Journal of Nutritional Sciences and Dietetics 2016. 2(2):.

Effects of Arginine and Citrulline on inflammatory and nutritional markers, and their relations in critically ill patients
Bahareh Barkhidarian, Shirin seyedhamzeh, Seyed Issac Hashemy, Mohsen Nematy, Ashraf Rahbari, Roya Ranjbar, Mohammad Safarian


Background: Arginine is a nonessential amino acid in the normal physiological state that becomes conditionally essential during periods of hypermetabolic stress. Recent literature supports the hypothesis that arginine plays an important role in the intermediary metabolism of the critically ill patients. Citrulline is also a nonessential amino acid that is a main precursor of Arginine and therefore could be a best alternative for arginine supplementation. In this study we compared effects of Arginine and Citrulline administration on inflammatory factors (CRP, IL6) and levels of serum pre-albumin, total protein and albumin and association of these factors levels with severity of illness in critically ill trauma patients.

Method: A total of 102 patients in 5 traumas ICU (on the basis of inclusion criteria) were divided into three groups: Arginine, Citrulline and Control. Patients received 10 g/d Arginine powder (Arginine Group) or 10 g/d Citrulline powder (Citrulline Group) for 10 days. Patients in Control Group received no supplement. All patients received standard hospital prepared feeding. Inflammatory factor (CRP, IL6), levels of serum Pre-albumin, Total protein and Albumin were determined in all patients before (day 0) and after intervention (day 11) and their correlation with APACHE II as an indicator of severity of disease were assessed.

Results: Our data shows that serum concentration of IL6 were decreased in Citrulline and Control groups (the mean changes was 1.9± 25.71, 10.87± 16.40, -1.24± 26.32 in Control, Citrulline and Arginine group respectively), so there were significant reduction in IL6 levels just in Citrulline group (p=0.009) also Serum levels of CRP decreased in both experimental group but it was elevated during study period in Control group (mean changes in control group were -0.28 ±19.66, in Citrulline group 11.16 and in arginine group it was 1.12) there were only a significant changes in Citrulline group (p= 0.025). Results showed that APACHE II score were decreased in all three groups but there were no significant differences between groups after 10 days intervention (P=0.77).Pre- albumin levels increased in Arginine and Control group but decreased in Citrulline group.  Mean changes in Arginine group were higher in comparison to Control group (-7.57± 24.85 vs -5.73± 23/04). During intervention albumin decreased in three groups, although this changes were significant within group but there were no significant differences between three groups in mean of changes (p=0.47).

Conclusion: Our data suggested that Citrulline could have modulatory effects on inflammatory response and therefore could have an effect on severity of illness and patient’s nutritional status and in this cases are more effective than arginine itself.


critically ill Patients; Arginine; Citrulline; Inflammatory factors; Nutritional markers; APACHE II


- Yvette C Luiking, Martijn Poeze, Graham Ramsay and Nicolaas EP Deutz, Reduced Citrullineproduction in sepsis is related to diminished de novo arginine and nitric oxide production, Am J Clin Nutr 2009, 89: 142-152.

- Yvette C. Luiking, Martijn Poeze, Graham Ramsay, and Nicolaas E. P. Deutz, The Role of Arginine in Infection and Sepsis, Journal of Parenteral and Enteral Nutrition,2005 , S70-S74

- Barbul A, Rettura G, Levenson SM, Seifter E. Wound healing and thymotrophic effects of arginine: a pituitary mechanism of action. Am J Clin Nutr. 1983;37:786-794.

- Barbul A. Arginine: biochemistry, physiology, and therapeutic implications. JPEN J Parenter Enteral Nutr. 1986;10:227-238.

- van Waardenburg DA, de Betue CT, Luiking YC, Engel M, Deutz NE (2007) Plasma arginine and Citrullineconcentrations in critically ill children: strong relation with inflammation. Am J

- Oberholzer A, Oberholzer C, Moldawer LL, Mitchell P. Cytokine signaling-regulation of the immune response in normal and critically ill states. Crit Care Med 2000;28(Suppl. 4):N3–N12.

- Calandra T, Gerain J, Heumann D, Baumgartner JD, Glauser MP. High circulating levels of interleukin-6 in patients with septic shock: evolution during sepsis, prognostic value, and interplay with other cytokines. The Swiss–Dutch J5 immunoglobulin study group. Am J Med 1991;91:23–9.

- Bozza FA, Salluh JI, Japiassu AM, Soares M, Assis EF, Gomes RN, et al. Cytokine profiles as markers of disease severity in sepsis: a multiplex analysis. Crit Care 2007;11:R49.

- Roumen RH, Hendriks T, van der Ven-Jongekrijg J, Nieuwenhuijzen GA, Sauerwein RW, van der Meer JWM, et al. Cytokine patterns in patients after major vascular surgery, hemorrhagic shock, and severe blunt trauma. Ann Surg 1993;218:769–76.

- Neidhardt R, Keel M, Steckholzer U, Safret A, Ungethuem U, Trentz O, et al. Relationship of interleukin-10 plasma levels to severity of injury and clinical outcome in injured patients. J Trauma 1997;42:863–71.

- Dimopoulou I, Armaganidis A, Douka E, Mavrou I, Augustatou C, Kopterides P, et al. Tumour necrosis factor-alpha (TNF-a) and interleukin-10 are crucial mediators in post-operative systemic inflammatory response and determine the occurrence of complication after major abdominal surgery. Cytokine 2007;37:55–61.

- Berney T, Gasche Y, Robert J, Jenny A, Mensi N, Grau G, et al. Serum profiles of interleukin-6, interleukin-8, and interleukin-10 in patients with severe and mild pancreatitis. Pancreas 1999;18:371–7.

- Yamada Y, Endo S, Inada K. Plasma cytokine levels in patients with severe burn injury-with reference to the relationship between infection and prognosis. Burns 1996;22:587–93

- Geppert A, Steiner A, Zorn G, Delle-Karth G, Koreny M, Haumer M, et al. Multiple organ failure in patients with cardiogenic shock is associated with high plasma levels of interleukin-6. Crit Care Med 2002;30:1987–94.

- Van Bokhorst-de van der Schueren MAE, von Blomberg-van-der Flier BME & Riezebos RK (1998): Differences in immune status between well nourished and malnourished head and neck cancer patients. Clin. Nutr. 17, 107 – 111

- Daly JM, Reynolds J & Thom A (1988): Immune and metabolic effects of arginine in the surgical patient. Ann. Surg. 208, 521– 523.

- Biffl WL, Moore EE, Moore FA, Peterson VM. Interleukin-6 in the injured patient: marker of injury or mediator of inflammation? Ann Surg. 1996;224:647-664

- Ueo H, Inoue H, Honda M, et al. Production of interleukin-6 at operative wound sites in surgical patients. J Am Coll Surg. 1994;179:326-332.

- Gebhard F, Pfetsch H, Steinbach G, Strecker W, Kinzl L, ckner U, Is Interleukin 6 an Early Marker of Injury Severity Following Major Trauma in Humans? ARCH SURG/VOL 135, MAR 2000

- van Os JP, Roumen RM, Schoots FJ, et al. Is early osteosynthesis safe in multiple trauma patients with severe thoracic trauma and pulmonary contusion? J Trauma. 1994;36:495-498.

- Issihiki H, Akira S, Sugita T, et al. Reciprocal expression of NFIL6 and C/EBP in hepatocytes: possible involvement of NF-IL6 in acute phase protein gene expression. New Biol 1991;3:63–70.

- Fleck A, Colley CM, Myers MA. Liver export proteins and trauma. Brit Med Bull 1985;41:265–73.

- Khorana J, Rerkasem K, Apichartpiyakul C, Sakonwasun C , Watcharasakslip W, Waniyapong T and et al, Immunonutrition and Cytokine Response in Patients with Head Injury, J Med Assoc Thai 2009; 92 (2): 188-94

- Asgeirsson T, Zhang S, Nunoo b, Mascarenas C, Dujovny N, Luchtefeld M, S. Cavey G, and Senagore A, Citrulline: A potential immunomodulator in sepsis, Surgery 2011;150:744-51


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