Randomized controlled multicentre study of albumin replacement therapy in septic shock (ARISS): protocol for a randomized controlled trial

Abstract

Background: Albumin is a key regulator of fluid distribution within the extracellular space and has several properties beyond its oncotic activity. The accumulating evidence suggests that supplementation of albumin may provide survival advantages only when the insult is severe as in patients with septic shock.

Methods/design: The randomized controlled multicentre study of albumin replacement therapy in septic shock (ARISS) investigates whether the replacement with albumin and the maintenance of its serum levels of at least 30 g/l for 28 days improve survival in patients with septic shock compared to resuscitation and volume maintenance without albumin. Adult patients (≥ 18 years) with septic shock are randomly assigned within a maximum of 24 h after the onset of septic shock after obtaining informed consents to treatment or control groups. Patients assigned to the treatment group receive a 60-g loading dose of human albumin 20% over 2-3 h. Serum albumin levels are maintained at least at 30 g/l in the ICU for a maximum of 28 days following randomization using 40-80 g human albumin 20% infusion. The control group is treated according to the usual practice with crystalloids as the first choice for the resuscitation and maintenance phase of septic shock. The primary endpoint is 90 days mortality and secondary endpoints include 28-day, 60-day, ICU, and in-hospital mortality, organ dysfunction/failure, total amount of fluid administration and total fluid balance in the ICU, and lengths of ICU and hospital stay. In total, 1412 patients need to be analysed, 706 per group. For the sample size estimation, a 15% reduction in 90-day mortality is assumed, i.e. an absolute reduction of 7.5% points to 42.5% (relative risk 1.18). Assuming a dropout rate of 15%, a total of 1662 patients need to be allocated.

Discussion: The results of the clinical trial may influence the treatment of patients with septic shock. The expected improvement in patient survival may result in a reduction in the resources currently used in the treatment of these patients and in the socioeconomic burden of this disease.

Trial registration: ClinicalTrials.gov NCT03869385 . Registration on 18 July 2019. Protocol version: Final 3.0.

Keywords: Albumin; Fluid resuscitation; Septic shock.

Fig. 1

Flow chart representing the study interventions. SAPS, Simplified Acute Physiology Score; SOFA, Sequential Organ Failure Assessment

Fig. 2

Schedule of the trial visits and study procedures. ¹After obtaining informed consent. ²Basic data: sex, age, weight, height, time of hospital admission, time of intensive care unit (ICU) admission, type of admission, referring facility prior to ICU admission, etc. from the 24-h period before randomization (data from ICU or normal ward). ³Albumin group: determination of serum albumin concentration before administration of the starting dose of the trial drug. ⁴Body temperature, respiratory rate, and haemodynamic parameters. ⁵Catecholamines, inotropic agents, diuretics, volume replacement therapy, including blood transfusion, adjunctive sepsis therapy. ⁶Recording of concomitant medication with catecholamines and inotropes at the corresponding time point (+/− 1 h); recording of concomitant medication with diuretics, volume therapeutics including transfusion therapy, adjunctive sepsis therapy of the previous 6 h. ⁷Haemoglobin, creatinine, bilirubin, C-reactive protein, procalcitonin, leucocytes, platelets, lactate, arterial blood gas analysis. ⁸24-h time period prior to randomization. ⁹Procedures, mechanical ventilation, haemodynamic monitoring. ¹⁰If adverse events (AEs) or serious adverse events (SAEs) are still “ongoing” after the end of treatment with the trial drug, observation will continue until the end of data collection (day 90). ¹¹Data on the vital status (alive/dead), if applicable date of death and cause of death, residence after discharge, if applicable, recording of “End of Life” decisions