Clinical trial NCT01775020: Dose-response Study of Arginine Supplementation in Severe Sepsis
Official title: Arginine and Nitric Oxide (NO) Metabolism in Sepsis; Dose-response Study on the Effect of L-arginine Supplementation on NO Metabolism and Gastric Perfusion in Severe Septic Patients.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: EARLY_PHASE1
Conditions: Sepsis
Septic Shock
Lead sponsor: Maastricht University Medical Center
Sponsor class: OTHER
Collaborators: name: Novartis Medical Nutrition
First posted: 2013-01-24
Enrollment: 8
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP

Brief summary: Pilot data in patients and data from pig studies indicate that arginine-NO metabolism is impaired in sepsis with changes in splanchnic metabolism and function, and reduced survival at low nitrate levels. Prolonged intravenous supplementation of L-arginine proved effective in pigs for increasing NO production, restoring gut function, and inhibiting an increase in pulmonary arterial pressure, without any deleterious systemic side effects. Prolonged intravenous L-arginine supplementation could therefore be useful in septic ICU patients.


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 (see appendix A; in Dutch).
* Patient must be relatively hemodynamically stable, defined as stable blood pressure (variation in mean arterial pressure \<15 mm Hg) during 2 h without necessity of increasing the vasopressor dose, inotropic support or rate of fluid administration.
* Systemic and pulmonary arterial catheters in place with continuous pressure monitoring.
* Patients in whom the clinician is prepared to provide full life support during the duration of the study, including a life expectance of \> 24 h.

Exclusion Criteria:

* Shock due to any cause other than sepsis (e.g. drug reaction or drug overdose, pulmonary embolus, burn injury etc.)
* Corticosteroid use (prolonged intake of \> 1mg/kg daily or intake of \> 70 mg/day for 7 consecutive days within 1 month preceding the study)
* Liver cirrhosis
* Chronic pancreatitis
* Diabetes mellitus type I
* Metastases, haematological malignancies or chemotherapy
* Patients on dialysis (CVVH or other)

Primary outcomes:
measure: Nitric oxide synthesis
timeFrame: 8 hours
Secondary outcomes:
measure: hemodynamics
timeFrame: 8 hours
measure: blood parameters
timeFrame: 8 hours
measure: gastric perfusion
timeFrame: 8 hours
Other outcomes:
Locations:
Study officials:
name: Nicolaas E Deutz, MD PhD
role: PRINCIPAL_INVESTIGATOR
References:
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: Poeze M, Bruins MJ, Kessels F, Luiking YC, Lamers WH, Deutz NE. Effects of L-arginine pretreatment on nitric oxide metabolism and hepatosplanchnic perfusion during porcine endotoxemia. Am J Clin Nutr. 2011 Jun;93(6):1237-47. doi: 10.3945/ajcn.110.007237. Epub 2011 Apr 20.