Dose-response Study of Arginine Supplementation in Severe Sepsis

Study Overview
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Brief Summary
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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.

Official Title
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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.

Conditions
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Sepsis, Septic Shock

Intervention / Treatment
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* Dietary Supplement: L-arginine


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: L-arginine<br>L-arginine | Dietary Supplement: L-arginine<br> <br> * Other names: L-arginine-HCl;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Nitric oxide synthesis | Nitric oxide synthesis at step-wise increasing doses of L-arginine infusion. Following a 2h baseline measurements, 3 stepwise increasing arginine doses each provided for 2h will be tested for the effect on NO synthesis. | 8 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| hemodynamics | Mean arterial pressure (MAP), pulmonary arterial pressure (PAP), cardiac output (CO), cardiac index (CI), heart rate (HR) | 8 hours | 
| blood parameters | Blood gasses, electrolytes, glucose, insulin, amino acids, whole body protein and arginine metabolism | 8 hours | 
| gastric perfusion | Regional (gastric) CO2 production measured with tonometry (PrCO2) | 8 hours |