title: Adenosine, lidocaine and Mg2+ (ALM) induces a reversible hypotensive state, reduces lung edema and prevents coagulopathy in the rat model of polymicrobial sepsis.
abstract: BACKGROUND
  No drug therapy has demonstrated improved clinical outcomes in the treatment of sepsis. A bolus of adenosine, lidocaine, and magnesium (ALM) has been shown to be cardioprotective and restore coagulopathy in different trauma states. We hypothesized that ALM therapy may improve hemodynamics, protect the lung, and prevent coagulopathy in the rat sepsis model.
  
  
  METHODS
  Nonheparinized, anesthetized Sprague-Dawley rats (350-450 g, n = 32) were randomly assigned to (1) shams (without sepsis), (2) saline controls, and (3) ALM treatment. Sepsis was induced by cecal ligation and puncture. A 0.3-mL bolus was administered intravenously, followed by a 4-hour intravenous infusion (1 mL/kg/h), and hemodynamics (mean arterial pressure [MAP], systolic arterial pressure, diastolic arterial pressure, and heart rate [HR]) and body temperature (BT) were monitored. Coagulation was assessed using prothrombin time and activated partial thromboplastin time (aPTT).
  
  
  RESULTS
  Shams displayed progressive falls in MAP, HR, and BT as well as a prolonged aPTT, which were related to surgery, not infection. At 4 hours, controls showed more pronounced falls in MAP (33%), HR (17%), and BT (3.3°C), and MAP continued to fall after the infusion was stopped. In contrast, ALM treatment resulted in a rapid fall in MAP from 111 mm Hg to 73 mm Hg at 30 minutes (p < 0.05 all groups) and was 59 mm Hg at 240 minutes (p < 0.05 shams), which immediately corrected after 4 hours (p < 0.05 controls). HR paralleled MAP changes in ALM rats, and BT was significantly higher than that of the controls but not that of shams. ALM rats had no arrhythmias compared with the controls or shams and had significantly lower lung wet-dry ratios. Prothrombin time in saline controls at 1 hour and 5 hours was prolonged but not in the shams or ALM rats. aPTT at 1 hour in the sham, control, and ALM groups was 158 ± 41 seconds, 161 ± 41 seconds, and 54 ± 23 seconds and at 5 hours was 104 ± 43 seconds, 205 ± 40 seconds, and 33 ± 3 seconds (p < 0.05), respectively.
  
  
  CONCLUSIONS
  An ALM bolus/infusion induces a stable, hypotensive hemodynamic state with no arrhythmias, significantly less pulmonary edema, and a higher BT and prevents coagulopathy compared with the controls.
authors.affiliation: From the Heart, Trauma and Sepsis Research Laboratory, Australian Institute of Tropical Health and Medicine, College of Medicine, James Cook University, Townsville, Queensland, Australia.
authors.forename: Maddison J
authors.initials: MJ
authors.lastname: Griffin
authors.forename: Hayley L
authors.initials: HL
authors.lastname: Letson
authors.forename: Geoffrey P
authors.initials: GP
authors.lastname: Dobson
mesh_terms: D000241:Adenosine / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D001778:Blood Coagulation Disorders / Q000209:etiology / Q000517:prevention & control*; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D004487:Edema / Q000209:etiology / Q000517:prevention & control*; D007022:Hypotension / Q000139:chemically induced*; D007262:Infusions, Intravenous; D008012:Lidocaine / Q000008:administration & dosage / Q000627:therapeutic use*; D008171:Lung Diseases / Q000209:etiology / Q000517:prevention & control*; D008274:Magnesium / Q000008:administration & dosage / Q000627:therapeutic use*; D008297:Male; D010314:Partial Thromboplastin Time; D011517:Prothrombin Time; D051381:Rats; D017207:Rats, Sprague-Dawley; D018805:Sepsis / Q000150:complications / Q000628:therapy*
chemical_list: D008012:Lidocaine; D008274:Magnesium; D000241:Adenosine