Thelma Craig

Simvastatin decreases lipopolysaccharide-induced pulmonary inflammation in healthy volunteers.

RATIONALE Simvastatin inhibits inflammatory responses in vitro and in murine models of lung inflammation in vivo. As simvastatin modulates a number of the underlying processes described in acute lung injury (ALI), it may be a potential therapeutic option. OBJECTIVES To investigate in vivo if simvastatin modulates mechanisms important in the development of ALI in a model of acute lung inflammation induced by inhalation of lipopolysaccharide (LPS) in healthy human volunteers. METHODS Thirty healthy subjects were enrolled in a double-blind, placebo-controlled study. Subjects were randomized to receive 40 mg or 80 mg of simvastatin or placebo (n = 10/group) for 4 days before inhalation of 50 microg LPS. Measurements were performed in bronchoalveolar lavage fluid (BALF) obtained at 6 hours and plasma obtained at 24 hours after LPS challenge. Nuclear translocation of nuclear factor-kappaB (NF-kappaB) was measured in monocyte-derived macrophages. MEASUREMENTS AND MAIN RESULTS Pretreatment with simvastatin reduced LPS-induced BALF neutrophilia, myeloperoxidase, tumor necrosis factor-alpha, matrix metalloproteinases 7, 8, and 9, and C-reactive protein (CRP) as well as plasma CRP (all P < 0.05 vs. placebo). There was no significant difference between simvastatin 40 mg and 80 mg. BALF from subjects post-LPS inhalation induced a threefold up-regulation in nuclear NF-kappaB in monocyte-derived macrophages (P < 0.001); pretreatment with simvastatin reduced this by 35% (P < 0.001). CONCLUSIONS Simvastatin has antiinflammatory effects in the pulmonary and systemic compartment in humans exposed to inhaled LPS.

A randomized clinical trial of hydroxymethylglutaryl- coenzyme a reductase inhibition for acute lung injury (The HARP Study).

RATIONALE There is no effective pharmacological treatment for acute lung injury (ALI). Statins are a potential new therapy because they modify many of the underlying processes important in ALI. OBJECTIVES To test whether simvastatin improves physiological and biological outcomes in ALI. METHODS We conducted a randomized, double-blinded, placebo-controlled trial in patients with ALI. Patients received 80 mg simvastatin or placebo until cessation of mechanical ventilation or up to 14 days. Extravascular lung water was measured using thermodilution. Measures of pulmonary and nonpulmonary organ function were assessed daily. Pulmonary and systemic inflammation was assessed by bronchoalveolar lavage fluid and plasma cytokines. Systemic inflammation was also measured by plasma C-reactive protein. MEASUREMENTS AND MAIN RESULTS Sixty patients were recruited. Baseline characteristics, including demographics and severity of illness scores, were similar in both groups. At Day 7, there was no difference in extravascular lung water. By Day 14, the simvastatin-treated group had improvements in nonpulmonary organ dysfunction. Oxygenation and respiratory mechanics improved, although these parameters failed to reach statistical significance. Intensive care unit mortality was 30% in both groups. Simvastatin was well tolerated, with no increase in adverse events. Simvastatin decreased bronchoalveolar lavage IL-8 by 2.5-fold (P = 0.04). Plasma C-reactive protein decreased in both groups but failed to achieve significance in the placebo-treated group. CONCLUSIONS Treatment with simvastatin appears to be safe and may be associated with an improvement in organ dysfunction in ALI. These clinical effects may be mediated by a reduction in pulmonary and systemic inflammation. Clinical trial registered with www.controlled-trials.com (ISRCTN70127774).

Extravascular lung water indexed to predicted body weight is a novel predictor of intensive care unit mortality in patients with acute lung injury

Objectives:Acute lung injury and the acute respiratory distress syndrome are characterized by noncardiogenic pulmonary edema, which can be assessed by measurement of extravascular lung water. Traditionally, extravascular lung water has been indexed to actual body weight (mL/kg). Because lung size is dependent on height rather than weight, we hypothesized indexing to predicted body weight may be a better predictor of mortality in acute lung injury/acute respiratory distress syndrome. Design:Prospective observational cohort study. Setting:A tertiary referral intensive care unit. Patients:Patients were recruited within 48 hrs of fulfilling the American European Consensus Conference definition of acute lung injury/acute respiratory distress syndrome. Interventions:None. Measurements and Main Results:Demographics, severity of illness scores, and respiratory parameters were collected. Extravascular lung water was measured using the PiCCO system. This was indexed to actual and predicted body weight. Statistically significant predictors of mortality identified using single regressor logistic regression and additional variables known to be associated with outcome were entered into a multiple logistic regression analysis. Receiver operator characteristic curves were generated. Forty-four patients were recruited (septic 34%). Using single regressor logistic regression, six variables were statistically significantly related to mortality: Acute Physiology and Chronic Health Evaluation II, PaO2, PaO2/Fio2 ratio, oxygenation index, actual extravascular lung water, and predicted extravascular lung water. In multiple logistic regression analysis, predicted extravascular lung water but not actual extravascular lung water was a predictor of mortality with an odds ratio of 4.3 (95% confidence interval, 1.5–12.9) per sd. Although the area under the curve for predicted extravascular lung water (0.8; confidence interval, 0.65–0.94) was larger than for actual extravascular lung water (0.72; confidence interval, 0.53–0.91), this was not statistically significant (p = .12). A baseline predicted extravascular lung water value of 16 mL/kg predicted intensive care unit mortality with a sensitivity of 0.75 (confidence interval, 0.47–0.91) and specificity of 0.78 (confidence interval, 0.61–0.89). Conclusions:Early measurement of predicted extravascular lung water is a better predictor than actual extravascular lung water to identify patients at risk for death in acute lung injury/acute respiratory distress syndrome.

Impaired endothelium-dependent vasodilatation is a novel predictor of mortality in intensive care

Objective:Endothelial function may be impaired in critical illness. We hypothesized that impaired endothelium-dependent vasodilatation is a predictor of mortality in critically ill patients. Design:Prospective observational cohort study. Setting:Seventeen-bed adult intensive care unit in a tertiary referral university teaching hospital. Patients:Patients were recruited within 24 hrs of admission to the intensive care unit. Interventions:The SphygmoCor Mx system was used to derive the aortic augmentation index from radial artery pulse pressure waveforms. Endothelium-dependent vasodilatation was calculated as the change in augmentation index in response to an endothelium-dependent vasodilator (salbutamol). Measurements and Main Results:Demographics, severity of illness scores, and physiological parameters were collected. Statistically significant predictors of mortality identified using single regressor analysis were entered into a multiple logistic regression model. Receiver operator characteristic curves were generated. Ninety-four patients completed the study. There were 80 survivors and 14 nonsurvivors. The Simplified Acute Physiology Score II, the Sequential Organ Failure Assessment score, leukocyte count, and endothelium-dependent vasodilatation conferred an increased risk of mortality. In logistic regression analysis, endothelium-dependent vasodilatation was the only predictor of mortality with an adjusted odds ratio of 26.1 (95% confidence interval [CI], 4.3–159.5). An endothelium-dependent vasodilatation value of 0.5% or less predicted intensive care unit mortality with a sensitivity of 79% (CI, 59–88%) and specificity of 98% (CI, 94–99%). Conclusions:In vivo bedside assessment of endothelium-dependent vasodilatation is an independent predictor of mortality in the critically ill. We have shown it to be superior to other validated severity of illness scores with high sensitivity and specificity.

Comparison of thermodilution measured extravascular lung water with chest radiographic assessment of pulmonary oedema in patients with acute lung injury

BackgroundAcute lung injury and the acute respiratory distress syndrome (ALI/ARDS) are characterized by pulmonary oedema, measured as extravascular lung water (EVLW). The chest radiograph (CXR) can potentially estimate the quantity of lung oedema while the transpulmonary thermodilution method measures the amount of EVLW. This study was designed to determine whether EVLW as estimated by a CXR score predicts EVLW measured by the thermodilution method and whether changes in EVLW by either approach predict mortality in ALI/ARDS.MethodsClinical data were collected within 48 hours of ALI/ARDS diagnosis and daily up to 14 days on 59 patients with ALI/ARDS. Two clinicians scored each CXR for the degree of pulmonary oedema, using a validated method. EVLW indexed to body weight was measured using the single indicator transpulmonary thermodilution technique.ResultsThe CXR score had a modest, positive correlation with the EVLWI measurements (r = 0.35, p < 0.001). There was a 1.6 ml/kg increase in EVLWI per 10-point increase in the CXR score (p < 0.001, 95% confidence interval 0.92-2.35). The sensitivity of a high CXR score for predicting a high EVLWI was 93%; similarly the negative predictive value was high at 94%; the specificity (51%) and positive predictive value (50%) were lower. The CXR scores did not predict mortality but the EVLW thermodilution did predict mortality.ConclusionEVLW measured by CXR was modestly correlated with thermodilution measured EVLW. Unlike CXR findings, transpulmonary thermodilution EVLWI measurements over time predicted mortality in patients with ALI/ARDS.

Simvastatin decreases the level of heparin-binding protein in patients with acute lung injury

BackgroundHeparin-binding protein is released by neutrophils during inflammation and disrupts the integrity of the alveolar and capillary endothelial barrier implicated in the development of acute lung injury and systemic organ failure. We sought to investigate whether oral administration of simvastatin to patients with acute lung injury reduces plasma heparin-binding protein levels and improves intensive care unit outcome.MethodsBlood samples were collected from patients with acute lung injury with 48 h of onset of acute lung injury (day 0), day 3, and day 7. Patients were given placebo or 80 mg simvastatin for up to 14 days. Plasma heparin-binding protein levels from patients with acute lung injury and healthy volunteers were measured by ELISA.ResultsLevels of plasma heparin-binding protein were significantly higher in patients with acute lung injury than healthy volunteers on day 0 (p = 0.011). Simvastatin 80 mg administered enterally for 14 days reduced plasma level of heparin-binding protein in patients. Reduced heparin-binding protein was associated with improved intensive care unit survival.ConclusionsA reduction in heparin-binding protein with simvastatin is a potential mechanism by which the statin may modify outcome from acute lung injury.Trial registrationCurrent controlled trials: ISRCTN70127774

Proteolytic cleavage of elafin by 20S proteasome may contribute to inflammation in acute lung injury

Rationale We hypothesise that elafin levels in acute lung injury (ALI) decrease over time due, in part, to proteolytic degradation as observed in other lung diseases. Objectives The aim of this study was to characterise temporal changes in elafin concentration in patients with ALI and to evaluate whether a decrease in elafin levels is due to elevated protease activity. Methods Bronchoalveolar lavage fluid (BALF) was obtained from patients with ALI within 48 h of onset of ALI (day 0), at day 3 and at day 7. Elafin levels were quantified by ELISA. Elafin susceptibility to proteolytic cleavage by ALI BALF was assessed by Western blot and by high-performance liquid chromatography–mass spectrometry. Measurements and main results Elafin levels were found to be significantly increased at the onset of ALI compared with healthy volunteers and fell significantly by day 7 compared with day 0. In contrast, levels of secretory leukocyte protease inhibitor did not decrease over time. This decrease in elafin was due to cleavage by the 20S proteasome which was significantly increased in ALI BALF. Incubation of ALI BALF with the proteasome inhibitor epoxomicin confirmed that 20S proteasome protease activity was responsible for proteolytic cleavage of elafin, resulting in diminished anti-elastase activity. In addition, free neutrophil elastase activity significantly increased in ALI BALF from day 0 to day 7. Conclusions Elafin concentrations fall within the pulmonary compartment over the course of ALI as a result of proteolytic degradation. This loss of elafin may predispose people, in part, to excessive inflammation in ALI.

S103 A decrease in elafin due to proteolytic cleavage may contribute to alveolar inflammation in patients with ALI

Introduction Unregulated protease activity is implicated in the pathogenesis of acute lung injury (ALI). Elafin is a potent serine protease inhibitor produced by epithelial and inflammatory cells with anti-inflammatory actions. Aim To assess the temporal changes in elafin concentration in patients with ALI and test the hypothesis that a decrease in elafin levels due to proteolytic degradation may drive pulmonary inflammation. Methods Patients with ALI within 48 h of onset of ALI (n=37), day 3 (n=19) and day 7 (n=9) as well as five healthy volunteers underwent bronchoalveolar lavage (BAL). Elafin was measured by ELISA. To determine whether elafin was susceptible to proteolytic cleavage, western blot analysis of recombinant elafin was incubated with BAL±protease inhibitors. Alveolar macrophages from healthy volunteers were isolated and pre-treated with 10 μg/ml elafin for 1 h, followed by 24 h stimulation with 100 ng/ml LPS. IL-8 was measured in supernatants by ELISA. Results Elafin was significantly increased at the onset of ALI compared to healthy volunteers (39±5 ng/ml vs 0.5±0.1 ng/ml; p<0.0004). Elafin levels fell significantly by day seven compared to baseline (16±4 ng/ml vs 39±5 ng/ml; p=0.02). Incubation of exogenous elafin with day 7 ALI BAL revealed that elafin underwent proteolytic cleavage (Abstract S103 Figure 1A). In contrast, proteolytic cleavage was not observed following incubation of exogenous elafin with day 0 ALI or healthy volunteer BAL. Pre-incubation of Day 7 ALI BAL with TLCK and Pefabloc abrogated this degradation suggesting that a trypsin-like protease may be responsible for the cleavage of elafin (Abstract S103 Figure 1A). Pretreatment of alveolar macrophages with elafin decreased LPS induced IL-8 production (Abstract S103 Figure 1B).Abstract S103 Figure 1 Conclusion Elafin concentrations fall in the pulmonary compartment over the course of ALI. This decrease was found to be due to proteolytic degradation. Furthermore elafin decreases LPS stimulated IL-8 release from alveolar macrophages. Together these data suggest loss of elafin in the alveolar airspace may result in dysregulated inflammation in ALI. Elafin augmentation may be a potential therapeutic strategy in ALI.