Efficacy and safety of early target-controlled plasma volume replacement with a balanced gelatine solution versus a balanced electrolyte solution in patients with severe sepsis/septic shock: study protocol, design, and rationale of a prospective, randomized, controlled, double-blind, multicentric, international clinical trial

Abstract

Background Sepsis is associated with capillary leakage and vasodilatation and leads to hypotension and tissue hypoperfusion. Early plasma volume replacement is required to achieve haemodynamic stability (HDS) and maintain adequate tissue oxygenation. The right choice of fluids to be used for plasma volume replacement (colloid or crystalloid solutions) is still a matter of debate, and large trials investigating the use of colloid solutions containing gelatine are missing. This study aims to investigate the efficacy and safety of plasma volume replacement using either a combined gelatine-crystalloid regime (1:1 ratio) or a pure crystalloid regime. Methods This is a prospective, controlled, randomized, double-blind, international, multicentric phase IV study with two parallel groups that is planned to be conducted at European intensive care units (ICUs) in a population of patients with hypovolaemia in severe sepsis/septic shock. A total of 608 eligible patients will be randomly assigned to receive either a gelatine-crystalloid regime (Gelaspan® 4% and Sterofundin® ISO, B. Braun Melsungen AG, in a 1:1 ratio) or a pure crystalloid regime (Sterofundin® ISO) for plasma volume replacement. The primary outcome is defined as the time needed to achieve HDS. Plasma volume replacement will be target-controlled, i.e. fluids will only be administered to volume-responsive patients. Volume responsiveness will be assessed through passive leg raising or fluid challenges. The safety and efficacy of both regimens will be assessed daily for 28 days or until ICU discharge (whichever occurs first) as the secondary outcomes of this study. Follow-up visits/calls will be scheduled on day 28 and day 90. Discussion This study aims to generate evidence regarding which regimen—a gelatine-crystalloid regimen or a pure crystalloid regimen—is more effective in achieving HDS in critically ill patients with hypovolaemia. Study participants in both groups will benefit from the increased safety of target-controlled plasma volume replacement, which prevents fluid administration to already haemodynamically stable patients and reduces the risk of harmful fluid overload. Trial registration The European clinical trial database EudraCT 2015-000057-20 and the ClinicalTrials.gov Protocol Registration and Results System ClinicalTrials.gov NCT02715466. Registered on 17 March 2016.

In Vivo Effects of Balanced Crystalloid or Gelatine Infusions on Functional Parameters of Coagulation and Fibrinolysis: A Prospective Randomized Crossover Study

“…Nevertheless, based on our observations, it seems that in the event of a delay in providing HR and achieving surgical control, balanced crystalloids may be a better choice than colloids for replenishing lost intravascular volume. Even more so, since the supposedly superior volume effect of gelatines is repeatedly undermined [ 26 , 27 ].…”

An Update on the Clinical Efficacy and Safety of Collagen Injectables for Aesthetic and Regenerative Medicine Applications

“…New experimentations using collagen-based formulations were performed for non-standard clinical applications such as facial nerve rehabilitation after palsy [ 160 , 211 ], organ protection during thermal ablation [ 129 ], COVID-19 related hyperinflammation [ 161 , 162 ] (NCT04517162), artery aneurysms closure [ 128 , 213 ], blood volume augmentation [ 127 , 214 ] and the treatment of chronic ischemic heart diseases [ 226 ].…”

“…Interestingly, collagen intravenous injections (Gelaspan ® , Gelofusione ® ) were successful for blood volume expansion in cases of dehydration, illness, trauma or severe sepsis/septic shock related surgery and were found to be more effective in achieving hemodynamic stability in critically ill patients compared to standard plasma volume replacement products, with no side effects [ 127 , 214 ].…”

Update on Current Concepts in Management of Severe Hemorrhagic Shock and Optimal Individualized Fluid Therapy in Critically Ill Polytrauma Patients

“…Colloids can contain blood components such as human albumin or can be synthetic or semi-synthetic such as Dextrans, Hydroxyethylstarch (HES) and Gelatines. Their main characteristic is that of plasma volume expansion and this process depends on and is directly influenced by the oncotic pressure, molecular weight, and half-life of the product [59].…”