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-Related Hormonal Release in Sepsis

Another aspect regarding a role of arginine in sepsis involves arginine-stimulated hormonal release, including insulin release.[84] Failure of insulin production has been described in sepsis.[85] Oral ingestion of arginine was recently attributed a role in glucose metabolism, although not by way of stimulated insulin secretion but by attenuating the increase in glucose and glucagon release in healthy subjects.[86] Plasma glucose levels are in general elevated in septic patients, and recent studies pointed at maintaining normal glucose levels by intensive insulin therapy as a therapeutic strategy to reduce morbidity and mortality in critically ill patients.[87] It could therefore be suggested that reduced arginine availability may affect glucose homeostasis in sepsis.

As described above, changes in arginine metabolism are present in sepsis, and arginine availability is probably limited. This raises the question: what are the clinical symptoms that may be related to these changes in arginine metabolism?

Sepsis, particularly septic shock, is characterized by elevated cardiac output and hypotension caused by vasodilatation, associated with maldistribution of blood flow and low peripheral vascular resistance. Other rheologic abnormalities in sepsis are aggregation of neutrophils and platelets, which may reduce blood flow and release active oxygen species that can directly damage cells. The balance between oxygen delivery and oxygen use may be disturbed and may contribute to a rise in blood lactate, disturbed acid base balance, and increased gastric CO2.[88,89] These characteristics of sepsis have been attributed to increased NO production by NOS-2,[28,90] as has been described in many reviews.[26,64,65,66,69,90,91,92,93] Moreover, elevated NO production in critically ill patients was suggested to impair substrate/oxygen utilization by enhanced protein nitrosylation and inhibition of mitochondrial respiration[94,95] and should therefore correlate inversely with global oxygen extraction ratios, and relate directly with blood lactate levels.[27]

An alternative aspect and hypothesis for the NO-related pathogenesis is the reduction of NOS-3 activity. NOS-3 expression is, under normal conditions, related to maintenance of organ perfusion. During sepsis, NOS-3 expression is decreased.[75,96] Increased NOS-2 expression could then be considered as an adaptive response to limit tissue injury in the acute setting by redistribution of blood flow.[65] Microcirculatory shutdown and shunting in sepsis contributes to reduced blood flow and tissue oxygen delivery, with impaired oxygen extraction and increased venous Po2 as a result.[88,97,98,99,100] An indication of diminished microcirculation in clinical sepsis is the reduced microvascular sublingual blood flow, which was related to outcome.[101] Correspondingly, in porcine endotoxemia, liver blood flow and oxygen delivery are both significantly reduced, with a marked increase in the hepatic oxygen extraction ratio and development of acidosis, indicative of inadequate organ perfusion.[98] Hyperperfusion and subsequent ischemia can therefore be considered present in sepsis. Because NOS-3-derived NO suppresses vascular smooth-muscle proliferation, inhibits platelet adhesion and aggregation, and interferes with leukocytes-endothelial cell interaction,[102,103] reduction of NOS-3 activity could contribute to aggregation of leukocytes and platelets in capillaries, characteristic of sepsis. NO also seems to be important for regulation of plasma volume and albumin escape in septic shock.[104] Moreover, disruption of gastrointestinal myoelectrical activity in sepsis[105,106] could be linked to diminished NO.[107] Thus, several features of sepsis refer back to reduced local NO synthesis, probably through reduced NOS-3 activity.

The general therapy in sepsis is directed toward correction of global hemodynamic variables as an important clinical target, but global hemodynamics is not an indication of adequate tissue flow.[108] There is ample evidence from experimental animal studies for the beneficial effects of vasodilators in models of sepsis in terms of vascular dilation with microcirculatory recruitment and improved tissue oxygenation.[89] Only a few clinical studies on the use of vasodilators with microcirculatory monitoring are available, but the studies indicate that promotion of blood flow may also be due to improved hemorrheology.[89]

In conclusion, clinical symptoms of sepsis that are related to changes in arginine metabolism in this condition are mainly hemodynamic alterations and diminished microcirculation. Increased NO production by NOS-2 and diminished NO production by NOS-3 seem to be important factors.

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