Acadesine during fluid resuscitation from shock and abdominal sepsis

Objective: To determine properties of acadesine, the prototype adenosine re gulating agent, in an experimental model in which abdominal sepsis is super imposed 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 sep sis. To produce hemorrhagic shock, 45% to 47% of the estimated blood volume was withdrawn.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 awak ened and observed for 48 hrs. At 48 hrs, cardiac function, bacterial cultur es from the septic focus, and inflammatory changes in the abdomen were quan tified. Measurements and Main Results: After resuscitation with acadesine vs. vehic le, we observed the following: a) arterial blood pressure and cardiac filli ng pressures were similar but cardiac index, systemic oxygen delivery, and systemic oxygen consumption were increased; b) plasma lactate was higher, s ystemic vascular resistance was lower, but ileal mucosal blood flow was not measurably altered; c) lipopolysaccharide-evoked tumor necrosis factor pro duction in whole blood ex vivo was reduced; d) in those animals that surviv ed 48 hrs (10/10 vs. 8/10), sepsis induced cardiac depression, amount of fr ee 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 hemodyn amic consequences and probably improved washout of metabolites from the rep erfused 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. H ow ever, at least in these extreme conditions, the acute salutary effects o f acadesine were probably overwhelmed by polymicrobial sepsis. Further stud ies must determine whether supplemental adjuvants to boost host defense dur ing recovery from trauma will optimize adenosine-based resuscitation soluti ons.