Background: Expansion of the intravascular compartment is common to treat haemodynamic instability in ICU patients. The most useful and accurate variables to guide and evaluate a fluid challenge remain debated and incompletely investigated resulting in significant variability in practice. The analogue mean systemic pressure has been reported as a measure of the intravascular volume state. Methods: This is a protocol and statistical analysis plan for a review of the application of an analogue of the mean systemic pressure and the use of derived variables to assess the volume state and volume responsiveness. A pulmonary artery catheter was used in 286 postoperative cardiac surgical patients to monitor cardiac output before and after a fluid bolus in addition to arterial and central venous pressures. With otherwise similar monitoring, echocardiography was used in 540 general ICU patients to determine cardiac outputs and indices related to intravascular filling. The responses to a fluid bolus or the passive leg raising manoeuvre will be investigated using continuous and dichotomous definitions of volume responsiveness. The results will be stratified according to the method of monitoring cardiac output. Conclusions: This study investigating 2 cohorts that encompass a wide variety of reasons for haemodynamic instability will illustrate the applicability of the analogue mean systemic pressure and derived variables to assess the volume state and responsiveness. The results may guide the rationale and design of interventional studies.