Clinical trial NCT00628381: L-citrulline Supplementation During Sepsis
Official title: Arginine and Nitric Oxide (NO) Metabolism in Sepsis; L-citrulline Enteral Supplementation for the Normalisation of the Arginine-NO Metabolism
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Sepsis
Multiple Organ Failure
Keywords: sepsis
microcirculation
nitric oxide
citrulline
Lead sponsor: Maastricht University Medical Center
Sponsor class: OTHER
Collaborators: name: ZonMw: The Netherlands Organisation for Health Research and Development
First posted: 2008-03-05
Enrollment: 48
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to study the stimulating effects of prolonged (8h) enteral L-citrulline supplementation on the normalisation of the plasma citrulline concentrations and the Arginine-NO metabolism, the microcirculation, the systemic hemodynamics, vascular permeability, and organ function and disease severity scores.

Detailed description: NO synthesis is compromised during sepsis through lack of arginine de novo synthesis and may thereby contribute to impaired microcirculation and organ dysfunction. Supplementation of L-citrulline in septic patients will increase NO production without increased arginase activity and these effects will be studied on arginine-NO metabolism,improved organ function, vascular permeability and microcirculation.

Eligibility criteria: Inclusion Criteria:

* Written informed consent from close relative
* Age \> 18 years
* Patient meets the general criteria for severe sepsis or septic shock, diagnosed less than 48 h prior to study inclusion.
* Patient must be relatively hemodynamically stable, defined as stable blood pressure (variation in mean arterial pressure \<15 mm Hg) during 2h without necessity of increasing the vasopressor dose, inotropic support or rate of fluid administration.
* Systemic arterial catheter in place with continuous pressure monitoring.
* Patients in whom the clinician is prepared to provide full life support during the duration of the study

Exclusion Criteria:

* Shock due to any cause other than sepsis (e.g. drug reaction or drug overdose, pulmonary embolus, burn injury etc.)
* Prolonged or high dose corticosteroid use
* Liver cirrhosis
* Chronic pancreatitis
* Insulin-dependent diabetes mellitus
* Metastases, haematological malignancies or chemotherapy
* Patients on dialysis (CVVH or other)
* Pre-existent renal failure (on dialysis)

Primary outcomes:
measure: To study stimulating effects of prolonged (8h) enteral L-citrulline supplementation on the normalisation of the arginine-NO metabolism
timeFrame: 8 hours
Secondary outcomes:
measure: Secondary study endpoints are the microcirculation, the vascular permeability and organ function scores.
timeFrame: within 8 hours
Other outcomes:
Locations:
city: Maastricht
country: Netherlands
facility: University Hospital Maastricht
state: Limburg
Study officials:
affiliation: Department of Surgery
name: Martijn Poeze, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Rouge C, Des Robert C, Robins A, Le Bacquer O, Volteau C, De La Cochetiere MF, Darmaun D. Manipulation of citrulline availability in humans. Am J Physiol Gastrointest Liver Physiol. 2007 Nov;293(5):G1061-7. doi: 10.1152/ajpgi.00289.2007. Epub 2007 Sep 27.
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: Lehr HA, Bittinger F, Kirkpatrick CJ. Microcirculatory dysfunction in sepsis: a pathogenetic basis for therapy? J Pathol. 2000 Feb;190(3):373-86. doi: 10.1002/(SICI)1096-9896(200002)190:33.0.CO;2-3.
citation: Wu G, Morris SM Jr. Arginine metabolism: nitric oxide and beyond. Biochem J. 1998 Nov 15;336 ( Pt 1)(Pt 1):1-17. doi: 10.1042/bj3360001.
citation: Hallemeesch MM, Lamers WH, Deutz NE. Reduced arginine availability and nitric oxide production. Clin Nutr. 2002 Aug;21(4):273-9. doi: 10.1054/clnu.2002.0571.