Background <p>Cardiac dysfunction is common in septic shock and may be influenced by intravenous (IV) fluid therapy. We aimed to investigate the effects of restrictive versus standard IV fluid therapy on plasma N-terminal pro B-type natriuretic peptide (NTproBNP), a marker of cardiac dysfunction, in adult intensive care unit (ICU) patients with septic shock.</p> Methods <p>This prospective exploratory sub-study of the randomised CLASSIC trial enrolled adult ICU patients with septic shock at one Danish and one Swedish ICU between February 2020 and October 2021. Patients were randomised to restrictive versus standard IV fluid therapy. Plasma NTproBNP was measured at randomisation (T0), the following morning (T1), the morning after (T2), and at ICU discharge or day 90 (T3). The exploratory outcome was the between-group difference in NTproBNP across timepoints assessed using mixed models.</p> Results <p>Fifty-four patients were included. NTproBNP levels did not differ significantly between groups at any timepoint. At T1, mean NTproBNP levels were 7667 ng/L in the restrictive group and 8913 ng/L in the standard group, with an estimated between-group difference of -1245 (95% CI -4065–1575). Similarly, no statistically significant differences were observed at T2 and T3. No group-by-time interaction was observed (<i>p</i> = 0.925).</p> Conclusions <p>No statistically significant difference in plasma NTproBNP between adult ICU patients with septic shock randomised to restrictive versus standard IV fluid therapy was seen. Uniformly elevated levels could suggest that NTproBNP in septic shock primarily reflects systemic inflammation rather than fluid-induced cardiac loading. Results should be interpreted with caution due to the small sample size.</p> Trial registration <p>ClinicalTrials.gov NCT04282252. Registered 31 January 2020.</p>