Objective <p>The overall objective of our research is to determine in children with septic shock whether the use of a fluid-sparing strategy results in improved clinical outcomes without an increased risk of adverse events compared to usual care. The specific objective of this pilot randomized controlled trial was to evaluate the feasibility of a definitive multicenter trial to answer our research question.</p> Design <p>Pragmatic, 2-arm, parallel group, open-label, prospective pilot randomized controlled trial including a nested biosample-based translational study.</p> Setting <p>Pediatric tertiary care center.</p> Patients <p>Children aged 29&#xa0;days to &lt;18&#xa0;years of age presenting to the emergency department or admitted to an inpatient ward (including the PICU) with suspected or confirmed septic shock and a need for ongoing resuscitation.</p> Interventions <p>Fluid-sparing vs. usual care resuscitation strategy continued until shock reversal. The fluid-sparing intervention comprised instructions to restrict fluid bolus therapy in conjunction with early initiation and/or preferential use of vasoactive medication support as a strategy to spare fluid while targeting the hemodynamic goals specified in the American College of Critical Care Medicine Surviving Sepsis Guidelines. The usual care strategy did not limit the use of fluid bolus therapy.</p> Measurements and main results <p>Fifty-three were randomized to usual care (<i>n</i> = 27) or fluid-sparing (<i>n</i> = 26). Fifty-one participants were available for primary outcome analysis. Primary feasibility outcomes related to participant enrollment and protocol adherence. Enrollment rate was 1.8 (51/29); 95% confidence interval [CI]: 1.3–2.3 participants/month. Study procedures were implemented in 49/51 (96.1%), 95% CI: 86.5–99.5% participants within 1&#xa0;h of randomization in a median (interquartile range [IQR]) of 8 (5, 15) minutes. The protocol required the use of an exception to consent process and consent for ongoing participation was 48/51 (94.1%), 95% CI: 83.8–98.8%. There were no serious adverse events.</p> Conclusions <p>We concluded the large multicenter SQUEEZE trial feasible to conduct.</p> Trial registration <p>ClinicalTrials.gov [NCT01973907]. Registered October 27, 2013, <a href="https://clinicaltrials.gov/study/NCT01973907">https://clinicaltrials.gov/study/NCT01973907</a>.</p>