Small-Volume Adenosine, Lidocaine, and Mg 2+ 4-Hour Infusion Leads to 88% Survival after 6 Days of Experimental Sepsis in the Rat without Antibiotics

Abstract

Innovative host-directed drug therapies are urgently required to treat sepsis. We tested the effect of a small-volume 0.9% NaCl adenosine, lidocaine, and Mg2+ (ALM) bolus and a 4-h intravenous infusion on survivability in the rat model of polymicrobial sepsis over 6 days. ALM treatment led to a significant increase in survivability (88%) compared to that of controls (25%). Four controls died on day 2 to 3, and two died on day 5. Early death was associated with elevated plasma and lung inflammatory markers (interleukin-6 [IL-6], IL-1β, C-reactive protein), reduced white blood cell (WBC) count, hypoxemia, hypercapnia, acidosis, hyperkalemia, and elevated lactate, whereas late death was associated with a massive cytokine storm, a neutrophil-dominated WBC rebound/overshoot, increased lung oxidant injury, edema, and persistent ischemia. On day 6, seven of eight ALM survivors had inflammatory and immunological profiles not significantly different from those of sham-treated animals. We conclude in the rat model of experimental sepsis that small-volume ALM treatment led to higher survivability at 6 days (88%) than that of controls (25%). Early death in controls (day 2 to 3) was associated with significantly elevated plasma levels of IL-1β, IL-6, and C-reactive protein, severe plasma lymphocyte deficiency, reduced neutrophils, and acute lung injury. Late death (day 5) was associated with a massive neutrophil inflammatory storm, increased lung injury, and persistent ischemia. Possible mechanisms of ALM protection are discussed.