Original Article

Comparison of L-arginine and L-citrulline oral supplementation in head trauma ICU patients receiving enteral nutrition: A randomized double blind clinical trial


Objective: This study aimed to compare the effect of L-arginine and L-citrulline supplementation on overall prognosis of critically ill patients.
Method: A total of 105 head trauma ICU patients were recruited in this double-blind randomized clinical trial. Patients in the treatment groups took 10 gr per day oral L-Arginine or L-citrulline for 10 days.  Demographic characteristics and anthropometric measurements were recorded. Nitric oxide (NOx), pre-albumin, pro-oxidant, anti-oxidant balance, fasting blood sugar, lipid profile, liver enzymes, serum electrolytes, blood urea nitrogen, creatinine and serum amino acids were measured. Gastrointestinal complications, ventilator need, length of hospital stay and 28-day mortality were recorded. The K2 testing system was used to compare the qualitative variables. Repeated measures ANOVA were used to compare means across variables. In case of significant time-group interaction, between group comparisons of changes at day 11 were done using ANOVA followed by Tukey or Mann Whitney analysis. When time effect factor was significant, the within-group comparison of values was performed by paired samples t test or Wilcoxon.
Results : We observed no significant changes in NOx and PAB (P= 0.8, P= 0.1 respectively). There was a significant increase in serum LDL (P= 0.02) which was higher in the control group after 10 days of supplementation. There was non-significant increase in serum L-arginine in all three groups (P=0.36). However, changes of serum L-arginine was significant in the citrulline group (P=0.048). Serum L-citrulline was higher in the citrulline group compare to the arginine group (P=0.04).
Conclusion:: L-arginine and L-citrulline supplementation did not increased NOx levels more than the control group. Also, PAB balance was not different among the intervention groups and the control group. L-arginine and L-citrulline had no significant effects on length of hospital stay, mortality rate, ventilator need and other factors evaluated in this study.




Ginguay A, De Bandt J-P, Cynober L. Indications and contraindications for infusing specific amino acids (leucine, glutamine, arginine, citrulline, and taurine) in critical illness. Current Opinion in Clinical Nutrition & Metabolic Care. 2016;19(2):161-9.

McClave SA, Martindale RG, Rice TW, Heyland DK. Feeding the critically ill patient. Critical care medicine. 2014;42(12):2600-10.

Zhou M, Martindale RG. Arginine in the critical care setting. The Journal of nutrition. 2007;137(6):1687S-92S.

Morris Jr SM. Recent advances in arginine metabolism. Current Opinion in Clinical Nutrition & Metabolic Care. 2004;7(1):45-51.

Satriano J. Arginine pathways and the inflammatory response: interregulation of nitric oxide and polyamines. Amino acids. 2004;26(4):321-9.

Pierre JF, Heneghan AF, Lawson CM, Wischmeyer PE, Kozar RA, Kudsk KA. Pharmaconutrition review: physiological mechanisms. Journal of Parenteral and Enteral Nutrition. 2013;37(5_suppl):51S-65S.

Wijnands KA, Castermans TM, Hommen MP, Meesters DM, Poeze M. Arginine and citrulline and the immune response in sepsis. Nutrients. 2015;7(3):1426-63.

Pekarova M, Lojek A. The crucial role of l-arginine in macrophage activation: what you need to know about it. Life sciences. 2015;137:44-8.

Curis E, Nicolis I, Moinard C, Osowska S, Zerrouk N, Bénazeth S, et al. Almost all about citrulline in mammals. Amino acids. 2005;29(3):177.

Galbán C, Montejo JC, Mesejo A, Marco P, Celaya S, Sánchez-Segura JM, et al. An immune-enhancing enteral diet reduces mortality rate and episodes of bacteremia in septic intensive care unit patients. Critical care medicine. 2000;28(3):643-8.

Atkinson S, Sieffert E, Bihari D. A prospective, randomized, double-blind, controlled clinical trial of enteral immunonutrition in the critically ill. Critical care medicine. 1998;26(7):1164-72.

Kudsk KA, Minard G, Croce MA, Brown RO, Lowrey TS, Pritchard FE, et al. A randomized trial of isonitrogenous enteral diets after severe trauma. An immune-enhancing diet reduces septic complications. Annals of surgery. 1996;224(4):531.

De Luis D, Arranz M, Aller R, Izaola O, Cuellar L, Terroba M. Immunoenhanced enteral nutrition, effect on inflammatory markers in head and neck cancer patients. European journal of clinical nutrition. 2005;59(1):145-7.

Barkhidarian Bahareh, Seyedhamzeh Shirin, Hashemi Seyed Issac, Nematy Mohsen, Rahbar Ashraf, Ranjbar Roya, et al. Effects of Arginine and Citrulline supplementation on inflammatory markers in critically ill patients. Journal of Nutritional Sciences and Dietetic. 2017 (in press).

Alamdari DH, Paletas K, Pegiou T, Sarigianni M, Befani C, Koliakos G. A novel assay for the evaluation of the prooxidant–antioxidant balance, before and after antioxidant vitamin administration in type II diabetes patients. Clinical biochemistry. 2007;40(3):248-54.

Ignarro LJ, Cirino G, Casini A, Napoli C. Nitric oxide as a signaling molecule in the vascular system: an overview. Journal of cardiovascular pharmacology. 1999;34(6):879-86.

Stamler JS, Lamas S, Fang FC. Nitrosylation: the prototypic redox-based signaling mechanism. Cell. 2001;106(6):675-83.

Stechmiller JK, Langkamp-Henken B, Childress B, Herrlinger-Garcia KA, Hudgens J, Tian L, et al. Arginine supplementation does not enhance serum nitric oxide levels in elderly nursing home residents with pressure ulcers. Biol Res Nurs. 2005;6(4):289-99.

El-Hattab AW, Almannai M, Scaglia F. Arginine and citrulline for the treatment of MELAS syndrome. J Inborn Errors Metab Screen. 2017;5.

Wijnands KA, Vink H, Briedé JJ, Van Faassen EE, Lamers WH, Buurman WA, et al. Citrulline a more suitable substrate than arginine to restore NO production and the microcirculation during endotoxemia. PloS one. 2012;7(5):e37439.

Bauer P, Charpentier C, Bouchet C, Nace L, Raffy F, Gaconnet N. Parenteral with enteral nutrition in the critically ill. Intensive care medicine. 2000;26(7):893-900.

Marshall W. Nutritional assessment: its role in the provision of nutritional support. Journal of clinical pathology. 2008;61(10):1083-8.

Marin VB, Rodriguez-Osiac L, Schlessinger L, Villegas J, Lopez M, Castillo-Duran C. Controlled study of enteral arginine supplementation in burned children: impact on immunologic and metabolic status. Nutrition. 2006;22(7):705-12.

West SG, Likos-Krick A, Brown P, Mariotti F. Oral L-arginine improves hemodynamic responses to stress and reduces plasma homocysteine in hypercholesterolemic men. The Journal of nutrition. 2005;135(2):212-7.

Monti L, Setola E, Lucotti P, Marrocco‐Trischitta M, Comola M, Galluccio E, et al. Effect of a long‐term oral l‐arginine supplementation on glucose metabolism: a randomized, double‐blind, placebo‐controlled trial. Diabetes, Obesity and Metabolism. 2012;10(14):893-900.

Jablecka A, Bogdanski P, Balcer N, Cieslewicz A, Skoluda A, Musialik K. The effect of oral L-arginine supplementation on fasting glucose, HbA1c, nitric oxide and total antioxidant status in diabetic patients with atherosclerotic peripheral arterial disease of lower extremities. Eur Rev Med Pharmacol Sci. 2012;16(3):342-50.

Sellmann C, Jin CJ, Engstler AJ, De Bandt J-P, Bergheim I. Oral citrulline supplementation protects female mice from the development of non-alcoholic fatty liver disease (NAFLD). European journal of nutrition. 2017;56(8):2519-27.

Grau T, Bonet A, Rubio M, Mateo D, Farre M, Acosta JA, et al. Liver dysfunction associated with artificial nutrition in critically ill patients. Crit Care. 2007;11(1):R10.

Jaja S, Ogungbemi S, Kehinde M, Anigbogu C. Supplementation with l-arginine stabilizes plasma arginine and nitric oxide metabolites, suppresses elevated liver enzymes and peroxidation in sickle cell anaemia. Pathophysiology. 2016;23(2):81-5.

Siani A, Pagano E, Iacone R, Iacoviello L, Scopacasa F, Strazzullo P. Blood pressure and metabolic changes during dietary L-arginine supplementation in humans. American journal of hypertension. 2000;13(5):547-51.

Osowska S, Moinard C, Loi C, Neveux N, Cynober L. Citrulline increases arginine pools and restores nitrogen balance after massive intestinal resection. Gut. 2004;53(12):1781-6.

Schwedhelm E, Maas R, Freese R, Jung D, Lukacs Z, Jambrecina A, et al. Pharmacokinetic and pharmacodynamic properties of oral L‐citrulline and L‐arginine: impact on nitric oxide metabolism. British journal of clinical pharmacology. 2008;65(1):51-9.

Heyland DK, Novak F, Drover JW, Jain M, Su X, Suchner U. Should immunonutrition become routine in critically ill patients?: A systematic review of the evidence. Jama. 2001;286(8):944-53.

IssueVol 4, No 2 (Spring 2018) QRcode
SectionOriginal Article(s)
L-arginine L-citrulline head trauma ICU

Rights and permissions
Creative Commons License This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
How to Cite
Barkhidarian B, Hashemy SI, Shabbidar S, Nematy M, Rahbari A, Ranjbar R, Tavallaei S, Samini F, Hashemi B, Safarian M. Comparison of L-arginine and L-citrulline oral supplementation in head trauma ICU patients receiving enteral nutrition: A randomized double blind clinical trial. J Nutr Sci & Diet. 2018;4(2).