Preclinical trial of L-arginine monotherapy alone or with N-acetylcysteine in septic shock.
OBJECTIVE
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.


METHODS
Randomized, placebo-controlled, and double-blinded (investigators, veterinarians, and pharmacists).


METHODS
Laboratory.


METHODS
Purpose-bred, 1- to 2-yr-old, 10- to 12-kg beagles.


METHODS
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 x kg(-1) x hr(-1)) and 15-fold (100 mg x kg(-1) x 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 x kg(-1) x hr(-1)) as an antioxidant to prevent peroxynitrite formation.


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.
Kalil
Andre C
AC
Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, MD, USA. akalil@unmc.edu
Sevransky
Jonathan E
JE
Myers
Daniela E
DE
Esposito
Claire
C
Vandivier
R William
RW
Eichacker
Peter
P
Susla
Greg M
GM
Solomon
Steven B
SB
Csako
Gyorgy
G
Costello
Rene
R
Sittler
Kelly J
KJ
Banks
Steve
S
Natanson
Charles
C
Danner
Robert L
RL
D000111:Acetylcysteine / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001120:Arginine / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D016166:Free Radical Scavengers / Q000494:pharmacology / Q000627:therapeutic use*; D007167:Immunotherapy / Q000379:methods*; D009569:Nitric Oxide / Q000378:metabolism; D010288:Parenteral Nutrition / Q000379:methods*; D016016:Proportional Hazards Models; D011897:Random Allocation; D012772:Shock, Septic / Q000628:therapy*; D016019:Survival Analysis
D016166:Free Radical Scavengers; D009569:Nitric Oxide; D001120:Arginine; D000111:Acetylcysteine