Simvastatin in Critically Ill Patients with Covid-19.

BACKGROUND: The efficacy of simvastatin in critically ill patients with coronavirus disease 2019 (Covid-19) is unclear. METHODS: In an ongoing international, multifactorial, adaptive platform, randomized, controlled trial, we evaluated simvastatin (80 mg daily) as compared with no statin (control) in critically ill patients with Covid-19 who were not receiving statins at baseline. The primary outcome was respiratory and cardiovascular organ support-free days, assessed on an ordinal scale combining in-hospital death (assigned a value of -1) and days free of organ support through day 21 in survivors; the analyis used a Bayesian hierarchical ordinal model. The adaptive design included prespecified statistical stopping criteria for superiority (>99% posterior probability that the odds ratio was >1) and futility (>95% posterior probability that the odds ratio was <1.2). RESULTS: Enrollment began on October 28, 2020. On January 8, 2023, enrollment was closed on the basis of a low anticipated likelihood that prespecified stopping criteria would be met as Covid-19 cases decreased. The final analysis included 2684 critically ill patients. The median number of organ support-free days was 11 (interquartile range, -1 to 17) in the simvastatin group and 7 (interquartile range, -1 to 16) in the control group; the posterior median adjusted odds ratio was 1.15 (95% credible interval, 0.98 to 1.34) for simvastatin as compared with control, yielding a 95.9% posterior probability of superiority. At 90 days, the hazard ratio for survival was 1.12 (95% credible interval, 0.95 to 1.32), yielding a 91.9% posterior probability of superiority of simvastatin. The results of secondary analyses were consistent with those of the primary analysis. Serious adverse events, such as elevated levels of liver enzymes and creatine kinase, were reported more frequently with simvastatin than with control. CONCLUSIONS: Although recruitment was stopped because cases had decreased, among critically ill patients with Covid-19, simvastatin did not meet the prespecified criteria for superiority to control. (REMAP-CAP ClinicalTrials.gov number, NCT02735707.).

Mucoactive agents for acute respiratory failure in the critically ill: a systematic review and meta-analysis.

PURPOSE: Acute respiratory failure (ARF) is a common cause of admission to intensive care units (ICUs). Mucoactive agents are medications that promote mucus clearance and are frequently administered in patients with ARF, despite a lack of evidence to underpin clinical decision making. The aim of this systematic review was to determine if the use of mucoactive agents in patients with ARF improves clinical outcomes. METHODS: We searched electronic and grey literature (January 2020). Two reviewers independently screened, selected, extracted data and quality assessed studies. We included trials of adults receiving ventilatory support for ARF and involving at least one mucoactive agent compared with placebo or standard care. Outcomes included duration of mechanical ventilation. Meta-analysis was undertaken using random-effects modelling and certainty of the evidence was assessed using Grades of Recommendation, Assessment, Development and Evaluation. RESULTS: Thirteen randomised controlled trials were included (1712 patients), investigating four different mucoactive agents. Mucoactive agents showed no effect on duration of mechanical ventilation (seven trials, mean difference (MD) -1.34, 95% CI -2.97 to 0.29, I2=82%, very low certainty) or mortality, hospital stay and ventilator-free days. There was an effect on reducing ICU length of stay in the mucoactive agent groups (10 trials, MD -3.22, 95% CI -5.49 to -0.96, I2=89%, very low certainty). CONCLUSION: Our findings do not support the use of mucoactive agents in critically ill patients with ARF. The existing evidence is of low quality. High-quality randomised controlled trials are needed to determine the role of specific mucoactive agents in critically ill patients with ARF. PROSPERO REGISTRATION NUMBER: CRD42018095408.

Cigarette smokers have exaggerated alveolar barrier disruption in response to lipopolysaccharide inhalation.

RATIONALE: Cigarette smoke exposure is associated with an increased risk of the acute respiratory distress syndrome (ARDS); however, the mechanisms underlying this relationship remain largely unknown. OBJECTIVE: To assess pathways of lung injury and inflammation in smokers and non-smokers with and without lipopolysaccharide (LPS) inhalation using established biomarkers. METHODS: We measured plasma and bronchoalveolar lavage (BAL) biomarkers of inflammation and lung injury in smokers and non-smokers in two distinct cohorts of healthy volunteers, one unstimulated (n=20) and one undergoing 50 µg LPS inhalation (n=30). MEASUREMENTS AND MAIN RESULTS: After LPS inhalation, cigarette smokers had increased alveolar-capillary membrane permeability as measured by BAL total protein, compared with non-smokers (median 274 vs 208 µg/mL, p=0.04). Smokers had exaggerated inflammation compared with non-smokers, with increased BAL interleukin-1ß (p=0.002), neutrophils (p=0.02), plasma interleukin-8 (p=0.003), and plasma matrix metalloproteinase-8 (p=0.006). Alveolar epithelial injury after LPS was more severe in smokers than non-smokers, with increased plasma (p=0.04) and decreased BAL (p=0.02) surfactant protein D. Finally, smokers had decreased BAL vascular endothelial growth factor (VEGF) (p<0.0001) with increased soluble VEGF receptor-1 (p=0.0001). CONCLUSIONS: Cigarette smoke exposure may predispose to ARDS through an abnormal response to a 'second hit,' with increased alveolar-capillary membrane permeability, exaggerated inflammation, increased epithelial injury and endothelial dysfunction. LPS inhalation may serve as a useful experimental model for evaluation of the acute pulmonary effects of existing and new tobacco products.

Aspirin as a potential treatment in sepsis or acute respiratory distress syndrome.

Sepsis is a common condition that is associated with significant morbidity, mortality and health-care cost. Pulmonary and non-pulmonary sepsis are common causes of the acute respiratory distress syndrome (ARDS). The mortality from ARDS remains high despite protective lung ventilation, and currently there are no specific pharmacotherapies to treat sepsis or ARDS. Sepsis and ARDS are characterised by activation of the inflammatory cascade. Although there is much focus on the study of the dysregulated inflammation and its suppression, the associated activation of the haemostatic system has been largely ignored until recently. There has been extensive interest in the role that platelet activation can have in the inflammatory response through induction, aggregation and activation of leucocytes and other platelets. Aspirin can modulate multiple pathogenic mechanisms implicated in the development of multiple organ dysfunction in sepsis and ARDS. This review will discuss the role of the platelet, the mechanisms of action of aspirin in sepsis and ARDS, and aspirin as a potential therapy in treating sepsis and ARDS.

Keratinocyte growth factor promotes epithelial survival and resolution in a human model of lung injury.

RATIONALE: Increasing epithelial repair and regeneration may hasten resolution of lung injury in patients with the acute respiratory distress syndrome (ARDS). In animal models of ARDS, keratinocyte growth factor (KGF) reduces injury and increases epithelial proliferation and repair. The effect of KGF in the human alveolus is unknown. OBJECTIVES: To test whether KGF can attenuate alveolar injury in a human model of ARDS. METHODS: Volunteers were randomized to intravenous KGF (60 µg/kg) or placebo for 3 days, before inhaling 50 µg LPS. Six hours later, subjects underwent bronchoalveolar lavage (BAL) to quantify markers of alveolar inflammation and cell-specific injury. MEASUREMENTS AND MAIN RESULTS: KGF did not alter leukocyte infiltration or markers of permeability in response to LPS. KGF increased BAL concentrations of surfactant protein D, matrix metalloproteinase (MMP)-9, IL-1Ra, granulocyte-macrophage colony-stimulating factor (GM-CSF), and C-reactive protein. In vitro, BAL fluid from KGF-treated subjects inhibited pulmonary fibroblast proliferation, but increased alveolar epithelial proliferation. Active MMP-9 increased alveolar epithelial wound repair. Finally, BAL from the KGF-pretreated group enhanced macrophage phagocytic uptake of apoptotic epithelial cells and bacteria compared with BAL from the placebo-treated group. This effect was blocked by inhibiting activation of the GM-CSF receptor. CONCLUSIONS: KGF treatment increases BAL surfactant protein D, a marker of type II alveolar epithelial cell proliferation in a human model of acute lung injury. Additionally, KGF increases alveolar concentrations of the antiinflammatory cytokine IL-1Ra, and mediators that drive epithelial repair (MMP-9) and enhance macrophage clearance of dead cells and bacteria (GM-CSF). Clinical trial registered with ISRCTN 98813895.

Effect of simvastatin on physiological and biological outcomes in patients undergoing esophagectomy: a randomized placebo-controlled trial.

OBJECTIVE: To test whether simvastatin improves physiological and biological outcomes in patients undergoing esophagectomy. BACKGROUND: One-lung ventilation during esophagectomy is associated with inflammation, alveolar epithelial and systemic endothelial injury, and the development of acute lung injury (ALI). Statins that modify many of the underlying processes are a potential therapy to prevent ALI. METHODS: We conducted a randomized double-blind placebo-controlled trial in patients undergoing esophagectomy. Patients received simvastatin 80 mg or placebo enterally for 4 days preoperatively and 7 days postoperatively. The primary end point was pulmonary dead space (Vd/Vt) at 6 hours after esophagectomy or before extubation. Inflammation was assessed by plasma cytokines and intraoperative exhaled breath condensate pH; alveolar type 1 epithelial injury was assessed by plasma receptor for advanced glycation end products and systemic endothelial injury by the urine albumin-creatinine ratio. RESULTS: Thirty-nine patients were randomized; 8 patients did not undergo surgery and were excluded. Fifteen patients received simvastatin and 16 received placebo. There was no difference in Vd/Vt or other physiological outcomes. Simvastatin resulted in a significant decrease in plasma MCP-1 on day 3 and reduced exhaled breath condensate acidification. Plasma receptor for advanced glycation end products was significantly lower in the simvastatin-treated group, as was the urine albumin-creatinine ratio on day 7 postsurgery. ALI developed in 4 patients in the placebo group and no patients in the simvastatin group although this difference was not statistically significant (P=0.1). CONCLUSIONS: In this proof of concept study, pretreatment with simvastatin in esophagectomy decreased biomarkers of inflammation as well as pulmonary epithelial and systemic endothelial injury.

Lung Ultrasound Reproducibly Outperforms Computed Tomography in the Detection of Extravascular Lung Water in Patients Undergoing Haemodialysis.

BACKGROUND: Lung ultrasound (LUS) is increasingly used as an extension of physical examination, informing clinical diagnosis, and decision making. There is particular interest in the assessment of patients with pulmonary congestion and extravascular lung water, although gaps remain in the evidence base underpinning this practice as a result of the limited evaluation of its inter-rater reliability and comparison with more established radiologic tests. METHODS: 30 patients undergoing haemodialysis were prospectively recruited to an observational cohort study (NCT01949402). Patients underwent standardised LUS assessment before, during and after haemodialysis; their total LUS B-line score was generated, alongside a binary label of whether appearances were consistent with an interstitial syndrome. LUS video clips were recorded and independently scored by two blinded expert clinician sonographers. Low-dose non-contrast thoracic CT, pre- and post dialysis, was used as a "gold standard" radiologic comparison. RESULTS: LUS detected a progressive reduction in B-line scores in almost all patients undergoing haemodialysis, correlating with the volume of fluid removed once individuals with no or minimal B-lines upon pre-dialysis examination were discounted. When comparing CT scans pre- and post dialysis, radiologic evidence of the change in fluid status was only identified in a single patient. CONCLUSIONS: This is the first study to demonstrate that LUS detects changes in extravascular lung water caused by changing fluid status during haemodialysis using a blinded outcome assessment and that LUS appears to be more sensitive than CT for this purpose. Further research is needed to better understand the role of LUS in this and similar patient populations, with the aim of improving clinical care and outcomes.

Clinical review: the role of ultrasound in estimating extra-vascular lung water.

The estimation of extra-vascular lung water (EVLW) is an essential component in the assessment of critically ill patients. EVLW is independently associated with mortality and its manipulation has been shown to improve outcome. Accurate assessment of lung water is possible with CT and MR imaging but these are impractical for real-time measurement in sick patients and have been superseded by single thermal dilution techniques. While useful, single thermo-dilution requires repeated calibration and is prone to error, suggesting a need for other monitoring methods. Traditionally the lung was not thought amenable to ultrasound examination owing to the high acoustic impedance of air; however, the identification of artefacts in diseased lung has led to increased use of ultrasound as a point of care investigation for both diagnosis and to monitor response to interventions. Following the initial description of B-lines in association with increased lung water, accumulating evidence has shown that they are a useful and responsive measure of the presence and dynamic changes in EVLW. Animal models have confirmed a correlation with lung gravimetry and the utility of B-lines has been demonstrated in many clinical situations and correlated against other established measures of EVLW. With increasing availability and expertise the role of ultrasound in estimating EVLW should be embedded in clinical practice and incorporated into clinical algorithms to aid decision making. This review looks at the evidence for ultrasound as a valid, easy to use, non-invasive point of care investigation to assess EVLW.

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

BACKGROUND: Heparin-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. METHODS: Blood 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. RESULTS: Levels 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. CONCLUSIONS: A reduction in heparin-binding protein with simvastatin is a potential mechanism by which the statin may modify outcome from acute lung injury. TRIAL REGISTRATION: Current controlled trials: ISRCTN70127774.

International Survey of High-Flow Nasal Therapy Use for Respiratory Failure in Adult Patients.

(1) Background: High-flow nasal therapy (HFNT) has shown several benefits in addressing respiratory failure. However, the quality of evidence and the guidance for safe practice are lacking. This survey aimed to understand HFNT practice and the needs of the clinical community to support safe practice. (2) Method: A survey questionnaire was developed and distributed to relevant healthcare professionals through national networks in the UK, USA and Canada; responses were collected between October 2020 and April 2021. (3) Results: In the UK and Canada, HFNT was used in 95% of hospitals, with the highest use being in the emergency department. HNFT was widely used outside of a critical care setting. HFNT was mostly used to treat acute type 1 respiratory failure (98%), followed by acute type 2 respiratory failure and chronic respiratory failure. Guideline development was felt to be important (96%) and urgent (81%). Auditing of practice was lacking in 71% of hospitals. In the USA, HFNT was broadly similar to UK and Canadian practice. (4) Conclusions: The survey results reveal several key points: (a) HFNT is used in clinical conditions with limited evidence; (b) there is a lack of auditing; (c) it is used in wards that may not have the appropriate skill mix; and (d) there is a lack of guidance for HFNT use.

Awake prone positioning in acute hypoxaemic respiratory failure: An international expert guidance.

BACKGROUND: Awake prone positioning (APP) of non-intubated patients with acute hypoxaemic respiratory failure (AHRF) has been inconsistently adopted into routine care of patients with COVID-19, likely due to apparent conflicting evidence from recent trials. This short guideline aims to provide evidence-based recommendations for the use of APP in various clinical scenarios. METHODS: An international multidisciplinary panel, assembled for their expertise and representativeness, and supported by a methodologist, performed a systematic literature search, summarized the available evidence derived from randomized clinical trials, and developed recommendations using GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) methodology. RESULTS: The panel strongly recommends that APP rather than standard supine care be used in patients with COVID-19 receiving advanced respiratory support (high-flow nasal cannula, continuous positive airway pressure or non-invasive ventilation). Due to lack of evidence from randomized controlled trials, the panel provides no recommendation on the use of APP in patients with COVID-19 supported with conventional oxygen therapy, nor in patients with AHRF due to causes other than COVID-19. CONCLUSION: APP should be routinely implemented in patients with COVID-19 receiving advanced respiratory support.

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).

Electronic nudge tool technology used in the critical care and peri-anaesthetic setting: a scoping review protocol.

INTRODUCTION: Electronic clinical decision support (eCDS) tools are used to assist clinical decision making. Using computer-generated algorithms with evidence-based rule sets, they alert clinicians to events that require attention. eCDS tools generating alerts using nudge principles present clinicians with evidence-based clinical treatment options to guide clinician behaviour without restricting freedom of choice. Although eCDS tools have shown beneficial outcomes, challenges exist with regard to their acceptability most likely related to implementation. Furthermore, the pace of progress in this field has allowed little time to effectively evaluate the experience of the intended user. This scoping review aims to examine the development and implementation strategies, and the impact on the end user of eCDS tools that generate alerts using nudge principles, specifically in the critical care and peri-anaesthetic setting. METHODS AND ANALYSIS: This review will follow the Arksey and O'Malley framework. A search will be conducted of literature published in the last 15 years in MEDLINE, EMBASE, CINAHL, CENTRAL, Web of Science and SAGE databases. Citation screening and data extraction will be performed by two independent reviewers. Extracted data will include context, e-nudge tool type and design features, development, implementation strategies and associated impact on end users. ETHICS AND DISSEMINATION: This scoping review will synthesise published literature therefore ethical approval is not required. Review findings will be published in topic relevant peer-reviewed journals and associated conferences.

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.

High-flow nasal cannula therapy for initial oxygen administration in acute hypercapnic respiratory failure: study protocol of randomised controlled unblinded trial.

INTRODUCTION: Acute respiratory failure is a common clinical condition accounting for nearly 116 000 admissions in the UK hospitals. Acute type 2 respiratory failure is also called acute hypercapnic respiratory failure (AHRF) and characterised by an elevated arterial CO2 level of >6 kPa due to pump failure. Acute exacerbation of chronic obstructive pulmonary disease is the most common cause of AHRF. High-flow nasal therapy (HFNT) is a new oxygen delivery system that uses an oxygen-air blender to deliver flow rates of up to 60 L/min. The gas is delivered humidified and heated to the patient via wide-bore nasal cannula. METHODS AND ANALYSIS: We hypothesised that HFNC as the initial oxygen administration method will reduce the number of patients with AHRF requiring non-invasive ventilation in patients at 6 hours post intervention when compared with low-flow nasal oxygen (LFO). A randomised single-centre unblinded controlled trial is designed to test our hypothesis. The trial will compare two oxygen administration methods, HFNT versus LFO. Patients will be randomised to one of the two arms if they fulfil the eligibility criteria. The sample size is 82 adult patients (41 HFNT and 41 LFO) presenting to the emergency department. ETHICS AND DISSEMINATION: Ethical approval was obtained from the Office for Research Ethics Committees Northern Ireland (REC reference: 20/NI/0049). Dissemination will be achieved in several ways: (1) the findings will be presented at national and international meetings with open-access abstracts online and (2) in accordance with the open-access policies proposed by the leading research funding bodies we aim to publish the findings in high-quality peer-reviewed open-access journals. TRIAL REGISTRATION NUMBER: The trial was prospectively registered at the clinicaltrials.gov registry (NCT04640948) on 20 November 2020.

High flow nasal oxygen for acute type two respiratory failure: a systematic review.

Background: Acute type two respiratory failure (AT2RF) is characterized by high carbon dioxide levels (PaCO 2 >6kPa). Non-invasive ventilation (NIV), the current standard of care, has a high failure rate. High flow nasal therapy (HFNT) has potential additional benefits such as CO 2 clearance, the ability to communicate and comfort. The primary aim of this systematic review is to determine whether HFNT in AT2RF improves 1) PaCO 2, 2) clinical and patient-centred outcomes and 3) to assess potential harms. Methods: We searched EMBASE, MEDLINE and CENTRAL  (January 1999-January 2021). Randomised controlled trials (RCTs) and cohort studies comparing HFNT with low flow nasal oxygen (LFO) or NIV were included. Two authors independently assessed studies for eligibility, data extraction and risk of bias. We used Cochrane risk of bias tool for RCTs and Ottawa-Newcastle scale for cohort studies. Results: From 727 publications reviewed, four RCTs and one cohort study (n=425) were included. In three trials of HFNT vs NIV, comparing PaCO 2 (kPa) at last follow-up time point, there was a significant reduction at four hours (1 RCT; HFNT median 6.7, IQR 5.6 - 7.7 vs NIV median 7.6, IQR 6.3 - 9.3) and no significant difference at  24-hours or five days. Comparing HFNT with LFO, there was no significant difference at 30-minutes. There was no difference in intubation or mortality. Conclusions: This review identified a small number of studies with low to very low certainty of evidence. A reduction of PaCO 2 at an early time point of four hours post-intervention was demonstrated in one small RCT. Significant limitations of the included studies were lack of adequately powered outcomes and clinically relevant time-points and small sample size. Accordingly, systematic review cannot recommend the use of HFNT as the initial management strategy for AT2RF and trials adequately powered to detect clinical and patient-relevant outcomes are urgently warranted.

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.

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.