Acadesine and lipopolysaccharide-evoked pulmonary dysfunction after resuscitation from traumatic shock.
BACKGROUND
We have reported that the purine precursor acadesine (AICAR) improved the microcirculation, repleted adenosine triphosphate, and attenuated local and lung neutrophil infiltration after intestinal reperfusion and that it quickly improved systemic hemodynamics after resuscitation from hemorrhagic shock. This study evaluated the therapeutic potential of AICAR after fluid resuscitated trauma.


METHODS
Anesthetized (fentanyl) mongrel pigs were subjected to tissue injury plus hemorrhage and randomized to receive resuscitation fluids comprised of shed 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 resuscitation. After 72 hours, and endotoxin challenge (0.5 microgram/kg, lipopolysaccharide [LPS]) was administered.


RESULTS
At 1 mg/kg (n = 9), AICAR had no obvious effect versus LR (n = 31). At 10 mg/kg AICAR (n = 11), the fluid required to stabilize hemodynamics after trauma was higher (66 +/- 5 versus 52 +/- 3 ml/kg/hr, p = 0.014), but there were fewer 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 versus 16 of 27, p = 0.074), and a longer survival time after LPS administration (4.5 +/- 0.3 versus 3.9 +/- 0.2 hr, p = 0.054). Deoxycoformycin had similar salutary effects on survival after LPS administration. LPS increased protein permeability of pulmonary capillaries, increased peak inspiratory pressures on constant tidal volume, increased dead space ventilation, and caused progressive arterial desaturation on 0.65 FiO2 (all p < 0.05). This pulmonary dysfunction was associated with a compensatory increase in cardiac output, decrease in systemic vascular resistance, increase in O2 consumption, and rise in plasma cortisol level (all p < 0.05). All these changes were blunted or eliminated with 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 was no effect versus LR on circulating leukocyte counts in vivo and no effect of AICAR on LPS-stimulated production of tumor necrosis factor in vitro or in vivo.


CONCLUSIONS
1. AICAR reduced the pulmonary dysfunction associated with posttrauma endotoxemia but had no effect on circulating leukocytes, so its mechanism could be related to an adenosine-mediated improvement in peripheral perfusion or O2 use. 2. AICAR is a generic compound that is safe and apparently efficacious in human beings, so AICAR prophylaxis could be cost-effectively administered to trauma patients.
Fabian
T C
TC
Department of Surgery, University of Tennessee Health Science Center, Memphis 38163, USA.
Fabian
M J
MJ
Yockey
J M
JM
Proctor
K G
KG
D000241:Adenosine / Q000502:physiology; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects; D006854:Hydrocortisone / Q000097:blood; D007958:Leukocyte Count; D008070:Lipopolysaccharides / Q000633:toxicity*; D008168:Lung / Q000187:drug effects*; D012151:Resuscitation; D012263:Ribonucleosides / Q000494:pharmacology*; D012774:Shock, Traumatic / Q000503:physiopathology*; D013552:Swine; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D008070:Lipopolysaccharides; D012263:Ribonucleosides; D014409:Tumor Necrosis Factor-alpha; D000620:Aminoimidazole Carboxamide; C011651:acadesine; D000241:Adenosine; D006854:Hydrocortisone