Restricted Fluids and Early Vasopressors versus Liberal Fluids and Later Vasopressors for Initial Resuscitation of Septic Shock: Protocol for a Systematic Review and Meta-Analysis

Abstract Introduction There is uncertainty around optimal haemodynamic management of community acquired septic shock presenting to the Emergency Department (ED), with current guidelines based on low quality evidence. Prior reviews have included mostly patients with hospital-acquired sepsis in the ICU who have received significant fluid resuscitation prior to randomisation. This review will assess whether restricted fluid administration with earlier vasopressor introduction, compared to liberal fluid administration with the potential for later vasopressor introduction, is associated with reduced mortality and improvements in other outcomes in ED patients with early septic shock. Methods Systematic review and meta-analysis of randomised controlled trials, conducted according to the PRISMA guidelines. There will be no restriction on language, year of publication or publication status. The population will be adult patients predominantly presenting to ED with septic shock. The intervention will be early vasopressor / restricted fluid resuscitation compared to more liberal fluid resuscitation / later vasopressors. The primary outcome is all cause 90-day mortality, with secondary outcomes related to adverse events, ICU interventions, functional status and quality of life up to six months. We will conduct subgroup analyses by pre-randomisation fluid volume and whether timing of initial vasopressor use was pre-specified. We will search major medical databases using structured searches. Studies will be screened for inclusion by two reviewers independently. Data will be extracted onto standardised forms by two reviewers independently. Differences on inclusion and data extraction will be resolved by consensus. A Bayesian framework will be used as the primary statistical approach, and a frequentist framework as the secondary approach. A random-effect model will be used in the analyses and pooled estimates of effect sizes as risk ratios (RRs) for binary outcomes, and mean differences for continuous outcomes will be presented. We will assess risk of bias using the Cochrane Risk of Bias tool (RoB-2) and assess for publication and incomplete outcome reporting. Certainty of evidence will be assessed using the GRADE approach. Results We will present the results of the review at national and international scientific meetings, and we will prepare a manuscript for submission for publication in a peer reviewed journal. Version (date) V 7.3 (8/8/25) Registration The protocol was registered with the prospective register of systematic reviews (PROSPERO) and published online on the pre-print server MedRxiv.org on 27th August 2025. Contributions PJ is the guarantor. PJ, AD, AH, SP and SM drafted the manuscript. All authors contributed to the development of the selection criteria, the risk of bias assessment strategy and data extraction criteria. LR, PJ, AH and AD developed the search strategy. AS provided statistical expertise. All authors read, provided feedback and approved the final version of the protocol. Support No specific funding was received for this project. Alisa Higgins is supported by an NHMRC investigator grant.