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

The rapidity and the quality of fluid resuscitation in patients with severe sepsis are important factors for the prevention of secondary multi-organ failure. Vascular filling may also have an impact on tolerability of enteral nutrition. The earliness and quantity of calories provided by enteral nutrition may have an impact on morbidity and mortality. This study will asses the effects of volume expansion on hemodynamics and tolerability of enteral nutrition in patients with severe sepsis. A Data Monitoring Committee will review regularly safety data of the study.

Study Overview

• Status: Completed
• Conditions: Sepsis
• Intervention / Treatment: Drug: 6 % Hydroxyethylstarch 130/0.4 = "Voluven®"; Drug: 0.9 % NaCl

• Study Type: Interventional
• Enrollment (Actual): 196
• Phase: Phase 3

Contacts and Locations

Study Locations

• France
  • Amiens, France, 80054
    • Hôpital Sud, Unité de Réanimation Médicale
  • Avignon, France, 84902
    • Centre Hospitalier d'Avignon, Service de Réanimation Polyvalente
  • Belfort, France, 90000
    • Centre Hospitalier de Belfort-Montbéliard, Service de Réanimation et Maladies Infectieuses, Site de Belfort
  • Bicêtre, France, 94270
    • CHU de Bicêtre, Dpt d'Anesthésie Réanimation Chir.
  • Bobigny, France, 93009
    • Hôpital Avicenne, Service de Réanimation
  • Bourg-en-Bresse, France, 01012
    • Centre Hospitalier Fleyriat, Service de Réanimation Polyvalente
  • Charleville-Mézières, France, 08011
    • CH Manchester, Service de Réanimation Polyvalente
  • Corbeil-Essonnes, France, 91106
    • CH Sud Francilien, Site Gilles de Corbeil, Réanimation Polyvalente
  • Dijon, France, 21079
    • CHU de Dijon - Hôpital du Bocage Service de Réanimation Médicale
  • Meaux, France, 77104
    • CH Meaux, Service de Réanimation
  • Metz, France, 57038
    • Centre Hospitalier de Metz, Réa Polyvalente
  • Montpellier, France, 34090
    • Hôpital Lapeyronie / CHU Montpellier, Département d'Anesthésie Réanimation
  • Nancy, France, 54035
    • Hôpital Central, Service Anesthésie-Réanimation, Chirurgicale CHU
  • Nîmes, France, 30029
    • CHU Nîmes, Service de Réanimation, Division Anesthésie-Réa Douleur Urgence, Groupe Hospitalo-Universitaire Caremeau,
  • Orléans, France, 45032
    • Hôpital de la Source, Réanimation Polyvalente
  • Paris, France, 75010
    • Hôpital St Louis, Département Anesthésie et Réanimation Chirurgicale
  • Paris, France, 75014
    • Hôpital Saint-Joseph, Service de Réanimation Polyvalente
  • Paris, France, 7551
    • Hôpital St Antoine, Réanimation Médicale
  • Roanne, France, 42328
    • CH Roanne, Service de Réanimation
  • St. Germain en Laye, France, 78100
    • CHI Poissy - St Germain en Laye, Site de St Germain en Laye
  • Strasbourg, France, 67091
    • Hôpital Civil de Strasbourg, Service de Réanimation Médicale
• Germany
  • Leipzig, Germany, 04103
    • Klinik und Poliklinik für Anästhesiologie und Intensivtherapie - Universitätsklinikum Leipzig AöR
  • Münster, Germany, 48149
    • Klinik und Poliklinik für Anästhesiologie und operative Intensivmedizin der Westf. Wilhelms-Universität
  • Tübingen, Germany, 72076
    • Universitatsklinikum Tubingen, Klinik fur Anasthesiologie und Intensivmedizin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Severe sepsis
• Requirement for fluid resuscitation

Exclusion Criteria:

• serum creatinine > 300µmol/L
• Chronic renal failure
• Anuria lasting more than 4 hours
• Requirement for renal support

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Voluven® Arm	Drug: 6 % Hydroxyethylstarch 130/0.4 = "Voluven®"; Voluven® was administered intravenously. Voluven® rates were not to exceed 50 mL/kg/day on the first day and 25 mL/kg/day on the second to fourth days, according to patient needs.; Other Names: Voluven®
Active Comparator: 0.9 % NaCl	Drug: 0.9 % NaCl; NaCl 0.9 % was administered intravenously. NaCl 0.9% rates were not to exceed 50 mL/kg/day on the first day and 25 mL/kg/day from the second to the fourth day, according to patient needs.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Amount of Study Drug Required to Achieve Initial Hemodynamic Stabilization	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.	until hemodynamic stabilization (up to 48 hours)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time From Start of Fluid Resuscitation With Study Drug to the Initial Hemodynamic Stabilization	Time from start of fluid resuscitation with study drug to the initial hemodynamic stabilization	until hemodynamic stabilization (up to 48 hours)
Quantity of Study Drug in 4 Days	Total quantity of study drug infused over four consecutive days in the ICU	4 days
Time From Start of Study Drug to Start of Enteral Nutrition in the Subgroup of Patients Who Received Enteral Nutrition	Time from start of fluid resuscitation with study drug to start of enteral nutrition.	Until start of enteral nutrition (up to 48 hours)
Time From Start of Fluid Resuscitation With Study Drug to Start of Enteral Nutrition After Hemodynamic Stabilization	Administration of enteral nutrition before initial hemodynamic stabilization was ignored in this analysis.	up to 48 hours
Total Amount of Enteral Calories During the First Seven Days of Enteral Nutrition	This amount will be calculated from start of enteral nutrition until 7 am of day 8	7 days
Length of Stay in the Intensive Care Unit (ICU)	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).	Until discharge from ICU (up to day 90)
Length of Stay in the ICU	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).	Until discharge from ICU (up to Day 90)
Length of Stay in the Hospital	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).	Until discharge from hospital (up to day 90)
Area Under the Curve (AUC) of Sepsis-related Organ Failure Assessment (SOFA) Score Per Day From Screening to Day 4	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).	From Screening to Day 4

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mortality	Mortality was reported for the time period from Screening until the end of follow-up.	From Screening to end of Follow-up
Changes in Renal Function: 1. Acute Renal Failure (ARF) at Any Time After Screening	Acute Renal Failure (ARF) was defined as a two fold increase in serum concentration over the value at screening at any time after screening.	From screening to end of follow-up (up to day 90)
Changes in Renal Function: 2. Acute Kidney Injury Network (AKIN) Classification	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.	From screening to end of follow-up
Changes in Renal Function: 3. Risk, Injury, Failure, Loss, End-stage Kidney Disease (RIFLE) Classification	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.	From screening to end of follow-up

Collaborators and Investigators

• Sponsor: Fresenius Kabi
• Investigators: Study Chair: Bertrand Guidet, Prof., MD, Hôpital St Antoine, Réanimation Médicale

Publications and helpful links

General Publications

• Guidet B, Martinet O, Boulain T, Philippart F, Poussel JF, Maizel J, Forceville X, Feissel M, Hasselmann M, Heininger A, Van Aken H. Assessment of hemodynamic efficacy and safety of 6% hydroxyethylstarch 130/0.4 vs. 0.9% NaCl fluid replacement in patients with severe sepsis: the CRYSTMAS study. Crit Care. 2012 May 24;16(3):R94. doi: 10.1186/cc11358.

Study record dates

Study Major Dates

• Study Start: July 1, 2007
• Primary Completion (Actual): May 1, 2010
• Study Completion (Actual): December 1, 2010

Study Registration Dates

• First Submitted: April 20, 2007
• First Submitted That Met QC Criteria: April 20, 2007
• First Posted (Estimate): April 23, 2007

Study Record Updates

• Last Update Posted (Estimate): January 11, 2012
• Last Update Submitted That Met QC Criteria: January 9, 2012
• Last Verified: August 1, 2011

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Sepsis; Toxemia; Plasma Substitutes; Blood Substitutes; Hydroxyethyl Starch Derivatives
• Other Study ID Numbers: 06-HE06-01; 2006-004350-25 (EudraCT Number)