In septic shock there is growing evidence of a state of hemodynamic disconnection with seemingly adequate macrocirculatory values despite actual microcirculation failing to meet cellular demand. Norepinephrine (NE) is recommended as first choice vasoactive agent for the treatment of septic shock. However, the dynamic effects of NE on macro- and microcirculation and perfusion parameters has not been described in detail in the context of septic shock, precluding rational individualized titration of NE and fluids, as recommended recently. In the present prospective observational multicenter study in adult septic shock patients, we intend to explore the effects of NE on preload dependency and tissue perfusion by evaluating the correlation and potential discrepancies between macro- and microcirculation both during titration of NE and after fluid resuscitation. The conclusions drawn from our study will contribute to the physiological knowledge necessary for establishing individualized evidence-based bedside management of hemodynamics in the setting of septic shock.