Jorrit J. Hofstra

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 incidence of low venous oxygen saturation on admission to the intensive care unit: a multi-center observational study in The Netherlands

BackgroundLow mixed or central venous saturation (S(c)vO2) can reveal global tissue hypoxia and therefore can predict poor prognosis in critically ill patients. Early goal directed therapy (EGDT), aiming at an ScvO2 ≥ 70%, has been shown to be a valuable strategy in patients with sepsis or septic shock and is incorporated in the Surviving Sepsis Campaign guidelines.MethodsIn this prospective observational multi-center study, we determined central venous pressure (CVP), hematocrit, pH, lactate and ScvO2 or SvO2 in a heterogeneous group of critically ill patients early after admission to the intensive care units (ICUs) in three Dutch hospitals.ResultsData of 340 acutely admitted critically ill patients were collected. The mean SvO2 value was > 65% and the mean ScvO2 value was > 70%. With mean CVP of 10.3 ± 5.5 mmHg, lactate plasma levels of 3.6 ± 3.6 and acute physiology, age and chronic health evaluation (APACHE II) scores of 21.5 ± 8.3, the in-hospital mortality of the total heterogeneous population was 32.0%. A subgroup of septic patients (n = 125) showed a CVP of 9.8 ± 5.4 mmHg, mean ScvO2 values of 74.0 ± 10.2%, where only 1% in this subgroup revealed a ScvO2 value < 50%, and lactate plasma levels of 2.7 ± 2.2 mmol/l with APACHE II scores 20.9 ± 7.3. Hospital mortality of this subgroup was 26%.ConclusionThe incidence of low ScvO2 values for acutely admitted critically ill patients is low in Dutch ICUs. This is especially true for patients with sepsis/septic shock.

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.

Nebulized antithrombin limits bacterial outgrowth and lung injury in Streptococcus pneumoniae pneumonia in rats.

IntroductionDisturbed alveolar fibrin turnover is a cardinal feature of severe pneumonia. Clinical studies suggest that natural inhibitors of coagulation exert lung-protective effects via anticoagulant and possibly also anti-inflammatory pathways. Intravenous infusion of the natural anticoagulants increases the risk of bleeding. Local administration may allow for higher treatment dosages and increased local efficacy while at the same time reducing the risk of bleeding. We evaluated the effect of nebulized anticoagulants on pulmonary coagulopathy and inflammation in a rat model of Streptococcus pneumoniae pneumonia.MethodsIn this randomized controlled in vivo laboratory study rats were challenged intratracheally with S. pneumoniae, inducing pneumonia, and randomized to treatment with normal saline (placebo), recombinant human activated protein C (rh-APC), plasma-derived antithrombin (AT), heparin or danaparoid, by means of nebulization.ResultsS. pneumoniae infection increased pulmonary levels of thrombin-antithrombin complexes and fibrin degradation products. All nebulized anticoagulants significantly limited pulmonary coagulopathy. None of the agents except danaparoid resulted in changes in systemic coagulopathy. Treatment with plasma-derived AT reduced outgrowth of S. pneumoniae and histopathologic damage in lungs. In vitro experiments confirmed outgrowth was reduced in bronchoalveolar lavage fluid (BALF) from rats treated with plasma-derived AT compared with placebo. Neutralizing of cationic components in BALF diminished the inhibitory effects on bacterial outgrowth of BALF, suggesting a role for cationic antimicrobial proteins.ConclusionsNebulization of anticoagulants attenuates pulmonary coagulopathy during S. pneumoniae pneumonia in rats while only danaparoid affects systemic coagulation. Nebulized plasma-derived AT reduces bacterial outgrowth and exerts significant lung-protective effects.

The effect of blood transfusion on pulmonary permeability in cardiac surgery patients: a prospective multicenter cohort study

BACKGROUND: There is an association between blood transfusion and pulmonary complications in cardiac surgery. Mediators of increased pulmonary vascular leakage after transfusion are unknown. We hypothesized that factors may include antibodies or bioactive lipids, which have been implicated in transfusion‐related acute lung injury.

Pulmonary activation of coagulation and inhibition of fibrinolysis after burn injuries and inhalation trauma

BACKGROUND Pulmonary coagulopathy is intrinsic to pneumonia and other forms of acute lung injury. We hypothesized patients with burn injuries and inhalation trauma to have similar alterations in pulmonary coagulation and fibrinolysis. METHODS We performed a prospective study on changes in pulmonary and systemic thrombin generation and fibrinolytic activity in patients with burn injuries and inhalation trauma requiring mechanical ventilation. Nondirected bronchial lavage was performed on alternate days. Patients requiring mechanical ventilation for nonpulmonary reasons who did not meet the North American European Consensus Conference criteria for acute lung injury functioned as control patients. RESULTS We studied 13 patients with burn injuries and inhalation trauma and 15 control patients. On admission, patients with burn injuries and inhalation trauma showed a significant increase in thrombin generation in the airways compared with control patients, as reflected by increased lavage fluid levels of thrombin-antithrombin complexes and fibrin degradation products, and decreased lavage fluid levels of activated protein C and antithrombin. Simultaneously, burn patients showed a significant decrease in fibrinolytic activity, as reflected by decreased lavage fluid levels of plasminogen activator activity. Pulmonary coagulopathy persisted throughout the period of mechanical ventilation and was accompanied by similar changes in systemic coagulation and fibrinolysis. There was no significant correlation between changes in coagulation and fibrinolysis and the extent of burn injury. CONCLUSIONS Patients with burn injuries and inhalation trauma requiring mechanical ventilation show a distinct and sustained procoagulant and antifibrinolytic shift in the pulmonary compartment. Pulmonary coagulopathy could be an important therapeutic target in these patients.

Nebulized anticoagulants limit pulmonary coagulopathy, but not inflammation, in a model of experimental lung injury.

BACKGROUND Pulmonary coagulopathy may contribute to an adverse outcome in lung injury. We assessed the effects of local anticoagulant therapy on bronchoalveolar and systemic haemostasis in a rat model of endotoxemia-induced lung injury. METHODS Male Sprague-Dawley rats were intravenously challenged with lipopolysaccharide (LPS) and treated with nebulized normal saline (placebo), recombinant human-activated protein C (APC), plasma-derived antithrombin (AT), heparin, or danaparoid. RESULTS Intravenous administration of LPS resulted in lung injury associated with elevated bronchoalveolar levels of thrombin-antithrombin complex (TATc), 6.9 +/- 0.8 ng/mL (placebo) versus 0.5 +/- 0.2 ng/mL (healthy control) (p < 0.01), and elevated bronchoalveolar levels of fibrin degradation products (FDP), 555 +/- 74 ng/mL versus 27 +/- 12 ng/mL (p < 0.01). Nebulized APC, AT, and danaparoid all significantly limited the rise of bronchoalveolar levels of TATc, 2.4 +/- 0.7 ng/mL), 1.5 +/- 0.2, 3.8 +/- 0.7, and 3.2 +/- 0.9 ng/mL, respectively (all p < 0.01 vs. placebo), and fibrin degradation products, 243 +/- 77, 113 +/- 20, 317 +/- 74, and 300 +/- 42 ng/mL (all p < 0.01 vs. placebo). Heparin and danaparoid also significantly affected systemic coagulopathy. However, pulmonary inflammatory responses [neutrophil influx into the lungs, bronchoalveolar levels of myeloperoxidase, and bronchoalveolar levels of tumor necrosis factor (TNF), interleukin (IL)-6 and CINC-3], and histopathology of lungs were not affected by nebulization of anticoagulants. CONCLUSIONS In conclusion, local treatment with APC, AT, heparin, or danaparoid attenuate pulmonary coagulopathy, but not inflammation, in rats with endotoxemia-induced lung injury.

Soluble urokinase-type plasminogen activator receptor levels in patients with burn injuries and inhalation trauma requiring mechanical ventilation: an observational cohort study

IntroductionSoluble urokinase-type plasminogen activator receptor (suPAR) has been proposed as a biologic marker of fibrinolysis and inflammation. The aim of this study was to investigate the diagnostic and prognostic value of systemic and pulmonary levels of suPAR in burn patients with inhalation trauma who need mechanical ventilation.MethodssuPAR was measured in plasma and nondirected lung-lavage fluid of mechanically ventilated burn patients with inhalation trauma. The samples were obtained on the day of inhalation trauma and on alternate days thereafter until patients were completely weaned from the mechanical ventilator. Mechanically ventilated patients without burns and without pulmonary disease served as controls.ResultsSystemic levels of suPAR in burn patients with inhalation trauma were not different from those in control patients. On admission and follow up, pulmonary levels of suPAR in patients with inhalation trauma were significantly higher compared with controls. Pulmonary levels of suPAR highly correlated with pulmonary levels of interleukin 6, a marker of inflammation, and thrombin-antithrombin complexes, markers of coagulation, but not plasminogen activator activity, a marker of fibrinolysis. Systemic levels of suPAR were predictive of the duration of mechanical ventilation and length of intensive care unit (ICU) stay. Duration of mechanical ventilation and length of ICU stay were significantly longer in burn-injury patients with systemic suPAR levels > 9.5 ng/ml.ConclusionsPulmonary levels of suPAR are elevated in burn patients with inhalation trauma, and they correlate with pulmonary inflammation and coagulation. Although pulmonary levels of suPAR may have diagnostic value in burn-injury patients, systemic levels of suPAR have prognostic value.

In the critically ill patient, diabetes predicts mortality independent of statin therapy but is not associated with acute lung injury: a cohort study

Objectives:Patients with diabetes mellitus form 23%–30% of published cohorts of critically ill patients. Conflicting published evidence links diabetes mellitus to both higher and lower mortality. Other cohort studies suggest that diabetes mellitus protects against acute lung injury. We hypothesized that diabetes mellitus is an independent risk factor for mortality. We further hypothesized that diabetes mellitus is a risk factor for cardiac overload and not for acute lung injury. Design:Retrospective cohort study. Setting:The intensive care unit of a tertiary referral hospital. Patients:From November 1, 2004, to October 1, 2007, a cohort of patients admitted ≥48 hrs to the intensive care unit. Interventions:None. Measurements and Main Results:Of 2,013 patients, 317 had diabetes mellitus. Ninety-day mortality was higher in the diabetes mellitus patients compared to patients without diabetes mellitus (hazard ratio 1.53, 95% confidence interval 1.29–1.80). This association strengthened after adjusting for confounders and for medication (hazard ratio 1.53, 95% confidence interval 1.07–2.17).We found no association between diabetes mellitus and acute lung injury (relative risk ratio 1.01, 95% confidence interval 0.78–1.32; adjusted relative risk ratio 0.99, 95% confidence interval 0.75–1.31), but diabetes mellitus was a risk factor for cardiac overload (relative risk ratio 1.91, 95% confidence interval 1.30–2.81; adjusted relative risk ratio 1.45, 95% confidence interval 0.97–2.18). Statins were associated with both a reduced risk of mortality (hazard ratio 0.74, 95% confidence interval 0.63–0.87; adjusted hazard ratio 0.53, 95% confidence interval 0.44–0.64) and a decreased risk of developing acute lung injury (relative risk ratio 0.71, 95% confidence interval 0.56–0.89; adjusted relative risk ratio 0.61, 95% confidence interval 0.47–0.79). Conclusions:Diabetes mellitus is an independent risk factor for mortality in critically ill patients and failure to adjust for statins underestimates the size of this association. Diabetes mellitus is not associated with acute lung injury but is associated with cardiac overload. A diagnosis of cardiac overload excludes a diagnosis of acute lung injury. Investigators who do not account for cardiac overload as a competing alternative outcome may therefore falsely conclude that diabetes mellitus protects from acute lung injury.