The Effect of L-Citrulline Supplementation on Outcomes of Critically Ill Patients under Mechanical Ventilation; a Double-Blind Randomized Controlled Trial

ntroduction:Effective parenteral and enteral amino acid replacement is crucial for critically ill patients with alteredamino acid metabolism. This study aimed to assess the effects of l-citrulline supplementation on the clinical and labo-ratory outcomes in critically patients.

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. Thepatients were assigned to either a placebo or an intervention group. The patients in the placebo group received 10 gr ofmicrocrystalline cellulose and the ones in the intervention group were given l-citrulline daily for 7 days. Serum levelsof fasting blood sugar (FBS), lipid profile, hepatic enzymes, serum electrolytes, urea nitrogen, creatinine, and C-reactiveprotein (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.Re-sults:Eighty-two patients completed the trial. No statistically significant differences were observed between the twogroups 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 HealthEvaluation (APACHE II) score (p = 0.58), risk factors (p = 0.13), ICU stay before randomization (p = 0.32), and reason ofadmission (p = 0.50) before the intervention. Citrulline group had a notable reduction in FBS (p = 0.04), total choles-terol (TC) (p = 0.02), low density lipoprotein (LDL-C) (p <0.001) and high-sensitivity CRP (hs-CRP) (p <0.001). Also, asignificant increase in lactate dehydrogenase (LDH) concentration (p <0.001) was observed in the intervention group atthe end of the trial. Total duration of invasive ventilation and the mean SOFA score on 7th day were significantly lowerin the citrulline group compared to the control group. Moreover, a significant increase in days alive and ventilator-freedays within 28 days after admission was found in the citrulline group at the end of the trial. Also, there were no signifi-cant differences between the groups in terms of mortality rate during intervention, serious adverse events, endotrachealintubation, the use of tracheotomy or non-invasive ventilation after extubation, length of ICU stay, ICU-free days at 28days, and CPIS and APACHE II scores. For mortality, in the citrulline group, there was two deaths compared to eightdeaths in the control group. This resulted in an absolute risk reduction (ARR) of 14.05% (95% CI: 0.39–27.71%) and anumber needed to treat (NNT) of 7.1 (95% CI: 3.6–29.5), regarding mortality.

The results of the presentstudy demonstrated the probable positive effects of citrulline supplementation on lipid profile, hs-CRP levels, durationof invasive ventilation, and SOFA score. Also, l-citrulline consumption may increase the probability of survival withoutmechanical ventilation.