Increased blood flow by insulin infusion targeting normoglycemia in patients with severe sepsis: friend or foe?

A small study in patients with severe sepsis suggested that insulin infused to normalize blood glucose levels increased forearm flow. This clinical observation supports the effect of insulin on the endothelium, as previously shown by in vitro studies and by in vivo animal models of critical illness, but the clinical consequences remain unclear.

In the previous issue of Critical Care, Dr Žuran and collaborators reported the results of an interesting, smallsized, open-label study investigating the eff ects of targeting diff erent levels of blood glucose with insulin in patients with severe sepsis [1]. As compared with a blood glucose target of 7 to 11 mmol/l, targeting a blood glucose level of 4.4 to 6.1 mmol/l increased forearm blood fl ow measured by the strain-gauge plethysmography method, at 24 and 72 hours after initiation of the intervention. Th ese diff erences occurred in the absence of detectable diff erences in hemodynamics or patient outcome. Th e authors concluded that these data corroborate a protective eff ect on the endothelium, and attribute this to the amount of insulin rather than to the level of blood glucose control.
Žuran and colleagues' study is an interesting clinical observation made in a diffi cult setting of clinical practice treating patients with sepsis and organ failure, for which the authors ought to be congratulated. Th e small sample size, with a trend for slightly diff erent baseline characteristics, particu larly concerning the severity of the shock, as well as the nonblinded nature of the study, however, may have played a confounding role. Nevertheless, if the increase in forearm fl ow is indeed evoked by the more intensive insulin therapy, it corroborates extensive data from basic research in in vitro cellular models [2][3][4] and from in vivo animal research [5,6], as well as observations in healthy subjects [7,8] and on tissue samples obtained from patients in the proof-of-concept study on blood glucose control performed in Leuven [9,10]. Together, these previous data suggested that insulin signaling mediates a direct and/or indirect protection of the endothelium and the cardiovascular system, but that this is antagonized by concomitant pronounced hyperglycemia.
Th e antagonistic eff ect between insulin signaling and hyperglycemia on infl ammation and blood fl ow is an interesting one, which is important to take into account when analyzing results of studies on the topic. In this light, the weak correlation in the current study by Žuran and colleagues between the forearm fl ow and the insulin doses, largely explained by one outlier, does not suffi ce to conclude that the concomitant prevention of hyperglycemia was not important, as both higher insulin doses and lower blood glucose levels were brought about simultaneously. Furthermore, it may be that a certain threshold of hyperglycemia needs to be avoided in order for insulin to exert a protective eff ect on the endothelium. In Žuran and colleagues' study, the large spread of the achieved blood glucose levels at all studied time points, and the very important overlap between the two study arms, does not allow one to defi ne such a threshold. Indeed, the studied intervention was a complex one; an insulin regimen targeting lower blood glucose levels, and thus a weak correlation with the forearm fl ow of one aspect of this complex intervention (insulin dose) and the absence of a correlation with the other aspect of this complex intervention (blood glucose level achieved)the latter quite diffi cult to quantify accurately over timedoes not allow one to discard the importance of one aspect over the other.

Abstract
A small study in patients with severe sepsis suggested that insulin infused to normalize blood glucose levels increased forearm fl ow. This clinical observation supports the eff ect of insulin on the endothelium, as previously shown by in vitro studies and by in vivo animal models of critical illness, but the clinical consequences remain unclear.
Th e clinical relevance of a reduction in forearm fl ow in patients with severe sepsis with intensifi ed insulin therapy remains unclear, as recognized adequately by the authors. Firstly, one could question the relevance of the small observed eff ect size on forearm fl ow and the apparently transient nature. Indeed, the patients in the two groups remained hemodynamically comparable throughout the study and did not require diff erent amounts of fl uids, vasopressors or inotropes; and neither did they reveal any diff erence in organ function. Secondly, it remains obscure whether a change in forearm fl ow is giving any information on the vital organ perfusion and oxygenation. Indeed, an increase in blood fl ow to the skeletal muscle may either refl ect an overall increase of fl ow to the body or instead may hint towards a steel phenomenon, hiding a decrease of fl ow to the vital organs. Th e clinical implications of these two possible interpretations are entirely diff erent, as they may range from a benefi cial protection of an important organ system to a deleterious silent risk for instability.
Despite these additional questions raised by the study presented by Žuran and colleagues, the elegant demonstration of the diff erence in forearm fl ow does indicate that the vasculature may indeed be aff ected by intensifi ed insulin therapy. Th e observation nicely corroborates previous basic science data, and therefore requires further detailed investigation. Understanding the under lying mechanisms and the clinical consequences will provide further insight into the controversy that currently surrounds the concept of glucose control in ICU patients [11].