Abstract

Background This study investigated whether levosimendan, an inotropic calcium sensitizer, when combined with moderate therapeutic hypothermia, may exert synergistic benefits on post-cardiac arrest myocardial dysfunction and improve outcomes. Methods and Results After 9.5-minute asphyxia-induced cardiac arrest and resuscitation, 48 rats were randomized equally into 4 groups following return of spontaneous circulation (ROSC), including normothermia, hypothermia, normothermia-levosimendan, and hypothermia-levosimendan groups. For the normothermia group, the target temperature was 37°C while for the hypothermia group, the target temperature was 32°C, both of which were to be maintained for 4 hours after ROSC. Levosimendan was administered after ROSC with a loading dose of 10 μg/kg and then infused at 0.1 μg/kg per min for 4 hours. In the hypothermia-levosimendan group, left ventricular systolic function and cardiac output increased significantly, whereas the heart rate and systemic vascular resistance decreased significantly compared with the normothermia group. Also, the concentrations of interleukin 1β at 4 hours post-ROSC and the production of NO between 1 hour and 4 hours post-ROSC were reduced significantly in the hypothermia-levosimendan group compared with the normothermia group. The 72-hour post-ROSC survival and neurological recovery were also significantly better in the hypothermia-levosimendan group compared with the normothermia group (survival, 100% versus 50%, χ² test, P=0.006). Conclusions Compared with normothermia, only combined moderate therapeutic hypothermia and levosimendan treatment could consistently improve post-cardiac arrest myocardial dysfunction and decrease the release of pro-inflammatory molecules, thereby improving survival and neurological outcomes. These findings suggest synergistic benefits between moderate therapeutic hypothermia and levosimendan.

Keywords: brain injury; cardiac arrest; cardiac dysfunction; hypothermia; inflammation; levosimendan; survival.

Figure 1. The study design and protocol for inducing cardiac arrest, resuscitation, treatments, and monitoring.

CA indicates cardiac arrest; CPR, cardiopulmonary resuscitation; and ROSC, return of spontaneous circulation.

Figure 2. Flow diagram of experimental group randomization.

CA indicates cardiac arrest; HT, hypothermia; Levo, levosimendan; NT, normothermia; and ROSC, return of spontaneous circulation.

Figure 3. Hemodynamic parameters of experimental groups from baseline to 4 h after cardiac arrest and cardiopulmonary resuscitation.

dP/dt₄₀ indicates dP/dt at a left ventricular pressure of 40 mm Hg; HT, hypothermia; Levo, levosimendan; NT, normothermia; and ROSC, return of spontaneous circulation. *Asterisks indicate statistical significance.

Figure 4. Kaplan–Meier survival curves of randomized groups.

HT indicates hypothermia; Levo, levosimendan; and NT, normothermia.

Figure 5. Neurological functioning scores of experimental groups 72 hours after cardiac arrest and cardiopulmonary resuscitation.

Data are presented as the mean±SD; P=0.036 by Mann–Whitney test. HT indicates hypothermia; Levo, levosimendan; and NT, normothermia.

Figure 6. Histological studies of brains in experimental groups.

Hematoxylin and eosin staining of hippocampus from rats surviving 72 hours after cardiac arrest. Microscopic magnification 400×. Data are presented as the mean±SD. HT indicates hypothermia; Levo, levosimendan; and NT, normothermia.