Vieni, Casey

Abstract Hemorrhagic shock is a common emergency that accounts for more than 10% of global mortality and up to 40% of trauma-related mortality. The Advanced Trauma Life Support (ATLS) guidelines outline resuscitation strategies in patients with massive hemorrhage based on clinical trial and observational data. Early intervention with fluids and/or blood products is recommended during resuscitation as key to maintaining vascular patency, stabilizing a patient’s blood pressure, maintaining tissue oxygenation, and limiting shock. From a transfusion perspective, there is wide heterogeneity in the quality of blood products due to donor and manufacturing variation. The optimal transfusion strategy for massive hemorrhage remains unclear. In silico models of resuscitation may offer a means to evaluate the effectiveness and safety of various resuscitation protocols. Here we describe a stochastic multicompartment model of fluid balance and resuscitation that includes (i) cardiovascular hemodynamics, (ii) body fluid compartments and capillary solute exchange, (iii) the ability to alter hemorrhage, resuscitation, and hemostasis parameters, and (iv) tissue oxygenation and capillary-alveolar gas exchange. Building upon deterministic frameworks, this stochastic model more faithfully reflects the clinical heterogeneity of bleeding patients at a level I trauma center. This allows for a proof of concept in silico trial comparing crystalloids, conventional component therapy (CCT), i.e. red cell, platelet and plasma components, to cold-stored low titer group O whole blood (LTOWB). In an in silico cohort of ATLS class III (>30% and ≤40% blood volume lost) hemorrhage, LTOWB resuscitation reduced the time spent in the critical hemostatic window (platelet count <50x109/L, INR≥2, hemoglobin (Hgb) <8 g/dL and fibrinogen <150 mg/dL) compared with CCT (90.59 vs. 147.62 minutes; p=0.04), with no difference in predicted event-free survival (t = 240 minutes; cardiac < 1.5, fluid overload > 10% or SBP > 150% of the starting SBP, or Hgb < 3.0 g/dL). In a separate cohort of ATLS class IV (>40% blood volume lost) hemorrhage, LTOWB yielded a higher predicted event-free survival (74%) versus the CCT arm (69%, p < 0.01). We demonstrate how this in silico platform can function as a digital twin for hemorrhagic trauma enabling precision transfusion strategies, and in parallel, an operational twin to support blood banks to forecast blood product demand and inform massive transfusion protocols and clinical trial design.

ABSTRACT Blood culture contamination can lead to false-positive blood culture results, potentially contributing to increased costs and unneeded antibiotic utilization. Initial specimen diversion devices (ISDD) have been proposed to reduce blood culture contamination rates. A single-center, observational study conducted at Mayo Clinic Rochester compared blood culture contamination rates using Steripath or Kurin ISDDs versus standard blood culture collection protocols. Over 255 phlebotomists were trained in the use of the ISDDs, with 31,215 blood cultures, 410 of which were contaminated, collected from adults in the emergency department and inpatient wards. Baseline contamination rates were 1.29%–2.53% with standard collection methods. The Steripath ISDD with direct-to-media inoculation of blood culture bottles (Steripath-DTM) reduced blood culture contamination compared to standard practice (0.34% vs. 1.43%, respectively, P < 0.001). Follow-up studies with the alternative Steripath configuration with an integrated syringe (Steripath-syringe), and then the Kurin ISDD with syringe collection (Kurin-syringe), did not meet the primary endpoint of <0.5% contamination (Steripath-syringe: 1.28%; Kurin-syringe: 1.76%). All three ISDD configurations failed to meet our goal of >75% utilization, with an average measured utilization of 26% for the Steripath-DTM, 26.4% for the Steripath ISDD (combined DTM and syringe) in a follow-up study, and 41.5% in the Kurin study. Additionally, a survey of phlebotomists revealed low staff satisfaction with both Steripath ISDD configurations. Staff reported multiple ergonomic barriers limiting the Steripath ISDD’s utility, which precluded implementation of the Steripath-DTM in routine clinical practice. IMPORTANCE We conducted a very large, real-world study of two blood diversion devices to determine whether either would meet goals for reduced blood culture contamination and a high rate of utilization by phlebotomists.

Abstract Uncontrolled hemorrhage accounts for up to 40% of trauma related mortality, and approximately 30% of trauma related deaths occur in the hospital within the first 1-4 hours of injury. The Advanced Trauma Life Support (ATLS) guidelines still recommend initial resuscitation with crystalloid fluid as an integral part of maintaining or restoring hemodynamic stability, but are starting to recognize the role of early resuscitation with blood products in patients with evidence of Class III and IV hemorrhage, in line with recent clinical trial and observational data. Although there is a growing body of evidence that early transfusion with blood products may be associated with improved survival compared with crystalloid infusion, the optimal transfusion strategy still remains unclear and is being actively investigated in clinical trials. In silico models of resuscitation offer a means to evaluate the effectiveness and safety of resuscitation protocols, including effects on body fluid compartment volumes, tissue oxygenation, and hemostatic factors. Here we describe our work extending earlier deterministic models of trauma resuscitation to incorporate hemodynamic, hemostatic, resuscitation, biomarker, and tissue-oxygenation domains into a single comprehensive model. Additionally, this model expands upon previous deterministic models to create a stochastic computational model of hemostatic resuscitation that accounts for variations in blood component composition and temporal features of transfusion therapy. Using this stochastic model, an in silico trial was piloted to compare conventional component therapy, i.e. red cell, platelet and plasma components, to cold-stored whole blood using the following starting assumptions: patient weight of 81.3±21.8 kg, hematocrit of 41.8±4.3%, initial bleeding rate between 50 and 150 mL/min, systolic blood pressure of 125±18 mmHg, fibrinogen of 293±88 mg/dL, international normalized ratio of 1.0±0.1 and platelet count of 239±62x109/L, with blood component and whole blood constituent distributions based on laboratory quality control data. This in silico trial demonstrated that resuscitation with whole blood was associated with a 28-minute reduction in the time spent in the critical window defined by platelet count &lt;50x109/L, INR≥2, hemoglobin &lt;9 g/dL and fibrinogen &lt;150 mg/dL compared with conventional component resuscitation over the course of a 4 hour simulation (p&lt;0.001 based on median regression). We demonstrate how stochastic models of hemostatic resuscitation can be used to perform in silico trials of resuscitation strategies. Our work can guide inclusion and exclusion criteria for future clinical trials and facilitate identification of patient subgroups most likely to benefit from certain resuscitation strategies. This work was partially funded by the AABB Foundation (formerly the National Blood Foundation).