Effects of Voluven on Hemodynamics and Tolerability of Enteral Nutrition in Patients With Severe Sepsis

Initial hemodynamic stabilization (HDS) was defined as normalization of mean arterial pressure (MAP) and at least two of the three parameters central venous pressure (CVP), urine output and central venous oxygen saturation and maintaining this normalization over a period of four hours, with no increase in the infusion of vasopressors, or ionotropic therapy and with no more than 1 L of additional study drug administration within these four hours.

Time frame: until hemodynamic stabilization (up to 48 hours)

Population: Full analysis set (FAS) = all randomized patients treated with study drug who reached hemodynamic stabilization.

The Sepsis-related Organ Failure Assessment (SOFA) score in this study is reported for entire days, not for exact time points on a day. Potentially, more than one SOFA score may be available for the same day. In this case, the mean of the respective total scores was used for that day for calculation of Area Under the Curve (AUC). The SOFA score includes sub-scores for Respiration, Coagulation, Liver, Cardiovascular, Central Nervous System and Renal function and may range from 0 (worst outcome) to 4 (best outcome).

Time frame: From Screening to Day 4

Population: Full analysis set (FAS) = all randomized patients treated with study drug who reached hemodynamic stabilization

Length of stay was analysed in two approaches. First, it was calculated and analysed only for patients who did not die before end of study of the individual patient. As a sensitivity analysis, the analysis was carried out including patients who died with the maximum possible length of stay (i.e., the worst possible value).

Time frame: Until discharge from hospital (up to Day 90)

Population: Full analysis set (FAS) = all randomized patients treated with study drug who reached hemodynamic stabilization.~Imputed with the longest possible duration for patients who died before end of the study of the individual patient.

Length of stay was analysed in two approaches. First, it was calculated and analysed only for patients who did not die before end of study of the individual patient. As a sensitivity analysis, the analysis was carried out including patients who died with the maximum possible length of stay (i.e., the worst possible value).

Time frame: Until discharge from hospital (up to day 90)

Population: Full analysis set (FAS) = all randomized patients treated with study drug who reached hemodynamic stabilization.~Calculated for patients who did not die before end of study of the individual patient.

Length of stay was analysed in two approaches. First, it was calculated and analysed only for patients who did not die before end of study of the individual patient. As a sensitivity analysis, the analysis was carried out including patients who died with the maximum possible length of stay (i.e., worst possible value).

Time frame: Until discharge from ICU (up to Day 90)

Population: Full analysis set (FAS) = all randomized patients treated with study drug who reached hemodynamic stabilization.~Imputed with the longest possible duration for patients who died before end of the study of the individual patient.

Length of stay was analysed in two approaches. First, it was calculated and analysed only for patients who did not die before end of study of the individual patient. As a sensitivity analysis, the analysis was carried out including patients who died with the maximum possible length of stay (i.e., the worst possible value).

Time frame: Until discharge from ICU (up to day 90)

Population: Full analysis set (FAS) = all randomized patients treated with study drug who reached hemodynamic stabilization.~Calculated for patients who did not die before end of study of the individual patient

Total quantity of study drug infused over four consecutive days in the ICU

Time frame: 4 days

Population: Full analysis set (FAS) = all randomized patients treated with study drug who reached hemodynamic stabilization

Administration of enteral nutrition before initial hemodynamic stabilization was ignored in this analysis.

Time frame: up to 48 hours

Population: Full analysis set (FAS) = all randomized patients treated with study drug who reached hemodynamic stabilization

Time from start of fluid resuscitation with study drug to the initial hemodynamic stabilization

Time frame: until hemodynamic stabilization (up to 48 hours)

Population: Full analysis set (FAS) = all randomized patients treated with study drug who reached hemodynamic stabilization

Time from start of fluid resuscitation with study drug to start of enteral nutrition.

Time frame: Until start of enteral nutrition (up to 48 hours)

Population: Full analysis set (FAS) = all randomized patients treated with study drug who reached hemodynamic stabilization

This amount will be calculated from start of enteral nutrition until 7 am of day 8

Time frame: 7 days

Population: Full analysis set (FAS) = all randomized patients treated with study drug who reached hemodynamic stabilization

Acute Renal Failure (ARF) was defined as a two fold increase in serum concentration over the value at screening at any time after screening.

Time frame: From screening to end of follow-up (up to day 90)

Population: Treated population (TRT) = all randomized patients treated with study drug. Patients without ARF were excluded from analysis if they had no creatinine value at Screening or no post-screening creatinine value.

Acute Kidney Injury Network (AKIN) Classification in this study is based on serum creatinine values and renal replacement therapy, i.e. ignoring criteria based on urine output, as fulfilment of urine output criteria cannot be determined from the data collected in the study. AKIN ranges from stage 1 to stage 3 (worst outcome). Stages differ in serum creatinine increase. Stage 1: Increase ≥ 0.3mg/dL or ≥ 150%-200% from reference; Stage 2: Increase ≥ 200%-300% from reference; Stage 3: Increase \>300% from reference with an acute increase of at least 0.5mg/dL or renal replacement therapy.

Time frame: From screening to end of follow-up

Population: Treated population (TRT) = all randomized patients treated with study drug

Risk, Injury, Failure, Loss, End-stage kidney disease (RIFLE) Classification in this study is based on serum creatinine values and renal replacement therapy, i.e. ignoring criteria based on urine output, as fulfilment of urine output criteria cannot be determined from the data collected in the study. RIFLE comprises five categories: Risk (R), Injury (I), Failure (F), Loss (L), End-stage kidney disease (E) (worst outcome). R, I and F are based on increase in serum creatinine. L and E are based on administration of renal replacement therapy.

Time frame: From screening to end of follow-up

Population: Treated population (TRT) = all randomized patients treated with study drug

Mortality was reported for the time period from Screening until the end of follow-up.

Time frame: From Screening to end of Follow-up

Population: Treated population (TRT) = all randomized patients treated with study drug. Two patients in the Voluven® arm died due to non-treatment emergent SAEs.