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

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).

Factor VIII: A Dynamic Modulator of Hemostasis and Thrombosis in Trauma

“…An ongoing prospective randomized controlled trial (TETHYS; NCT03338218) is likely to inform about the efficacy and safety of 6% HES 130/0.4 in the modern practice of trauma resuscitation. 68…”

“…67 An ongoing prospective randomized controlled trial (TETHYS; NCT03338218) is likely to inform about the efficacy and safety of 6% HES 130/0.4 in the modern practice of trauma resuscitation. 68 THERAPEUTIC IMPLICATIONS Low FVIII and VWF are infrequent, and clinical experience of desmopressin mainly focuses on potential reversal of P2Y 12 inhibitors in TBI. There is a paucity of robust data that supports or refutes the role of desmopressin (0.3 µg/kg) in this setting.…”

A Critical Reassessment of the Kidney Risk Caused by Tetrastarch Products in the Perioperative and Intensive Care Environments

“…The outcomes and the investigators’ critical remarks can be found in Table 2 . Two trials (Safety and Efficacy of a 6% Hydroxyethyl Starch Solution vs. an Electrolyte Solution in Trauma Patients (TETHYS); Safety and Efficacy of 6% Hydroxyethyl Starch Solution vs. an Electrolyte Solution in Patients Undergoing Elective Abdominal Surgery (PHOENICS)) are officially registered (NCT03338218, NCT03278548), but no results have been published to date [ 36 , 37 ].…”

Hydroxyethyl starch for perioperative fluid management: a critical appraisal

“…However, the lack of significant and consistent benefits in clinical outcomes and the potential for harm make it difficult to justify the use of HES in clinical practice. In this context, the findings of two ongoing surgical trials on 6% HES 130/0.4 (PHOENICS and TETHYS studies) 17 , 18 are urgently needed to add evidence to this controversial discussion.…”