Sepsis: An Arginine Deficiency State?

Yvette C. Luiking, PhD; Martijn Poeze, MD, PhD; Cornelis H. Dejong, MD, PhD; Graham Ramsay, MD, PhD; Nicolaas E. Deutz, MD, PhD

Crit Care Med. 2004;32(10) 

In This Article

Abstract and Introduction

Objective: Sepsis is a major health problem considering its significant morbidity and mortality rate. The amino acid l-arginine has recently received substantial attention in relation to human sepsis. However, knowledge of arginine metabolism during sepsis is limited. Therefore, we reviewed the current knowledge about arginine metabolism in sepsis.
Data Source: This review summarizes the literature on arginine metabolism both in general and in relation to sepsis. Moreover, arginine-related therapies are reviewed and discussed, which includes therapies of both nitric oxide (NO) and arginine administration and therapies directed toward inhibition of NO.
Data: In sepsis, protein breakdown is increased, which is a key process to maintain arginine delivery, because both endogenous de novo production from citrulline and food intake are reduced. Arginine catabolism, on the other hand, is markedly increased by enhanced use of arginine in the arginase and NO pathways. As a result, lowered plasma arginine levels are usually found. Clinical symptoms of sepsis that are related to changes in arginine metabolism are mainly related to hemodynamic alterations and diminished microcirculation. NO administration and arginine supplementation as a monotherapy demonstrated beneficial effects, whereas nonselective NO synthase inhibition seemed not to be beneficial, and selective NO synthase 2 inhibition was not beneficial overall.
Conclusions: Because sepsis has all the characteristics of an arginine-deficiency state, we hypothesise that arginine supplementation is a logical option in the treatment of sepsis. This is supported by substantial experimental and clinical data on NO donors and NO inhibitors. However, further evidence is required to prove our hypothesis.

Sepsis is defined as a systemic response to an infection.[1,2] It is a major health problem because of its significant morbidity and overall mortality rate of about 30% and generally requires intensive care treatment.[3] Considerable efforts have been undertaken to understand the pathogenesis of sepsis and to improve its therapeutic modalities.[4] The amino acid arginine has recently received substantial attention in relation to human sepsis. However, from this discussion it became clear that knowledge of arginine metabolism during sepsis is limited. Moreover, therapeutic interventions based on both stimulation and inhibition of arginine metabolism have produced seemingly contradictory results. Therefore, we will review the current knowledge about arginine metabolism in sepsis, which indicates that sepsis is an arginine-deficiency state. This hypothesis regarding sepsis as an arginine deficient disease makes arginine supplementation a logical option in the treatment of sepsis.

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