Background Fluid removal can reduce the burden of fluid overload after initial resuscitation. According to the Frank-Starling model, iatrogenic hypovolemia should induce a decrease in cardiac index. We hypothesized that inadequate refilling detected by haemoconcentration during fluid removal or an increase in cardiac index (CI) during passive leg raising (PLR) could predict CI decrease during mechanical fluid removal with continuous renal replacement therapy (CRRT). Methods We conducted a single-centre prospective diagnostic accuracy study. The primary objective was to investigate the diagnostic performance of plasma protein concentration variations in detecting a CI decrease >= 12% during mechanical fluid removal. Secondary objective was to assess other predictive factors of CI change. The attending physician prescribed a fluid removal challenge consisting of a mechanical fluid removal challenge of 500 mL for one hour. Plasma protein concentration, haemoglobin level, PLR and transpulmonary thermodilution were done before and after the fluid removal challenge. Results We included 69 adult patients between December 2016 and April 2020. Sixteen patients had a significant CI decrease (23% [95% CI 14-35]). Haemoconcentration and PLR before fluid removal challenge or CI trending failed to predict CI decrease. Conclusion Haemoconcentration variables, preload dependence status and CI trending failed to predict CI decrease during fluid removal challenge. [GRAPHICS]