PragmaTic, prospEctive, randomized, controlled, double-blind, mulTi-centre, multinational study on the safety and efficacy of a 6% HydroxYethyl Starch (HES) solution versus an electrolyte solution in trauma patients: study protocol for the TETHYS study

Trials, vol. 23, pp. 456

Abstract

BACKGROUND: Trauma may be associated with significant to life-threatening blood loss, which in turn may increase the risk of complications and death, particularly in the absence of adequate treatment. Hydroxyethyl starch (HES) solutions are used for volume therapy to treat hypovolemia due to acute blood loss to maintain or re-establish hemodynamic stability with the ultimate goal to avoid organ hypoperfusion and cardiovascular collapse. The current study compares a 6% HES 130 solution (Volulyte 6%) versus an electrolyte solution (Ionolyte) for volume replacement therapy in adult patients with traumatic injuries, as requested by the European Medicines Agency to gain more insights into the safety and efficacy of HES in the setting of trauma care. METHODS: TETHYS is a pragmatic, prospective, randomized, controlled, double-blind, multicenter, multinational trial performed in two parallel groups. Eligible consenting adults ≥ 18 years, with an estimated blood loss of ≥ 500 ml, and in whom initial surgery is deemed necessary within 24 h after blunt or penetrating trauma, will be randomized to receive intravenous treatment at an individualized dose with either a 6% HES 130, or an electrolyte solution, for a maximum of 24 h or until reaching the maximum daily dose of 30 ml/kg body weight, whatever occurs first. Sample size is estimated as 175 patients per group, 350 patients total (α = 0.025 one-tailed, power 1-β = 0.8). Composite primary endpoint evaluated in an exploratory manner will be 90-day mortality and 90-day renal failure, defined as AKIN stage ≥ 2, RIFLE injury/failure stage, or use of renal replacement therapy (RRT) during the first 3 months. Secondary efficacy and safety endpoints are fluid administration and balance, changes in vital signs and hemodynamic status, changes in laboratory parameters including renal function, coagulation, and inflammation biomarkers, incidence of adverse events during treatment period, hospital, and intensive care unit (ICU) length of stay, fitness for ICU or hospital discharge, and duration of mechanical ventilation and/or RRT. DISCUSSION: This pragmatic study will increase the evidence on safety and efficacy of 6% HES 130 for treatment of hypovolemia secondary to acute blood loss in trauma patients. TRIAL REGISTRATION: Registered in EudraCT, No.: 2016-002176-27 (21 April 2017) and ClinicalTrials.gov, ID: NCT03338218 (09 November 2017).

Authors 16

1. Clementina Duran Palma

   Kimberley Hospital

   Affiliation as printed

   Trident Clinical Homestead Medical Center, Kimberley, South Africa

2. Musawenkosi Mamba
   Affiliation as printed

   Gama Research Center, Soshanguve, Gauteng, South Africa

3. Johan Geldenhuys
   Affiliation as printed

   FCRN Clinical Trials Centre, Vereeniging, South Africa

4. Oluwafolajimi Fadahun
   Affiliation as printed

   Gama Research Centre, Leratong Hospital, Johannesburg, South Africa

5. Rolf Rossaint Aachen

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   RWTH University Hospital, Rhineland-Westfalen Technical University, Aachen, Germany

6. Kai D. Zacharowski

   Goethe University Frankfurt · University Hospital Frankfurt

   Affiliation as printed

   Frankfurt University Hospital, Johannes Goethe University, Frankfurt, Germany

7. Martin Brand

   Steve Biko Hospital

   Affiliation as printed

   Steve Biko Academic Hospital, Pretoria, South Africa

8. Óscar Díaz‐Cambronero

   Universitat de València · Hospital Universitari i Politècnic La Fe

   Affiliation as printed

   Universitari i Politècnic La Fe Hospital, University of Valencia, Valencia, Spain

9. Javier Belda

   Universitat de València · Hospital Clínico Universitario de Valencia

   Affiliation as printed

   Hospital Clínico Universitario, University of Valencia, Valencia, Spain

10. Martin Westphal

    Fresenius (Germany)

    Affiliation as printed

    Fresenius Kabi Deutschland GmbH, Bad Homburg, Germany

11. Ute Brauer

    B. Braun (Germany)

    Affiliation as printed

    B. Braun Melsungen AG, Melsungen, Germany

12. Tamara Dehnhardt

    B. Braun (Germany)

    Affiliation as printed

    B. Braun Melsungen AG, Melsungen, Germany

13. Martin Hernandez-Gonzalez

    Fresenius (Germany)

    Affiliation as printed

    Fresenius Kabi Deutschland GmbH, Bad Homburg, Germany

14. Sonja Schmier

    B. Braun (Germany)

    Affiliation as printed

    B. Braun Melsungen AG, Melsungen, Germany

15. Frank Plani

    Chris Hani Baragwanath Hospital

    Affiliation as printed

    Chris Hani Baragwanath Hospital, Soweto, South Africa

16. Wolfgang Bühre corresponding

    Maastricht University Medical Centre

    Affiliation as printed

    Department of Anesthesiology and Pain Medicine, Maastricht University Medical Centre, Maastricht, the Netherlands. wolfgang.buhre@mumc.nl

    Division of Acute and Critical Medicine, Maastricht University Medical Centre, Maastricht, the Netherlands. wolfgang.buhre@mumc.nl

    Division of Acute and Critical Medicine, Maastricht University Medical Centre, Maastricht, the Netherlands