Clinical trial NCT02370030: Effect of Citrulline on the Clinical and Biochemical Evolution of Patients With Sepsis.
Official title: Controlled Randomized Multi-centric Clinical Trial on the Effect of Citrulline on the Clinical and Biochemical Evolution of Patients With Sepsis.
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE1
PHASE2
Conditions: Sepsis
Keywords: sepsis
citrulline
endothelial
toxemia
endothelial determination of progression
with vs without citrulline
Lead sponsor: Instituto Mexicano del Seguro Social
Sponsor class: OTHER_GOV
First posted: 2015-02-24
Enrollment: 160
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Triple blind placebo-controlled study to determine if administering citrulline in patients with sepsis and severe sepsis slows progression to multiple organ failure and death, measuring biomarkers of endothelial dysfunction. Patients are divided into placebo or citrulline and followed up for 1 month.

Detailed description: Consecutive patients with sepsis are being recited from intensive care unite of IMSS at the CMN Siglo XXI and CMN La Raza over the period of november 2015 through june 2016. After signing an informed consent they will be randomized into 80 for intervention arm and 80 for the placebo arm. All patients will receive usual medical treatment; and during seven days citurlline arm subjects will receive supplementation with oral or nasogastric citrulline (10 g/day), while other group patients will receive during seven days oral or nasogastric placebo (10 g/day) with no visible difference between these. Microalbuminuria and interleukines 1, 6, and 10 will be measured at randomization and at day 7. All subjects will be followed for 28 days, and after the follow-up period results will be analyzed to determine de efficacy and safety of citrulline, primary outcome are the incidence of multiple organic failure and death, also microalbuminuria levels 1,6,10-interleukines. We will use Student-t and Chi2 for statistical analysis.

Eligibility criteria: Inclusion Criteria:

* Sepsis
* Severe sepsis
* Diagnosis of sepsis in the first 36 hours of hospitalization.
* Informed Consent
* Intestinal tract intact

Exclusion Criteria:

* Terminal cancer
* Acute and chronic liver diseases
* Chronic renal failure.
* Acute renal failure AKIN III.
* Pregnant and postpartum women
* Dying patients.
* Patients with cardiac arrest.
* Active gastrointestinal bleeding.
* Steroids or immunosuppressants.
* Enrolled in another study intervention.
* Citrulline allergy.

Primary outcomes:
measure: Multiple organ failure
timeFrame: 1 month
Secondary outcomes:
Other outcomes:
Locations:
city: Mexico City
country: Mexico
facility: CME Centro Mèdico Siglo XXI
state: DF
city: Mexico City
country: Mexico
facility: CME La Raza
state: DF
Study officials:
affiliation: Coordinación de Investigación en Salud, México.
name: Eduardo Almeida Gutierrez, MSc
role: STUDY_DIRECTOR
References:
citation: Kao CC, Bandi V, Guntupalli KK, Wu M, Castillo L, Jahoor F. Arginine, citrulline and nitric oxide metabolism in sepsis. Clin Sci (Lond). 2009 Jun 2;117(1):23-30. doi: 10.1042/CS20080444.
citation: Barr FE, Tirona RG, Taylor MB, Rice G, Arnold J, Cunningham G, Smith HA, Campbell A, Canter JA, Christian KG, Drinkwater DC, Scholl F, Kavanaugh-McHugh A, Summar ML. Pharmacokinetics and safety of intravenously administered citrulline in children undergoing congenital heart surgery: potential therapy for postoperative pulmonary hypertension. J Thorac Cardiovasc Surg. 2007 Aug;134(2):319-26. doi: 10.1016/j.jtcvs.2007.02.043.
citation: Piton G, Manzon C, Monnet E, Cypriani B, Barbot O, Navellou JC, Carbonnel F, Capellier G. Plasma citrulline kinetics and prognostic value in critically ill patients. Intensive Care Med. 2010 Apr;36(4):702-6. doi: 10.1007/s00134-010-1751-6.
citation: Piton G, Belon F, Cypriani B, Regnard J, Puyraveau M, Manzon C, Navellou JC, Capellier G. Enterocyte damage in critically ill patients is associated with shock condition and 28-day mortality. Crit Care Med. 2013 Sep;41(9):2169-76. doi: 10.1097/CCM.0b013e31828c26b5.
citation: 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 Jan;89(1):142-52. doi: 10.3945/ajcn.2007.25765. Epub 2008 Dec 3.
citation: Kao C, Hsu J, Bandi V, Jahoor F. Alterations in glutamine metabolism and its conversion to citrulline in sepsis. Am J Physiol Endocrinol Metab. 2013 Jun 15;304(12):E1359-64. doi: 10.1152/ajpendo.00628.2012. Epub 2013 Apr 23.
citation: Wijnands KA, Vink H, Briede JJ, van Faassen EE, Lamers WH, Buurman WA, Poeze M. Citrulline a more suitable substrate than arginine to restore NO production and the microcirculation during endotoxemia. PLoS One. 2012;7(5):e37439. doi: 10.1371/journal.pone.0037439. Epub 2012 May 29.
citation: Ware LB, Magarik JA, Wickersham N, Cunningham G, Rice TW, Christman BW, Wheeler AP, Bernard GR, Summar ML. Low plasma citrulline levels are associated with acute respiratory distress syndrome in patients with severe sepsis. Crit Care. 2013 Jan 17;17(1):R10. doi: 10.1186/cc11934.
citation: Cynober L. Citrulline: just a biomarker or a conditionally essential amino acid and a pharmaconutrient in critically ill patients? Crit Care. 2013 Mar 11;17(2):122. doi: 10.1186/cc12534.