Background: Hypercapnia may contribute to a functional impairment of static cerebral autoregulation in patients with septic shock (Taccone et al, 2010). This may predispose to irreversible brain damage by rendering the brain particularly susceptible to hypo- and hyperperfusion upon decreases and increases in mean arterial blood pressure (MAP), respectively. In the present study we hypothesized that mechanical hyperventilation would enhance static cerebral autoregulation in critically ill patients with sepsis. Methods: Six mechanically ventilated patients with severe sepsis were enrolled in the study following ethical approval and informed consent from the next of kin. Invasive MAP and middle cerebral artery blood flow velocity (MCAv) measured by transcranial Doppler ultrasonography were recorded before (baseline) and after mechanical hyperventilation with an intended reduction in PaCO2 of 1 kPa. Steady state testing of autoregulation was achieved by increasing MAP approximately 30 mmHg by means of an intravenous infusion of norepinephrine. Data are reported as median with corresponding interquartile range (IQR). Results: Baseline infusion of norepinephrine (from 0.09 (0.02-0.22) to 0.16 (0.11-0.29) μg × kg-1 × min-1) increased MAP from 73 (69-79) to 98 (96-107) mmHg (p<0.05). The concomitant MCAv values were 38 (36-48) and 47 (43-61) cm × sec-1. Mechanical hyperventilation decreased PaCO2 by 0.7 (0.6-0.8) kPa with a concomitant increase in pH from 7.42 (7.35-7.43) to 7.46 (7.41-7.48) (both p<0.05). During hyperventilation, MAP was increased from 78 (74-82) to 105 (97-110) mmHg (p<0.05) by increasing the norepinephrine infusion rate from 0.09 (0.02-0.22) to 0.20 (0.14-0.29) μg × kg-1 × min-1. The concomitant values of MCAv values were 34 (27-40) and 33 (27-49) cm × sec-1, respectively. The slope of the regression line between MAP and MCAv decreased from 0.19 (0.11-0.42) at baseline to 0.09 (-0.01-0.20) cm × sec-1 × mmHg-1 during mechanical hyperventilation (p<0.05). Conclusion: Our findings may indicate that mechanical hyperventilation enhances static cerebral autoregulation in patients with severe sepsis, which highlights this intervention as a potential neuroprotective intervention in the critical care setting.