Abstract
BackgroundThe role of recombinant activated protein C (aPC) during sepsis is still controversial. It showed anti-inflammatory effect and improved the microvascular perfusion in experimental models of septic shock. The present study was aimed at testing the hypothesis that recombinant aPC therapy improves the microcirculation during severe sepsis.MethodsProspective observational study on patients admitted in a 12-beds intensive care unit of a university hospital from July 2010 to December 2011, with severe sepsis and at least two sepsis-induced organ failures occurring within 48 hours from the onset of sepsis, who received an infusion of aPC (24 mcg/kg/h for 96 hours) (aPC group). Patients with contraindications to aPC administration were also monitored (no-aPC group).At baseline (before starting aPC infusion, T0), after 24 hours (T1a), 48 hours (T1b), 72 hours (T1c) and 6 hours after the end of aPC infusion (T2), general clinical and hemodynamic parameters were collected and the sublingual microcirculation was evaluated with sidestream dark-field imaging. Total vessel density (TVD), perfused vessel density (PVD), De Backer score, microvascular flow index (MFIs), the proportion of perfused vessels (PPV) and the flow heterogeneity index (HI) were calculated for small vessels. The perfused boundary region (PBR) was measured as an index of glycocalyx damage. Variables were compared between time points and groups using non parametric or parametric statistical tests, as appropriate.ResultsIn the 13 aPC patients mean arterial pressure (MAP), base excess, lactate, PaO2/FiO2 and the Sequential Organ Failure Assessment (SOFA) score significantly improved over time, while CI and ITBVI did not change. MFIs, TVD, PVD, PPV significantly increased over time and the HI decreased (p < 0.05 in all cases), while the PBR did not change. No-aPC patients (n = 9) did not show any change in the microcirculation over time. A positive correlation was found between MFIs and MAP. TVD, PVD and De Backer score negatively correlated with norepinephrine dose, and the SOFA score negatively correlated with MFIs, TVD and PVD.ConclusionsaPC significantly improves the microcirculation in patients with severe sepsis/septic shock.Trial registrationNCT01806428
Highlights
The role of recombinant activated protein C during sepsis is still controversial
The sample size was calculated on the Microvascular Flow Index (MFI): 13 patients proved to be sufficient to demonstrate a change in MFI of 0.5 with a power of 90% and an alpha error of 0.05
All the microvascular parameters improved over time, with significant increases in MFI, MFIs (Figure 1A), Total vessel density (TVD) (Figure 1C), perfused vessel density (PVD) (Figure 1D) and proportion of perfused vessels (PPV) (Figure 1E) and a decrease in the heterogeneity index (HI)
Summary
The role of recombinant activated protein C (aPC) during sepsis is still controversial It showed antiinflammatory effect and improved the microvascular perfusion in experimental models of septic shock. APC is an endogen protein with anti-inflammatory, anticoagulant and profibrinolitic properties; it showed to inhibit the generation of thrombin by inactivating factor Va and factor VIIIa [8] and this was thought to be the most important mechanism for its therapeutic action in sepsis This theory was abandoned as its anti-inflammatory action seemed to be of major relevance: preclinical studies demonstrated a host of beneficial effects targeting NF-kB pathway [9] together with the ability to reduce the apoptosis and decrease citonecrosis during sepsis [10]. One study was conducted so far on severely septic patients in order to translate these experimental evidences into a clinical setting [18]
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