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

Andre C Kalil, Jonathan E. Sevransky, Daniela E. Myers, Claire Esposito, R. William Vandivier, Peter Eichacker, Greg M. Susla, Steven B. Solomon, Gyorgy Csako, Rene Costello, Kelly J. Sittler, Steve Banks, Charles Natanson, Robert L. Danner

Research output: Contribution to journalArticle

45 Citations (Scopus)

Abstract

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. 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·hr) and 15-fold (100 mg·kg·hr) 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·hr) 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.

Original languageEnglish (US)
Pages (from-to)2719-2728
Number of pages10
JournalCritical care medicine
Volume34
Issue number11
DOIs
StatePublished - Nov 1 2006

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Acetylcysteine
Septic Shock
Arginine
Ornithine
Nitrites
Nitrates
Tissue Survival
Peroxynitrous Acid
Veterinarians
Total Parenteral Nutrition
Blood Urea Nitrogen
Bicarbonates
Peritonitis
Serum
Pharmacists
Critical Illness
Canidae
Shock
Creatinine
Sepsis

Keywords

  • Immunonutrition
  • L-arginine
  • N-acetylcysteine
  • Nitric oxide
  • Sepsis

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine

Cite this

Kalil, A. C., Sevransky, J. E., Myers, D. E., Esposito, C., Vandivier, R. W., Eichacker, P., ... Danner, R. L. (2006). Preclinical trial of L-arginine monotherapy alone or with N-acetylcysteine in septic shock. Critical care medicine, 34(11), 2719-2728. https://doi.org/10.1097/01.CCM.0000242757.26245.03

Preclinical trial of L-arginine monotherapy alone or with N-acetylcysteine in septic shock. / Kalil, Andre C; Sevransky, Jonathan E.; Myers, Daniela E.; Esposito, Claire; Vandivier, R. William; Eichacker, Peter; Susla, Greg M.; Solomon, Steven B.; Csako, Gyorgy; Costello, Rene; Sittler, Kelly J.; Banks, Steve; Natanson, Charles; Danner, Robert L.

In: Critical care medicine, Vol. 34, No. 11, 01.11.2006, p. 2719-2728.

Research output: Contribution to journalArticle

Kalil, AC, Sevransky, JE, Myers, DE, Esposito, C, Vandivier, RW, Eichacker, P, Susla, GM, Solomon, SB, Csako, G, Costello, R, Sittler, KJ, Banks, S, Natanson, C & Danner, RL 2006, 'Preclinical trial of L-arginine monotherapy alone or with N-acetylcysteine in septic shock', Critical care medicine, vol. 34, no. 11, pp. 2719-2728. https://doi.org/10.1097/01.CCM.0000242757.26245.03
Kalil, Andre C ; Sevransky, Jonathan E. ; Myers, Daniela E. ; Esposito, Claire ; Vandivier, R. William ; Eichacker, Peter ; Susla, Greg M. ; Solomon, Steven B. ; Csako, Gyorgy ; Costello, Rene ; Sittler, Kelly J. ; Banks, Steve ; Natanson, Charles ; Danner, Robert L. / Preclinical trial of L-arginine monotherapy alone or with N-acetylcysteine in septic shock. In: Critical care medicine. 2006 ; Vol. 34, No. 11. pp. 2719-2728.
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AU - Kalil, Andre C

AU - Sevransky, Jonathan E.

AU - Myers, Daniela E.

AU - Esposito, Claire

AU - Vandivier, R. William

AU - Eichacker, Peter

AU - Susla, Greg M.

AU - Solomon, Steven B.

AU - Csako, Gyorgy

AU - Costello, Rene

AU - Sittler, Kelly J.

AU - Banks, Steve

AU - Natanson, Charles

AU - Danner, Robert L.

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N2 - 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. 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·hr) and 15-fold (100 mg·kg·hr) 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·hr) 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.

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