Pieter R. Tuinman

Blood transfusion during cardiac surgery is associated with inflammation and coagulation in the lung: a case control study

IntroductionBlood transfusion is associated with increased morbidity and mortality in cardiac surgery patients, but cause-and-effect relations remain unknown. We hypothesized that blood transfusion is associated with changes in pulmonary and systemic inflammation and coagulation occurring in patients who do not meet the clinical diagnosis of transfusion-related acute lung injury (TRALI).MethodsWe performed a case control study in a mixed medical-surgical intensive care unit of a university hospital in the Netherlands. Cardiac surgery patients (n = 45) were grouped as follows: those who received no transfusion, those who received a restrictive transfusion (one two units of blood) or those who received multiple transfusions (at least five units of blood). Nondirected bronchoalveolar lavage fluid (BALF) and blood were obtained within 3 hours postoperatively. Normal distributed data were analyzed using analysis of variance and Dunnetts post hoc test. Nonparametric data were analyzed using the Kruskal-Wallis and Mann-Whitney U tests.ResultsRestrictive transfusion increased BALF levels of interleukin (IL)-1β and D-dimer compared to nontransfused controls (P < 0.05 for all), and IL-1β levels were further enhanced by multiple transfusions (P < 0.01). BALF levels of IL-8, tumor necrosis factor α (TNFα) and thrombin-antithrombin complex (TATc) were increased after multiple transfusions (P < 0.01, P < 0.001 and P < 0.01, respectively) compared to nontransfused controls, but not after restrictive transfusions. Restrictive transfusions were associated with increased pulmonary levels of plasminogen activator inhibitor 1 compared to nontransfused controls with a further increase after multiple transfusions (P < 0.001). Concomitantly, levels of plasminogen activator activity (PAA%) were lower (P < 0.001), indicating impaired fibrinolysis. In the systemic compartment, transfusion was associated with a significant increase in levels of TNFα, TATc and PAA% (P < 0.05).ConclusionsTransfusion during cardiac surgery is associated with activation of inflammation and coagulation in the pulmonary compartment of patients who do not meet TRALI criteria, an effect that was partly dose-dependent, suggesting transfusion as a mediator of acute lung injury. These pulmonary changes were accompanied by systemic derangement of coagulation.

Nebulized anticoagulants for acute lung injury - a systematic review of preclinical and clinical investigations

BackgroundData from interventional trials of systemic anticoagulation for sepsis inconsistently suggest beneficial effects in case of acute lung injury (ALI). Severe systemic bleeding due to anticoagulation may have offset the possible positive effects. Nebulization of anticoagulants may allow for improved local biological availability and as such may improve efficacy in the lungs and lower the risk of systemic bleeding complications.MethodWe performed a systematic review of preclinical studies and clinical trials investigating the efficacy and safety of nebulized anticoagulants in the setting of lung injury in animals and ALI in humans.ResultsThe efficacy of nebulized activated protein C, antithrombin, heparin and danaparoid has been tested in diverse animal models of direct (for example, pneumonia-, intra-pulmonary lipopolysaccharide (LPS)-, and smoke inhalation-induced lung injury) and indirect lung injury (for example, intravenous LPS- and trauma-induced lung injury). Nebulized anticoagulants were found to have the potential to attenuate pulmonary coagulopathy and frequently also inflammation. Notably, nebulized danaparoid and heparin but not activated protein C and antithrombin, were found to have an effect on systemic coagulation. Clinical trials of nebulized anticoagulants are very limited. Nebulized heparin was found to improve survival of patients with smoke inhalation-induced ALI. In a trial of critically ill patients who needed mechanical ventilation for longer than two days, nebulized heparin was associated with a higher number of ventilator-free days. In line with results from preclinical studies, nebulization of heparin was found to have an effect on systemic coagulation, but without causing systemic bleedings.ConclusionLocal anticoagulant therapy through nebulization of anticoagulants attenuates pulmonary coagulopathy and frequently also inflammation in preclinical studies of lung injury. Recent human trials suggest nebulized heparin for ALI to be beneficial and safe, but data are very limited.

Recombinant human activated protein C in the treatment of acute respiratory distress syndrome : A randomized clinical trial

Rationale Pulmonary coagulopathy may play a pathogenetic role in acute respiratory distress syndrome (ARDS), by contributing to alveolocapillary inflammation and increased permeability. Recombinant human activated protein C (rh-APC) may inhibit this process and thereby improve patient outcome. Methods A prospective randomized, saline-controlled, single-blinded clinical trial was performed in the intensive care units of two university hospitals, and patients with ARDS were included within 24 h after meeting inclusion criteria. Intervention A 4-day course of intravenous rh-APC (24 mcg/kg/h) (n = 33) versus saline (n = 38). Outcomes The primary outcome parameter was the pulmonary leak index (PLI) of 67Gallium-transferrin as a measure of alveolocapillary permeability and secondary outcomes were disease severity scores and ventilator-free days, among others. Results Baseline characteristics were similar; in 87% of patients the PLI was above normal and in 90% mechanical or non-invasive ventilation was instituted at a median lung injury score of 2.5. There was no evidence that Rh-APC treatment affected the PLI or attenuated lung injury and sequential organ failure assessment scores. Mean ventilator-free days amounted to 14 (rh-APC) and 12 days (saline, P = 0.35). 28-day mortality was 6% in rh-APC- and 18% in saline-treated patients (P = 0.12). There was no difference in bleeding events. The study was prematurely discontinued because rh-APC was withdrawn from the market. Conclusion There is no evidence that treatment with intravenous rh-APC during 4 days for infectious or inflammatory ARDS ameliorates increased alveolocapillary permeability or the clinical course of ARDS patients. We cannot exclude underpowering. Trial Registration Nederlands Trial Register ISRCTN 52566874

High-dose acetylsalicylic acid is superior to low-dose as well as to clopidogrel in preventing lipopolysaccharide-induced lung injury in mice.

Background Use of aspirin (acetylsalicylic acid [ASA]) was found to improve outcome in animal models of acute lung injury (ALI) or its more severe form, acute respiratory distress syndrome. In patients with acute respiratory distress syndrome, data indicating a protective effect of ASA are less convincing. We hypothesize that ASA in a high dose is superior to low-dose ASA in preventing lung injury. Also, the effect on lung injury of inhibiting platelet activation by clopidogrel was investigated. Methods Acute lung injury was induced by intranasal instillation of 10 &mgr;g lipopolysaccharide (LPS). Before LPS, BALB/c mice were pretreated with either high dose of ASA (100 &mgr;g/g intraperitoneally, low-dose ASA (12.5 &mgr;g/g i.p), clopidogrel (50 &mgr;g/g i.p), or clopidogrel in combination with low dose of ASA. Controls received vehicle or LPS without intervention. Five hours after LPS, bronchoalveolar lavage fluid (BALF) and plasma were obtained. Measurements and Main Results All treatment regimens reduced neutrophil influx in the BALF compared with LPS controls (high-dose ASA 75% ± 2% [mean ± SD], low-dose ASA 86% ± 3%, clopidogrel 82% ± 1%, and low-dose ASA–clopidogrel 82% ± 3% vs. LPS control 88% ± 2%; P ⩽ 0.05). High-dose ASA reduced BALF levels of protein compared with LPS controls (median [interquartile range], 0.2 [15] vs. 75 [20] pg/mL; P < 0.01), to a greater extent than after low-dose ASA (48 [32] pg/mL), clopidogrel (37 [23] pg/mL), or low-dose ASA–clopidogrel (57 [8] pg/mL). Conclusions High-dose ASA is superior to low-dose ASA, clopidogrel, and to a combination of clopidogrel and low-dose ASA in attenuating LPS-induced lung injury in mice, suggesting high-dose ASA to be the antiplatelet therapy of choice in further research on preventing ALI.

Methylprednisolone fails to attenuate lung injury in a mouse model of transfusion related acute lung injury

Transfusion‐related acute lung injury (TRALI) is the leading cause of transfusion‐related morbidity and mortality. Anecdotally, TRALI patients have been treated with corticosteroids. However, evidence for its therapeutic rationale in TRALI is lacking. We determined the effects of corticosteroids on lung injury in a “two‐hit” mouse model of antibody‐mediated TRALI.

Contribution of damage-associated molecular patterns to transfusion-related acute lung injury in cardiac surgery.

BACKGROUND The incidence of transfusion-related acute lung injury (TRALI) in cardiac surgery patients is high and this condition contributes to an adverse outcome. Damage-associated molecular pattern (DAMP) molecules, HMGB1 and S100A12, are thought to mediate inflammatory changes in acute respiratory distress syndrome. We aimed to determine whether DAMP are involved in the pathogenesis of TRALI in cardiac surgery patients. MATERIALS AND METHODS This was a secondary analysis of a prospective observational trial in cardiac surgery patients admitted to the Intensive Care Unit of a university hospital in the Netherlands. Fourteen TRALI cases were randomly matched with 32 transfused and non-transfused controls. Pulmonary levels of HMGB1, S100A12 and inflammatory cytokines (interleukins-1β, -6, and -8 and tumour necrosis factor-α) were determined when TRALI evolved. In addition, systemic and pulmonary levels of soluble receptor for advanced glycation end products (sRAGE) were determined. RESULTS HMGB1 expression and levels of sRAGE in TRALI patients did not differ from those in controls. There was a trend towards higher S100A12 levels in TRALI patients compared to the controls. Furthermore, S100A12 levels were associated with increased levels of markers of pulmonary inflammation, prolonged cardiopulmonary bypass, hypoxemia and duration of mechanical ventilation. CONCLUSION No evidence was found that HMGB1 and sRAGE contribute to the development of TRALI. S100A12 is associated with duration of cardiopulmonary bypass, pulmonary inflammation, hypoxia and prolonged mechanical ventilation and may contribute to acute lung injury in cardiac surgery patients.

Coagulopathy as a Therapeutic Target for TRALI: Rationale and Possible Sites of Action

Transfusion-related acute lung injury (TRALI) is a subcategory of acute lung injury (ALI). As such, there are many similarities between the syndromes, both clinically and pathophysiologically. Pulmonary changes in fibrin turnover have emerged as a hallmark of ALI, thereby initiating studies investigating the potential of therapeutic interventions aimed at ameliorating this so-called pulmonary coagulopathy. Enhanced coagulation and impaired fibrinolysis are probably also important features of TRALI. In particular, platelets play an important role in mediating injury during a TRALI reaction. In this narrative review, the evidence of the role of coagulopathy and platelet activation in TRALI is discussed. Given that host risk factors for acquiring TRALI have been identified and that there is a time frame in which a preventive strategy in patients at risk for TRALI can be executed, preventive strategies are suggested. In this review, we discuss potential preventive anticoagulant interventions.

Soluble CD40 ligand, a mediator of sepsis or of transfusion-related adverse effects?

Dr Lorente and colleagues [1] report on the interesting association between serum soluble CD40 ligand (sCD40L) levels and mortality in patients with sepsis. Some variables that can influence outcome in sepsis were accounted for in their analysis. However, the amount of transfused blood products, which may influence levels of sCD40L, was not reported. sCD40L accumulates to biologically relevant levels during storage of blood products [2,3], in particular of platelet products. Following transfusion, blood products can induce an inflammatory reaction - by activating CD40-positive cells - associated with the occurrence of acute lung injury and other potential serious complications [3]. Levels of sCD40L were also found to be elevated in patients with lung injury following transfusion [2]. Even more, transfusion itself contributes to mortality in the critically ill [4], as well as to adverse outcome of sepsis [5]. Taken together, we suggest that blood transfusion could have potentially influenced both serum sCD40L levels and outcome in the study performed by Lorente and colleagues. The authors state that modulation of sCD40L levels could represent a therapeutic target. Would it not be more appropriate to question whether sCD40L from (stored) blood products contributed to elevated serum levels in their trial, before embarking on therapeutic interventions?

Renal resistive index as an early predictor and discriminator of acute kidney injury in critically ill patients; A prospective observational cohort study

Background Acute kidney injury (AKI) complicates shock. Diagnosis is based on rising creatinine, a late phenomenon. Intrarenal vasoconstriction occurs earlier. Measuring flow resistance in the renal circulation, Renal Resistive Index (RRI), could become part of vital organ function assessment using Doppler ultrasound. Our aim was to determine whether RRI on ICU admission is an early predictor and discriminator of AKI developed within the first week. Methods In this prospective cohort of mixed ICU patients with and without shock, RRI was measured <24-h of admission. Besides routine variables, sublingual microcirculation and bioelectrical impedance were measured. AKI was defined by the Kidney Disease Improving Global Outcomes criteria. Uni- and multivariate regression and Receiver Operating Characteristics curve analyses were performed. Results Ninety-nine patients were included, median age 67 years (IQR 59–75), APACHE III score 67 (IQR 53–89). Forty-nine patients (49%) developed AKI within the first week. AKI patients had a higher RRI on admission than those without: 0.71 (0.69–0.73) vs. 0.65 (0.63–0.68), p = 0.001. The difference was significant for AKI stage 2: RRI = 0.72 (0.65–0.80) and 3: RRI = 0.74 (0.67–0.81), but not for AKI stage 1: RRI = 0.67 (0.61–0.74). On univariate analysis, RRI significantly predicted AKI 2–3: OR 1.012 (1.006–1.019); Area Under the Curve (AUC) of RRI for AKI 2–3 was 0.72 (0.61–0.83), optimal cut-off 0.74, sensitivity 53% and specificity 87%. On multivariate analysis, RRI remained significant, independent of APACHE III and fluid balance; adjusted OR: 1.008 (1.000–1.016). Conclusions High RRI on ICU admission was a significant predictor for development of AKI stage 2–3 during the first week. High RRI can be used as an early warning signal RRI, because of its high specificity. A combined score including RRI, APACHE III and fluid balance improved AKI prediction, suggesting that vasoconstriction or poor vascular compliance, severity of disease and positive fluid balance independently contribute to AKI development. Trial registration ClinicalTrials.gov NCT02558166.

Antiplatelet Therapy in Bleeding Trauma Patients: Tales of the Unexpected

Critical Care Medicine www.ccmjournal.org e187 To the Editor: We read with interest the results from the study of Harr et al (1), which reports on the association between preinjury antiplatelet therapy (APT) and a decreased risk of lung dysfunction and multiple organ failure in severely injured blunt trauma patients who received blood transfusions. These results are in line with evidence from preclinical studies on the role of platelets in lung injury, and we acknowledge the authors for their effort to further explore the role of APT in inflammatory states and transfusion in a clinical setting. A potential recommendation arising from the results of this trial may be to expose bleeding trauma patients to APT. Given the potential of worsening bleeding from APT, associations should be interpreted with caution. We would like to raise some uncertainties in the presentation of the model. The purpose of the logistic regression model used was to quantify the net relationship of APT with lung injury and multiple organ failure and mortality as dependent variables. In the results, we read: “after the adjustment for possible confounders, we identified a significant interaction between blood transfusion and APT,” suggesting that interaction is investigated after adjustment for possible confounders (1). However, interaction must be assessed before assessment of confounding. If a covariate contributes to effect modification as shown by the significance of the interaction term, it cannot also be used as a confounder. If significant interaction is found, an adjustment for confounding for that same variable is inappropriate (2). Furthermore, results are drawn from a secondary cohort analysis, which carries a considerable risk of confounders not accounted for. Of these, we would like to address transfusion practice. No description of the transfusion protocols in the different centers was given. There are many possible confounders related to transfusion, including use of packed RBCs versus leukocyte-reduced RBCs, age of blood products, the ratio of transfused blood products, and the use of tranexamic acid (3–5). Most likely of all transfusion-related confounders, platelet transfusion may supposedly influence the effect of APT on outcome. Thereby, we would like to suggest that analysis of the predictive than others in relation to clinical outcomes. However, all five methods (1, 2) of measuring cell-free hemoglobin described in patients with sepsis have shown significant associations with poor clinical outcomes, adding strength to the argument that this association is real rather than an effect of measurement technique. More importantly, cell-free hemoglobin was consistently detectable in the majority of patients with sepsis, a finding that had not been previously described in sepsis. Our use of the Hemocue device (HemoCue, Angelholm, Sweeden) for measurement of cell-free hemoglobin is in no way an endorsement of this method but does provide evidence that a point-of-care device that can produce results within seconds may be useful in future clinical trials in patients with sepsis that require rapid determination of cell-free hemoglobin levels. Hartmann and de Groot’s summary of our current knowledge of the role of cell-free hemoglobin in the pathophysiology of sepsis points out the large gaps in the understanding of this topic. Specifically, neither our analysis (2) nor past analyses (1) of patients with sepsis have been able to delineate a potential mechanism for the associated increase in mortality. Although studies of free hemoproteins in animals and nonseptic humans suggest that acute kidney injury due to lipid peroxidation (3), nitric oxide consumption, and vasoconstriction (4) are potential mechanisms, our study did not show an association of cellfree hemoglobin with acute kidney injury. In addition, more detailed mechanistic studies are needed to determine why hemoglobin is released from red cells in sepsis and what role endogenous scavengers of cell-free hemoglobin, such as haptoglobin, play in the development of poor outcomes. Finally, looking ahead, it is important to remember that the pathophysiologic mechanisms underlying disease associated with cell-free hemoglobin are many, and a variety of potential therapeutic scavengers and inhibitors of cell-free hemoglobin are available. Therefore, future studies may need to involve multiple interventions, perhaps through factorial designs, to better elucidate the most important mechanisms and parsimonious therapeutic options. Acetaminophen, haptoglobin, hemopexin, and albumin are all potential therapeutic options for study and also may provide impetus for reanalysis of past studies that have shown potential protective effects of these hemoprotein scavengers and inhibitors in patients with sepsis (5). Drs. Janz and Ware received funding support from the National Institutes of Health.