Acadesine during fluid resuscitation from shock and abdominal sepsis

Objective: To determine properties of acadesine, the prototype adenosine regulating agent, in an experimental model in which abdominal sepsis is superimposed onto hemorrhagic shock. Design: Randomized, blinded animal study. Setting: University based animal research facility. Subjects: Twenty-eight anesthetized mongrel pigs (35.5 +/- 1.1 kg). Interventions: The cecum was ligated and punctured to produce abdominal sepsis. To produce hemorrhagic shock, 45% to 47% of the estimated blood volume was withdrawn. After 1 hr, shed blood plus supplemental crystalloid (twice the shed blood volume) plus either acadesine (5 mg/kg bolus + 1 mg/kg x 60 min, n = 10)or its vehicle (n = 10)was administered. All animals were awakened and observed for 48 hrs. At 48 hrs, cardiac function, bacterial cultures from the septic focus, and inflammatory changes in the abdomen were quantified. Measurements and Main Results: After resuscitation with acadesine vs. vehicle, we observed the following: a) arterial blood pressure and cardiac filling pressures were similar but cardiac index, systemic oxygen delivery, and systemic oxygen consumption were increased; b) plasma lactate was higher, systemic vascular resistance was lower, but ileal mucosal blood flow was not measurably altered; c) lipopolysaccharide-evoked tumor necrosis factor production in whole blood ex vivo was reduced; d) in those animals that survived 48 hrs (10/10 vs. 8/10), sepsis induced cardiac depression, amount of free intraperitoneal fluid, extra abscess inflammatory reaction, abscess wall formation, abscess bacterial counts, and peritoneal bacterial counts, were all similar, but blood bacterial counts were higher. Conclusions: Fluid resuscitation with acadesine produced no adverse hemodynamic consequences and probably improved washout of metabolites from the reperfused microcirculation in sites other than the small intestine or heart. Taken together, these observations suggest that adenosine regulating agents might have therapeutic potential during fluid resuscitation from trauma. How ever, at least in these extreme conditions, the acute salutary effects of acadesine were probably overwhelmed by polymicrobial sepsis. Further studies must determine whether supplemental adjuvants to boost host defense during recovery from trauma will optimize adenosine-based resuscitation solutions.