Preservation of recipient plasma sphingosine-1-phosphate levels reduces transfusion-related acute lung injury.

Cold-stored (CS) platelets are once again being reintroduced for clinical use. Transfused CS platelets offer benefits over room temperature-stored (RTS) platelets such as increased hemostatic effects and prolongation of shelf-life. Despite these advantages little is known about their association with transfusion-related acute lung injury (TRALI). TRALI is associated with prolonged storage of RTS platelets and has a mortality of >15%. Determining the safety of CS platelets is important considering their proposed use in TRALI-vulnerable populations with inflammation such as surgical patients or patients with trauma. Donor platelet-derived ceramide causes TRALI, whereas donor platelet sphingosine-1-phosphate (S1P) is barrier protective. Females have higher plasma levels of S1P than males. Cold temperatures increase S1P levels in cells. Therefore, we hypothesized that female (donors or recipients) and/or CS platelets would decrease TRALI. To test this, we compared how male and female donor and recipient allogeneic platelet transfusions of CS (4°C) versus RTS (23°C) platelets stored for 5 days influence murine TRALI. Transfusion of CS platelets significantly reduced recipient lung tissue wet-to-dry ratios, bronchoalveolar lavage total protein, lung tissue myeloperoxidase enzyme activity, histological lung injury scores, and increased plasma sphingosine-1-phosphate (S1P) levels compared with RTS platelet transfusions. Female as opposed to male recipients had less TRALI and higher plasma S1P levels. Female donor mouse platelets had higher S1P levels than males. Mouse and human CS platelets had increased S1P levels compared with RTS platelets. Higher recipient plasma S1P levels appear protective considering females, and males receiving platelets from females or male CS platelets had less TRALI.NEW & NOTEWORTHY Transfusion-related acute lung injury (TRALI) though relatively rare represents a severe lung injury. The sphingolipid sphingosine-1-phosphate (S1P) regulates the severity of platelet-mediated TRALI. Female platelet transfusion recipient plasmas or stored platelets from female donors have higher S1P levels than males, which reduces TRALI. Cold storage of murine platelets preserves platelet-S1P, which reduces TRALI in platelet-transfused recipients.

Mortality-associated risk factors for transfusion-associated circulatory overload.

BACKGROUND AND OBJECTIVES: Respiratory transfusion reactions associate strongly with morbidity and mortality, and transfusion-associated circulatory overload (TACO) is the leading cause of reaction-related deaths. Risk factors for TACO include transfusion speed and volume and cardiorenal comorbidities. MATERIALS AND METHODS: An academic health network haemovigilance database was interrogated to assess variables associating with 371 cases of TACO and involved-visit outcomes, using univariate and multivariate regression analysis. RESULTS: TACO reactions over 11 years were reported in 179 males and 192 females, median age (interquartile range) 65 (53-75) years. In-hospital and 28-day mortality were 17.5% and 12.9%, respectively. In univariate regression modelling, male sex, injury severity grade, product volume administered, the use of platelets and intensive care admissions were each associated with in-hospital and 28-day mortality (p < 0.05). However, after multivariate regression analysis, only male sex in transfusion recipients independently associated with mortality (p < 0.05). CONCLUSION: In this cohort, male recipient sex and platelet administration were associated with TACO-involving admissions not ending in survival.

Echocardiographic assessment of cardiovascular physiology of preterm miniature piglets supported with a pumped artificial placenta system.

OBJECTIVES: We evaluated fetal cardiovascular physiology and mode of cardiac failure in premature miniature piglets on a pumped artificial placenta (AP) circuit. METHODS: Fetal pigs were cannulated via the umbilical vessels and transitioned to an AP circuit composed of a centrifugal pump and neonatal oxygenator and maintained in a fluid-filled biobag. Echocardiographic studies were conducted to measure ventricular function, umbilical blood flow, and fluid status. In utero scans were used as control data. RESULTS: AP fetuses (n = 13; 102±4d gestational age [term 115d]; 616 ± 139 g [g]; survival 46.4 ± 46.8 h) were tachycardic and hypertensive with initially supraphysiologic circuit flows. Increased myocardial wall thickness was observed. Signs of fetal hydrops were present in all piglets. Global longitudinal strain (GLS) measurements increased in the left ventricle (LV) after transition to the circuit. Right ventricle (RV) and LV strain rate decreased early during AP support compared with in utero measurements but recovered toward the end of the experiment. Fetuses supported for >24 h had similar RV GLS to in utero controls and significantly higher GLS compared to piglets surviving only up to 24 h. CONCLUSIONS: Fetuses on a pump-supported AP circuit experienced an increase in afterload, and redistribution of blood flow between the AP and systemic circulations, associated with elevated end-diastolic filling pressures. This resulted in heart failure and hydrops. These preterm fetuses were unable to tolerate the hemodynamic changes associated with connection to the current AP circuit. To better mimic the physiology of the native placenta and preserve normal fetal cardiovascular physiology, further optimization of the circuit will be required.

Extracellular vesicles: effectors of transfusion-related acute lung injury.

Respiratory transfusion reactions represent some of the most severe adverse reactions related to receiving blood products. Of those, transfusion-related acute lung injury (TRALI) is associated with elevated morbidity and mortality. TRALI is characterized by severe lung injury associated with inflammation, pulmonary neutrophil infiltration, lung barrier leak, and increased interstitial and airspace edema that cause respiratory failure. Presently, there are few means of detecting TRALI beyond clinical definitions based on physical examination and vital signs or preventing/treating TRALI beyond supportive care with oxygen and positive pressure ventilation. Mechanistically, TRALI is thought to be mediated by the culmination of two successive proinflammatory hits, which typically comprise a recipient factor (1st hit-e.g., systemic inflammatory conditions) and a donor factor (2nd hit-e.g., blood products containing pathogenic antibodies or bioactive lipids). An emerging concept in TRALI research is the contribution of extracellular vesicles (EVs) in mediating the first and/or second hit in TRALI. EVs are small, subcellular, membrane-bound vesicles that circulate in donor and recipient blood. Injurious EVs may be released by immune or vascular cells during inflammation, by infectious bacteria, or in blood products during storage, and can target the lung upon systemic dissemination. This review assesses emerging concepts such as how EVs: 1) mediate TRALI, 2) represent targets for therapeutic intervention to prevent or treat TRALI, and 3) serve as biochemical biomarkers facilitating TRALI diagnosis and detection in at-risk patients.

Platelet extracellular vesicles mediate transfusion-related acute lung injury by imbalancing the sphingolipid rheostat.

Transfusion-related acute lung injury (TRALI) is a hazardous transfusion complication with an associated mortality of 5% to 15%. We previously showed that stored (5 days) but not fresh platelets (1 day) cause TRALI via ceramide-mediated endothelial barrier dysfunction. As biological ceramides are hydrophobic, extracellular vesicles (EVs) may be required to shuttle these sphingolipids from platelets to endothelial cells. Adding to complexity, EV formation in turn requires ceramide. We hypothesized that ceramide-dependent EV formation from stored platelets and EV-dependent sphingolipid shuttling induces TRALI. EVs formed during storage of murine platelets were enumerated, characterized for sphingolipids, and applied in a murine TRALI model in vivo and for endothelial barrier assessment in vitro. Five-day EVs were more abundant, had higher long-chain ceramide (C16:0, C18:0, C20:0), and lower sphingosine-1-phosphate (S1P) content than 1-day EVs. Transfusion of 5-day, but not 1-day, EVs induced characteristic signs of lung injury in vivo and endothelial barrier disruption in vitro. Inhibition or supplementation of ceramide-forming sphingomyelinase reduced or enhanced the formation of EVs, respectively, but did not alter the injuriousness per individual EV. Barrier failure was attenuated when EVs were abundant in or supplemented with S1P. Stored human platelet 4-day EVs were more numerous compared with 2-day EVs, contained more long-chain ceramide and less S1P, and caused more endothelial cell barrier leak. Hence, platelet-derived EVs become more numerous and more injurious (more long-chain ceramide, less S1P) during storage. Blockade of sphingomyelinase, EV elimination, or supplementation of S1P during platelet storage may present promising strategies for TRALI prevention.

Cold-stored platelets for acute bleeding in cardiac surgical patients: a narrative review.

PURPOSE: Cold-stored platelets (CSP) are an increasingly active topic of international research. They are maintained at 1-6 °C, in contrast to standard room-temperature platelets (RTP) kept at 20-24 °C. Recent evidence suggests that CSP have superior hemostatic properties compared with RTP. This narrative review explores the application of CSP in adult cardiac surgery, summarizes the preclinical and clinical evidence for their use, and highlights recent research. SOURCE: A targeted search of MEDLINE and other databases up to 24 February 2022 was conducted. Search terms combined concepts such as cardiac surgery, blood, platelet, and cold-stored. Searches of trial registries ClinicalTrials.gov and WHO International Clinical Trials Registry Platform were included. Articles were included if they described adult surgical patients as their population of interest and an association between CSP and clinical outcomes. References of included articles were hand searched. PRINCIPAL FINDINGS: When platelets are stored at 1-6 °C, their metabolic rate is slowed, preserving hemostatic function for increased storage duration. Cold-stored platelets have superior adhesion characteristics under physiologic shear conditions, and similar or superior aggregation responses to physiologic agonists. Cold-stored platelets undergo structural, metabolic, and molecular changes which appear to "prime" them for hemostatic activity. While preliminary, clinical evidence supports the conduct of trials comparing CSP with RTP for patients with platelet-related bleeding, such as those undergoing cardiac surgery. CONCLUSION: Cold-stored platelets may have several advantages over RTP, including increased hemostatic capacity, extended shelf-life, and reduced risk of bacterial contamination. Large clinical trials are needed to establish their potential role in the treatment of acutely bleeding patients.

RéSUMé: OBJECTIF: Les plaquettes conservées au froid (PCF) sont un sujet de recherche internationale de plus en plus populaire. Ces plaquettes sont maintenues à une température de 1-6 °C, contrairement aux plaquettes standard conservées à température ambiante (PTA), maintenues à 20­24 °C. Des données probantes récentes suggèrent que les PCF ont des propriétés hémostatiques supérieures aux PTA. Ce compte rendu narratif explore l'application de PCF en chirurgie cardiaque chez l'adulte, résume les données probantes précliniques et cliniques de leur utilisation, et met en évidence les recherches récentes. SOURCES: Une recherche ciblée dans MEDLINE et d'autres bases de données jusqu'au 24 février 2022 a été effectuée. Les termes de recherche combinaient des concepts en anglais tels que cardiac surgery, blood, platelet et cold-stored (soit chirurgie cardiaque, plaquette, et entreposage frigorifique). Des recherches dans les registres d'études ClinicalTrials.gov et le système d'enregistrement international des essais cliniques (ICTRP) de l'OMS ont été incluses. Les articles ont été inclus s'ils décrivaient des patient·es adultes de chirurgie en tant que population d'intérêt et une association entre les PCF et les issues cliniques. Les références des articles inclus ont fait l'objet d'une recherche manuelle. CONSTATATIONS PRINCIPALES: Lorsque les plaquettes sont conservées entre 1 et 6 °C, leur taux métabolique est ralenti, préservant la fonction hémostatique pour une durée d'entreposage accrue. Les plaquettes conservées au froid ont des caractéristiques d'adhésion supérieures dans des conditions de cisaillement physiologique et des réponses d'agrégation similaires ou supérieures aux agonistes physiologiques. Les plaquettes conservées au froid subissent des changements structurels, métaboliques et moléculaires qui semblent les « amorcer ¼ pour une activité hémostatique. Bien que préliminaires, les données probantes cliniques appuient la réalisation d'études comparant les PCF aux PTA chez la patientèle présentant des saignements liés aux plaquettes, tels que les personnes bénéficiant d'une chirurgie cardiaque. CONCLUSION: Les plaquettes conservées au froid peuvent présenter plusieurs avantages par rapport aux PTA, notamment une capacité hémostatique accrue, une durée de conservation prolongée et un risque réduit de contamination bactérienne. De grands essais cliniques sont nécessaires pour établir leur rôle potentiel dans le traitement de la patientèle en hémorragie aiguë.

Inflammasome activation in acute lung injury.

Inflammasomes are multiprotein complexes tasked with sensing endogenous or exogenous inflammatory signals and integrating this signal into a downstream response. Inflammasome activation has been implicated in a variety of pulmonary diseases, including pulmonary hypertension, bacterial pneumonia, COPD, and asthma. Of increasing interest is the contribution of inflammasome activation in the context of acute lung injury/acute respiratory distress syndrome (ALI/ARDS). Inflammasome activation in both the lung parenchyma and resident immune cells generates intereukin-1ß (IL-1ß) and IL-18, both of which drive the cascade of lung inflammation forward. Blockade of these responses has been shown to be beneficial in animal models and is a focus of translational research in the field. In this review, we will discuss the assembly and regulation of inflammasomes during lung inflammation, highlighting therapeutically viable effector steps. We will examine the importance of IL-1ß and IL-18, two key products of inflammasome activation, in ALI, as well as the contribution of the pulmonary endothelial cell to this process. Finally, we will explore translational research moving toward anti-inflammasome therapies for ALI/ARDS and speculate toward future directions for the field.

Frequency and timing of all-cause deaths in visits involving suspected transfusion reactions, and the significance of cardiopulmonary disturbances.

BACKGROUND/OBJECTIVES: Transfusion reactions (TRs) may cause or contribute to death. Cardiopulmonary TRs are distressing, and collectively account for most transfusion fatalities, though the degree to which they alter survival more broadly is unclear. Deaths (and their timing) after TRs may provide further insights. MATERIALS/METHODS: Adult (tri-hospital network) haemovigilance data (2013-2016) recorded referrals with conclusions ranging from unrelated to transfusion (UTR) to entities such as: septic TRs, serologic/haemolytic reactions, transfusion-associated circulatory overload (TACO), transfusion-associated dyspnoea (TAD), transfusion-related acute lung injury (TRALI), allergic transfusion reaction (ATR), and others. For (in- or out-patient) visits involving suspected TRs (VISTRs), all-cause mortalities (% [95% confidence interval]) and associated time-to-death (TTD) (median days, [interquartile range]) were compared. Diagnoses were defined inclusively (possible-to-definite) or strictly (probable-to-definite). RESULTS: Of 1144 events, rank order VISTR mortality following (possible-to-definite) TRs, and associated TTDs, were led by: DHTR 33% [6-19], 1 death at 123d; TRALI 32% [15-54], 6 deaths: 3d [2-20]; BaCon 21% [14-31], 17 deaths: 10d [3-28]; TACO 18% [12-26], 23 deaths: 16d [6-28]; TAD 17% [11-26]: 18 deaths, 6d [3-12]. Higher-certainty TRs ranked similarly (DHTR 50% [9-91]; BaCon 29% [12-55], 4 deaths: 12d [3-22]; and TACO 25% [16-38], 15 deaths: 21d [6-28]). VISTR mortality after TACO or TRALI significantly exceeded ATR (3·3% [2·4-5·8], P < 0·00001) but was not different from UTR events (P = 0·3). CONCLUSIONS: Only half of cardiopulmonary TRs constituted high certainty diagnoses. Nevertheless, cardiopulmonary TRs and suspected BaCon marked higher VISTR mortality with shorter TTDs. Short (<1 week) TTDs in TAD, BaCon or TRALI imply either contributing roles in death, treatment refractoriness and/or applicable TR susceptibilities in the dying.

Efficacy and safety of decontamination for N95 respirator reuse: a systematic literature search and narrative synthesis.

PURPOSE: Under times of supply chain stress, the availability of some medical equipment and supplies may become limited. The current pandemic involving severe acute respiratory syndrome coronavirus 2 has highlighted limitations to the ordinary provision of personal protective equipment (PPE). For perioperative healthcare workers, N95 masks provide a stark example of PPE in short supply necessitating the creation of scientifically valid protocols for their decontamination and reuse. METHODS: We performed a systematic literature search of MEDLINE, Embase, Cochrane CENTRAL databases, and ClinicalTrials.gov to identify peer-reviewed articles related to N95 mask decontamination and subsequent testing for the integrity of mask filtration and facial seal. To expand this search, we additionally surveyed the official statements from key health agencies, organizations, and societies for relevant citations. RESULTS: Our initial database search resulted in five articles that met inclusion criteria, with 26 articles added from the expanded search. Our search did not reveal any relevant randomized clinical trials or cohort studies. We found that moist mask heating (65-80°C at 50-85% relative humidity for 20-30 min) and vaporous hydrogen peroxide treatment were supported by the literature to provide consistent viral decontamination without compromising mask seal and filtration efficiency. Other investigated decontamination methods lacked comprehensive scientific evidence for all three of these key criteria. CONCLUSIONS: N95 mask reprocessing using either moist heat or vaporous hydrogen peroxide is recommended to ensure healthcare worker safety.

RéSUMé: OBJECTIF: Lorsque les chaînes d'approvisionnement sont mises sous pression, la disponibilité de certains équipements et fournitures médicaux pourrait devenir restreinte. La pandémie actuelle du syndrome respiratoire aigu sévère du coronavirus 2 a mis en lumière les limites de l'approvisionnement usuel des équipements de protection individuelle (EPI). Pour les travailleurs de la santé périopératoires, les masques N95 sont un exemple frappant d'EPI pouvant rapidement venir à manquer et nécessitant l'élaboration de protocoles scientifiquement rigoureux pour leur décontamination et leur réutilisation. MéTHODE: Nous avons réalisé une recherche de littérature systématique dans les bases de données MEDLINE, Embase, Cochrane CENTRAL et sur ClinicalTrials.gov afin d'identifier les articles révisés par les pairs portant sur la décontamination des masques N95 et les tests subséquents pour vérifier l'intégrité de la filtration du masque et son étanchéité sur le visage. Afin d'étendre notre recherche, nous avons également passé en revue les énoncés officiels émanant des agences de santé, ainsi que des organismes et sociétés médicales majeurs pour en extraire les citations pertinentes. RéSULTATS: Notre recherche initiale des bases de données nous a permis d'extraire cinq articles respectant nos critères d'inclusion, et 26 articles ont été ajoutés à la suite de notre recherche étendue. Notre recherche n'a pas découvert d'études cliniques randomisées ou d'études de cohorte pertinentes. Nous avons observé que la décontamination du masque par chaleur humide (65­80°C à une humidité relative de 50­85 % pendant 20-30 min) et le traitement par vapeur de peroxyde d'hydrogène constituaient les deux mesures endossées par la littérature. En effet, ces modalités offrent une décontamination virale constante sans pour autant compromettre l'étanchéité du masque ou son efficacité de filtration. Les autres méthodes de décontamination étudiées ne possédaient pas de données probantes scientifiques exhaustives quant à ces trois critères clés. CONCLUSION: Le retraitement des masques N95 à l'aide de chaleur humide ou de vapeur de peroxyde d'oxygène est recommandé pour assurer la sécurité des travailleurs de la santé.

Association between preoperative hemoglobin levels after iron supplementation and perioperative blood transfusion requirements in children undergoing scoliosis surgery.

BACKGROUND AND AIMS: In this study, we assessed the association between preoperative hemoglobin and red blood cell transfusion in children undergoing spine surgery after the implementation of our preoperative iron supplementation protocol. METHOD: We performed a retrospective analysis of patients who underwent posterior spinal fusion surgery between January 2013 and December 2017 and received preoperative iron supplementation. We used uni- and multivariable logistic regression to determine the association between preoperative hemoglobin level and red blood cell transfusion in patients receiving iron supplementation. RESULTS: A total of 382 patients treated with preoperative oral iron were included. Of these, 175 (45.5%) patients were transfused intraoperatively. Multivariable logistic regression analysis revealed nonidiopathic etiology of the scoliosis (OR 4.178 [95% CI: 2.277-7.668], P < .001), the Cobb angle (OR 1.025 [95% CI: 1.010-1.040], P = .001), and number of vertebrae fused (OR 1.169 [95% CI: 1.042-1.312], P = .008) were associated with red blood cell transfusion. In addition, patients with a preoperative hemoglobin ≥ 140 g/L (OR 0.157 [95% CI: 0.046-0.540], P = .003), and hemoglobin between 130 and 140 g/L (OR 0.195 [95% CI: 0.057-0.669], P = .009) were less likely to be transfused compared with patients with preoperative hemoglobin between 120 and 130 g/L (OR 0.294 [95% CI: 0.780-1.082], P = .066) or <120 g/L (reference). CONCLUSION: Our study suggests that higher preoperative hemoglobin levels (>130 g/L) are associated with a reduced need for red blood cell transfusion in pediatric patients who have received iron supplementation before undergoing posterior spinal fusion in our institution. The effect of iron supplementation, the optimal dosing, and duration of supplemental iron therapy remains unclear at this time.

Extracellular vesicles in lung health, disease, and therapy.

Both physiological homeostasis and pathological disease processes in the lung typically result from complex, yet coordinated multicellular responses that are synchronized via paracrine and endocrine intercellular communication pathways. Of late, extracellular vesicles have emerged as important information shuttles that can coordinate and disseminate homeostatic and disease signals. In parallel, extracellular vesicles in biological fluids such as sputum, mucus, epithelial lining fluid, edema fluid, the pulmonary circulation, pleural fluid, and lymphatics have emerged as promising candidate biomarkers for diagnosis and prognosis in lung disease. Extracellular vesicles are small, subcellular, membrane-bound vesicles containing cargos from parent cells such as lipids, proteins, genetic information, or entire organelles. These cargos endow extracellular vesicles with biologically active information or functions by which they can reprogram their respective target cells. Recent studies show that extracellular vesicles found in lung-associated biological fluids play key roles as biomarkers and effectors of disease. Conversely, administration of naïve or engineered extracellular vesicles with homeostatic or reparative effects may provide a promising novel protective and regenerative strategy to treat lung disease. To highlight this rapidly developing field, the American Journal of Physiology-Lung Cellular and Molecular Physiology is now launching a special Call for Papers on extracellular vesicles in lung health, disease, and therapy. This review aims to set the stage for this call by introducing extracellular vesicles and their emerging roles in lung physiology and pathobiology.

T regulatory cells and dendritic cells protect against transfusion-related acute lung injury via IL-10.

Transfusion-related acute lung injury (TRALI) is the leading cause of transfusion-related fatalities and is characterized by acute respiratory distress following blood transfusion. Donor antibodies are frequently involved; however, the pathogenesis and protective mechanisms in the recipient are poorly understood, and specific therapies are lacking. Using newly developed murine TRALI models based on injection of anti-major histocompatibility complex class I antibodies, we found CD4+CD25+FoxP3+ T regulatory cells (Tregs) and CD11c+ dendritic cells (DCs) to be critical effectors that protect against TRALI. Treg or DC depletion in vivo resulted in aggravated antibody-mediated acute lung injury within 90 minutes with 60% mortality upon DC depletion. In addition, resistance to antibody-mediated TRALI was associated with increased interleukin-10 (IL-10) levels, and IL-10 levels were found to be decreased in mice suffering from TRALI. Importantly, IL-10 injection completely prevented and rescued the development of TRALI in mice and may prove to be a promising new therapeutic approach for alleviating lung injury in this serious complication of transfusion.

Transfusion-related Acute Lung Injury in the Perioperative Patient.

Transfusion-related acute lung injury is a leading cause of death associated with the use of blood products. Transfusion-related acute lung injury is a diagnosis of exclusion which can be difficult to identify during surgery amid the various physiologic and pathophysiologic changes associated with the perioperative period. As anesthesiologists supervise delivery of a large portion of inpatient prescribed blood products, and since the incidence of transfusion-related acute lung injury in the perioperative patient is higher than in nonsurgical patients, anesthesiologists need to consider transfusion-related acute lung injury in the perioperative setting, identify at-risk patients, recognize early signs of transfusion-related acute lung injury, and have established strategies for its prevention and treatment.

Targeting Transfusion-Related Acute Lung Injury: The Journey From Basic Science to Novel Therapies.

OBJECTIVES: Transfusion-related acute lung injury is characterized by the onset of respiratory distress and acute lung injury following blood transfusion, but its pathogenesis remains poorly understood. Generally, a two-hit model is presumed to underlie transfusion-related acute lung injury with the first hit being risk factors present in the transfused patient (such as inflammation), whereas the second hit is conveyed by factors in the transfused donor blood (such as antileukocyte antibodies). At least 80% of transfusion-related acute lung injury cases are related to the presence of donor antibodies such as antihuman leukocyte or antihuman neutrophil antibodies. The remaining cases may be related to nonantibody-mediated factors such as biolipids or components related to storage and ageing of the transfused blood cells. At present, transfusion-related acute lung injury is the leading cause of transfusion-related fatalities and no specific therapy is clinically available. In this article, we critically appraise and discuss recent preclinical (bench) insights related to transfusion-related acute lung injury pathogenesis and their therapeutic potential for future use at the patients' bedside in order to combat this devastating and possibly fatal complication of transfusion. DATA SOURCES: We searched the PubMed database (until August 22, 2017). STUDY SELECTION: Using terms: "Transfusion-related acute lung injury," "TRALI," "TRALI and therapy," "TRALI pathogenesis." DATA EXTRACTION: English-written articles focusing on transfusion-related acute lung injury pathogenesis, with potential therapeutic implications, were extracted. DATA SYNTHESIS: We have identified potential therapeutic approaches based on the literature. CONCLUSIONS: We propose that the most promising therapeutic strategies to explore are interleukin-10 therapy, down-modulating C-reactive protein levels, targeting reactive oxygen species, or blocking the interleukin-8 receptors; all focused on the transfused recipient. In the long-run, it may perhaps also be advantageous to explore other strategies aimed at the transfused recipient or aimed toward the blood product, but these will require more validation and confirmation first.

Acid sphingomyelinase mediates murine acute lung injury following transfusion of aged platelets.

Pulmonary complications from stored blood products are the leading cause of mortality related to transfusion. Transfusion-related acute lung injury is mediated by antibodies or bioactive mediators, yet underlying mechanisms are incompletely understood. Sphingolipids such as ceramide regulate lung injury, and their composition changes as a function of time in stored blood. Here, we tested the hypothesis that aged platelets may induce lung injury via a sphingolipid-mediated mechanism. To assess this hypothesis, a two-hit mouse model was devised. Recipient mice were treated with 2 mg/kg intraperitoneal lipopolysaccharide (priming) 2 h before transfusion of 10 ml/kg stored (1-5 days) platelets treated with or without addition of acid sphingomyelinase inhibitor ARC39 or platelets from acid sphingomyelinase-deficient mice, which both reduce ceramide formation. Transfused mice were examined for signs of pulmonary neutrophil accumulation, endothelial barrier dysfunction, and histological evidence of lung injury. Sphingolipid profiles in stored platelets were analyzed by mass spectrophotometry. Transfusion of aged platelets into primed mice induced characteristic features of lung injury, which increased in severity as a function of storage time. Ceramide accumulated in platelets during storage, but this was attenuated by ARC39 or in acid sphingomyelinase-deficient platelets. Compared with wild-type platelets, transfusion of ARC39-treated or acid sphingomyelinase-deficient aged platelets alleviated lung injury. Aged platelets elicit lung injury in primed recipient mice, which can be alleviated by pharmacological inhibition or genetic deletion of acid sphingomyelinase. Interventions targeting sphingolipid formation represent a promising strategy to increase the safety and longevity of stored blood products.

Microparticles as biomarkers of lung disease: enumeration in biological fluids using lipid bilayer microspheres.

Extracellular vesicles, specifically microparticles (MPs), are rapidly gaining attention for their capacity to act as biomarkers for diagnosis, prognosis, or responsiveness to therapy in lung disease, in keeping with the concept of precision medicine. However, MP analysis by high-sensitivity flow cytometry (FCM) is complicated by a lack of accurate means for MP enumeration. To address this gap, we report here an enhanced FCM MP gating and enumeration technique based on the use of novel engineered lipid bilayer microspheres (LBMs). By comparison of LBM-based MP enumeration with conventional bead- or fluorescent-based FCM enumeration techniques and a gravimetric consumption gold standard, we found LBMs to be superior to commercial bead preparations, showing the smallest fixed bias and limits of agreement in Bland Altman analyses. LBMs had simultaneous capacity to aid FCM enumeration of MPs in plasma, BAL, and cell culture supernatants. LBM enumeration detected differences in MP counts in mice exposed to intraperitoneal lipopolysaccharide or saline. LBMs provided for 1) higher sensitivity for gating MPs populations, 2) reduced background within MP gates, 3) more appropriate size, and 4) an inexpensive alternative amenable to different fluorescent tags. LBM-based MP enumeration was useful for a series of different FCM systems assessed, whereas LBM gating benefited high- but not low-sensitivity FCM systems compared with fluorescence gating. By offering exclusive advantages over current means of gating and enumerating MPs, LBMs are uniquely suited to realizing the potential of MPs as biomarkers in biological lung fluids and facilitating precision medicine in lung disease.

Physician-assisted death and the anesthesiologist.

Although physician-assisted death (PAD) is established in certain countries, the legality and ethics of this issue have been debated for decades in Canada. The Supreme Court of Canada has now settled the issue of legality nationally, and as a result of the decision in Carter v. Canada, PAD (which includes both physician-assisted suicide and euthanasia) will become legal on February 6, 2016. It is difficult to predict the potential demand for PAD in Canada. This paper highlights other countries' experiences with PAD in order to shed light on this question and to forecast issues that Canadian physicians will face once the change to the law comes into effect. At present, there is no legislative scheme in place to regulate the conduct of PAD. Physicians and their provincial colleges may find themselves acting as the de facto regulators of PAD if a regulatory vacuum persists. With their specialized knowledge of pharmacology and interdisciplinary leadership, anesthesiologists may be called upon to develop protocols for the administration of PAD as well as to administer euthanasia. Canadian anesthesiologists currently have a unique opportunity to consider the complex ethical issues they will face when PAD becomes legal and to contribute to the creation of a regulatory structure that will govern PAD in Canada.

Liver transplantation in patients with end-stage liver disease requiring intensive care unit admission and intubation.

Data regarding transplantation outcomes in ventilated intensive care unit (ICU)-dependent patients with end-stage liver disease (ESLD) are conflicting. This single-center cohort study investigated the outcomes of patients with ESLD who were intubated with mechanical support before liver transplantation (LT). The ICU plus intubation group consisted of 42 patients with decompensated cirrhosis and mechanical ventilation before transplantation. LT was considered for intubated ICU patients if the fraction of inspired oxygen was ≤40% with a positive end-expiratory pressure ≤ 10, low pressor requirements, and the absence of an active infection. Intubated ICU patients were compared to 80 patients requiring ICU admission before transplantation without intubation and to 126 matched non-ICU-bound patients. Patients requiring ICU care with intubation and ICU care alone had more severe postoperative complications than non-ICU-bound patients. Intubation before transplantation was associated with more postoperative pneumonias (15% in intubated ICU transplant candidates, 5% in ICU-bound but not intubated patients, and 3% in control group patients; P = 0.02). Parameters of reperfusion injury and renal function on postoperative day (POD) 2 and POD 7 were similar in all groups. Bilirubin levels were higher in the ICU plus intubation group at POD 2 and POD 7 after transplantation but were normalized in all groups within 3 months. The ICU plus intubation group versus the ICU-only group and the non-ICU group had decreased 1-, 3-, and 5-year graft survival (81% versus 84% versus 92%, 76% versus 78% versus 87%, and 71% versus 77% versus 84%, respectively; P = 0.19), but statistical significance was not reached. A Glasgow coma scale score of <7 versus >7 before transplantation was associated with high postoperative mortality in ICU-bound patients requiring intubation (38% versus 23%; P = 0.01). In conclusion, ICU admission and mechanical ventilation should not be considered contraindications for LT. With careful patient selection, acceptable long-term outcomes can be achieved despite increased postoperative complications.