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

Conclusion and Hypothesis

In sepsis, arginine availability is reduced by increased arginine catabolism, mainly through arginase pathways, and reduced availability through diminished endogenous arginine synthesis[36] and food intake (Fig. 2). This makes arginine a near essential amino acid in sepsis, as was suggested before,[177] and limits arginine availability for NO production[178] and other arginine-consuming pathways. This is illustrated by the observation that exogenous arginine administration can increase NO production.[68]

Although increased NO production by NOS-2 in sepsis is linked to systemic hypotension, many characteristics of sepsis could be linked to locally diminished NO availability. For example, impaired NO synthesis by NOS-3 may be related to loss of ability to autoregulate microcirculation.[179] Increased NO from NOS-2 could then be regarded as a compensatory mechanism to improve blood flow. This could also explain why nonselective NOS inhibitors, which inhibit both NOS-3 and NOS-2, are not beneficial. Arginine might improve microcirculation by increasing NO production, mainly by delivering adequate amounts of substrate for NOS-3. The fact that in our hypothesis the reduction of NOS-3 expression is important in the pathophysiology of sepsis makes the supplementation of arginine a more logical step than selective inhibition of NOS-2. Although this latter therapy may reduce the exaggerated induction of NOS-2 and therefore treat the sepsis-induced hypotension, it will not compensate for the prolonged reduction in arginine availability, which causes a considerable number of sepsis-related features.

The importance of adequate arginine levels and NO production is further supported by the observations that marked reduction in serum arginine is a predictor of mortality in patients with sepsis[34] and that patients surviving septic shock had higher plasma nitrate levels than nonsurvivors.[180] However, debate exists concerning this last argument.[27,55] Adequate arginine levels may also reduce the production of superoxide and peroxynitrite by NOS, as this occurs in conditions of reduced levels of arginine or cofactor tetrahydrobiopterin.[181] Moreover, arginine has anabolic effects and contributes to protein synthesis (e.g., acute phase proteins).[139] Although arginine-containing immunonutrition did not improve survival, further studies are needed with arginine supplementation as a monotherapy. It would be interesting to focus on the effect of arginine supplementation (both intravenously and enterally) on microcirculation and subsequent organ function, on protein metabolism, and ultimately, on survival. Well-designed and controlled studies are therefore needed.

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