Albumin and Crystalloid Administration in Septic Shock

Study Overview
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Brief Summary
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The current guideline emphasizes fluid resuscitation as the mainstay of initial management for septic shock. Albumin has the oncotic activity to maintain intravascular volumes with additional beneficial properties in sepsis. Prior studies showed that the replacement of albumin might have survival advantages in patients with septic shock. The investigators aim to assess whether the early administration of albumin with crystalloid as initial fluid resuscitation improves survival in patients with septic shock compared to resuscitation without albumin.

Detailed Description
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Sepsis is a leading cause of mortality worldwide, contributing to an estimated 11 million deaths in 2017-or 20% of all global deaths. Due to recent advances in the medical management and treatment of sepsis, the mortality of sepsis has been declined in these years, but still stayed at a high level. From 2004, the Surviving Sepsis Campaign (SSC) suggested a protocolized bundle therapy to facilitate implementation at the bedside with a defined target. Recent guideline states that this resuscitation bundle treatment should be initiated within 1 h of the emergency department (ED) triage time, named as 1-h bundle. Fluid resuscitation, which is the mainstay of treatment to restore a patient's tissue perfusion, is associated with outcome in emergency department patients. The current guideline recommends that crystalloid for initial fluid resuscitation in sepsis and albumin can be additionally administered when patients require substantial amounts of crystalloid. Besides its oncotic functions to provide adequate intravascular volume, albumin has several beneficial properties for sepsis patients, including binding and transport of various endogenous molecules, anti-inflammatory and anti-oxidative effects, and modulation of nitric oxide metabolism. In 2004, a large randomized, prospective, double-blind study was performed in 7000 critically ill patients (SAFE study) to evaluate the effect of volume replacement therapy with human albumin on the outcome compared to only crystalloid. Although the survival rates were similar between the groups, a post hoc analysis of 1218 patients with severe sepsis showed improved survival in the albumin group compared to crystalloid alone. Furthermore, the ALBumin Italian Outcome Sepsis (ALBIOS) study investigated the effect of albumin administration and maintenance of serum albumin concentrations to at least 30 g/l on outcome in patients with severe sepsis and septic shock. This study showed a similar result to SAFE study that no difference on the outcome between the groups. Nevertheless, in the 1121 patients with septic shock, 90-day mortality was lower in the albumin group (564 patients) than in the non-albumin group (43.6 vs. 49%, p = 0.03). Recently, a retrospective study which evaluated the effect of administration of albumin combined with crystalloids in septic patients showed improved survival in 28 days. Therefore, accumulating evidence suggests that early albumin administration may provide a survival benefit in patients with severe and advanced sepsis. However, no prospective, randomized trial has adequately studied this hypothesis in patients with septic shock. The aim of the ALCAMIST (ALbumin and Crystalloid AdMinistration In SepTic shock) study is to investigate the effect of albumin and crystalloid administration as an initial fluid choice in septic shock compared to crystalloid alone on patient survival.

Official Title
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Albumin and Crystalloid Administration in Septic Shock (ALCAMIST): Multi-center, Open Labelled Randomized Controlled Trial

Conditions
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Septic Shock

Intervention / Treatment
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* Drug: Treatment
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult patients (≥ 18 years) who visit an ED directly and are suspected of sepsis with shock Shock is defined as hypotension (mean arterial blood pressure (MAP) < 65 or systolic blood pressure < 80) and tissue hypoperfusion such as an initial serum lactate level ≥ 4 mmol/dL. Exclusion Criteria: patients who are transferred from another hospital after initial fluid administration patients who have set limitations on treatment (e.g. patients with a signed do-not-resuscitate order) patients with moribund conditions with life expectancy less than 28 days due to secondary diseases or advanced malignant disease and palliative situations with life expectancy less than 6 months patients who have been administered albumin before enrollment patients who have known hypersensitivity to albumin Clinical conditions, where albumin administration may be unfavorable (e.g. pulmonary edema, congestive heart failure, traumatic brain injury) lactation patients who do not voluntarily consent to participate in the trial.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Treatment<br>For the treatment group, 200cc of 20% human albumin with 15 cc per kg of crystalloid will be administered over 1 2h for initial fluid resuscitation. | Drug: Treatment<br>* For the treatment group, 200cc of 20% human albumin with 15 cc per kg of crystalloid will be administered over 1 2h for initial fluid resuscitation. The treating physicians can choose the type of fluid, such as balanced fluid or isotonic saline.<br>* Other names: Albumin and crystalloid;|
| Placebo Comparator: Control<br>For the control group, 30 cc per kg of crystalloid will be administered according to the usual practice. | Drug: Placebo<br>* For the control group, 30 cc per kg of crystalloid will be administered according to the usual practice. The treating physicians can choose the type of fluid, such as balanced fluid or isotonic saline.<br>* Other names: Crystalloid only;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 28-day all-cause mortality | The 28-day all-cause mortality in septic shock patient after admission will be evaluated | 28-days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 90-day all-cause mortality | All-cause death within 90 days | 90 days | 
| ICU mortality | All-cause death during ICU admission | 28 days | 
| Hospital mortality | All-cause death during hospitalization | 28 days | 
| The Sequential organ Failure Assessment (SOFA) score | The SOFA score will be recorded daily up to 28 days after randomization. Death within 72 hours will be counted as the maximum SOFA score. | 28 days | 
| Intensive Care Unit (ICU) stay | The total length of ICU stay will be determined from the date of ICU admission until the patient is discharged from the ICU or the date of death from any cause, assessed up to 90 days after the first day of admission. | 90 days | 
| 7-day mortality | All-cause death within 7 days | 7 days | 
| Ventilator free days | Days without ventilator within 28 days from admission | 28 days | 
| Vasopressor free days | Days without vasopressor within 28 days from admission | 28 days | 
| Total amount of fluid administration | Total amount of fluid administration during hospital admission | 3 day, 7 day, 28 day | 
| Total fluid balance | Fluid balance will be recorded daily up to 28 days after randomization | 28 days | 
| Maximum dose of vasopressor use | Maximum dose of vasopressor during hospital admission | 28 days | 
| Renal replacement therapy | Whether renal replacement therapy was initiated during hospital admission after randomization. | 28 days | 
| Safety-related parameters | Occurrence of adverse event, serious adverse event (e.g. anaphylactic shock, hypervolemia, pulmonary edema) | 28 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Septic shock, Fluid resuscitation, Albumin, Crystalloid