In health, arginine is considered a nonessential amino acid but can become an essential amino acid (ie, conditionally essential amino acid) during periods of metabolic or traumatic stress as endogenous arginine supply is inadequate to meet physiologic demands. Arginine depletion in critical illness is associated with impairments in microcirculatory blood flow, impaired wound healing, and T-cell dysfunction. The purpose of this review is to (1) describe arginine metabolism and role in health and critical illness, (2) describe the relationship between arginine and asymmetric dimethylarginine, and (3) review studies of supplemental arginine in critically ill patients.
FacchinettiFLongoMPiccininiFNeriIVolpeA.L-arginine infusion reduces blood pressure in preeclamptic women through nitric oxide release. J Soc Gynecol Investig. 1999;6(4):202-207.
5.
MehtaSStewartDJLanglebenDLevyRD.Short-term pulmonary vasodilation with L-arginine in pulmonary hypertension. Circulation. 1995;92(6):1539-1545.
6.
BarbulAFishelRSShimazuS. Intravenous hyperalimentation with high arginine levels improves wound healing and immune function. J Surg Res. 1985;38(4):328-334.
7.
MorrisCRKuypersFALavrishaL. A randomized, placebo-controlled trial of arginine therapy for the treatment of children with sickle cell disease hospitalized with vaso-occlusive pain episodes. Haematologica. 2013;98(9):1375-1382.
8.
ZhouMMartindaleRG.Arginine in the critical care setting. J Nutr. 2007;137(6)(suppl 2):1687S-1692S.
9.
ZhouMMartindaleRG.Immune-modulating enteral formulations: optimum components, appropriate patients, and controversial use of arginine in sepsis. Curr Gastroenterol Rep. 2007;9(4):329-337.
10.
WindmuellerHGSpaethAE.Source and fate of circulating citrulline. Am J Physiol. 1981;241(6):E473-E480.
11.
DhanakotiSNBrosnanJTHerzbergGRBrosnanME.Renal arginine synthesis: studies in vitro and in vivo. Am J Physiol. 1990;259(3, pt 1):E437-E342.
12.
BaranyiAAmouzadeh-GhadikolaiORothenhauslerHB. Nitric oxide–related biological pathways in patients with major depression. PLoS One. 2015;10(11):e0143397.
13.
BersaniFSWolkowitzOMLindqvistD. Global arginine bioavailability, a marker of nitric oxide synthetic capacity, is decreased in PTSD and correlated with symptom severity and markers of inflammation. Brain Behav Immun. 2016;52:153-160.
14.
TangWHWangZChoLBrennanDMHazenSL.Diminished global arginine bioavailability and increased arginine catabolism as metabolic profile of increased cardiovascular risk. J Am Coll Cardiol. 2009;53(22):2061-2067.
BarbulA.Proline precursors to sustain mammalian collagen synthesis. J Nutr. 2008;138(10):2021S-2024S.
17.
RodriguezPCZeaAHCulottaKSZabaletaJOchoaJBOchoaAC.Regulation of T cell receptor CD3zeta chain expression by L-arginine. J Biol Chem. 2002;277(24):21123-21129.
18.
RodriguezPCZeaAHDeSalvoJ. L-arginine consumption by macrophages modulates the expression of CD3 zeta chain in T lymphocytes. J Immunol. 2003;171(3):1232-1239.
19.
ZeaAHRodriguezPCCulottaKS. L-arginine modulates CD3zeta expression and T cell function in activated human T lymphocytes. Cell Immunol. 2004;232(1-2):21-31.
20.
KalilACDannerRL.L-arginine supplementation in sepsis: beneficial or harmful?Curr Opin Crit Care. 2006;12(4):303-308.
21.
MorrisSMJr.Recent advances in arginine metabolism: roles and regulation of the arginases. Br J Pharmacol. 2009;157(6):922-930.
22.
BansalVOchoaJB.Arginine availability, arginase, and the immune response. Curr Opin Clin Nutr Metab Care. 2003;6(2):223-228.
23.
PreiserJCIchaiCOrbanJCGroeneveldAB.Metabolic response to the stress of critical illness. Br J Anaesth. 2014;113(6):945-954.
24.
MarikPEFlemmerM.The immune response to surgery and trauma: implications for treatment. J Trauma Acute Care Surg. 2012;73(4):801-808.
25.
CuencaAGDelanoMJKelly-ScumpiaKM. A paradoxical role for myeloid-derived suppressor cells in sepsis and trauma. Mol Med. 2011;17(3-4):281-292.
26.
FletcherMRamirezMESierraRA. L-arginine depletion blunts antitumor T-cell responses by inducing myeloid-derived suppressor cells. Cancer Res. 2015;75(2):275-283.
27.
PribisJPZhuXVodovotzYOchoaJB.Systemic arginine depletion after a murine model of surgery or trauma. JPEN J Parenter Enteral Nutr. 2012;36(1):53-59.
28.
DellingerRPLevyMMRhodesA. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med. 2013;39(2):165-228.
29.
De BackerDOrbegozo CortesDDonadelloKVincentJL. Pathophysiology of microcirculatory dysfunction and the pathogenesis of septic shock. Virulence. 2014;5(1):73-79.
30.
LuikingYCDeutzNE.Exogenous arginine in sepsis. Crit Care Med. 2007;35(9)(suppl):S557-S563.
31.
SettergrenMBohmFMalmstromREChannonKMPernowJ.L-arginine and tetrahydrobiopterin protects against ischemia/reperfusion-induced endothelial dysfunction in patients with type 2 diabetes mellitus and coronary artery disease. Atherosclerosis. 2009;204(1):73-78.
32.
KarhadkarSBarbulA. Is it important to deliver enhanced levels of arginine to critically ill patients? In: DeutschmanCSNeliganPJ, eds. Evidence-Based Practice of Critical Care. Philadelphia, PA: Saunders Elsevier; 2010:457-460.
Bode-BogerSMScaleraFIgnarroLJ.The L-arginine paradox: importance of the L-arginine/asymmetrical dimethylarginine ratio. Pharmacol Ther. 2007;114(3):295-306.
35.
DavisJSDarcyCJYeoTW. Asymmetric dimethylarginine, endothelial nitric oxide bioavailability and mortality in sepsis. PLoS One. 2011;6(2):e17260.
36.
GoughMSMorganMAMackCM. The ratio of arginine to dimethylarginines is reduced and predicts outcomes in patients with severe sepsis. Crit Care Med. 2011;39(6):1351-1358.
37.
KochAWeiskirchenRKunzeJ. Elevated asymmetric dimethylarginine levels predict short- and long-term mortality risk in critically ill patients. J Crit Care. 2013;28(6):947-953.
38.
VisserMVermeulenMARichirMC. Imbalance of arginine and asymmetric dimethylarginine is associated with markers of circulatory failure, organ failure and mortality in shock patients. Br J Nutr. 2012;107(10):1458-1465.
39.
GalbanCMontejoJCMesejoA. An immune-enhancing enteral diet reduces mortality rate and episodes of bacteremia in septic intensive care unit patients. Crit Care Med. 2000;28(3):643-648.
40.
AtkinsonSSieffertEBihariD.A prospective, randomized, double-blind, controlled clinical trial of enteral immunonutrition in the critically ill. Guy’s Hospital Intensive Care Group. Crit Care Med. 1998;26(7):1164-1172.
41.
BowerRHCerraFBBershadskyB. Early enteral administration of a formula (impact) supplemented with arginine, nucleotides, and fish oil in intensive care unit patients: results of a multicenter, prospective, randomized, clinical trial. Crit Care Med. 1995;23(3):436-449.
42.
CaparrosTLopezJGrauT.Early enteral nutrition in critically ill patients with a high-protein diet enriched with arginine, fiber, and antioxidants compared with a standard high-protein diet: the effect on nosocomial infections and outcome. JPEN J Parenter Enteral Nutr. 2001;25(6):299-309.
43.
van ZantenARSztarkFKaisersUX. High-protein enteral nutrition enriched with immune-modulating nutrients vs standard high-protein enteral nutrition and nosocomial infections in the ICU: a randomized clinical trial. JAMA. 2014;312(5):514-524.
44.
McClaveSATaylorBEMartindaleRG. Guidelines for the provision and assessment of nutrition support therapy in the adult critically ill patient: Society of Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.). JPEN J Parenter Enteral Nutr. 2016;40(2):159-211.
45.
DroverJWDhaliwalRWeitzelLWischmeyerPEOchoaJBHeylandDK.Perioperative use of arginine-supplemented diets: a systematic review of the evidence. J Am Coll Surg. 2011;212(3):385-399, 399.e1.
46.
MarimuthuKVaradhanKKLjungqvistOLoboDN.A meta-analysis of the effect of combinations of immune modulating nutrients on outcome in patients undergoing major open gastrointestinal surgery. Ann Surg. 2012;255(6):1060-1068.
47.
OslandEHossainMBKhanSMemonMA.Effect of timing of pharmaconutrition (immunonutrition) administration on outcomes of elective surgery for gastrointestinal malignancies: a systematic review and meta-analysis. JPEN J Parenter Enteral Nutr. 2014;38(1):53-69.
48.
HegaziRAHusteadDSEvansDC.Preoperative standard oral nutrition supplements vs immunonutrition: results of a systematic review and meta-analysis. J Am Coll Surg. 2014;219(5):1078-1087.
49.
RosenthalMDMooreFA.Persistent inflammatory, immunosuppressed, catabolic syndrome (PICS): a new phenotype of multiple organ failure. J Adv Nutr Hum Metab. 2015;1(1):e784.
50.
LuikingYCPoezeMRamsayGDeutzNE.Reduced citrulline production in sepsis is related to diminished de novo arginine and nitric oxide production. Am J Clin Nutr. 2009;89(1):142-152.
51.
LopezALorenteJASteingrubJ. Multiple-center, randomized, placebo-controlled, double-blind study of the nitric oxide synthase inhibitor 546C88: effect on survival in patients with septic shock. Crit Care Med. 2004;32(1):21-30.
52.
LeonPRedmondHPSteinTP. Arginine supplementation improves histone and acute-phase protein synthesis during gram-negative sepsis in the rat. JPEN J Parenter Enteral Nutr. 1991;15(5):503-508.
53.
LorenteJADelgadoMATejedorC. Modulation of systemic hemodynamics by exogenous L-arginine in normal and bacteremic sheep. Crit Care Med. 1999;27(11):2474-2479.
54.
KalilACSevranskyJEMyersDE. Preclinical trial of L-arginine monotherapy alone or with N-acetylcysteine in septic shock. Crit Care Med. 2006;34(11):2719-2728.
55.
BertoliniGIapichinoGRadrizzaniD. Early enteral immunonutrition in patients with severe sepsis: results of an interim analysis of a randomized multicentre clinical trial. Intensive Care Med. 2003;29(5):834-840.
56.
DentDHeylandDLevyH.Immunonutrition may increase mortality in critically ill patients with pneumonia: results of a randomized trial. Crit Care Med. 2003;30:A17.
57.
KieftHRoosANvan DrunenJDBindelsAJBindelsJGHofmanZ.Clinical outcome of immunonutrition in a heterogeneous intensive care population. Intensive Care Med. 2005;31(4):524-532.
58.
RadrizzaniDBertoliniGFacchiniR. Early enteral immunonutrition vs. parenteral nutrition in critically ill patients without severe sepsis: a randomized clinical trial. Intensive Care Med. 2006;32(8):1191-1198.
59.
LorenteJALandinLDe PabloRRenesEListeD.L-arginine pathway in the sepsis syndrome. Crit Care Med. 1993;21(9):1287-1295.
60.
LuikingYCPoezeMHendrikxM.Continuous L-arginine infusion does not deteriorate the haemodynamic condition in patients with severe sepsis. Clin Nutr. 2005;24:612-613.
61.
LuikingYCPoezeMPreiserJCBreedveldPZwavelingJDeutzNE.L-arginine infusion in severely septic patients does not enhance protein nitrosylation or haemodynamic instability [abstract]. e-ESPEN. 2006;1:14-15.
62.
LuikingYCPoezeMDeutzNE.Arginine infusion in patients with septic shock increases nitric oxide production without haemodynamic instability. Clin Sci (Lond). 2015;128(1):57-67.
