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Increasing microcirculation after drotrecogin alfa (activated)

In severe sepsis, microcirculatory dysfunction caused by inflammation, endothelial activation and procoagulant response leads to mithocondrial dysfunction (termed microcirculatory and mitochondrial distress syndrome). If undetected, this condition can lead to parenchymal cellular distress and so to organ failure. As regional and microcirculatory distress are independent of systemic hemodynamic-derived and oxygen-derived variables, we recorded the course of microvascular parameters with a Microscan Video Microscope (Microvision, The Netherlands) in four patients with severe sepsis. We studied the sublingual region because of its embryologic correlation to splanchnic circulation, its thin mucosa. The instrument used a new improved imaging modality for observation of the microcirculation called sidestream dark-field imaging. We consider here four patients with severe sepsis related to esophagectomy, severe polytrauma with splanchnic organ damage and mediastinitis treated with drotrecogin alpha (activated) (DA) at 24 μg/kg/hour for 96 hours. The patients were admitted to the ICU, ventilated mechanically, monitored hemodynamically via a PICCO system and supported with dobutamine. Videomicroscopy was made before administration of DA and was repeated every 24 hours during the treatment with DA and at 24 hours after its suspension. We recorded values of blood pressure, cardiac function, lactate levels, acid–base balance, temperature and dobutamine dosage.

At admission the sublingual microcirculation showed a low capillary density, vessel heterogeneity with a qualitative low flow and flow–no flow. After the first 24 hours from the beginning of DA infusion, sublingual flow showed an increase of vessel density, particularly of the number of small vessels, and the number of continuously perfused vessels increased during and post therapy with DA. We analyzed the microvascular flow with a simple semi-quantitative method dividing the images into four equal quadrants and quantificating flow (hyperdynamic, continuous, sluggish, flow–no flow, no flow) for each cohort of vessel diameter (small, medium, large). We analyzed the mean value of results of three images for each patient pre and post DA therapy. Data are presented as the median. Before starting therapy with DA, the microvascular flow index (MFI) was 2.06 for small vessels, 2.09 for medium vessels, and 2.37 for large vessels. After DA infusion, the MFI was 3, 3, and 3, respectively, for small, medium and large vessels. Differences between groups were assessed using the Mann–Whitney U test. We showed a statistically significant difference with P < 0.0001 between MFI before and post DA therapy. We demonstrated a quantitative and qualitative improvement of sublingual microcirculation with an increase of capillary density distribution (area–width) and average velocity versus vessel width. The course of microvascular blood flow may play an important role in sepsis and septic shock because of its relation to the development of multiple organ failure and death. Several studies have demonstrated that changes in microvascular perfusion are an independent predictor of outcome. The improvement of the microcirculation and vascular tone in septic shock by DA is probably related to its anticoagulant/antithrombotic and antiinflammatory action, to the decrease of TNFα production and inhibition of iNOS induction, and to improvement of endothelial barrier function and inhibition of chemotaxis, but further investigations are required to elucidate the exact mechanisms. These observations could suggest that DA could have a particular interest in the early management of severe sepsis.

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Donati, A., Romanelli, M., Romagnoli, L. et al. Increasing microcirculation after drotrecogin alfa (activated). Crit Care 11 (Suppl 2), P55 (2007).

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