Type-specific whole blood still has a role in the era of low titer O universal donor transfusion for severe trauma hemorrhage.

ABSTRACT: Whole blood can be ABO-type specific (TSWB) or Low-Titer O universal donor (LTOWB). Having previously used LTOWB, the US Armed Forces Blood Program began using TSWB in 1965 as a method of increasing the donor pool. In contrast to military practice, the AABB (Association for the Advancement of Blood and Biotherapies), from its first guidelines in 1958 until 2018, permitted only TSWB. Attempting to reduce time to transfusion, the US military reintroduced LTOWB in the deployed environment in 2015; this practice was endorsed by the AABB in 2018 and is progressively being implemented by military and civilian providers worldwide. LTOWB is the only practical solution prehospital. However, there are several reasons to retain the option of TSWB in hospitals with a laboratory. These include 1. as-yet ill-defined risks of immunological complications from ABO-incompatible plasma (even when this has low titres of anti A and B); 2. risks of high volumes of LTOWB including published historical advice (based on clinical experience) not to transfuse type-specific blood for 2-3 weeks following a substantial LTOWB transfusion; 3. uncertainty as to the optimal definition of "low titre"; and 4. expanding the potential donor pool by allowing type-specific transfusion. Several large randomised controlled trials currently underway are comparing LTOWB to component therapy, but none address the question of LTOWB vs. TSWB. There is sufficient data to suggest the additional risks of transfusing LTOWB to non-group O recipients should be avoided by using TSWB as soon as possible. Combined with the advantage of maintaining an adequate supply of blood products in times of high demand, this suggests retaining TSWB within the civilian and military blood supply system is desirable. TSWB should be preferred when patient blood group is confirmed in facilities with a hematology laboratory, with LTOWB reserved for patients whose blood group is unknown.

Effect of level of sedation on outcomes in critically ill adult patients: a systematic review of clinical trials with meta-analysis and trial sequential analysis.

Background: Sedation is routinely administered to critically ill patients to alleviate anxiety, discomfort, and patient-ventilator asynchrony. However, it must be balanced against risks such as delirium and prolonged intensive care stays. This study aimed to investigate the effects of different levels of sedation in critically ill adults. Methods: Systematic review with meta-analysis and trial sequential analysis (TSA) of randomised clinical trials including critically ill adults admitted to the intensive care unit. CENTRAL, MEDLINE, Embase, LILACS, and Web of Science were searched from their inception to 13 June 2023. Risks of bias were assessed using the Cochrane risk of bias tool. Primary outcome was all-cause mortality. Aggregate data were synthesised with meta-analyses and TSA, and the certainty of the evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. This study is registered with PROSPERO: CRD42023386960. Findings: Fifteen trials randomising 4352 patients were included, of which 13 were assessed high risk of bias. Meta-analyses comparing lighter to deeper sedation showed no evidence of a difference in all-cause mortality (risk ratio (RR) 0.94, 95% confidence interval (CI) 0.83-1.06; p = 0.28; 15 trials; moderate certainty evidence), serious adverse events (RR 0.99, CI 0.92-1.06; p = 0.80; 15 trials; moderate certainty evidence), or delirium (RR 1.01, 95% CI 0.94-1.09; p = 0.78; 11 trials; moderate certainty evidence). TSA showed that when assessing mortality, a relative risk reduction of 16% or more between the compared interventions could be rejected. Interpretation: The level of sedation has not been shown to affect the risks of death, delirium, and other serious adverse events in critically ill adult patients. While TSA suggests that additional trials are unlikely to significantly change the conclusion of the meta-analyses, the certainty of evidence was moderate. This suggests a need for future high-quality studies with higher methodological rigor. Funding: None.

Alpha 2 agonists for sedation to produce better outcomes from critical illness (A2B trial): protocol for a mixed-methods process evaluation of a randomised controlled trial.

INTRODUCTION: An association between deep sedation and adverse short-term outcomes has been demonstrated although this evidence has been inconsistent. The A2B (alpha-2 agonists for sedation in critical care) sedation trial is designed to determine whether the alpha-2 agonists clonidine and dexmedetomidine, compared with usual care, are clinically and cost-effective. The A2B intervention is a complex intervention conducted in 39 intensive care units (ICUs) in the UK. Multicentre organisational factors, variable cultures, perceptions and practices and the involvement of multiple members of the healthcare team add to the complexity of the A2B trial. From our pretrial contextual exploration it was apparent that routine practices such as type and frequency of pain, agitation and delirium assessment, as well as the common sedative agents used, varied widely across the UK. Anticipated challenges in implementing A2B focused on the impact of usual practice, perceptions of risk, ICU culture, structure and the presence of equipoise. Given this complexity, a process evaluation has been embedded in the A2B trial to uncover factors that could impact successful delivery and explore their impact on intervention delivery and interpretation of outcomes. METHODS AND ANALYSIS: This is a mixed-methods process evaluation guided by the A2B intervention logic model. It includes two phases of data collection conducted during and at the end of trial. Data will be collected using a combination of questionnaires, stakeholder interviews and routinely collected trial data. A framework approach will be used to analyse qualitative data with synthesis of data within and across the phases. The nature of the relationship between delivery of the A2B intervention and the trial primary and secondary outcomes will be explored. ETHICS AND DISSEMINATION: All elements of the A2B trial, including the process evaluation, are approved by Scotland A Research Ethics Committee (Ref. 18/SS/0085). Dissemination will be via publications, presentations and media engagement. TRIAL REGISTRATION NUMBER: NCT03653832.

Transforming research to improve therapies for trauma in the twenty-first century.

Improvements have been made in optimizing initial care of trauma patients, both in prehospital systems as well as in the emergency department, and these have also favorably affected longer term outcomes. However, as specific treatments for bleeding are largely lacking, many patients continue to die from hemorrhage. Also, major knowledge gaps remain on the impact of tissue injury on the host immune and coagulation response, which hampers the development of interventions to treat or prevent organ failure, thrombosis, infections or other complications of trauma. Thereby, trauma remains a challenge for intensivists. This review describes the most pressing research questions in trauma, as well as new approaches to trauma research, with the aim to bring improved therapies to the bedside within the twenty-first century.

Patient blood management guideline for adults with critical bleeding.

INTRODUCTION: The management of patients with critical bleeding requires a multidisciplinary approach to achieve haemostasis, optimise physiology, and guide blood component use. The 2011 Patient blood management guidelines: module 1 - critical bleeding/massive transfusion were updated and published. Systematic reviews were conducted for pre-specified research questions, and recommendations were based on meta-analyses of included studies. MAIN RECOMMENDATIONS: The critical bleeding/massive transfusion guideline includes seven recommendations and 11 good practice statements addressing: major haemorrhage protocols (MHPs) facilitating a multidisciplinary approach to haemorrhage control, correction of coagulopathy and normalisation of physiological derangement; measurement of physiological, biochemical and metabolic parameters in critical bleeding/massive transfusion; the optimal ratio of red blood cells to other blood components; the use of tranexamic acid; viscoelastic haemostatic assays; and cell salvage. CHANGES IN MANAGEMENT AS A RESULT OF THE GUIDELINE: The new guideline recommends MHPs be established as standard of care in all institutions managing patients with critical bleeding. In addition to routine physiological markers, the new guideline recommends temperature, biochemistry and coagulation profiles be measured early and frequently, providing parameters that define critical derangements. Ratio-based MHPs should include no fewer than four units of fresh frozen plasma and one adult unit of platelets for every eight units of red blood cells. In the setting of trauma and obstetric haemorrhage, administration of tranexamic acid within three hours of bleeding onset is recommended. The use of recombinant activated factor VII (rFVIIa) is not recommended. There was insufficient evidence to make recommendations on the use of viscoelastic haemostatic assays or cell salvage as part of MHPs.

Natural language processing diagnosed behavioural disturbance phenotypes in the intensive care unit: characteristics, prevalence, trajectory, treatment, and outcomes.

BACKGROUND: Natural language processing (NLP) may help evaluate the characteristics, prevalence, trajectory, treatment, and outcomes of behavioural disturbance phenotypes in critically ill patients. METHODS: We obtained electronic clinical notes, demographic information, outcomes, and treatment data from three medical-surgical ICUs. Using NLP, we screened for behavioural disturbance phenotypes based on words suggestive of an agitated state, a non-agitated state, or a combination of both. RESULTS: We studied 2931 patients. Of these, 225 (7.7%) were NLP-Dx-BD positive for the agitated phenotype, 544 (18.6%) for the non-agitated phenotype and 667 (22.7%) for the combined phenotype. Patients with these phenotypes carried multiple clinical baseline differences. On time-dependent multivariable analysis to compensate for immortal time bias and after adjustment for key outcome predictors, agitated phenotype patients were more likely to receive antipsychotic medications (odds ratio [OR] 1.84, 1.35-2.51, p < 0.001) compared to non-agitated phenotype patients but not compared to combined phenotype patients (OR 1.27, 0.86-1.89, p = 0.229). Moreover, agitated phenotype patients were more likely to die than other phenotypes patients (OR 1.57, 1.10-2.25, p = 0.012 vs non-agitated phenotype; OR 4.61, 2.14-9.90, p < 0.001 vs. combined phenotype). This association was strongest in patients receiving mechanical ventilation when compared with the combined phenotype (OR 7.03, 2.07-23.79, p = 0.002). A similar increased risk was also seen for patients with the non-agitated phenotype compared with the combined phenotype (OR 6.10, 1.80-20.64, p = 0.004). CONCLUSIONS: NLP-Dx-BD screening enabled identification of three behavioural disturbance phenotypes with different characteristics, prevalence, trajectory, treatment, and outcome. Such phenotype identification appears relevant to prognostication and trial design.

Prehospital Tranexamic Acid for Severe Trauma.

BACKGROUND: Whether prehospital administration of tranexamic acid increases the likelihood of survival with a favorable functional outcome among patients with major trauma and suspected trauma-induced coagulopathy who are being treated in advanced trauma systems is uncertain. METHODS: We randomly assigned adults with major trauma who were at risk for trauma-induced coagulopathy to receive tranexamic acid (administered intravenously as a bolus dose of 1 g before hospital admission, followed by a 1-g infusion over a period of 8 hours after arrival at the hospital) or matched placebo. The primary outcome was survival with a favorable functional outcome at 6 months after injury, as assessed with the use of the Glasgow Outcome Scale-Extended (GOS-E). Levels on the GOS-E range from 1 (death) to 8 ("upper good recovery" [no injury-related problems]). We defined survival with a favorable functional outcome as a GOS-E level of 5 ("lower moderate disability") or higher. Secondary outcomes included death from any cause within 28 days and within 6 months after injury. RESULTS: A total of 1310 patients were recruited by 15 emergency medical services in Australia, New Zealand, and Germany. Of these patients, 661 were assigned to receive tranexamic acid, and 646 were assigned to receive placebo; the trial-group assignment was unknown for 3 patients. Survival with a favorable functional outcome at 6 months occurred in 307 of 572 patients (53.7%) in the tranexamic acid group and in 299 of 559 (53.5%) in the placebo group (risk ratio, 1.00; 95% confidence interval [CI], 0.90 to 1.12; P = 0.95). At 28 days after injury, 113 of 653 patients (17.3%) in the tranexamic acid group and 139 of 637 (21.8%) in the placebo group had died (risk ratio, 0.79; 95% CI, 0.63 to 0.99). By 6 months, 123 of 648 patients (19.0%) in the tranexamic acid group and 144 of 629 (22.9%) in the placebo group had died (risk ratio, 0.83; 95% CI, 0.67 to 1.03). The number of serious adverse events, including vascular occlusive events, did not differ meaningfully between the groups. CONCLUSIONS: Among adults with major trauma and suspected trauma-induced coagulopathy who were being treated in advanced trauma systems, prehospital administration of tranexamic acid followed by an infusion over 8 hours did not result in a greater number of patients surviving with a favorable functional outcome at 6 months than placebo. (Funded by the Australian National Health and Medical Research Council and others; PATCH-Trauma ClinicalTrials.gov number, NCT02187120.).

The Australian Delirium Clinical Care Standard: not just another brick in the wall.

Delivering delirium care is challenging. Systems may not be set up to facilitate good delirium practice and staff may have low baseline understanding of how to spot, stop and treat delirium. In this context, delirium guidelines are especially important. In this article, we review the 2021 Australian Delirium Clinical Care Standards. The care standards are different to guidelines insofar as they focus on main presentations and represent eight quality statements describing the best evidence-based care patients with delirium should be offered. The standards speak to three different audiences: consumer, clinician and healthcare organisations. As such, they provide some system-level solutions to practice-level problems. They incorporate latest evidence and reflect the sway away from prescribing to treat delirium, stating that antipsychotics should be avoided. Furthermore, they promote inclusivity of families and carers in delirium care processes as an important medium to engender good practice. Limitations include the fact that they extend to delirium in multiple settings where different approaches may be necessary. They also lack the granularity of being able to provide recommendations on a greater range of drugs that might be used and assume settings are ready to introduce best delirium practice. In sum, they represent an important step forward for delirium knowledge translation and are particularly relevant for patients in the geriatric setting. The guidelines though are constrained as to what they can advocate due to research gaps especially into treatment of delirium.

Pre-hospital freeze-dried plasma for critical bleeding after trauma: A pilot randomized controlled trial.

OBJECTIVES: Transfusion of a high ratio of plasma to packed red blood cells (PRBCs), to treat or prevent acute traumatic coagulopathy, has been associated with survival after major trauma. However, the effect of prehospital plasma on patient outcomes has been inconsistent. The aim of this pilot trial was to assess the feasibility of transfusing freeze-dried plasma with red blood cells (RBCs) using a randomized controlled design in an Australian aeromedical prehospital setting. METHODS: Patients attended by helicopter emergency medical service (HEMS) paramedics with suspected critical bleeding after trauma managed with prehospital RBCs were randomized to receive 2 units of freeze-dried plasma (Lyoplas N-w) or standard care (no plasma). The primary outcome was the proportion of eligible patients enrolled and provided the intervention. Secondary outcomes included preliminary data on effectiveness, including mortality censored at 24 h and at hospital discharge, and adverse events. RESULTS: During the study period of June 1 to October 31, 2022, there were 25 eligible patients, of whom 20 (80%) were enrolled in the trial and 19 (76%) received the allocated intervention. Median time from randomization to hospital arrival was 92.5 min (IQR 68-101.5 min). Mortality may have been lower in the freeze-dried plasma group at 24 h (RR 0.24, 95% CI 0.03-1.73) and at hospital discharge (RR 0.73, 95% CI 0.24-2.27). No serious adverse events related to the trial interventions were reported. CONCLUSIONS: This first reported experience of freeze-dried plasma use in Australia suggests prehospital administration is feasible. Given longer prehospital times typically associated with HEMS attendance, there is potential clinical benefit from this intervention and rationale for a definitive trial.

Delayed Tracheoesophageal Fistula and Refractory Respiratory Failure Caused by Inhalation Burns and Emergency Venovenous ECMO to Facilitate Its Management: A Case Report.

Acquired tracheoesophageal fistulae are uncommon in burn patients but can occur as a complication of inhalation injury. We report a case of a 30-yr-old male patient presenting after suffering from inhalation and 25% total body surface area burns. On postburns day 14, he developed a massive tracheoesophageal fistula causing refractory acute respiratory failure. Veno-venous extracorporeal membrane (VV ECMO) oxygenation was initiated without systemic anticoagulation via bi-femoral cannulation under transthoracic echocardiography guidance. He underwent successful 5-hr apnoeic ventilation-assisted surgical repair of the fistula via a right posterolateral thoracotomy. ECMO was discontinued after 36 hr, and he was discharged to the ward after 33 d in the intensive care unit. Inhalation burn injury can cause a delayed life-threatening tracheoesophageal fistula. Surgical repair can be successfully performed for this condition. VV- ECMO can be used to facilitate prolonged apnoeic surgery and to manage refractory respiratory failure due to this condition.

Whose side are you on? Complexities arising from the non-combatant status of military medical personnel.

Since the mid-1800s, clergy, doctors, other clinicians, and military personnel who specifically facilitate their work have been designated "non-combatants", protected from being targeted in return for providing care on the basis of clinical need alone. While permitted to use weapons to protect themselves and their patients, they may not attempt to gain military advantage over an adversary. The rationale for these regulations is based on sound arguments aimed both at reducing human suffering, but also the ultimate advantage of the nation-state fielding non-combatant staff. However, this is sometimes not immediately apparent to combatant colleagues. Clinicians in the armed force are also military officers, owing a "dual loyalty" that can create conflict if their non-combatant status is not well understood. Historical examples of doctors breaching their responsibilities include prioritisation of combat capability over the rights of individual soldiers (as occurred when scarce medical resources were allocated to soldiers more likely to return to battle in preference to those most likely to die without them), use of physicians to facilitate prisoner interrogation, medical research or treatment to enhance physical performance at the expense of health, application of Medical Rules of Eligibility according to factors other than clinical need, provision of treatment contingent upon support for military objectives, and use of medical knowledge to enhance weapons. However, not being a combatant party to a conflict does not imply that the non-combatant clinician cannot act in the national interest. Indeed, by adhering to the same universal ethics as their civilian colleagues, military clinicians provide optimal care to their own troops, facilitate freedom of action in host nations, and build positive international relationships during the conflict and in the post-conflict state.

Dexmedetomidine and Propofol Sedation in Critically Ill Patients and Dose-associated 90-Day Mortality: A Secondary Cohort Analysis of a Randomized Controlled Trial (SPICE III).

Rationale: The SPICE III (Sedation Practice in Intensive Care Evaluation) trial reported significant heterogeneity in mortality with dexmedetomidine treatment. Supplemental propofol was commonly used to achieve desirable sedation. Objectives: To quantify the association of different infusion rates of dexmedetomidine and propofol, given in combination, with mortality and to determine if this is modified by age. Methods: We included 1,177 patients randomized in SPICE III to receive dexmedetomidine and given supplemental propofol, stratified by age (>65 or ⩽65 yr). We used double stratification analysis to produce quartiles of steady infusion rates of dexmedetomidine while escalating propofol dose and vice versa. We used Cox proportional hazard and multivariable regression adjusted for relevant clinical variable to evaluate the association of sedative dose with 90-day mortality. Measurements and Main Results: Younger patients (598 of 1,177 [50.8%]) received significantly higher doses of both sedatives compared with older patients to achieve comparable sedation depth. On double stratification analysis, escalating infusion rates of propofol to 1.27 mg/kg/h at a steady dexmedetomidine infusion rate (0.54 µg/kg/h) was associated with reduced adjusted mortality in younger but not older patients. This was consistent with multivariable regression modeling (hazard ratio, 0.59; 95% confidence interval, 0.43-0.78; P < 0.0001) adjusted for baseline risk and interaction with dexmedetomidine dose. In contrast, among younger patients, using multivariable regression, escalating dexmedetomidine infusion rate was associated with increased adjusted mortality (hazard ratio, 1.30; 95% confidence interval, 1.03-1.65; P = 0.029). Conclusions: In patients ⩽65 years of age sedated with dexmedetomidine and propofol combination, preferentially increasing the dose of propofol was associated with decreased adjusted 90-day mortality. Conversely, increasing dexmedetomidine may be associated with increased mortality. Clinical trial registered with www.clinicaltrials.gov (NCT01728558).

Transfusion practices in intensive care units: An Australian and New Zealand point prevalence study.

Objective: To describe current transfusion practices in intensive care units (ICUs) in Australia and New Zealand, compare them against national guidelines, and describe how viscoelastic haemostatic assays (VHAs) are used in guiding transfusion decisions. Design setting and participants: Prospective, multicentre, binational point-prevalence study. All adult patients admitted to participating ICUs on a single day in 2021. Main outcome measures: Transfusion types, amounts, clinical reasons, and triggers; use of anti-platelet medications, anti-coagulation, and VHA. Results: Of 712 adult patients in 51 ICUs, 71 (10%) patients received a transfusion during the 24hr period of observation. Compared to patients not transfused, these patients had higher Acute Physiology and Chronic Health Evaluation II scores (19 versus 17, p = 0.02), a greater proportion were mechanically ventilated (49.3% versus 37.3%, p < 0.05), and more had systemic inflammatory response syndrome (70.4% versus 51.3%, p < 0.01). Overall, 63 (8.8%) patients received red blood cell (RBC) transfusions, 10 (1.4%) patients received platelet transfusions, 6 (0.8%) patients received fresh frozen plasma (FFP), and 5 (0.7%) patients received cryoprecipitate. VHA was available in 42 (82.4%) sites but only used in 6.6% of transfusion episodes when available. Alignment with guidelines was found for 98.6% of RBC transfusions, but only 61.6% for platelet, 28.6% for FFP, and 20% for cryoprecipitate transfusions. Conclusions: Non-RBC transfusion decisions are often not aligned with guidelines and VHA is commonly available but rarely used to guide transfusions. Better evidence to guide transfusions in ICUs is needed.

Perspective: the top 11 priorities to improve trauma outcomes, from system to patient level.

BACKGROUND: The Haemorrhage, Airway, Breathing, Circulation, Disability, Exposure/Environmental control approach to individual patient management in trauma is well established and embedded in numerous training courses worldwide. Further improvements in trauma outcomes are likely to result from a combination of system-level interventions in prevention and quality improvement, and from a sophisticated approach to clinical innovation. TOP ELEVEN TRAUMA PRIORITIES: Based on a narrative review of remaining preventable mortality and morbidity in trauma, the top eleven priorities for those working throughout the spectrum of trauma care, from policy-makers to clinicians, should be: (1) investment in effective trauma prevention (likely to be the most cost-effective intervention); (2) prioritisation of resources, quality improvement and innovation in prehospital care (where the most preventable mortality remains); (3) building a high-performance trauma team; (4) applying evidence-based clinical interventions that stop bleeding, open & protect the airway, and optimise breathing most effectively; (5) maintaining enough circulating blood volume and ensuring adequate cardiac function; (6) recognising the role of the intensive care unit in modern damage control surgery; (7) prioritising good intensive care unit intercurrent care, especially prophylaxis for thromboembolic disease; (8) conducting a thorough tertiary survey, noting that on average the intensive care unit is where approximately 15% of injuries are detected; (9) facilitating early extubation; (10) investing in formal quantitative and qualitative quality assurance and improvement; and (11) improving clinical trial design. CONCLUSION: Dramatic reductions in population trauma mortality and injury case fatality rate over recent decades have demonstrated the value of a comprehensive approach to trauma quality and process improvement. Continued attention to these principles, targeting areas with highest remaining preventable mortality while also prioritising functional outcomes, should remain the focus of both clinician and policy-makers.

Stress response during early sedation with dexmedetomidine compared with usual-care in ventilated critically ill patients.

BACKGROUND: Sedative agents may variably impact the stress response. Dexmedetomidine is a sympatholytic alpha2-adrenergic agonist mainly used as a second-line sedative agent in mechanically ventilated patients. We hypothesised that early sedation with dexmedetomidine as the primary agent would result in a reduced stress response compared to usual sedatives in critically ill ventilated adults. METHODS: This was a prospective sub-study nested within a multi-centre randomised controlled trial of early sedation with dexmedetomidine versus usual care. The primary outcome was the mean group differences in plasma levels of stress response biomarkers measured over 5 days following randomisation. Other hormonal, biological and physiological parameters were collected. Subgroup analyses were planned for patients with proven or suspected sepsis. RESULTS: One hundred and three patients were included in the final analysis. Baseline illness severity (APACHE II score), the proportion of patients receiving propofol and the median dose of propofol received were comparable between groups. More of the usual-care patients received midazolam (57.7% vs 33.3%; p = 0.01) and at higher dose (median (95% interquartile range) 0.46 [0.20-0.93] vs 0.14 [0.08-0.38] mg/kg/day; p < 0.01). The geometric mean (95% CI) plasma level of the stress hormones, adrenaline (0.32 [0.26-0.4] vs 0.38 [0.31-0.48]), noradrenaline (4.27 [3.12-5.85] vs 6.2 [4.6-8.5]), adrenocorticotropic hormone (17.1 [15.1-19.5] vs 18.1 [15.9-20.5]) and cortisol (515 [409-648] vs 618 [491-776)] did not differ between dexmedetomidine and usual-care groups, respectively. There were no significant differences in any other assayed biomarkers or physiological parameters Sensitivity analyses showed no effect of age or sepsis. CONCLUSIONS: Early sedation with dexmedetomidine as the primary sedative agent in mechanically ventilated critically ill adults resulted in comparable changes in physiological and blood-borne parameters associated with the stress-response as with usual-care sedation.

Fingolimod does not prevent syndecan-4 shedding from the endothelial glycocalyx in a cultured human umbilical vein endothelial cell model of vascular injury.

BACKGROUND: Shedding of the endothelial glycocalyx (EG) is associated with poor outcomes in a range of conditions including sepsis. Fresh frozen plasma (FFP) restores the damaged EG to baseline thickness, however the mechanism for this effect is unknown, and some components of FFP have adverse effects unrelated to the EG. There is some limited evidence that sphingosine-1-phosphate (S1P) within FFP restores the EG by activating the endothelial cell S1P receptor 1 (S1PR1). However, there are disadvantages to using S1P clinically as an EG restorative therapy. A potential alternative is the S1PR agonist fingolimod (FTY720). The aim of this study was to assess whether FTY720 prevents EG shedding in injured cultured human umbilical vein endothelial cells. METHODS: Shedding of the EG was induced in cultured human umbilical vein endothelial cells (HUVECs) by exposure to adrenaline, TNF-α and H2O2. The cells were then assigned to one of six conditions for 4 h: uninjured and untreated, injured and untreated, injured and treated with FTY720 with and without the S1PR1 inhibitor W146, and injured and treated with 25% FFP with and without W146. Syndecan-4, a component of the EG, was measured in cell supernatants, and syndecan-4 and thrombomodulin mRNA expression was quantitated in cell lysates. RESULTS: The injury resulted in a 2.1-fold increase in syndecan-4 (p < 0.001), consistent with EG shedding. Syndecan-4 and thrombomodulin mRNA expression was increased (p < 0.001) and decreased (p < 0.05), respectively, by the injury. Syndecan-4 shedding was not affected by treatment with FTY720, whereas FFP attenuated syndecan-4 shedding back to baseline levels in the injured cells and this was unaffected by W146. Neither treatment affected syndecan-4 or thrombomodulin mRNA expression. CONCLUSIONS: FTY720 did not prevent syndecan-4 shedding from the EG in the HUVEC model of endothelial injury, suggesting that activation of S1PR does not prevent EG damage. FFP prevented syndecan-4 shedding from the EG via a mechanism that was independent of S1PR1 and upregulation of SDC-4 production. Further studies to examine whether FTY720 or another S1PR agonist might have EG-protective effects under different conditions are warranted, as are investigations seeking the mechanism of EG protection conferred by FFP in this experimental model.

Transfusion-related acute lung injury (TRALI): Potential pathways of development, strategies for prevention and treatment, and future research directions.

Transfusion-related acute lung injury (TRALI) can occur during or after a transfusion, and remains a leading cause of transfusion-associated morbidity and mortality. TRALI is caused by the transfusion of either anti-leukocyte antibodies or biological response modifiers (BRMs). Experimental evidence suggests at least six different pathways that antibody-mediated TRALI might follow: (i) two hit neutrophil activation; (ii) monocyte and neutrophil dependent; (iii) endothelial cell, neutrophil Fc receptor, platelet and neutrophil extracellular trap dependent; (iv) direct monocyte activation; (v) direct endothelial cell activation; and (vi) endothelial cell, complement and monocyte dependent. Two of these pathways (i and v) also apply to BRM-mediated TRALI. Different antibodies or BRMs might initiate different pathways. Even though six pathways are described, these might not be distinct, and might instead be interlinked or proceed concurrently. The different pathways converge upon reactive oxygen species release which damages pulmonary endothelium, precipitating fluid leakage and the clinical symptoms of TRALI. Additional pathways to the six described are likely to also contribute to TRALI pathogenesis, and this requires further investigation. This review also discusses evidence of protective mechanisms and their implications for clinical TRALI treatment. Finally, it suggests directions for future research to support the translation of these findings into strategies to prevent and treat clinical TRALI.