ACADESINE AND LIPOPOLYSACCHARIDE-EVOKED PULMONARY DYSFUNCTION AFTER RESUSCITATION FROM TRAUMATIC SHOCK

Background. We have reported that the purine precursor acadesine (AICA R) improved the microcirculation, repleted adenosine triphosphate, and attenuated local and lung neutrophil infiltration after intestinal re perfusion and that it quickly improved systemic hemodynamics after res uscitation from hemorrhagic shock. This study evaluated the therapeuti c potential of AICAR after fluid resuscitated trauma. Methods. Anesthe tized (fentanyl) mongrel pigs were subjected to tissue injury plus hem orrhage and randomized to receive resuscitation fluids comprised of sh ed blood plus either lactated Ringer's solution (LR) or AICAR (1 or 10 mg/kg bolus + 0.5 mg/kg/min x 30 min). Thereafter either LR or AICAR (1 or 10 mg/kg) was administered at 12-hour intervals for 72 hours. In a smaller series (n = 7) a single bolus (0.5 mg/kg) of the adenosine deaminase inhibitor deoxycoformycin was administered at the time of re suscitation. After 72 hours, an endotoxin challenge (0.5 mu g/kg, lipo polysaccharide [LPS]) was administered. Results. A 1 mg/kg (n = 9), AI CAR had no obvious effect versus LR (n = 31). At 10 mg/kg AICAR (n = 1 1), the fluid required to stabilize hemodynamics after trauma was high er (66 +/- 5 versus 52 +/- 3 ml/kg/hr, p = 0.014). but there were fewe r deaths 3 days after trauma versus LR (0 of 11 versus 4 of 31, p = 0. 210), fewer deaths within 5 hours after LPS administration (3 of 11 ve rsus 16 of 27, p = 0.074), and a longer survival time after PS adminis tration (4.5 +/- 0.3 versus 3.9 +/- 0.2 hr, p = 0.054). Deoxycoformyci n had similar salutary effects on survival after LPS administration. L PS increased protein permeability of pulmonary capillaries, increased peak inspiratory pressures on constant tidal volume, increased dead sp ace ventilation, and caused progressive arterial desaturation on 0.65 FiO(2) (all p < 0.05). This pulmonary dysfunction was associated with a compensatory increase in cardiac output, decrease in systemic vascul ar resistance, increase in O-2 consumption, and rise in plasma cortiso l level (all p < 0.05). All these changes were blunted or eliminated w ith 10 mg/kg AICAR. Hematocrit and systemic pressures were maintained relatively constant after LPS administration with fluid resuscitation, but less was required with AICAR versus LR (40 +/- 8 versus 83 +/- 14 ml/kg/hr, p = 0.023). AICAR caused a concentration-related reduction in CD18 expression on LPS-stimulated neutrophils in vitro, but there w as no effect versus LR on circulating leukocyte counts in vivo and no effect on AICAR on LPS-stimulated production of tumor necrosis factor in vitro or in vivo. Conclusions. 1. AICAR reduced the pulmonary dysfu nction associated with posttrauma endotoxemia but had no effect on cir culating leukocytes, so its mechanism could be related to an adenosine -mediated improvement in peripheral perfusion or O-2 use. 2. AICAR is a generic compound that is safe and apparently efficacious in human be ings, so AICAR prophylaxis could be cost effectively administered to t rauma patients.