Microvascular and macrovascular flow are uncoupled in early polymicrobial sepsis

Abstract

Microvascular dysfunction is considered to play an important pathophysiological role in sepsis. We addressed the hypothesis that macrovascular and microvascular flow are uncoupled in early sepsis, using a rodent model with well-characterized haemodynamic and biochemical markers of severity and subsequent mortality. Male Wistar rats received either an intraperitoneal injection of faecal slurry (sepsis, n=14) or sterile saline (sham, n=6). Identical i.v. fluid resuscitation regimens were administered 2 h later through tethered lines while conscious. At 6 h post-sepsis and in sham-operated controls, sidestream dark-field microvascular imaging of the left vastus lateralis muscle and transthoracic echocardiography were undertaken, again under anaesthesia. Non-operated rats (naive; n=5) served as negative controls. Mild and severe sepsis were defined a priori, based on the established predictive relationship between stroke volume and mortality in this model. Compared with sham-operated animals, there was a 19 (12-19)% and 62 (54-66)% decline in cardiac output in mild (n=8) and severe sepsis (n=6), respectively [median (inter-quartile range), P<0.0001]. Blinded assessment of microvascular imaging revealed that the microvascular flow index (MFI) was impaired in sepsis and in sham-operated controls (P<0.01), regardless of the degree of reduction in stroke volume and cardiac output. The MFI heterogeneity index revealed that only naive rats displayed a normal microvascular flow pattern. Microvascular flow is impaired during early sepsis and uncoupled from macrovascular function. The severity of macrovascular/cardiovascular compromise in early sepsis is not reflected by microvascular changes. Furthermore, surgery alone causes significant microvascular derangement, highlighting the importance of appropriate control subjects when using this technique.