Implementation of additional site-specific coagulation parameters (fibrinogen, AT, platelets absolute) – mandatory for site Innsbruck, optional for all other sites. Changes of exclusion criteria including: “moribund patients as defined by ASA ≥ class V” was added to further specify “death expected within 48 h”; ‘hyperkalemia and hypercalcemia’ were modified to exclude ‘requiring medical treatment’; “severe cardiac insufficiency (defined as New York Heart Association (NYHA) ≥III)” was changed to “severe congestive cardiac failure”; “chronic renal failure with oliguria or anuria’ was replaced with “renal failure with oliguria or anuria”; and definition of “burns” was added to further specify this exclusion criterion. Addition of explanation of patient number assignment to RBC stratum. Addition of secondary variables assessments to planned statistical analysis. Harmonization of one clinical criterion for RRT replacement (i.e., “urine output <0.3 mL/kg/h for > 24 h or absolute anuria for 12 h with current guidelines”) Further specification of recording and reporting procedure for AE/SAEs, reporting timeframes and DSMB involvement in safety evaluations Added text from Gelaspan SmPC for drug interactions with respect to potential risks and potential AEs as well as information on precautionary measures. Added definition of drop-out patients and patient selection for analyses.

Addition of new study sites and prolongation of total study duration due to slow recruitment Changes or re-wordings for clarity of inclusion criteria, including: deletion of upper BMI limit (i.e. changed from ”BMI ≥ 18 kg/m2 and ≤ 35 kg/m2 “ to BMI ≥ 18 kg/m2 “); rewording of inclusion criterion to specify that patients on antibiotic therapy started prior to randomization are only eligible; further specification of fluid responsiveness definition (changed from “increase of at least 10% in MAP after PLR’ to “increase of > 10%”); change of exclusion criterion “administration of artificial colloids within the 24 h prior to randomization” to facilitate patient recruitment; further definition of exclusion criterion “patients receiving heparin / anticoagulation therapy”; clarification on lactate measurements, mechanical ventilation, and concomitant medication documentation. Change of APACHE II score documentation Rewording of the planned subgroup analyses “APACHE II score” and addition of subgroup analyses “Administration of gelatin solution prior randomization” Clarification on the informed consent procedure (specified time after randomization), RBC-pre-treatment 24 h prior randomization stratum and patient number Clarification on drug accountability procedure, destruction of dedicated infusion lines on-site, and definition of maintenance infusion rate Clarification on HDS criteria, ICU discharge criteria Further explanation and specification on the dedicated performance of the volume algorithm in both treatment phases Exclusion of “Administration of sodium bicarbonate” from the list of not permitted concomitant medication

Addition of hypersensitivity to galactose-α-1,3-galactose (alpha-Gal) to exclusion criteria Update of precautionary measures referenced in the protocol to refer to allergen galactose-α-1,3-galactose Update of potential risks and potential AEs to include cross-references for hypersensitivity to galactose-α-1,3-galactose

Prolongation of study recruitment period

Deletion of the secondary variable SAPS II score in all concerned sections as all necessary information could be concluded from APACHE II and SOFA scores documentation. Deletion of upper age limit and lower BMI limit from the respective inclusion criteria to ease patient enrollment. Update of the fluid responsiveness definition in inclusion criteria to allow also a volume challenge (including altered age and weight criteria) instead of PLR for assessment to enroll patients where PLR was generally not feasible. Deletion of exclusion criterion “Patients whose medical condition does preclude the PLR maneuver” as volume challenge would be allowed for assessment. Addition of the exclusion criterion “Patients with confirmed acute SARS-CoV-2 (COVID-19) infection (as available from routine medical records/ patient chart)”. Deletion of secondary variables including: 1) urine creatinine and Ccr as renal function could properly be assessed by the remaining renal function variables; 2) non-mandatory secondary variables ROTEM, perfusion index, pCO2 gap, ITBVI, EVLWI, CFI, and SVRI to ease data documentation; 3) Mg2+ and PO43- as these parameters were not routinely measured by participating sites. Clarification added that KDIGO score, arterial oxygen content, and DO2 are calculated. Update of the visit schedule for temperature, fluid output, and concomitant medications (antibiotics, contrast agents, coagulation therapy) to reflect clinical routine procedures at participating sites Re-wording of the conditions to use inotropes and/or vasopressors to further clarify the HDS criteria and update of the definition of burns.