Ventilator-associated pneumonia is characterized by excessive release of neutrophil proteases in the lung

Ventilator-associated pneumonia (VAP) is characterized by neutrophils infiltrating the alveolar space. VAP is associated with high mortality, and accurate diagnosis remains difficult. We hypothesized that proteolytic enzymes from neutrophils would be significantly increased and locally produced inhibitors of human neutrophil elastase (HNE) would be decreased in BAL fluid (BALF) from patients with confirmed VAP. We postulated that in suspected VAP, neutrophil proteases in BALF may help identify "true" VAP.

How Outcomes Are Defined in Clinical Trials of Mechanically Ventilated Adults and Children

Systematic reviews have considerable potential to provide evidence-based data to aid clinical decision-making. However, there is growing recognition that trials involving mechanical ventilation lack consistency in the definition and measurement of ventilation outcomes, creating difficulties in combining data for meta-analyses. To address the inconsistency in outcome definitions, international standards for trial registration and clinical trial protocols published recommendations, effectively setting the “gold standard” for reporting trial outcomes. In this Critical Care Perspective, we review the problems resulting from inconsistent outcome definitions and inconsistent reporting of outcomes (outcome sets). We present data highlighting the variability of the most commonly reported ventilation outcome definitions. Ventilation outcomes reported in trials over the last 6 years typically fall into four domains: measures of ventilator dependence; adverse outcomes; mortality; and resource use. We highlight the need, first, for agreement on outcome definitions and, second, for a minimum core outcome set for trials involving mechanical ventilation. A minimum core outcome set would not restrict trialists from measuring additional outcomes, but would overcome problems of variability in outcome selection, measurement, and reporting, thereby enhancing comparisons across trials.

Weaning from mechanical ventilation: a scoping review of qualitative studies

Background; Weaning from mechanical ventilation is influenced by patient, clinician, and organizational factors.

Objective: To identify factors that may influence weaning and adoption of weaning strategies and tools, clinicians’ perceptions of weaning strategies, and weaning experiences of patients and patients’ families.

Method: A scoping review of indexed and nonindexed publications (1990–2012) was done. Qualitative studies of health care providers, patients, and patients’ families involved in weaning were included. Two investigators independently screened 8350 publications and extracted data from 43 studies. Study themes were content analyzed to identify common categories and themes within the categories.

Results: The study sample consisted of nurses in 15 studies, nurses and patients in 1 study, various health care providers in 11, patients in 10, and physicians in 4. Categories identified were as follows: for nurses, role or scope of practice, informing decision making, and influence on weaning outcome; for health care providers, factors influencing weaning decisions or use of protocols, role or scope of practice related to weaning, and organizational structure or practice environment; for patients, experience of mechanical ventilation and weaning, experience of the intensive care environment, psychological phenomena, and enabling success in weaning; and for physicians, tools or factors to facilitate weaning decisions and perceptions of nurses’ role and scope of practice.

Conclusions: Important issues identified were perceived importance of interprofessional collaboration and communication, need to combine subjective knowledge of the patient with objective clinical data, balancing of weaning systematization with individual needs, and appreciation of the physical and psychological work of weaning.

Lung Clearance Index Is a Repeatable and Sensitive Indicator of Radiological Changes in Bronchiectasis

RATIONALE: In bronchiectasis there is a need for improved markers of lung function to determine disease severity and response to therapy.

OBJECTIVES: To assess whether the lung clearance index is a repeatable and more sensitive indicator of computed tomography (CT) scan abnormalities than spirometry in bronchiectasis.

METHODS: Thirty patients with stable bronchiectasis were recruited and lung clearance index, spirometry, and health-related quality of life measures were assessed on two occasions, 2 weeks apart when stable (study 1). A separate group of 60 patients with stable bronchiectasis was studied on a single visit with the same measurements and a CT scan (study 2).

MEASUREMENTS AND MAIN RESULTS: In study 1, the intervisit intraclass correlation coefficient for the lung clearance index was 0.94 (95% confidence interval, 0.89 to 0.97; P < 0.001). In study 2, the mean age was 62 (10) years, FEV1 76.5% predicted (18.9), lung clearance index 9.1 (2.0), and total CT score 14.1 (10.2)%. The lung clearance index was abnormal in 53 of 60 patients (88%) and FEV1 was abnormal in 37 of 60 patients (62%). FEV1 negatively correlated with the lung clearance index (r = -0.51, P < 0.0001). Across CT scores, there was a relationship with the lung clearance index, with little evidence of an effect of FEV1. There were no significant associations between the lung clearance index or FEV1 and health-related quality of life.

CONCLUSIONS: The lung clearance index is repeatable and a more sensitive measure than FEV1 in the detection of abnormalities demonstrated on CT scan. The lung clearance index has the potential to be a useful clinical and research tool in patients with bronchiectasis.

Statin Use and Risk of Delirium in the Critically Ill

Rationale: Delirium is common in intensive care unit (ICU) patients and is a predictor of worse outcomes and neuroinflammation is a possible mechanism. The antiinflammatory actions of statins may reduce delirium.

Objectives: To determine whether critically ill patients receiving statin therapy had a reduced risk of delirium than those not on statins.

Methods: A prospective cohort analysis of data from consecutive ICU patients admitted to a UK mixed medical and surgical critical care unit between August 2011 and February 2012; the Confusion Assessment Method for ICU was used to determine the days each patient was assessed as being free of delirium during ICU admission.

Measurements and Main Results: Delirium-free days, daily administration of statins, and serum C-reactive protein (CRP) were recorded. Four hundred and seventy consecutive critical care patients were followed, of whom 151 patients received statins. Using randomeffects multivariable logistic regression, statin administration the previous evening was associated with the patient being assessed as free of delirium (odds ratio, 2.28; confidence interval, 1.01-5.13; P , 0.05) and with lower CRP (b = 20.52; P , 0.01) the following day. When the association between statin and being assessed as free of delirium was controlled for CRP, the effect size became nonsignificant (odds ratio, 1.56; confidence interval, 0.64-3.79; P = 0.32).

Conclusions: Ongoing statin therapy is associated with a lower daily risk of delirium in critically ill patients. An ongoing clinical trial, informed by this study, is investigating if statins are a potential therapy for delirium in the critically ill.Copyright © 2014 by the American Thoracic Society.

The Beta Agonist Lung Injury Trial Prevention:A Randomized Controlled Trial

Rationale: Experimental studies suggest that pretreatment with b-agonists might prevent acute lung injury (ALI).

Objectives: To determine if in adult patients undergoing elective esophagectomy, perioperative treatment with inhaled b-agonists effects the development of early ALI.

Methods:We conducted a randomized placebo-controlled trial in 12 UK centers (2008-2011). Adult patients undergoing elective esophagectomy were allocated to prerandomized, sequentially numbered treatment packs containing inhaled salmeterol (100 mg twice daily) or a matching placebo. Patients, clinicians, and researchers were masked to treatment allocation. The primary outcome was development of ALI within 72 hours of surgery. Secondary outcomes were ALI within 28 days, organ failure, adverse events, survival, and health-related quality of life. An exploratory substudy measured biomarkers of alveolar-capillary inflammation and injury.

Measurements and Main Results: A total of 179 patients were randomized to salmeterol and 183 to placebo. Baseline characteristics were similar. Treatment with salmeterol did not prevent early lung injury (32 [19.2%] of 168 vs. 27 [16.0%] of 170; odds ratio [OR], 1.25; 95% confidence interval [CI], 0.71-2.22). There was no difference in organ failure, survival, or health-related quality of life.Adverse events were less frequent in the salmeterol group (55 vs. 70; OR, 0.63; 95% CI, 0.39-0.99), predominantly because of a lower number of pneumonia (7 vs. 17; OR, 0.39; 95% CI, 0.16-0.96). Salmeterol reduced some biomarkers of alveolar inflammation and epithelial injury.

Conclusion: Perioperative treatment with inhaled salmeterol was well tolerated but did not prevent ALI.

Clinical trial registered with International Standard Randomized Controlled Trial Register (ISRCTN47481946) and European Union database of randomized Controlled Trials (EudraCT 2007-004096-19).Copyright © 2014 by the American Thoracic Society.

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 50μg lipopolysaccharide. 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 (SP-D), MMP-9, IL-1Ra, GM-CSF and CRP. In vitro, BAL fluid from KGF-treated subjects (KGF BAL) inhibited pulmonary fibroblast proliferation, but increased alveolar epithelial proliferation. Active MMP-9 increased alveolar epithelial wound repair. Finally, BAL from the KGF pre-treated 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 SP-D, a marker of type II alveolar epithelial cell proliferation in a human model of ALI. Additionally KGF increases alveolar concentrations of the anti-inflammatory cytokine IL-1Ra, and mediators that drive epithelial repair (MMP-9) and enhance macrophage clearance of dead cells and bacteria (GM-CSF).

Simvastatin in the Acute Respiratory Distress Syndrome

Background

Studies in animals and in vitro and phase 2 studies in humans suggest that statins may be beneficial in the treatment of the acute respiratory distress syndrome (ARDS). This study tested the hypothesis that treatment with simvastatin would improve clinical outcomes in patients with ARDS.

Methods

In this multicenter, double-blind clinical trial, we randomly assigned (in a 1:1 ratio) patients with an onset of ARDS within the previous 48 hours to receive enteral simvastatin at a dose of 80 mg or placebo once daily for a maximum of 28 days. The primary outcome was the number of ventilator-free days to day 28. Secondary outcomes included the number of days free of nonpulmonary organ failure to day 28, mortality at 28 days, and safety.

Results

The study recruited 540 patients, with 259 patients assigned to simvastatin and 281 to placebo. The groups were well matched with respect to demographic and baseline physiological variables. There was no significant difference between the study groups in the mean (±SD) number of ventilator-free days (12.6±9.9 with simvastatin and 11.5±10.4 with placebo, P=0.21) or days free of nonpulmonary organ failure (19.4±11.1 and 17.8±11.7, respectively; P=0.11) or in mortality at 28 days (22.0% and 26.8%, respectively; P=0.23). There was no significant difference between the two groups in the incidence of serious adverse events related to the study drug.

Conclusions

Simvastatin therapy, although safe and associated with minimal adverse effects, did not improve clinical outcomes in patients with ARDS. (Funded by the U.K. National Institute for Health Research Efficacy and Mechanism Evaluation Programme and others; HARP-2 Current Controlled Trials number, ISRCTN88244364.)

The effect of inhaled IFN-β on worsening of asthma symptoms caused by viral infections. a randomized trial

Rationale: Ex vivo, bronchial epithelial cells from people with asthma are more susceptible to rhinovirus infection caused by deficient induction of the antiviral protein, IFN-b. Exogenous IFN-b restores antiviral activity.

Objectives: To compare the efficacy and safety of inhaled IFN-b with placebo administered to people with asthma after onset of cold symptoms to prevent or attenuate asthma symptoms caused by respiratory viruses.

Methods: A total of 147 people with asthma on inhaled corticosteroids (British Thoracic Society Steps 2–5), with a history of virus-associated exacerbations, were randomized to 14-day treatment with inhaled IFN-b (n = 72) or placebo (n = 75) within 24 hours of developing cold symptoms and were assessed clinically, with relevant samples collected to assess virus infection and antiviral responses.

Measurements and Main Results: A total of 91% of randomized patients developed a defined cold. In this modified intention-to-treat population, asthma symptoms did not get clinically significantly worse
(mean change in six-item Asthma Control Questionnaire ,0.5) and IFN-b treatment had no significant effect on this primary endpoint, although it enhanced morning peak expiratory flow recovery (P = 0.033), reduced the need for additional treatment, and boosted innate immunity as assessed by blood and sputum biomarkers. In an exploratory analysis of the subset ofmore difficult-to-treat, Step 4-5 peoplewith asthma (n = 27 IFN-b; n = 31 placebo), Asthma Control Questionnaire-6 increased significantly on placebo; this was prevented by IFN-b (P = 0.004).

Conclusions: Although the trial did not meet its primary endpoint, it suggests that inhaled IFN-b is a potential treatment for virus-induced deteriorations of asthma in difficult-to-treat people with asthma and supports the needforfurther, adequately powered, trialsin this population. Clinical trial registered with www.clinicaltrials.gov (NCT 01126177).

An efficacy and mechanism evaluation study of Levosimendan for the Prevention of Acute oRgan Dysfunction in Sepsis (LeoPARDS): Protocol for a randomized controlled trial

Background

Organ dysfunction consequent to infection (‘severe sepsis’) is the leading cause of admission to an intensive care unit (ICU). In both animal models and early clinical studies the calcium channel sensitizer levosimendan has been demonstrated to have potentially beneficial effects on organ function. The aims of the Levosimendan for the Prevention of Acute oRgan Dysfunction in Sepsis (LeoPARDS) trial are to identify whether a 24-hour infusion of levosimendan will improve organ dysfunction in adults who have septic shock and to establish the safety profile of levosimendan in this group of patients.

This is a multicenter, randomized, double-blind, parallel group, placebo-controlled trial. Adults fulfilling the criteria for systemic inflammatory response syndrome due to infection, and requiring vasopressor therapy, will be eligible for inclusion in the trial. Within 24 hours of meeting these inclusion criteria, patients will be randomized in a 1:1 ratio stratified by the ICU to receive either levosimendan (0.05 to 0.2 μg.kg^-1.min^-1 or placebo for 24 hours in addition to standard care. The primary outcome measure is the mean Sequential Organ Failure Assessment (SOFA) score while in the ICU. Secondary outcomes include: central venous oxygen saturations and cardiac output; incidence and severity of renal failure using the Acute Kidney Injury Network criteria; duration of renal replacement therapy; serum bilirubin; time to liberation from mechanical ventilation; 28-day, hospital, 3 and 6 month survival; ICU and hospital length-of-stay; and days free from catecholamine therapy. Blood and urine samples will be collected on the day of inclusion, at 24 hours, and on days 4 and 6 post-inclusion for investigation of the mechanisms by which levosimendan might improve organ function. Eighty patients will have additional blood samples taken to measure levels of levosimendan and its active metabolites OR-1896 and OR-1855. A total of 516 patients will be recruited from approximately 25 ICUs in the United Kingdom.

This trial will test the efficacy of levosimendan to reduce acute organ dysfunction in adult patients who have septic shock and evaluate its biological mechanisms of action.

Automated versus non-automated weaning for reducing the duration of mechanical ventilation for critically ill adults and children: a cochrane systematic review and meta-analysis

IntroductionAutomated weaning systems may improve adaptation of mechanical support for a patient’s ventilatory needs and facilitate systematic and early recognition of their ability to breathe spontaneously and the potential for discontinuation of ventilation. Our objective was to compare mechanical ventilator weaning duration for critically ill adults and children when managed with automated systems versus non-automated strategies. Secondary objectives were to determine differences in duration of ventilation, intensive care unit (ICU) and hospital length of stay (LOS), mortality, and adverse events.MethodsElectronic databases were searched to 30 September 2013 without language restrictions. We also searched conference proceedings; trial registration websites; and article reference lists. Two authors independently extracted data and assessed risk of bias. We combined data using random-effects modelling.ResultsWe identified 21 eligible trials totalling 1,676 participants. Pooled data from 16 trials indicated that automated systems reduced the geometric mean weaning duration by 30% (95% confidence interval (CI) 13% to 45%), with substantial heterogeneity (I2 = 87%, P <0.00001). Reduced weaning duration was found with mixed or medical ICU populations (42%, 95% CI 10% to 63%) and Smartcare/PS™ (28%, 95% CI 7% to 49%) but not with surgical populations or using other systems. Automated systems reduced ventilation duration with no heterogeneity (10%, 95% CI 3% to 16%) and ICU LOS (8%, 95% CI 0% to 15%). There was no strong evidence of effect on mortality, hospital LOS, reintubation, self-extubation and non-invasive ventilation following extubation. Automated systems reduced prolonged mechanical ventilation and tracheostomy. Overall quality of evidence was high.ConclusionsAutomated systems may reduce weaning and ventilation duration and ICU stay. Due to substantial trial heterogeneity an adequately powered, high quality, multi-centre randomized controlled trial is needed.

miR-31 Dysregulation in Cystic Fibrosis Airways Contributes to Increased Pulmonary Cathepsin S Production

Rationale:
Cathepsin S (CTSS) activity is increased in bronchoalveolar lavage (BAL) fluid from patients with cystic fibrosis (CF). This activity contributes to lung inflammation via degradation of antimicrobial proteins, such as lactoferrin and members of the β-defensin family.

Objectives:
In this study, we investigated the hypothesis that airway epithelial cells are a source of CTSS, and mechanisms underlying CTSS expression in the CF lung.

Methods:
Protease activity was determined using fluorogenic activity assays. Protein and mRNA expression were analyzed by ELISA, Western blotting, and reverse-transcriptase polymerase chain reaction.Measurements and Main Results: In contrast to neutrophil elastase, CTSS activity was detectable in 100% of CF BAL fluid samples from patients without Pseudomonas aeruginosa infection. In this study, we identified epithelial cells as a source of pulmonary CTSS activity with the demonstration that CF airway epithelial cells express and secrete significantly more CTSS than non-CF control cells in the absence of proinflammatory stimulation. Furthermore, levels of the transcription factor IRF-1 correlated with increased levels of its target gene CTSS. We discovered that miR-31, which is decreased in the CF airways, regulates IRF-1 in CF epithelial cells. Treating CF bronchial epithelial cells with a miR-31 mimic decreased IRF-1 protein levels with concomitant knockdown of CTSS expression and secretion.

Conclusions:
The miR-31/IRF-1/CTSS pathway may play a functional role in the pathogenesis of CF lung disease and may open up new avenues for exploration in the search for an effective therapeutic target.