Volume Therapy With Crystalloids and Colloids and Hemodynamic Monitoring in Patients With Severe Sepsis
Volume Therapy With Crystalloids and Colloids and Hemodynamic Monitoring in Patients With Severe Sepsis
The primary alternative hypothesis is that less time (minutes) is required, to achieve the
 initial hemodynamic stabilization, with Volulyte® compared to Jonosteril®.

 -  H01: Minutes with Volulyte® ≥ Minutes with Jonosteril®

 -  H11: Minutes with Volulyte® < Minutes with Jonosteril®
Comparative, multicenter, active-controlled, parallel-group, double-blind, randomized study.

 Patients who meet the inclusion criteria (at Screening, see below for definition) will be
 randomized immediately in a ratio of 1:1 to either receive intravenous Volulyte® or
 Jonosteril® for fluid resuscitation (on RAND). Fluid resuscitation with study drug will be
 started immediately in order to reach initial hemodynamic stabilization. Assessment of the
 effects of fluid resuscitation to achieve the primary and secondary endpoints will be
 performed up to 24 hours following the randomization.

 Initial hemodynamic stabilization is defined as normalization of mean arterial pressure
 (MAP), central venous oxygen saturation (ScvO2) and PPV (pulse pressure variation) or
 response to PLR (passive leg rising) as defined below and maintaining this normalization over
 a period of 1 hour, with no increase in the infusion of vasopressors, or inotropic therapy
 and with ≤ 250ml of additional study drug administration within this 1 hour. The
 normalization of the parameters MAP and PPV (pulse pressure variation) or PLR (passive leg
 rising) and ScvO2 is defined as follows:

 -  MAP: ≥ 65 mmHg

 -  ScvO2: ≥ 70%

 -  PPV: ≤ 12% (premise: sinus rhythm, no spontaneous breathing efforts and mechanical
 ventilation with VT: 5 - < 6 ml/kg).

 If PPV is not applicable, response to PLR-manoeuvre is used (see below).

 ● PLR: < 10% change in cardiac output (CO)
Inclusion Criteria:

 1. Prior written informed consent of the patient. If this is not possible, it will be
 necessary for the investigator to obtain initial informed consent according to the
 requirements. The legally authorized representative has to provide the written
 informed consent or in his absence a declaration for inclusion in an emergency
 situation is to be signed by a consultant physician who is not involved in the study
 and who is independent of the investigational team. If the patient dies following the
 inclusion in the clinical trial based on the consulting physician´s vote and no
 legally authorized representative is available / able to give informed consent, no
 additional informed consent will be needed and the consultant physician´s vote will be
 considered sufficient.

 2. Male or female patient aged 18 years or older

 3. Presence of severe sepsis defined as:

 -  Sepsis due to a known or suspected infection with two or more of the modified
 systemic inflammatory response syndrome (SIRS) criteria (46).

 -  Temperature (> 38°C or < 36°C)

 -  Heart rate (> 90 beats / minute)

 -  Respiratory rate (>20 breaths / minute) or arterial carbon dioxide (PaCO2) <
 32 mmHg (< 4.3 kPa)

 -  White blood cells (WBC) > 12.000 cells/mm3, < 4000 cells/mm3, or > 10%
 immature (band) forms

 -  Severe sepsis for less than 24 hours with at least one of the following
 characteristics:

 -  Ratio of partial pressure of oxygen to the fraction of inspired oxygen
 (PaO2/FiO2) < 250

 -  Arterial pH < 7.3 or serum lactate level > 1.5 × ULN (upper limit of normal)

 -  Hypotension: Inadequately fluid resuscitated patients with a systolic blood
 pressure ≤ 90 mmHg or MAP ≤ 70 mmHg, or adequately fluid resuscitated
 patients requiring vasopressors to maintain blood pressure within normal
 ranges

 -  Urine output < 0.5 ml/kg/hour (patients who are inadequately fluid
 resuscitated)

 -  Platelet count < 80.000/ mm3

 -  Acute alteration of mental status

 4. Requirement for fluid resuscitation as defined by the measured hemodynamic parameters
 MAP, ScvO2 and PPV or PLR.

 Exclusion Criteria:

 1. Volume expansion with a dosage of HES administered prior to randomization rendering a
 patient unsuitable for inclusion based on the treating physician´s discretion in
 consideration of the suggested maximal dose/day.

 2. Known volume expansion with any dosage of HES 200.000 prior to inclusion during the
 actual hospital admission.

 3. Participation in another clinical study with an investigational drug or an
 investigational medical device within 30 days before screening or planned during the
 study period.

 4. Known hypersensitivity to any components of the investigated solutions.

 5. Known pregnancy; female patients must be surgically sterile; or postmenopausal for at
 least two years; or if of childbearing potential must have a negative serum or urine
 dipstick pregnancy test (if a test result is not available at the time of
 randomization, a patient may be randomized and treated initially, however, has to be
 withdrawn immediately from the study as soon as the test result becomes available and
 is positive).

 6. Known serum creatinine > 300 μmol/L, corresponding to 3.4 mg/dL (if a serum creatinine
 value is not available at the time of randomization or an available value is older
 than 24 hours, a patient may be randomized and treated. If a creatinine value of > 300
 μmol/L becomes available later, treatment with the study drug may be continued if the
 risk/benefit ratio for the individual patient is regarded as positive by the
 investigator.)

 7. Known history of chronic renal failure (hemodialysis)

 8. Anuria lasting more than 8 hours (<50ml urine output / 8 hours) despite fluid
 resuscitation prior to randomization.

 9. Requirement for renal support (either continuous or discontinuous techniques,
 including intermittent hemodialysis, hemofiltration and hemodiafiltration)

 10. History of known hemostatic disorders with clinical bleeding (hemophilia and known or
 suspected Willebrand disease)

 11. Burns >20% of body surface

 12. State of brain death

 13. Known co-morbidities: Hematologic malignant disorders, neutropenia (polymorphonuclear
 leukocytes [PMN] < 500/mm3), proven liver cirrhosis, Aquired immunodeficiency syndrome
 (AIDS) Expected requirement for concomitant cancer therapy (e.g.
 chemotherapradiotherapy or surgery) from randomization until Day 4 Requirement for
 concomitant cancer therapy (e.g. chemotherapy, radiotherapy or surgery) from
 randomization until Day 4

 14. Known fluid overload (EVLWI > 10 ml/kg BW)

 15. Need for fluid restriction

 16. Refractory septic shock defined as severe sepsis with hypotension unresponsive to
 adequate fluid resuscitation, along with the presence of hypoperfusion abnormalities
 or organ dysfunction as defined by Bone et al., 1992. Patients receiving inotropic or
 vasopressor agents may no longer be hypotensive by the time they manifest
 hypoperfusion abnormalities or organ dysfunction, yet they would still be considered
 to have septic shock. Patients treated with low dose vasopressors are not excluded
 provided they are responsive to fluid resuscitation as demonstrated by an individual
 fluid challenge. Patients receiving norepinephrine (noradrenaline) or epinephrine
 (adrenaline) at a dose > 0.5 μg/kg/min or dopamine at a dose > 15 μg/kg/min at the
 timepoint of Screening are not eligible for the study.

 17. Intracranial bleeding

 18. Any condition rendering a patient unsuitable for inclusion based on the treating
 physician´s discretion