24 Oct 06
Preclinical trial of l-arginine monotherapy alone or with N-acetylcysteine in septic shock
By AC Kalil, JE Sevransky, DE Myers, C Esposito, RW Vandivier, P Eichacker, G Susla et al
Critical Care Medicine 2006;34:2719-2728
l-arginine supplementation in sepsis is controversial. Septic shock has been alternatively viewed as an l-arginine-deficient state or as a syndrome caused by excess nitric oxide, an end-product of l-arginine metabolism.
Design
Randomized, placebo-controlled, and double-blinded (investigators, veterinarians, and pharmacists).
Setting
Laboratory.
Subjects
Purpose-bred, 1- to 2-yr-old, 10- to 12-kg beagles.
Interventions
The effects of parenteral l-arginine alone or in combination with N-acetylcysteine were compared with vehicle alone in a well-characterized canine model of Escherichia coli peritonitis. Two doses were studied that delivered approximately 1.5-fold (10 mg·kg-1·hr-1) and 15-fold (100 mg·kg-1·hr-1) the l-arginine dose typically administered with standard total parenteral nutrition. Animals in the low- and high-dose l-arginine arms were further randomized to receive vehicle alone or N-acetylcysteine (20 mg·kg-1·hr-1) as an antioxidant to prevent peroxynitrite formation.
Measurements and Main Results
The main measurements were hemodynamics, plasma arginine and ornithine, serum nitrate/nitrite, laboratory studies for organ injury, and survival. Both doses of l-arginine similarly increased mortality (p = .02), and worsened shock (p = .001 for reduced mean arterial pressure). These effects were associated with significant increases in plasma arginine (p = .0013) and ornithine (p = .0021). In addition, serum nitrate/nitrite (p = .02), liver enzymes (p = .08), and blood urea nitrogen/creatinine ratios (p = .001) rose, whereas arterial pH (p = .001) and bicarbonate levels (p = .001) fell. N-acetylcysteine did not significantly decrease any of the harmful effects of l-arginine. Thus, parenteral l-arginine monotherapy was markedly harmful in animals with septic shock.
Conclusions
These findings suggest that supplemental parenteral l-arginine, at doses above standard dietary practices, should be avoided in critically ill patients with septic shock.