The Effect of L-Citrulline Supplementation on Outcomes of Critically Ill Patients under Mechanical Ventilation; a Double-Blind Randomized Controlled Trial
Archives of Academic Emergency Medicine,
Vol. 11 No. 1 (2023),
15 November 2022
Introduction: Effective parenteral and enteral amino acid replacement is crucial for critically ill patients with altered amino acid metabolism. This study aimed to assess the effects of l-citrulline supplementation on the clinical and laboratory outcomes in critically patients.
Methods: This was a double-blind placebo-controlled randomized clinical trial. 82 critically ill patients who were expected to receive mechanical ventilation for more than 72 hours were selected. The patients were assigned to either a placebo or an intervention group. The patients in the placebo group received 10 gr of microcrystalline cellulose and the ones in the intervention group were given l-citrulline daily for 7 days. Serum levels of fasting blood sugar (FBS), lipid profile, hepatic enzymes, serum electrolytes, urea nitrogen, creatinine, and C-reactive protein (CRP) were evaluated before and after the intervention. Duration of invasive ventilation, intensive care unit (ICU) length of stay, ventilator-free days, and 28-day mortality rate were recorded and compared between groups.
Results: Eighty-two patients completed the trial. No statistically significant differences were observed between the two groups in terms of age (p = 0.46), sex (p = 0.49), body mass index (BMI) (p = 0.41), Sequential Organ Failure Assessment (SOFA) Score (p = 0.08), Clinical Pulmonary Infection Score (CPIS) score (p = 0.76), Acute Physiology and Chronic Health Evaluation (APACHE II) score (p = 0.58), risk factors (p = 0.13), ICU stay before randomization (p = 0.32), and reason of admission (p = 0.50) before the intervention. Citrulline group had a notable reduction in FBS (p = 0.04), total cholesterol (TC) (p = 0.02), low density lipoprotein (LDL-C) (p <0.001) and high-sensitivity CRP (hs-CRP) (p <0.001). Also, a significant increase in lactate dehydrogenase (LDH) concentration (p <0.001) was observed in the intervention group at the end of the trial. Total duration of invasive ventilation and the mean SOFA score on 7th day were significantly lower in the citrulline group compared to the control group. Moreover, a significant increase in days alive and ventilator-free days within 28 days after admission was found in the citrulline group at the end of the trial. Also, there were no significant differences between the groups in terms of mortality rate during intervention, serious adverse events, endotracheal intubation, the use of tracheotomy or non-invasive ventilation after extubation, length of ICU stay, ICU-free days at 28 days, and CPIS and APACHE II scores.
For mortality, in the citrulline group, there was two deaths compared to eight deaths in the control group. This resulted in an absolute risk reduction (ARR) of 14.05% (95% CI: 0.39–27.71%) and a number needed to treat (NNT) of 7.1 (95% CI: 3.6–29.5), regarding mortality.
Conclusions: The results of the present study demonstrated the probable positive effects of citrulline supplementation on lipid profile, hs-CRP levels, duration of invasive ventilation, and SOFA score. Also, l-citrulline consumption may increase the probability of survival without mechanical ventilation.
- Intensive care units
- critical illness
- intensive care units
- treatment outcome
- clinical trial
How to Cite
Ginguay A, De Bandt JP, Cynober L. Indications and contraindications for infusing specific amino acids (leucine, glutamine, arginine, citrulline, and taurine) in critical illness. Curr Opin Clin Nutr Metab Care. 2016;19(2):161-9.
Kany S, Vollrath JT, Relja B. Cytokines in Inflammatory Disease. Int J Mol Sci. 2019 Nov 28;20(23):6008.
Herndon DN, Hart DW, Wolf SE, Chinkes DL, Wolfe RR. Reversal of catabolism by beta-blockade after severe burns. N Engl J Med. 2001;345(17):1223-9.
Hofford JM, Milakofsky L, Vogel WH, Sacher RS, Savage GJ, Pell S. The nutritional status in advanced emphysema associated with chronic bronchitis. A study of amino acid and catecholamine levels. Am Rev Respir Dis. 1990;141(4 Pt 1):902-8.
Ottenheijm CA, Heunks LM, Sieck GC, Zhan WZ, Jansen SM, Degens H, et al. Diaphragm dysfunction in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2005;172(2):200-5.
Barkhidarian B, Hashemi SI, Nematy M, Rahbar A, Ranjbar R, Safarian M. Effects of arginine and citrulline supplementation on inflammatory markers in critically ill patients. JNSD. 2017;2(2).
Zhou M, Martindale RG. Immune-modulating enteral formulations: optimum components, appropriate patients, and controversial use of arginine in sepsis. Curr Gastroenterol Rep. 2007;9(4):329-37.
Luiking YC, Poeze M, Ramsay G, Deutz NE. Reduced citrulline production in sepsis is related to diminished de novo arginine and nitric oxide production. Am J Clin Nutr. 2009;89(1):142-52.
Zhou M, Martindale RG. Arginine in the critical care setting. J Nutr. 2007;137(6 Suppl 2):1687s-92s.
Morris SM, Jr. Recent advances in arginine metabolism. Curr Opin Clin Nutr Metab Care. 2004;7(1):45-51.
van Waardenburg DA, de Betue CT, Luiking YC, Engel M, Deutz NE. Plasma arginine and citrulline concentrations in critically ill children: strong relation with inflammation. Am J Clin Nutr. 2007;86(5):1438-44.
Oberholzer A, Oberholzer C, Moldawer LL. Cytokine signaling--regulation of the immune response in normal and critically ill states. Crit Care Med. 2000;28(4 Suppl):N3-12.
Von Blomberg-van der Flier B, Riezebos R, Scholten P, Quak J, Snow G, Van Leeuwen P. Differences in immune status between well-nourished andmalnourished head and neck cancer patients. Clin Nutr. 1998;17(3):107-11.
Windmueller HG, Spaeth AE. Source and fate of circulating citrulline. Am J Physiol. 1981;241(6):E473-80.
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. Br J Clin Pharmacol. 2008;65(1):51-9.
Jones AM, Thompson C, Wylie LJ, Vanhatalo A. Dietary Nitrate and Physical Performance. Annu Rev Nutr. 2018;38:303-28.
Margaritelis NV, Paschalis V, Theodorou AA, Kyparos A, Nikolaidis MG. Redox basis of exercise physiology. Redox Biol. 2020;35:101499.
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):177-205.
Bahareh B, Seyed Issac H, Sakineh S, Mohsen N, Ashraf R, Roya R, et al. Comparison of L-arginine and L-citrulline oral supplementation in head trauma ICU patients receiving enteral nutrition: A randomized double blind clinical trial. JNSD. 2018;4(2).
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. Crit Care Med. 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. Guy's Hospital Intensive Care Group. Crit Care Med. 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. Ann Surg. 1996;224(4):531-40; discussion 40-3.
Poole A, Deane A, Summers M, Fletcher J, Chapman M. The relationship between fasting plasma citrulline concentration and small intestinal function in the critically ill. J Crit Care. 2016;19(1):1-8.
Piton G, Manzon C, Monnet E, Cypriani B, Barbot O, Navellou J-C, et al. Plasma citrulline kinetics and prognostic value in critically ill patients. Intensive Care Med. 2010;36(4):702-6.
Piton G, Belon F, Cypriani B, Regnard J, Puyraveau M, Manzon C, et al. Enterocyte damage in critically ill patients is associated with shock condition and 28-day mortality. Crit Care Med. 2013;41(9):2169-76.
Cynober L. Citrulline: just a biomarker or a conditionally essential amino acid and a pharmaconutrient in critically ill patients? Critic care. 2013;17(2):1-3.
Barkhidarian B, seyedhamzeh S, Hashemi SI, Nematy M, Rahbar A, Ranjbar R, et al. Effects of Arginine and Citrulline supplementation on inflammatory markers in critically ill patients. JNSD. 2017;2(2).
Vermeulen MA, van de Poll MC, Ligthart-Melis GC, Dejong CH, van den Tol MP, Boelens PG, et al. Specific amino acids in the critically ill patient--exogenous glutamine/arginine: a common denominator? Crit Care Med. 2007;35(9 Suppl):S568-76.
Weeks DL, Noteboom JT. Using the number needed to treat in clinical practice. Arch Phys M. 2004;85(10):1729-31.
Azizi S, Mahdavi R, Mobasseri M, Aliasgharzadeh S, Abbaszadeh F, Ebrahimi‐Mameghani MJPR. The impact of L‐citrulline supplementation on glucose homeostasis, lipid profile, and some inflammatory factors in overweight and obese patients with type 2 diabetes: A double‐blind randomized placebo‐controlled trial. Phytother Res. 2021;35(6):3157-66.
Kudo M, Yoshitomi H, Momoo M, Suguro S, Yamagishi Y, Gao MJB, et al. Evaluation of the effects and mechanism of L-Citrulline on anti-obesity by appetite suppression in obese/diabetic KK-Ay mice and high-fat diet fed SD rats. Biol Pharm Bull. 2017;40(4):524-30.
Capel F, Chabrier G, Pitois E, Rigaudière JP, Plenier SL, Durand C, et al. Combining citrulline with atorvastatin preserves glucose homeostasis in a murine model of diet‐induced obesity. Br J Pharmacol. 2015;172(20):4996-5008.
Li Y, Xu S, Mihaylova MM, Zheng B, Hou X, Jiang B, et al. AMPK phosphorylates and inhibits SREBP activity to attenuate hepatic steatosis and atherosclerosis in diet-induced insulin-resistant mice. Cell Metab. 2011;13(4):376-88.
Joffin N, Jaubert A-M, Durant S, Barouki R, Forest C, Noirez P. Citrulline counteracts overweight-and aging-related effects on adiponectin and leptin gene expression in rat white adipose tissue. Biochimie open. 2015;1:1-5.
Abudukadier A, Fujita Y, Obara A, Ohashi A, Fukushima T, Sato Y, et al. Tetrahydrobiopterin has a glucose-lowering effect by suppressing hepatic gluconeogenesis in an endothelial nitric oxide synthase–dependent manner in diabetic mice. Diabetes. 2013;62(9):3033-43.
Cardaci S, Filomeni G, Ciriolo MR. Redox implications of AMPK-mediated signal transduction beyond energetic clues. J Cell Sci. 2012;125(9):2115-25.
Villareal MO, Matsukawa T, Isoda H. L-Citrulline Supplementation-Increased Skeletal Muscle PGC-1α Expression is Associated With Exercise Performance and Increased Skeletal Muscle Weight. Mol Nutr Food Res. 2018;62(14):e1701043.
Darabi Z, Darand M, Yari Z, Agah S, Hrkmat doust A. Effects of Citrulline on Non-alcoholic Fatty Liver Disease: A Randomized-controlled Clinical Trial. Iranian-J-Nutr-Sci-Food-Technol. 2019;14(3):1-9.
Hashemi SR, Arab HA, Seifi B, Muhammadnejad S. A comparison effects of l-citrulline and l-arginine against cyclosporine-induced blood pressure and biochemical changes in the rats. Hipertens Riesgo Vasc. 2021;38(4):170-7.
Lauterbach R, Pawlik D, Lauterbach JPJSOMCR. L-citrulline supplementation in the treatment of pulmonary hypertension associated with bronchopulmonary dysplasia in preterm infant: A case report. SAGE Open Med Case Rep. 2018;6:2050313X18778730.
Sopi RB, Zaidi SI, Mladenov M, Sahiti H, Istrefi Z, Gjorgoski I, et al. L-citrulline supplementation reverses the impaired airway relaxation in neonatal rats exposed to hyperoxia. Respir Res. 2012;13(1):1-9.
Vadivel A, Aschner JL, Rey-Parra GJ, Magarik J, Zeng H, Summar M, et al. L-citrulline attenuates arrested alveolar growth and pulmonary hypertension in oxygen-induced lung injury in newborn rats. Pediatr Res. 2010;68(6):519-25.
Mahboobi S, Tsang C, Rezaei S, Jafarnejad S. RETRACTED ARTICLE: Effect of l-citrulline supplementation on blood pressure: a systematic review and meta-analysis of randomized controlled trials. J Hum Hypertens. 2019;33(1):10-21.
Cuartas PA, Santos HT, Levy BM, Gong MN, Powell T, Chuang E. Modeling Outcomes Using Sequential Organ Failure Assessment (SOFA) Score-Based Ventilator Triage Guidelines During the COVID-19 Pandemic. Disaster Med Public Health Prep. 2022:1-4.
Romero MJ, Yao L, Sridhar S, Bhatta A, Dou H, Ramesh G, et al. L-citrulline protects from kidney damage in type 1 diabetic mice. Front immunol. 2013;4:480.
Adam J, Brandmaier S, Leonhardt J, Scheerer MF, Mohney RP, Xu T, et al. Metformin effect on nontargeted metabolite profiles in patients with type 2 diabetes and in multiple murine tissues. Diabetes. 2016;65(12):3776-85.
Irving BA, Carter RE, Soop M, Weymiller A, Syed H, Karakelides H, et al. Effect of insulin sensitizer therapy on amino acids and their metabolites. Metabolism. 2015;64(6):720-8.
Irving BA, Spielmann GJD. Does citrulline sit at the nexus of metformin’s pleotropic effects on metabolism and mediate its salutatory effects in individuals with type 2 diabetes? Diabetes. 2016;65(12):3537-40.
Kameda N, Okigawa T, Kimura T, Fujibayashi M, Asada T, Kinoshita R, et al. The effect of L-citrulline ingestion on ECG QT interval and autonomic nervous system activity. J Physiol Anthropol. 2011;30(2):41-5.
Abbaszadeh F, Azizi S, Mobasseri M, Ebrahimi-Mameghani M. The effects of citrulline supplementation on meta-inflammation and insulin sensitivity in type 2 diabetes: a randomized, double-blind, placebo-controlled trial. Diabetol Metab Syndr. 2021;13(1):1-9.
Breuillard C, Bonhomme S, Couderc R, Cynober L, De Bandt J-P. In vitro anti-inflammatory effects of citrulline on peritoneal macrophages in Zucker diabetic fatty rats. Br J Nutr. 2015;113(1):120-4.
de Winther MP, Kanters E, Kraal G, Hofker MH. Nuclear factor kappaB signaling in atherogenesis. Arterioscler Thromb Vasc Biol. 2005;25(5):904-14.
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