title: Small-Volume Adenosine, Lidocaine, and Mg2+ 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.
authors: Heart, Trauma and Sepsis Research Laboratory, Australian Institute of Tropical Health and Medicine, College of Medicine and Dentistry, James Cook University, Queensland, Australia.
authors: Maddison Jade
authors: MJ
authors: Griffin
authors: Heart, Trauma and Sepsis Research Laboratory, Australian Institute of Tropical Health and Medicine, College of Medicine and Dentistry, James Cook University, Queensland, Australia.
authors: Hayley Louise
authors: HL
authors: Letson
authors: Heart, Trauma and Sepsis Research Laboratory, Australian Institute of Tropical Health and Medicine, College of Medicine and Dentistry, James Cook University, Queensland, Australia geoffrey.dobson@jcu.edu.au.
authors: Geoffrey Phillip
authors: GP
authors: Dobson
mesh_terms: D000138:Acidosis / Q000209:etiology / Q000276:immunology / Q000382:microbiology; D000241:Adenosine / Q000008:administration & dosage* / Q000627:therapeutic use; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000627:therapeutic use; D002097:C-Reactive Protein / Q000032:analysis; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D004487:Edema / Q000276:immunology / Q000382:microbiology; D006947:Hyperkalemia / Q000209:etiology / Q000276:immunology / Q000382:microbiology; D007262:Infusions, Intravenous; D053583:Interleukin-1beta / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D008012:Lidocaine / Q000008:administration & dosage* / Q000627:therapeutic use; D008278:Magnesium Sulfate / Q000008:administration & dosage* / Q000627:therapeutic use; D008297:Male; D051381:Rats; D018805:Sepsis / Q000188:drug therapy* / Q000276:immunology* / Q000382:microbiology
chemical_list: D000900:Anti-Bacterial Agents; D016207:Cytokines; D053583:Interleukin-1beta; D015850:Interleukin-6; D008278:Magnesium Sulfate; D002097:C-Reactive Protein; D008012:Lidocaine; D000241:Adenosine