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

Arginine Availability in Sepsis

In septic patients, plasma and intracellular muscle arginine levels were found to be markedly decreased compared with control values of healthy subjects or control hospital patients,[34,35,36] although other amino acids besides arginine may also decrease,[35] and a decrease may also exist in nonseptic, stressed patients[37] ( Table 1X ). An additional important factor is that plasma arginine concentrations were found to be significantly lower in those patients who died of sepsis compared with patients surviving sepsis.[34] In well-controlled animal models of sepsis, induction of sepsis decreased the total blood amino acid concentration, including arginine.[38,39]

Reduced arginine levels in sepsis suggest that arginine metabolism has changed or transport across the cell membrane is increased. Plasma arginine production, which is the total production of arginine from protein breakdown and from de novo synthesis, was not different between pediatric septic patients and healthy adults[40] or between adult septic patients and nonseptic intensive care unit controls.[36] However, arginine production during endotoxemia in pigs was increased, mainly from muscle protein breakdown.[39] In particular, the intestinal-renal pathway resulting in de novo arginine synthesis from citrulline has been considered as the primary pathway responsible for maintenance of the plasma arginine level.[12,13,32,41] We recently observed a diminished de novo arginine synthesis in septic patients when compared with healthy adults and with nonseptic intensive care unit patients with moderate inflammation, in line with lowered plasma arginine level in the septic patients.[36] This may point to lack of adaptation to the enhanced arginine need in sepsis, which is normally through up-regulation of endogenous arginine production, and may be due to lack of citrulline[9,36] or renal failure.[42]

Exogenous daily arginine supply by nutritional intake is normally about 5-6 grams,[43,44] which is still a substantial amount compared with the endogenous daily arginine production of about 15-20 gram.[14,45] Because septic patients are often not fed during their initial stay in the intensive care unit, arginine supply relies completely on endogenous arginine synthesis. The importance of endogenous arginine synthesis is also demonstrated by the normal physiologic adaptation to a low-protein diet. It has been suggested that large amounts of arginine are then metabolized into citrulline in the small bowel to bypass the liver, and citrulline is subsequently converted back to arginine in the kidney.[12,22] This saves arginine from being converted to urea and therefore being wasted. However, even when septic patients are fed, arginine availability may still be compromised due to impaired intestinal absorption[46] or impaired intestinal function through citrulline production[36] when nutrition is given enterally.

In conclusion, diminished endogenous de novo production of arginine is probably an important factor that reduces the availability of arginine in sepsis. This may be worsened by reduced arginine intake and increased arginine catabolism, as is discussed in detail in the next paragraph.

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