Crystalloids vs. Synthetic Plasma for Fluid Resuscitation in Children with Sepsis - REsuscitation of SEpsis Trial (RESET): A Comparative and Feasibility Study This research study, called the REsuscitation of SEpsis Trial (RESET), is a randomized clinical trial comparing crystalloids and synthetic plasma for fluid resuscitation in children with sepsis. Below, we explain some key aspects you should be aware of. What is a Clinical Trial? A clinical trial is a type of medical research designed to gather more information on how our bodies respond to medications or other treatments. Most new medical treatments must be evaluated in clinical trials before they can be approved by government agencies. These agencies ensure that new treatments are not only safe but also beneficial for patients-what medicine refers to as being "safe and effective." If a new treatment has not yet been approved, it is considered "experimental." Researchers analyze the results of multiple clinical trials to determine which medications work best and how they function. The advancement of medical science requires the participation of many people in numerous studies worldwide. What is the Purpose of This Study? This study evaluates whether Octaplas LG helps children and adolescents with sepsis and whether it improves the function of blood vessels inflamed due to infection. Sepsis occurs when an infection severely affects a person's health. Octaplas LG is a medication approved for use in Colombia. It is known as pharmaceutical plasma and is obtained from voluntary donors worldwide. It undergoes an ultra-detailed sterilization process using the most advanced techniques for processing blood derivatives. In medicine, fresh frozen plasma (FFP) is typically used, which is the equivalent of Octaplas LG but with far fewer industrial sterilization processes. These additional processes in Octaplas LG significantly reduce the risk of transmitting infections. Although Octaplas LG is approved by INVIMA, its use for fluid resuscitation has not yet been approved. This study will compare Octaplas LG with normal saline solution and Ringer's lactate, which are commonly used for rehydrating patients. All three treatments will be administered in the same manner. Why is My Child Being Asked to Participate? Your child is being invited to participate in this clinical study because: They are receiving care in the pediatric intensive care unit (PICU). They are between one month and 18 years old. They have been diagnosed with sepsis and require fluid resuscitation. Your child's participation is voluntary. If you decide not to participate, your child will not lose any medical benefits. Your child's doctor has determined that they may be a good candidate for this study. You are free to discuss participation with your family, friends, or another physician. Some members of your child's healthcare team may also be involved in this research. They are dedicated to your child's care as well as the objectives of this study. However, you are not obligated to participate. If you choose to enroll your child, you will be asked to sign an informed consent form. How Will My Child Be Assigned to a Treatment Group? Upon admission to the pediatric intensive care unit (PICU), if your child has a confirmed sepsis diagnosis and requires intravenous fluids or plasma to support heart function, they will be randomly assigned to one of the three treatment groups. Randomization is a research method used in clinical trials to assign patients to study groups in an unbiased way-similar to drawing numbers from a hat. Neither you, your child's doctor, nor the researchers will choose which group your child is placed in. Instead, a computer will randomly assign them to a group. Treatment Groups: Group 1: Normal Saline (0.9% Sodium Chloride) Your child will receive the standard treatment for sepsis, including antibiotics, intravenous fluids, heart function monitoring, mechanical ventilation if needed, and blood pressure medications (vasopressors) if necessary. Group 2: Ringer's Lactate In addition to standard sepsis management, your child will receive Ringer's lactate, another commonly used resuscitation fluid in pediatric sepsis. Group 3: Octaplas LG In addition to standard sepsis management, your child will receive pharmaceutical synthetic plasma, which contains proteins and essential blood components that have undergone advanced processing to eliminate the risk of infectious disease transmission. How Many Children Will Participate in This Study? At Fundación Cardioinfantil-Instituto de Cardiología, we are seeking the participation of approximately 150 children in this study. How Long Will My Child Be in the Study? Your child will remain in their assigned treatment group for up to 28 days from PICU admission or until they no longer require intensive care hospitalization.
Protocol Title: Randomized Clinical Trial Comparing Crystalloids vs. Synthetic Plasma for Fluid Resuscitation in Children with Sepsis - REsuscitation of Sepsis Trial (RESET): Feasibility and Comparative Study Development Phase: Phase IV Study Sponsor: Fundación Cardioinfantil - Instituto de Cardiología Children's Hospital of Pittsburgh - Center for Trauma and Transfusion Medicine Research, University of Pittsburgh, Pittsburgh, USA Medical Sponsor and International Coordinator Dr. Jaime Fernández - Pediatric Intensivist, Head of the Pediatric Intensive Care Unit, Fundación Cardioinfantil, Bogotá, Colombia Dr. Phillip Spinella, MD, FCCM - Pediatric Intensivist, Department of Surgery and Anesthesia, Children's Hospital of Pittsburgh; Emeritus Professor, Department of Surgery and Critical Care, University of Pittsburgh; Director, Center for Trauma and Transfusion Medicine Research, University of Pittsburgh, Pittsburgh, USA Drug Manufacturer: Octapharma Study Center: Fundación Cardioinfantil - Bogotá, Colombia Study Objectives Primary Objective: To evaluate the feasibility in terms of efficacy and safety of crystalloids versus synthetic fresh plasma as the initial resuscitation fluid in children presenting with septic shock. Feasibility study. Secondary Objectives: 1. Compare hemodynamic parameters using continuous non-invasive cardiac output monitoring (iCON®) between groups. 2. Assess intravascular volume via echocardiography at 6 ± 2, 24 ± 8, and 48 ± 8 hours across groups. 3. Compare the total volume of normal saline, lactate, or plasma administered for resuscitation within the first 6, 24, and 48 hours. 4. Evaluate net fluid balance at 24 and 48 hours. 5. Compare oxygenation parameters (S/F ratio, P/F ratio, oxygenation index) between the two groups at 0, 6, 24, and 48 hours in ventilated children. 6. Assess organ dysfunction scores (PELOD, pSOFA, and NP-MODS) daily for 48 hours. 7. Compare peak inotropic scores daily over 48 hours. 8. Evaluate endothelial injury markers and hemostatic parameters. 9. Assess inflammatory markers and coagulation activation measures. 10. Monitor transfusion-related reactions. 11. Compare healthcare-associated infections. 12. Assess 28-day mortality and cause of death. Study Design A prospective, randomized, open-label, feasibility-controlled trial. Investigational Medicinal Product Patients diagnosed with septic shock who meet the inclusion criteria will be randomly assigned to one of three intervention arms: * Group A: Bolus dose of 10 mL/kg normal saline (NS) (max. 500 mL) administered over \<15 minutes. * Group B: Bolus dose of 10 mL/kg Ringer's lactate (max. 500 mL) administered over \<15 minutes. * Group C: Pharmaceutical fresh frozen plasma (OCTAPLAS LG®), bolus dose of 10 mL/kg (max. 500 mL) administered over \<15 minutes. The commercial product OCTAPLAS LG® has been registered with INVIMA in Colombia for five years and is used as a plasma replacement in cardiac surgery, hematologic diseases, or intensive care settings where blood bank plasma is unavailable. Study Population Children aged 1 month to 18 years diagnosed with sepsis, admitted to the Pediatric Intensive Care Unit (PICU) at Fundación Cardioinfantil over a 12-month period, and meeting eligibility criteria.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
150
OCTAPLAS LG® has been registered with INVIMA in Colombia for five years and is used as a plasma replacement in cardiac surgery, hematologic diseases, or intensive care settings where blood bank plasma is unavailable
Bolus dose of 10 mL/kg normal saline (NS) (max. 500 mL) administered over \<15 minutes.
Bolus dose of 10 mL/kg Ringer's lactate (max. 500 mL) administered over \<15 minutes.
Fundacion CardioInfantil - Instituto de Cardiología
Bogotá, Bogota D.C., Colombia
Feasibility in terms of efficacy and safety of crystalloids versus synthetic fresh plasma as the initial resuscitation fluid in children presenting with septic shock: Rate of Signed Informed Consent
Proportion of patients for whom signed informed consent is obtained prior to the intervention.
Time frame: Within the first 2 hours after presentation to the PICU. Percentage (%)
Feasibility in terms of efficacy and safety of crystalloids versus synthetic fresh plasma as the initial resuscitation fluid in children presenting with septic shock: Time to Plasma Administration
Time elapsed from clinical indication to administration of the assigned plasma product.
Time frame: Within the first 24 hours after admission. Minutes (min)
Feasibility in terms of efficacy and safety of crystalloids versus synthetic fresh plasma as the initial resuscitation fluid in children presenting with septic shock: Follow-up Rate
Proportion of patients with complete follow-up until PICU discharge or day 28, whichever comes first.
Time frame: From PICU admission until day 28 or PICU discharge. Percentage (%)
Feasibility in terms of efficacy and safety of crystalloids versus synthetic fresh plasma as the initial resuscitation fluid in children presenting with septic shock: Ability to Obtain and Process Biological Samples
Percentage of biological samples (for clinical laboratory tests, inflammatory markers, and endothelial biomarkers) successfully collected and processed according to protocol.
Time frame: During the first 24 hours post-intervention. Percentage (%)
Feasibility in terms of efficacy and safety of crystalloids versus synthetic fresh plasma as the initial resuscitation fluid in children presenting with septic shock: Incidence of Clinical Outcomes
Incidence of clinical outcomes such as mechanical ventilation, inotropic support, multiple organ dysfunction, or mortality.
Time frame: Up to 28 days post-intervention or until PICU discharge. Number of events (n), Percentage (%)
Efficacy of crystalloids versus synthetic fresh plasma as the initial resuscitation fluid in children presenting with septic shock in clinical variables and supports: Oxygenation as Assessed by PaO₂/FiO₂ Ratio
Evaluation of oxygenation using the PaO₂/FiO₂ ratio.
Time frame: Within the first 24 hours of intervention. Ratio (unitless)
Efficacy of crystalloids versus synthetic fresh plasma as the initial resuscitation fluid in children presenting with septic shock in clinical variables and supports: Oxygenation Index (OI)
Oxygenation Index calculated as (FiO₂ × MAP / PaO₂) × 100.
Time frame: Within the first 24 hours of intervention. Unitless value
Efficacy of crystalloids versus synthetic fresh plasma as the initial resuscitation fluid in children presenting with septic shock in clinical variables and supports: Intravascular Volume Status
Assessment of intravascular volume status based on clinical and hemodynamic parameters.
Time frame: Within the first 24 hours of intervention. Categorized as improved / no change / worsened (qualitative)
Efficacy of crystalloids versus synthetic fresh plasma as the initial resuscitation fluid in children presenting with septic shock in clinical variables and supports: Inotropic Score
Quantification of cardiovascular support based on standard inotropic scoring systems.
Time frame: Maximum value during the first 24 hours post-intervention. Inotropic score (numeric)
Efficacy of crystalloids versus synthetic fresh plasma as the initial resuscitation fluid in children presenting with septic shock in clinical variables and supports: Endothelial Injury Markers
Measurement of circulating endothelial biomarkers such as syndecan-1, angiopoietin-2, or others defined in protocol.
Time frame: Baseline and within 24 hours post-intervention. ng/mL
Efficacy of crystalloids versus synthetic fresh plasma as the initial resuscitation fluid in children presenting with septic shock in clinical variables and supports: Hemostatic Measures
Evaluation of coagulation parameters including PT, aPTT, fibrinogen, and D-dimer levels.
Time frame: Baseline and within 24 hours post-intervention. Seconds (for PT/aPTT), mg/dL or ng/mL (as applicable)
Efficacy of crystalloids versus synthetic fresh plasma as the initial resuscitation fluid in children presenting with septic shock in clinical variables and supports: Incidence of New or Progressive Organ Failure
Number of patients with new or worsening organ dysfunction during hospitalization.
Time frame: Up to 28 days post-intervention or until PICU discharge. Number of patients (n), Percentage (%)
Efficacy of crystalloids versus synthetic fresh plasma as the initial resuscitation fluid in children presenting with septic shock in clinical variables and supports: 28-Day All-Cause Mortality
Death from any cause within 28 days of randomization.
Time frame: Up to day 28. Number of deaths (n), Percentage (%)
Efficacy of crystalloids versus synthetic fresh plasma as the initial resuscitation fluid in children presenting with septic shock in clinical variables and supports: Cause of Death
Categorization of causes of death (e.g., refractory shock, respiratory failure, neurologic injury).
Time frame: Up to 28 days post-randomization. Categorical (by cause)
Compare hemodynamic parameters using continuous non-invasive cardiac output monitoring (iCON®) between groups: Systemic Vascular Resistance (SVR)
Measurement of systemic vascular resistance using non-invasive cardiac output monitoring (iCON®).
Time frame: During the 24-hour intervention period. dyn·s/cm⁵
Compare hemodynamic parameters using continuous non-invasive cardiac output monitoring (iCON®) between groups: Cardiac Output (CO)
Measurement of cardiac output using iCON® monitoring.
Time frame: During the 24-hour intervention period. Liters per minute (L/min)
Compare hemodynamic parameters using continuous non-invasive cardiac output monitoring (iCON®) between groups: Cardiac Index (CI)
Measurement of cardiac index using iCON® monitoring.
Time frame: During the 24-hour intervention period. Liters per minute per square meter (L/min/m²)
Compare hemodynamic parameters using continuous non-invasive cardiac output monitoring (iCON®) between groups: Stroke Volume Variability (SVV)
Measurement of stroke volume variability using iCON® monitoring.
Time frame: During the 24-hour intervention period. Percentage (%)
Compare hemodynamic parameters using continuous non-invasive cardiac output monitoring (iCON®) between groups: Pulse Pressure Variation (PPV)
Measurement of pulse pressure variation using iCON® monitoring.
Time frame: During the 24-hour intervention period. Percentage (%)
Total Volume of Resuscitation Fluid Administered Within the First 6, 24, and 48 Hours
Cumulative volume (in milliliters) of the assigned resuscitation fluid (normal saline, lactated Ringer's, or synthetic plasma) administered at three time points: 6 hours, 24 hours, and 48 hours after admission. Volumes will be obtained from the electronic medical records and reported as total volume per patient per time point.
Time frame: At 6, 24, and 48 hours after admission. Milliliters (mL)
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Evaluate endothelial injury markers and hemostatic parameters, and assess inflammatory markers and coagulation activation measures: Plasma Concentration of IL-1 at 0, 6, and 24 Hours
Quantification of interleukin-1 (IL-1) in plasma at baseline, 6 hours, and 24 hours post-intervention.
Time frame: 0, 6, and 24 hours after fluid administration. pg/mL
Evaluate endothelial injury markers and hemostatic parameters, and assess inflammatory markers and coagulation activation measures: Plasma Concentration of IL-6 at 0, 6, and 24 Hours
Quantification of interleukin-6 (IL-6) in plasma at baseline, 6 hours, and 24 hours.
Time frame: 0, 6, and 24 hours. pg/mL
Evaluate endothelial injury markers and hemostatic parameters, and assess inflammatory markers and coagulation activation measures: Plasma Concentration of IL-10 at 0, 6, and 24 Hours
Quantification of interleukin-10 (IL-10) in plasma at baseline, 6 hours, and 24 hours.
Time frame: 0, 6, and 24 hours. pg/mL
Evaluate endothelial injury markers and hemostatic parameters, and assess inflammatory markers and coagulation activation measures: Plasma Concentration of TNF-alpha at 0, 6, and 24 Hours
Quantification of tumor necrosis factor alpha in plasma at baseline, 6 hours, and 24 hours.
Time frame: 0, 6, and 24 hours. pg/mL
Evaluate endothelial injury markers and hemostatic parameters, and assess inflammatory markers and coagulation activation measures: Plasma Concentration of Syndecan-1 at 0, 6, and 24 Hours
Measurement of endothelial injury marker Syndecan-1.
Time frame: 0, 6, and 24 hours. ng/mL
Evaluate endothelial injury markers and hemostatic parameters, and assess inflammatory markers and coagulation activation measures: Plasma Concentration of Soluble E-selectin (sE-selectin)
Measurement of soluble E-selectin levels at 0, 6, and 24 hours.
Time frame: 0, 6, and 24 hours. ng/mL
Evaluate endothelial injury markers and hemostatic parameters, and assess inflammatory markers and coagulation activation measures: Plasma Concentration of Thrombomodulin
Measurement of thrombomodulin as a marker of endothelial injury.
Time frame: 0, 6, and 24 hours. ng/mL
Evaluate endothelial injury markers and hemostatic parameters, and assess inflammatory markers and coagulation activation measures: Plasma Concentration of VEGF and VEGFR-1
Quantification of vascular endothelial growth factor (VEGF) and VEGF receptor 1 (VEGFR1) at baseline and post-intervention.
Time frame: 0, 6, and 24 hours. pg/mL
Evaluate endothelial injury markers and hemostatic parameters, and assess inflammatory markers and coagulation activation measures: Plasma Concentration of Coagulation Activation Markers (TAT Complexes, PF-1, PF-2)
Measurement of thrombin-antithrombin complexes (TAT), and platelet factor-1 and -2 (PF-1, PF-2) at specified time points.
Time frame: 0, 6, and 24 hours. ng/mL
Safety endpoints, transfusion reactions: Number of Participants with Transfusion-Related Acute Lung Injury (TRALI)
Incidence of TRALI within 24 hours of resuscitation fluid administration, based on clinical criteria (acute lung injury, hypoxemia, and temporal relationship to transfusion).
Time frame: Within 24 hours of intervention. Number of participants
Safety endpoints, transfusion reactions: Number of Participants with Transfusion-Associated Circulatory Overload (TACO)
Incidence of TACO based on clinical signs (e.g., hypertension, pulmonary edema, increased BNP, positive fluid balance) within 24 hours post-transfusion.
Time frame: Within 24 hours of intervention. Number of participants
Safety endpoints. Transfusion reactions: Number of Participants with Febrile Non-Hemolytic Transfusion Reactions
Number of febrile non-hemolytic transfusion reactions as defined by unexplained fever during or shortly after transfusion.
Time frame: Within 24 hours of intervention. Number of participants
Safety endpoints, transfusion reactions: Number of Participants with Allergic Transfusion Reactions
Incidence of allergic reactions (rash, urticaria, pruritus, or anaphylaxis) occurring within 24 hours of transfusion.
Time frame: Within 24 hours of intervention. Number of participants