Alexander P. J. Vlaar

Ventilation with lower tidal volumes as compared with conventional tidal volumes for patients without acute lung injury: a preventive randomized controlled trial

IntroductionRecent cohort studies have identified the use of large tidal volumes as a major risk factor for development of lung injury in mechanically ventilated patients without acute lung injury (ALI). We compared the effect of conventional with lower tidal volumes on pulmonary inflammation and development of lung injury in critically ill patients without ALI at the onset of mechanical ventilation.MethodsWe performed a randomized controlled nonblinded preventive trial comparing mechanical ventilation with tidal volumes of 10 ml versus 6 ml per kilogram of predicted body weight in critically ill patients without ALI at the onset of mechanical ventilation. The primary end point was cytokine levels in bronchoalveolar lavage fluid and plasma during mechanical ventilation. The secondary end point was the development of lung injury, as determined by consensus criteria for ALI, duration of mechanical ventilation, and mortality.ResultsOne hundred fifty patients (74 conventional versus 76 lower tidal volume) were enrolled and analyzed. No differences were observed in lavage fluid cytokine levels at baseline between the randomization groups. Plasma interleukin-6 (IL-6) levels decreased significantly more strongly in the lower-tidal-volume group ((from 51 (20 to 182) ng/ml to 11 (5 to 20) ng/ml versus 50 (21 to 122) ng/ml to 21 (20 to 77) ng/ml; P = 0.01)). The trial was stopped prematurely for safety reasons because the development of lung injury was higher in the conventional tidal-volume group as compared with the lower tidal-volume group (13.5% versus 2.6%; P = 0.01). Univariate analysis showed statistical relations between baseline lung-injury score, randomization group, level of positive end-expiratory pressure (PEEP), the number of transfused blood products, the presence of a risk factor for ALI, and baseline IL-6 lavage fluid levels and the development of lung injury. Multivariate analysis revealed the randomization group and the level of PEEP as independent predictors of the development of lung injury.ConclusionsMechanical ventilation with conventional tidal volumes is associated with sustained cytokine production, as measured in plasma. Our data suggest that mechanical ventilation with conventional tidal volumes contributes to the development of lung injury in patients without ALI at the onset of mechanical ventilation.Trial registrationISRCTN82533884

Transfusion-related acute lung injury: a clinical review

Three decades ago, transfusion-related acute lung injury (TRALI) was considered a rare complication of transfusion medicine. Nowadays, the US Food and Drug Administration acknowledge the syndrome as the leading cause of transfusion-related mortality. Understanding of the pathogenesis of TRALI has resulted in the design of preventive strategies from a blood-bank perspective. A major breakthrough in efforts to reduce the incidence of TRALI has been to exclude female donors of products with high plasma volume, resulting in a decrease of roughly two-thirds in incidence. However, this strategy has not completely eradicated the complication. In the past few years, research has identified patient-related risk factors for the onset of TRALI, which have empowered physicians to take an individualised approach to patients who need transfusion.

Risk factors and outcome of transfusion-related acute lung injury in the critically ill: A nested case-control study

Objectives:To determine the incidence, risk factors, and outcome of transfusion-related acute lung injury in a cohort of critically ill patients. Design:In a retrospective cohort study, patients with transfusion-related acute lung injury were identified using the consensus criteria of acute lung injury within 6 hrs after transfusion. Inclusion criterion was a length of intensive care unit admission >48 hrs. Patients developing transfusion-related acute lung injury were matched (on age, sex, and admission diagnosis) to transfused control subjects and patients developing acute lung injury from another origin. Setting:Tertiary referral hospital. Patients:All first-admitted patients from November 1, 2004, until October 1, 2007, to the intensive care unit. Interventions:None. Measurements and Main Results:Of 5208 admitted patients, 2024 patients had a length of stay >48 hrs, of whom 109 were suspected transfusion-related acute lung injury cases. Compared with transfused control subjects, risk factors for transfusion-related acute lung injury were emergency cardiac surgery (odds ratio, 17.6 [1.8–168.5]), hematologic malignancy (odds ratio, 13.1 [2.7–63.8]), massive transfusion (odds ratio, 4.5 [2.1–9.8]), sepsis (odds ratio, 2.5 [1.2–5.2]), mechanical ventilation (odds ratio, 3.0 [1.3–7.1], and high Acute Physiology and Chronic Health Evaluation II score (odds ratio, 1.1 [1.0–1.1]; p < .03 for all). The volume of platelets and plasma transfused was associated with transfusion-related acute lung injury in the univariate analysis. However, this association disappeared in the multivariate analysis. Compared with acute lung injury control subjects, risk factors for transfusion-related acute lung injury were sepsis (odds ratio, 2.4 [1.1–5.3]) and high Acute Physiology and Chronic Health Evaluation II score (odds ratio, 1.1 [1.0–1.1]), whereas pneumonia (odds ratio, 0.4 [0.2–0.7]) was a negative predictive factor. Patients with transfusion-related acute lung injury had a longer duration of mechanical ventilation compared with transfused control subjects and acute lung injury control subjects (231 [138–472] vs. 71 [46–163] and 70 [42–121] hrs, p < .001). Also, 90-day survival of patients with transfusion-related acute lung injury was lower compared with transfused control subjects and acute lung injury control subjects (53% vs. 75% and 83%, p < .02). Conclusions:Transfusion-related acute lung injury is common in critically ill patients. Transfusion-related acute lung injury may contribute to an adverse outcome associated with transfusion. This study identifies transfusion-related acute lung injury risk factors, which may aid in assessing the risks and benefits of transfusion in critically ill patients.

The incidence, risk factors and outcome of transfusion-related acute lung injury in a cohort of cardiac surgery patients: a prospective nested case control study

Transfusion-related acute lung injury (TRALI) is the leading cause of transfusion-related morbidity and mortality. Both antibodies and bioactive lipids that have accumulated during storage of blood have been implicated in TRALI pathogenesis. In a single-center, nested, case-control study, patients were prospectively observed for onset of TRALI according to the consensus definition. Of 668 patients, 16 patients (2.4%) developed TRALI. Patient-related risk factors for onset of TRALI were age and time on the cardiopulmonary bypass. Transfusion-related risk factors were total amount of blood products (odds ratio [OR] = 1.2; 95% confidence interval [CI], 1.03-1.44), number of red blood cells stored more than 14 days (OR = 1.6; 95% CI, 1.04-2.37), total amount of plasma (OR = 1.2; 95% CI, 1.03-1.44), presence of antibodies in donor plasma (OR = 8.8; 95% CI, 1.8-44), and total amount of transfused bioactive lipids (OR = 1.0; 95% CI, 1.00-1.07). When adjusted for patient risk factors, only the presence of antibodies in the associated blood products remained a risk factor for TRALI (OR = 14.2; 95% CI, 1.5-132). In-hospital mortality of TRALI was 13% compared with 0% and 3% in transfused and nontransfused patients, respectively (P < .05). In conclusion, the incidence of TRALI is high in cardiac surgery patients and associated with adverse outcome. Our results suggest that cardiac surgery patients may benefit from exclusion of blood products containing HLA/HNA antibodies.

The divergent clinical presentations of transfusion-related acute lung injury illustrated by two case reports.

Background:Transfusion of erythrocytes is associated with increased morbidity in certain patient groups. Storage time of erythrocytes may contribute to respiratory complications. Using a syngeneic in vivo transfusion model, we investigated whether transfusion of stored rat erythrocytes causes lung injury in healthy and in lipopolysaccharide-primed rats in a “two-hit” model of lung injury. Methods:Rats were infused with aged rat erythrocytes (14 days of storage) and washed aged erythrocytes or supernatant of aged erythrocytes. Controls received fresh rat erythrocytes (0 days of storage) or saline. In the “two-hit” model of lung injury, lipopolysaccharide was used as a “first hit” before transfusion. Rat and control human erythrocyte products were analyzed for lysophosphatidylcholine accumulation. Results:In healthy rats, transfusion of aged erythrocytes caused mild pulmonary inflammation but no coagulopathy. In lipopolysaccharide-pretreated rats, transfusion of aged erythrocytes augmented lung injury by inducing coagulopathy, both in the pulmonary and systemic compartment, when compared with transfusion with fresh erythrocytes. When transfused separately, supernatant of aged erythrocytes, but not washed aged erythrocytes, mediated coagulopathy in the “two-hit” model. Analysis of the supernatant of aged erythrocytes (rat and human) showed no lysophosphatidylcholine accumulation. Conclusions:Transfusion of aged erythrocytes induces lung injury in healthy rats. In a “two-hit” model, injury induced by aged erythrocytes was characterized by coagulopathy and was abrogated by washing. Washing of aged erythrocytes may decrease pulmonary complications in patients with an inflammatory condition who are exposed to a blood transfusion.

Ventilator-induced lung injury is mediated by the NLRP3 inflammasome

Background: The innate immune response is important in ventilator-induced lung injury (VILI) but the exact pathways involved are not elucidated. The authors studied the role of the intracellular danger sensor NLRP3 inflammasome. Methods: NLRP3 inflammasome gene expression was analyzed in respiratory epithelial cells and alveolar macrophages obtained from ventilated patients (n = 40). In addition, wild-type and NLRP3 inflammasome deficient mice were randomized to low tidal volume (approximately 7.5 ml/kg) and high tidal volume (approximately 15 ml/kg) ventilation. The presence of uric acid in lung lavage, activation of caspase-1, and NLRP3 inflammasome gene expression in lung tissue were investigated. Moreover, mice were pretreated with interleukin-1 receptor antagonist, glibenclamide, or vehicle before start of mechanical ventilation. VILI endpoints were relative lung weights, total protein in lavage fluid, neutrophil influx, and pulmonary and systemic cytokine and chemokine concentrations. Data represent mean ± SD. Results: Mechanical ventilation up-regulated messenger RNA expression levels of NLRP3 in alveolar macrophages (1.0 ± 0 vs. 1.70 ± 1.65, P less than 0.05). In mice, mechanical ventilation increased both NLRP3 and apoptosis-associated speck-like protein messenger RNA levels, respectively (1.08 ± 0.55 vs. 3.98 ± 2.89; P less than 0.001 and 0.95 ± 0.53 vs. 6.0 ± 3.55; P less than 0.001), activated caspase-1, and increased uric acid levels (6.36 ± 1.85 vs. 41.9 ± 32.0, P less than 0.001). NLRP3 inflammasome deficient mice displayed less VILI due to high tidal volume mechanical ventilation compared with wild-type mice. Furthermore, treatment with interleukin-1 receptor antagonist or glibenclamide reduced VILI. Conclusions: Mechanical ventilation induced a NLRP3 inflammasome dependent pulmonary inflammatory response. NLRP3 inflammasome deficiency partially protected mice from VILI.

Transfusion-related acute lung injury in cardiac surgery patients is characterized by pulmonary inflammation and coagulopathy: a prospective nested case-control study.

Objective: Transfusion-related acute lung injury is the leading cause of transfusion-related morbidity and mortality. Clinical data on the pathogenesis of transfusion-related acute lung injury are sparse. The objective of the present study was to determine inflammation and coagulation pathways involved in the onset of transfusion-related acute lung injury. Design: Nested case-control study. Setting: Operating theatre and intensive care department of a tertiary referral hospital. Patients: Elective cardiac surgery patients requiring postsurgery intensive care admission. Interventions: None. Measurements: Cardiac surgery patients (n = 668) were prospectively screened for the onset of transfusion-related acute lung injury. Transfusion-related acute lung injury cases (n = 16) were randomly assigned to transfused and nontransfused cardiac surgery controls in a 1:2 ratio. Blood samples were taken pre- and postoperatively and at onset of transfusion-related acute lung injury. In addition, at onset of transfusion-related acute lung injury, bronchoalveolar lavage fluid was obtained. In plasma and bronchoalveolar lavage fluid, levels of interleukin-6, interleukin-8, elastase-&agr;(1)-antitrypsin complexes, thrombin–antithrombin complexes, plasminogen activator activity, and plasminogen activator inhibitor-1 were determined by means of enzyme-linked immunosorbent assay. Main Results: In all patients, cardiac surgery was associated with systemic inflammation, evidenced by an increase in plasma levels of interleukin-6, interleukin-8, and elastase-&agr;(1)-antitrypsin complexes compared with presurgery levels (p < .001). Prior to onset of transfusion-related acute lung injury, systemic interleukin-8 and interleukin-6 levels were higher compared with nontransfused controls (p < .01). In transfusion-related acute lung injury cases, bronchoalveolar lavage fluid levels of interleukin-8, interleukin-6, and elastase-&agr;(1)-antitrypsin complexes were elevated compared with control groups (p < .05). Both plasma and bronchoalveolar lavage fluid levels of thrombin–antithrombin complexes were enhanced in transfusion-related acute lung injury cases compared with control groups (p < .01). Bronchoalveolar lavage fluid levels of plasminogen activator activity were decreased due to an increase in plasminogen activator inhibitor-1 levels in transfusion-related acute lung injury cases compared with control groups (p < .01), indicating suppressed fibrinolysis. Conclusions: Prior to onset of transfusion-related acute lung injury, there is systemic inflammation and neutrophil sequestration. Transfusion-related acute lung injury is characterized by both systemic and pulmonary inflammation and activation of neutrophils, as well as enhanced coagulation and suppressed fibrinolysis.

TRANSFUSION-RELATED RISK OF SECONDARY BACTERIAL INFECTIONS IN SEPSIS PATIENTS: A RETROSPECTIVE COHORT STUDY

There is a need for insight into factors that contribute to late mortality of sepsis patients. Immunomodulatory effects have been ascribed to blood transfusion. This retrospective cohort study investigates the association between the development of nosocomial bacterial infection and transfusion of leukodepleted red blood cells (RBCs) or platelets (PLTs) in survivors of the initial phase of sepsis. Patients diagnosed with sepsis after admission to the intensive care unit of a tertiary referral hospital were included. Of 134 patients with sepsis, 67 received a blood transfusion (50%). A secondary infection developed in 19 patients (14%). A multiple logistic regression model revealed that the use of immunosuppressive medication with an odds ratio (OR) of 1.17 (95% confidence interval [CI], 1.04-1.31), but not Acute Physiology and Chronic Health Evaluation II score, malignancy, HIV infection, alcohol abuse, or diabetes mellitus, was a risk factor for nosocomial infection. In an adjusted model, the amount of transfused RBCs was associated with secondary infection with an OR of 1.18 (95% CI, 1.01-1.37). Storage time of RBCs was a relevant confounder of the effect of the amount of RBCs on infection, with an adjusted OR of 1.25 (95% CI, 1.04-1.51), P = 0.02. Also, the amount of transfused PLTs was associated with secondary infection, with an OR of 1.36 (95% CI, 1.05-1.78). In conclusion, transfusion of RBCs and PLTs is associated with the onset of secondary bacterial infection in sepsis patients. Storage time of RBCs influences this increased risk. These findings suggest that immunomodulatory effects of blood transfusion contribute to adverse outcome in the convalescent phase of sepsis.

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.

A survey of physicians' reasons to transfuse plasma and platelets in the critically ill: a prospective single-centre cohort study

Data on the rationality of transfusion practice of fresh frozen plasma (FFP) and platelets in the critically ill are sparse and may contribute to efforts to reduce transfusion rates. To provide insight into determinants of the decision of intensive care unit (ICU)‐physicians to transfuse, a survey study was performed. The reasons of ICU‐physicians to transfuse FFP and platelets were determined during a 10‐week period. Transfusion triggers were assessed, as well as correction of prolonged coagulation test results. Of 310 admissions, 44 patients (14%) received a transfusion of FFP and 35 patients (11%) received a platelet transfusion. In 67% patients, FFPs were transfused in bleeding patients and in 33% in non‐bleeding patients. FFP was transfused at a prothrombin time (PT) of 19 s (17–22). After FFP transfusion, PT levels of 15–18, 18–20 and 20–26 s decreased with a median of 0.7, 1.9 and 3.5 s, respectively. On average, 3.2 FFP units were ordered, of which 28% was not transfused. The major reason to transfuse platelets was bleeding. Platelets were transfused at a platelet count of 95 (36–116) × 109 L−1 in bleeding and 13 (10–18) × 109 L−1 in non‐bleeding patients. On average, 1.4 platelet units were ordered, of which 20% was not transfused. The agreement between physicians reporting a major bleeding and a definition of bleeding was poor (κ < 0.10 for FFP and 0.20 for platelets). In conclusion, one‐third of FFP transfusions was given to non‐bleeding patients. FFP transfusion failed to normalize prolonged coagulation test results in the majority of the patients. Transfusion of platelets was restrictive in non‐bleeding patients and liberal in bleeding patients. Education on indications of FFP transfusion and improved identification of bleeding may reduce transfusion rates.