Materials and methodsPatientsAfter approval by the local Institutional Ethics Committee, the present study was performed in an 18-bed multidisciplinary ICU at the Department Y27632 of Anesthesiology and Intensive Care of the University of Rome “La Sapienza.” Informed consent was obtained from the patients’ next of kin. Enrollment of patients started in November 2008 and ended in March 2010. We enrolled patients who fulfilled the criteria of septic shock [1] and required NE to maintain MAP �� 65 mmHg despite appropriate volume resuscitation (pulmonary arterial occlusion pressure (PAOP) = 12 to 18 mmHg and right atrial pressure (RAP) = 8 to 12 mmHg) [1].Exclusion criteria were: age < 18 years, pronounced cardiac dysfunction (that is, cardiac index (CI) �� 2.

2 L/minute/m2 in the presence of PAOP > 18 mmHg), severe liver dysfunction, significant valvular heart disease, present coronary artery disease, pregnancy, present or suspected acute mesenteric ischemia or vasospastic diathesis (for example, Raynaud’s syndrome or related diseases).All patients underwent lung-protective mechanical ventilation using a volume-controlled mode, which was adjusted to maintain plateau < 30 cmH2O [1]. In all patients, positive end-expiratory pressure was set at a level ranging from 7 to 15 cmH2O. The ventilatory settings remained unchanged throughout the study period. All patients were appropriately analgo-sedated using sufentanil and midazolam and received intravenous hydrocortisone (300 mg/day) as a continuous infusion. Activated protein C was administered at the discretion of the attending physician.

MeasurementsSystemic hemodynamic monitoring of the patients included the use of a pulmonary artery catheter (7.5-French; Edwards Lifesciences, Irvine, CA, USA) and a radial artery catheter. MAP, RAP, mean pulmonary arterial pressure (MPAP) and PAOP were measured at end-expiration. Heart rate was analyzed by continuous recording of Batimastat an electrocardiogram with ST segments monitored. CI was measured using the continuous thermodilution technique (Vigilance II; Edwards Lifesciences). Arterial and mixed venous blood samples were taken to measure oxygen tension and saturation as well as carbon dioxide tension, standard bicarbonate and base excess (BE). Mixed venous oxygen saturation (SvO2) was measured discontinuously by intermittent mixed venous blood gas analyses.Microvascular networkMicrovascular blood flow was visualized by means of a SDF imaging device (MicroScan; MicroVision Medical, Amsterdam, The Netherlands) equipped with a 5�� magnification lens [8]. The optical probe was applied to the sublingual mucosa after gentle removal of saliva with a gauze swab. Three discrete fields were captured with caution to minimize motion artefacts.