Assessment of stored red blood cells through lab-on-a-chip technologies for precision transfusion medicine.

Transfusion of red blood cells (RBCs) is one of the most valuable and widespread treatments in modern medicine. Lifesaving RBC transfusions are facilitated by the cold storage of RBC units in blood banks worldwide. Currently, RBC storage and subsequent transfusion practices are performed using simplistic workflows. More specifically, most blood banks follow the "first-in-first-out" principle to avoid wastage, whereas most healthcare providers prefer the "last-in-first-out" approach simply favoring chronologically younger RBCs. Neither approach addresses recent advances through -omics showing that stored RBC quality is highly variable depending on donor-, time-, and processing-specific factors. Thus, it is time to rethink our workflows in transfusion medicine taking advantage of novel technologies to perform RBC quality assessment. We imagine a future where lab-on-a-chip technologies utilize novel predictive markers of RBC quality identified by -omics and machine learning to usher in a new era of safer and precise transfusion medicine.

Migration of di(2-ethylhexyl) phthalate, diisononylcyclohexane-1,2-dicarboxylate and di(2-ethylhexyl) terephthalate from transfusion medical devices in labile blood products: A comparative study.

BACKGROUND AND OBJECTIVES: Polyvinyl chloride (PVC) plasticized with di(2-ethylhexyl) phthalate (DEHP) is a widely used material for medical transfusion devices. Not covalently bound to PVC, DEHP can migrate into blood products during storage. Recognized as an endocrine disruptor and raising concerns about its potential carcinogenicity and reprotoxicity, DEHP is gradually being withdrawn from the medical device market. Therefore, the use of alternative plasticizers, such as diisononylcyclohexane-1,2-dicarboxylate (DINCH) and di(2-ethylhexyl) terephthalate (DEHT), as potential candidates for the replacement of DEHP in medical transfusion devices has been investigated. The purpose of this study was to evaluate the quantity of PVC-plasticizers in the blood components according to their preparation, storage conditions and in function of the plasticizer. MATERIALS AND METHODS: Whole blood was collected, and labile blood products (LBPs) were prepared by the buffy-coat method with a PVC blood bag plasticized either with DEHP, DINCH or DEHT. DINCH and DEHT equivalent concentrations were quantified in LBPs by liquid chromatography-tandem mass spectrometry or coupled with UV and compared to DEHP equivalent concentrations. RESULTS: The plasticizer equivalent concentration to which a patient is exposed during a transfusion depends on the preparation of LBPs as well as their storage conditions, that is, temperature and storage time. At day 1, for all LBPs, the migration of DEHP is 5.0 and 8.5 times greater than DINCH and DEHT, respectively. At the end of the 49 days storage period, the DEHP equivalent concentration in red blood cells concentrate is statistically higher when compared to DINCH and DEHT, with maximal values of 1.85, 1.13 and 0.86 µg/dm2 /mL, respectively. CONCLUSION: In addition to lower toxicity, transfused patients using PVC-DEHT or PVC-DINCH blood bags are less exposed to plasticizers than using PVC-DEHP bags with a ranging exposure reduction from 38.9% to 87.3%, due to lower leachability into blood components.

Novel device for automating exchange transfusions through umbilical venous route in neonates.

Manually performed double-volume exchange transfusion (DVET) is tedious, error-prone, and may incur the risk of embolism. We aimed to develop a device that automates the DVET procedure performed through the umbilical venous route. We evaluated changes in blood passing through the device during DVET. We developed an electro-mechanical device with accessories (tubing and valve assembly) to perform a complete DVET. It comprises two syringes driven by a common pump that moves back and forth to withdraw aliquots of the patient's blood and infuse equal volumes of donor blood. In tandem, it draws donor blood from a blood bank bag and pushes the patient blood drawn from the previous cycle into a waste bag, respectively. One-way duckbill valves and a two-way pinch valve ensure the separation of the donor and patient blood. A sensor detects bubbles and clots. A dashboard displays set and measured parameters. We tested the accuracy of the delivered flow rate and volume, electrical safety, embolus detection, and changes in hematological and biochemical values. The delivered flow and volume were within 5% of the set parameters. All electrical safety parameters were within normal limits. The sensor consistently detected microbubbles and clots. There were no clinically significant differences in laboratory parameters between samples drawn directly from the blood bank bag and drawn from the exit port at 80, 100, 120, and 160 s with a fixed aliquot volume. CONCLUSIONS: Our prototype of a novel device can safely automate a DVET. Further trials of this device are warranted. WHAT IS KNOWN: • Double volume exchange transfusion is often performed manually, but this is time-consuming and error-prone. • Previous attempts at automation were not widely adopted because they involved inserting two catheters and did not have mechanisms to prevent embolism. WHAT IS NEW: • This novel device fully automates double volume exchange transfusions through a single-lumen umbilical venous catheter. • It prevents air and clot embolism and has a screen for input and output parameters and alarms.

Specification and Evaluation of Plasticizer Migration Simulants for Human Blood Products: A Delphi Study.

Potentially toxic plasticizers are commonly added to polyvinyl chloride medical devices for transfusion in order to improve their flexibility and workability. As the plasticizers are not chemically bonded to the PVC, they can be released into labile blood products (LBPs) during storage. Ideally, LBPs would be used in laboratory studies of plasticizer migration from the medical device. However, short supply (i.e., limited stocks of human blood in collection centres) has prompted the development of specific simulants for each type of LBP in the evaluation of new transfusion devices. We performed a Delphi study with a multidisciplinary panel of 24 experts. In the first (qualitative) phase, the panel developed consensus definitions of the specification criteria to be met by each migration simulant. Next, we reviewed the literature on techniques for simulating the migration of plasticizers into LBPs. A questionnaire was elaborated and sent out to the experts, and the replies were synthesized in order to obtain a consensus. The qualitative study established specifications for each biological matrix (whole blood, red blood cell concentrate, plasma, and platelet concentrate) and defined the criteria required for a suitable LBP simulant. Ten criteria were suggested: physical and chemical characteristics, opacity, form, stability, composition, ability to mimic a particular clinical situation, ease and safety of use, a simulant-plastic interaction correlated with blood, and compatibility with analytical methods. The questionnaire data revealed a consensus on the use of natural products (such as pig's blood) to mimic the four LBPs. Opinions diverged with regard to synthetic products. However, an isotonic solution and a rheological property modifier were considered to be of value in the design of synthetic simulants. Consensus reached by the Delphi group could be used as a database for the development of simulants used to assess the migration of plasticizers from PVC bags into LBPs.

The Story of Blood for Shock Resuscitation: How the Pendulum Swings.

Whole blood transfusion (WBT) began in 1667 as a treatment for mental illness, with predictably poor results. Its therapeutic utility and widespread use were initially limited by deficiencies in transfusion science and antisepsis. James Blundell, a British obstetrician, was recognized for the first allotransfusion in 1825. However, WBT did not become safe and therapeutic until the early 20th century, with the advent of reliable equipment, sterilization, and blood typing. The discovery of citrate preservation in World War I allowed a separation of donor from recipient and introduced the practice of blood banking. During World War II, Elliott and Strumia were the first to separate whole blood into blood component therapy (BCT), producing dried plasma as a resuscitative product for "traumatic shock." During the 1970s, infectious disease, blood fractionation, and financial opportunities further drove the change from WBT to BCT, with few supporting data. Following a period of high-volume crystalloid and BCT resuscitation well into the early 2000s, measures to avoid the resulting iatrogenic resuscitation injury were developed under the concept of damage control resuscitation. Modern transfusion strategies for hemorrhagic shock target balanced BCT to reapproximate whole blood. Contemporary research has expanded the role of WBT to therapy for the acute coagulopathy of trauma and the damaged endothelium. Many US trauma centers are now using WBT as a front-line treatment in tandem with BCT for patients suffering hemorrhagic shock. Looking ahead, it is likely that WBT will once again be the resuscitative fluid of choice for patients in hemorrhagic shock.

Minimal tactical impact and maximal donor safety after a buddy transfusion: A study on elite soldier performances in both laboratory and field environments.

BACKGROUND: The major causes of death of combat casualties in austere environments are related to hemorrhage and occur early after injury. The implementation of a walking blood bank may overcome the logistical issues raised using blood component therapy. Nonetheless, it is important to ensure that this buddy transfusion is not going to compromise the mission success by altering the donor's performance. The results available so far cannot rule out this issue with certainty. Therefore, this study aimed at investigating the immediate effect of a 450-ml blood donation on the performances of elite soldiers in laboratory and field environments. STUDY DESIGN AND METHODS: This double-blind, randomized controlled study included two experiments. For both experiments, subjects were randomly assigned either to a control group (n1  = n2  = 7) or to a 450-ml-blood-bag donation group (n1  = 7 and n2  = 8). All participants underwent before and after a potential blood donation a multifactorial assessment including adapted physical tasks, hematological variables, vigilance parameters, and subjective assessments. RESULTS: No significant results were evidenced in this study. There was no impact of blood donation on the participants' performances in both the hospital and the combat-like environments. CONCLUSION: From a donor's point of view, a 450-ml blood donation has no impact on the required abilities of our elite soldiers to fulfill a demanding tactical mission. Thus, the results of this study support the fact that buddy transfusions could be part of the operational clinical armamentarium in austere environments for elite soldiers when no blood components are available.

More sophisticated than a drink cooler or an old sphygmomanometer but still not adequate for prehospital blood: A market review of commercially available equipment for prehospital blood transport and administration.

BACKGROUND: Hemorrhage is the leading cause of death in trauma patients with most fatalities occurring before reaching a higher level of care-this applies to both the civilian setting and the military combat setting. Hemostatic resuscitation with increased emphasis on blood transfusion while limiting use of crystalloids has become routine in trauma care. However, the prehospital setting-especially in combat-presents unique challenges with regard to storage, transport, and administration. We sought to evaluate available technology on the market for storage and administration technology that is relevant to the prehospital setting. STUDY DESIGN AND METHODS: We conducted a market review of available technology through subject-matter expert inquiry, reviews of published literature, reviews of Federal Drug Administration databases, internal military publications, and searches of Google. RESULTS: We reviewed and described a total of 103 blood transporters, 22 infusers, and 6 warmers. CONCLUSIONS: The risk of on-scene fatality in trauma patients and recent developments in trauma care demonstrate the need for prehospital transfusion. These transfusions have been logistically prohibited in many operations. We have reviewed the current commercially available equipment and recommended pursuit of equipment that improves accessibility to field transfusion. Current technology has limited applicability for the prehospital setting and is further limited for the military setting.

Performance assessment of intravenous catheters for massive transfusion: A pragmatic in vitro study.

BACKGROUND: Rapid infusion of warmed blood products is the cornerstone of trauma resuscitation and treatment of surgical and obstetric massive hemorrhage. Integral to optimizing this delivery is selection of an intravenous (IV) catheter and use of a rapid infusion device (RID). We investigated which IV catheter and RID system enabled the greatest infusion rate of blood products and the governing catheter characteristics. STUDY DESIGN AND METHODS: The maximum flow rates of nine IV catheters were measured while infusing a mixture of packed red blood cells and fresh frozen plasma at a 1:1 ratio using a RID with and without a patient line extension. To account for IV catheters that achieved the RID's maximum 1000 ml/min, the conductance of each infusion circuit configuration was calculated. RESULTS: IV catheters of 7-Fr caliber or higher reached the maximum pressurized flow rate. The 9-Fr multi-lumen access catheter (MAC) achieved the greatest conductance, over sevenfold greater than the 18 g peripheral catheter (4.6 vs. 0.6 ml/min/mmHg, p < .001). Conductance was positively correlated with internal radius (ß = 1.098, 95% CI 4.286-5.025, p < .001) and negatively correlated with length (ß= - 0.495, 95% CI -0.007 to 0.005, p < .001). Use of an extension line (ß= - 0.094, 95% CI -0.505 to -0.095, p = .005) was independently associated with reduced conductance in large caliber catheters. CONCLUSION: Short, large-diameter catheters provided the greatest infusion rates of massive transfusion blood products for the least pressure. For patients requiring the highest transfusion flow rates, extension tubing should be avoided when possible.

The Impact of Rapid Infuser Use on the Platelet Count, Platelet Function, and Hemostatic Potential of Whole Blood.

BACKGROUND: Rapid infusion pumps employing filters, roller pumps, and heat exchangers for the administration of blood products are not approved for platelets or cryoprecipitate. This technology may decrease platelet count and degrade coagulation proteins. The effect of rapid infusers on the hemostatic potential of whole blood is unknown. METHODS: Five units of low titer O+ whole blood were obtained from anonymous donors. Each unit was subjected to infusion by five different techniques: (1) gravity infusion without a filter, (2) gravity infusion with a filter, (3) Belmont rapid infuser at 70 mL/min, (4) Belmont at 100 mL/min, and (5) pressurized infusion with a pneumatic pressure bag and filter. After infusion, platelet count, platelet function, thrombin generation, and hemostatic potential were measured for each aliquot. Infusion techniques were compared, using gravity infusion without a filter as the control. RESULTS: There was a significant decrease in platelet count from baseline (168,000) in the BELMONT70 (97,000) and BELMONT100 (94,000) groups (P < 0.05). However, there were no differences in platelet function (all P > 0.20). While there were no differences in thromboelastography parameters between control and infusion models (all P > 0.20), there were significant increases in thrombin generation parameters by CAT in both the BELMONT70 and BELMONT100 groups (all P < 0.05). CONCLUSIONS: The use of a rapid infuser decreases the platelet count of WB but does not decrease platelet function or overall hemostatic potential. In fact, thrombin generation and thrombin potential are actually increased. Rapid infusers are safe for the transfusion of WB.

Intraosseous access in the resuscitation of trauma patients: a literature review.

PURPOSE: Intraosseous (IO) catheters continue to be recommended in trauma resuscitation. Their utility has recently been debated due to concerns regarding inadequate flow rates during blood transfusion, and the potential for haemolysis. The objective of this review was to examine the evidence for intraosseous catheters in trauma resuscitation, and to highlight areas for future research. METHODS: A PubMed and Embase search for articles published from January 1990 to August 2018 using the terms ("intra-osseous access" or "intraosseous access" or "IO access") AND trauma was performed. Original articles describing the use of an IO catheter in the resuscitation of one or more trauma patients were eligible. Animal, cadaveric studies and those involving healthy volunteers were excluded. RESULTS: Nine studies, comprising of 1218 trauma patients and 1432 device insertions, were included. The insertion success rate was 95% and the incidence of complications 0.9%. Flow-rate data and evidence of haemolysis were poorly reported. CONCLUSION: Intraosseous catheters have high insertion success rates and a low incidence of complications in trauma patients. Existing evidence suggests that IO transfusion is not associated with haemolysis, however, further studies in humans are needed. There is a paucity of flow rate data for blood transfusion via IO catheters in this population, although much anecdotal evidence advocating their use exists.

Intravenous and Intraosseous Blood Transfusion With Three Different Pediatric Pressure Transfusion Strategies in an Immature Swine (Sus scrofa) Model of Hemorrhagic Shock: A Pilot Study.

INTRODUCTION: Exsanguination remains the leading cause of preventable death in military conflicts, and pediatric casualties are common. Transfusion is crucial to preserve life, but vascular access is challenging in children, so intraosseous (IO) access is often required. However, the optimal transfusion method is unclear. There was therefore the need for feasibility testing of a model for contrasting the efficacy of blood infusion devices via intravenous (IV) and IO access in immature swine with bone densities similar to children. MATERIALS AND METHODS: Eighteen immature swine (21 ± 1 kg) were bled 31% of estimated blood volume and then received autologous blood delivered by pressure bag, push-pull (PP), or LifeFlow Rapid Infuser via IO (15-gauge IO needle placed in the humeral head) or IV (auricular 20-gauge), with monitoring for 60 minutes. RESULTS: Flow rates for LifeFlow (172 ± 28 mL/kg) were 4-fold higher than pressure bag (44 ± 13 mL/kg, P < 0.001) and 80% higher than PP (95 ± 28 mL/kg, P < 0.02). However, higher hemolysis was evident in the IV LifeFlow condition, with 6-fold more plasma-free hemoglobin than other conditions (P < 0.0001). CONCLUSIONS: IV LifeFlow conferred higher flows, but higher hemolysis in this pilot study demonstrates the feasibility of an immature swine model toward determining optimal methods for resuscitating children with hemorrhagic shock.

Continuous hemoglobin and plethysmography variability index monitoring can modify blood transfusion practice and is associated with lower mortality.

To determine the effect of implementing an algorithm of fluid and blood administration based on continuous monitoring of hemoglobin (SpHb) and PVI (plethysmography variability index) on mortality and transfusion on a whole hospital scale. This single-center quality program compared transfusion at 48 h and mortality at 30 days and 90 days after surgery between two 11-month periods in 2013 and 2014 during which all the operating and recovery rooms and intensive care units were equipped with SpHb/PVI monitors. The entire team was trained to use monitors and the algorithm. Team members were free to decide whether or not to use devices. Each device was connected to an electronic wireless acquired database to anonymously acquire parameters on-line and identify patients who received the monitoring. All data were available from electronic files. Patients were divided in three groups; 2013 (G1, n = 9285), 2014 without (G2, n = 5856) and with (G3, n = 3575) goal-directed therapy. The influence of age, ASA class, severity and urgency of surgery and use of algorithm on mortality and blood use were analyzed with cox-proportional hazard models. Because in 2015, SpHb/PVI monitors were no longer available, we assessed post-study mortality observed in 2015 to measure the impact of team training to adjust vascular filling on a patient to patient basis. During non-cardiac surgery, blood was more often transfused during surgery in G3 patients as compared to G2 (66.6% vs. 50.7%, p < 0.001) but with fewer blood units per patient. After adjustment, survival analysis showed a lower risk of transfusion at 48 h in G3 [OR 0.79 (0.68-0.93), p = 0.004] but not in G2 [OR 0.90 (0.78-1.04) p = 0.17] as compared to G1. When adjusting to the severity of surgery as covariable, there was 0.5 and 0.7% differences of mortality at day 30 and 90 whether patients had goal directed therapy (GDT). After high risk surgery, the mortality at day 30 is reduced by 4% when using GDT, and 1% after intermediate risk surgery. There was no difference for low risk surgery. G3 Patients had a lower risk of death at 30 days post-surgery [OR 0.67 (0.49-0.92) p = 0.01] but not G2 patients [OR 1.01, (0.78-1.29), p = 0.96]. In 2015, mortality at 30 days and 90 days increased again to similar levels as those of 2013, respectively 2.18 and 3.09%. Monitoring SpHb and PVI integrated in a vascular filling algorithm is associated with earlier transfusion and reduced 30 and 90-day mortality on a whole hospital scale.

Massive transfusion in The Netherlands.

OBJECTIVES: Massive transfusion protocols (MTPs) may improve survival in patients with uncontrolled haemorrhage. An MTP was introduced into the Dutch transfusion guidelines in 2011, the ninth edition of the advanced trauma life support course in 2012 and the third version of the European guideline in 2013. This is the first survey of MTPs in Dutch trauma centres. METHODS: The aim of the study was to compare MTP strategies in level 1 trauma centres in The Netherlands, and with (inter)national guidelines. A contact in each government assigned level 1 trauma centre in The Netherlands and the Dutch Ministry of Defence was approached to share their MTPs and elucidate their protocol in a survey and oral follow-up interview. RESULTS: All 11 level 1 trauma centres responded. The content of the packages and transfusion ratios (red blood cells/plasma/platelets) were 3:3:1, 5:5:1, 5:3:1, 2:3:1, 4:4:1, 5:2:1, 2:2:1 and 4:3:1. Tranexamic acid was used in all centres and an additional dose was administered in eight centres. Fibrinogen was given directly (n=4), with persistent bleeding (n=3), based on Clauss fibrinogen (n=3) or rotational thromboelastometry (n=1). All centres used additional medication in patients in the form of anticoagulants, but their use was ambiguous. CONCLUSION: MTPs differed between institutes and guidelines. The discrepancies in transfusion ratios can be explained by (inter)national differences in preparation and volume of blood components and/or interpretation of the '1:1:1' guideline. We recommend updating MTPs every year using the latest guidelines and evaluating the level of evidence for treatment during massive transfusion.

Clinical utility of the Quantra® point-of-care haemostasis analyser during urgent cardiac surgery.

Coagulopathic bleeding during and after cardiac surgery is associated with increased morbidity and mortality. Viscoelastic testing is increasingly used instead of laboratory testing. Our aim was to compare a new viscoelastic point-of-care device, the Quantra® System, with thromboelastography and standard laboratory testing. After ethical approval and with written informed consent, we prospectively recruited adult patients undergoing urgent cardiac surgery at increased risk of bleeding. Clot time and clot stiffness values were compared before, during and after cardiopulmonary bypass. We prospectively recruited 52 patients, of whom 34 (65%) were transfused with red blood cells. Our usual transfusion thresholds for fibrinogen (1.5 g.l-1 ), platelets (100,000.µl-1 ), prothrombin time (20 s), activated partial thromboplastin time (48 s) and maximum amplitude on thromboelastography (50 mm) corresponded to Quantra values of fibrinogen clot stiffness 2.0 hPa, platelet clot stiffness 13.5 hPa, clot time 159 s, clot time 183 s and clot stiffness 17.0 hPa, respectively. These Quantra thresholds showed high negative predictive value for low platelets (platelet clot stiffness, 97.4%), prolonged activated partial thromboplastin time (clot time, 92.6%) and reduced maximum amplitude on thromboelastography (clot stiffness, 93.6%). The Quantra predicted clinical need for transfusion of platelets (area under the curve 0.71, p = 0.001) but all tests performed poorly at predicting the need for fresh frozen plasma transfusion. We have shown that point-of-care testing using the novel Quantra system provides useful data for guiding transfusion management.

[A Capacitive Venous Transfusion Alertor Based on NB-IoT].

This capacitive venous transfusion alertor is based on rise time of RC circuit and input capture function of timer in the microcontroller. The measure element of alertor is integrated with circuit board, it has the advantages of simple structure and low cost. Combined with narrow band intent of things(NB-IoT) technology to upload data, it can reduce the workload of medical personnel and caregivers, avoid unnecessary trouble and danger.

Aerial drones for blood delivery.

Aerial drone technology is now in use to improve medical care, especially blood delivery. The use of aerial drones is broader than just this and includes aerial photography, express shipping and delivery, disaster management, search and rescue operations, crop monitoring, weather tracking, law enforcement, and structural assessment. This wide use promises to accelerate and, ideally, reduce the cost of technological advances of drones. By doing so, drone use offers the opportunity of improving health care, particularly in remote and/or underserved environments by decreasing lab testing turnaround times, enabling just-in-time lifesaving medical supply/device delivery, and reducing costs of routine prescription care in rural areas.