Despite decreasing mortality rates in acute lung injury (ALI), studies of long term physical function in ALI survivors have consistently reported poorer quality of life persisting years into recovery for reasons that are not completely understood. We sought to determine if pulmonary dysfunction is independently associated with functional impairment among ALI survivors, and to determine if high resolution computed tomography could be used to predict its development.
Secondary analysis of data from a randomized controlled trial in ALI.
Intensive care units at three academic medical centers.
Patients diagnosed with ALI who had high resolution computed tomography scans performed at 14 and/or 180 days after diagnosis.
Measurements and main results
An objective radiologic scoring system was used to quantify patterns present on chest high resolution computed tomography obtained at 14 and 180 days in patients with ALI. These scores were correlated in univariable and multivariable analyses with pulmonary function testing and quality of life survey data obtained at 180 days. Eighty-nine patients had evaluable data at day 14, and 47 at 180 days. At 180 days, increased radiologic scores for reticulation were associated with a decreased total lung capacity, forced vital capacity, and diffusing capacity for carbon monoxide (p values all <0.002). Decrements in quality of life attributable to pulmonary dysfunction were most strongly associated with higher radiologic scores. Additionally, radiologic scores at 14 days independently predicted poorer quality of life at 180 days, accounting for age, severity of illness, pneumonia as the ALI risk factor, and length of time on mechanical ventilation.
Among survivors of ALI, increasing chest high resolution computed tomography involvement correlated with restrictive physiology and poorer health related quality of life, implicating pulmonary dysfunction as a potential contributor to activity limitation in these patients.
reticulation; biomarker; restriction; fibroproliferation; radiologic; pulmonary function
This study sought to determine the utilization of speech-language pathologist (SLPs) for the diagnosis and treatment of post-extubation dysphagia in survivors of mechanical ventilation.
We designed, validated, and mailed a survey to 1,966 inpatient SLPs who routinely evaluate patients for post-extubation dysphagia.
The majority of SLP diagnostic evaluations (60%; 95% CI = 59–62%) were performed using clinical techniques with uncertain accuracy. Instrumental diagnostic tests (such as fluoroscopy and endoscopy) are more likely to be available at university than community hospitals. After adjusting for hospital size and academic affiliation, instrumental test use varied significantly by geographical region. Treatments for post-extubation dysphagia usually involved dietary adjustment (76%; 95% CI = 73–79%) and postural changes/compensatory maneuvers (86%; 95% CI = 84–88%), rather than on interventions aimed to improve swallowing function (24%; 95% CI = 21–27%).
SLPs frequently evaluate acute respiratory failure survivors. However, diagnostic evaluations rely mainly upon bedside techniques with uncertain accuracy. The use of instrumental tests varies by geographic location and university affiliation. Current diagnostic practices and feeding decisions for critically ill patients should be viewed with caution until further studies determine the accuracy of bedside detection methods.
Mechanical Ventilation; Intratracheal Intubation; Respiratory Aspiration; Dysphagia; Swallowing Disorders
The goal of this paper is to present strategies utilized to support K scholar research mentors. K scholars are generally assistant professors who are close to developing independent research programs. Of all the various types of mentees, K scholars offer the greatest challenges, as well as the greatest rewards, for research mentors. To see one's mentee achieve independent PI status and become an established investigator is one of the great joys of being a research mentor. Research mentors for K scholars, however, may not directly benefit from their mentoring relationship, neither in terms of obtaining data to support their research program or laboratory, nor in assistance with grants or scientific papers. There is a pressing need for the research community to address the workload, institutional expectations and reward system for research mentors. The dearth of research mentors and role models in clinical translational science parallels the decreasing number of physicians choosing careers in clinical research. While there is limited empirical information on the effectiveness of mentor support mechanisms, this white paper concludes that providing mentor support is critical to expanding the available pool of mentors, as well as providing training opportunities for K scholars.
translational research; salary; protected time; resources
Mentoring is an important element in the training of new investigators, particularly for KL2, K12, K08, and K23 funded scholars who are often physicians or other clinicians with limited prior research experience. Matching K scholars with appropriate mentors who have the mentoring skills and available time is an ongoing challenge for most universities. The goal of this paper is to present a variety of strategies used to select mentors for K awardees. The information presented in this special communication is derived from the literature, a national survey of CTSA leaders, as well as K scholar and K mentor focus groups.
Some of the mentor selection methods discussed in this paper include a) having the scholar find a mentor as part of the application process for the award, b) selecting mentors post award, c) expecting the chair of the department to identify a mentor(s), d) using a committee to match the scholar and a mentor based on a pool of approved mentors e) selecting additional mentors as the scholar’s research program develops. The paper concludes that mentor selection requires an ongoing programmatic approach with the active participation of K scholars, CTSA program leaders, center directors, research deans and chairs.
research mentor selection
Alcohol use disorders (AUDs) are associated with an increased susceptibility to a variety of common and devastating pulmonary diseases including community- and hospital-acquired pneumonias, as well as the acute respiratory distress syndrome (ARDS). Alveolar macrophages play an important role in preventing the development of these disorders through maintaining lung sterility and resolving lung inflammation. Although alcohol exposure has been associated with aberrant alveolar macrophage function in animal models, the clinical relevance of these observations in humans is not established. Therefore, we sought to determine the effects of AUDs on human alveolar macrophage gene expression.
Whole genome microarray analysis was performed on alveolar macrophages obtained by bronchoalveolar lavage from a test cohort of subjects with AUDs (n=7), and controls (n=7) who were pair-matched on age, gender, and smoking. Probe set expression differences in this cohort were validated by real time reverse transcription-polymerase chain reaction (RT RT-PCR). Functional analysis with web-based bioinformatics tools was utilized with microarray data to assess differentially expressed candidate genes (p<0.01) based on alcohol consumption. Alveolar macrophage mRNA samples from a second cohort of subjects with AUDs (n=7) and controls (n=7) were used to confirm gene expression differences related to AUDs. Results: In both the test and confirmatory cohorts, AUDs were associated with upregulation of alveolar macrophage gene expression related to apoptosis, including perforin-1, granzyme A, and CXCR4 (fusin). Pathways governing the regulation of progression through cell cycle and immune response were also affected, as was upregulation of gene expression for mitochondrial superoxide dismutase. Overall, 12 genes’ expression was affected by AUDs independent of smoking.
AUDs are associated with unique changes in human alveolar macrophage gene expression. Novel therapies targeting alveolar macrophage gene expression in the setting of AUDs may prove to be clinically useful in limiting susceptibility for pulmonary disorders in these individuals.
pneumonia; acute lung injury; apoptosis; perforin; human
Acute lung injury (ALI) and severe sepsis are common critical illnesses associated with the mobilization of bone marrow–derived cells into the circulation. By identifying and determining these cells' functional characteristics, unique prognostic biomarkers can be developed to help investigators understand the mechanisms underlying the pathophysiology of these disorders. We previously demonstrated an increased colony-forming unit (CFU) ability of circulating peripheral blood mononuclear cells (PBMCs) in patients with ALI, compared with healthy control subjects, that also correlated with improved survival. Here we hypothesized that the increased CFUs in ALI are associated with lung injury, and therefore ALI will result in an increased number of CFUs compared with patients exhibiting severe sepsis. To test this, blood was collected from 80 patients (63 with ALI, and 17 with severe sepsis) within 72 hours of diagnosis, and from 5 healthy control subjects. A CFU assay was performed on isolated PBMCs. Lung injury scores and the need for mechanical ventilation were greater in patients with ALI than in patients with severe sepsis (P < 0.0001 for each). CFU numbers were highest in patients with ALI compared with patients manifesting severe sepsis or control subjects (median CFU number [25–75% quartiles] of 61 [13–104] versus 17 [3–34] versus 5 [2–13], P < 0.0005). A trend toward improved survival was demonstrated in patients with high (≥ 48) CFUs (P = 0.06). No relationship between CFUs and mechanical ventilation was evident. Our findings suggest that increased colony-forming ability by PBMCs in ALI results from lung injury, independent of sepsis and mechanical ventilation. Factors contributing to colony formation by PBMCs in ALI, and the role PBMCs play in its pathogenesis remain to be fully established.
endothelium; critical illness; repair; prognosis; ARDS
The goal of this study was to determine, in lung transplant patients, if laparoscopic antireflux surgery (LARS) is an effective means to prevent aspiration as defined by the presence of pepsin in the bronchoalveolar lavage fluid (BALF).
Between September 2009 and November 2010, we collected BALF from 64 lung transplant patients at multiple routine surveillance assessments for acute cellular rejection, or when clinically indicated for diagnostic purposes. The BALF was tested for pepsin by enzyme-linked immunosorbent assay (ELISA). We then compared pepsin concentrations in the BALF of healthy controls (n = 11) and lung transplant patients with and without gastroesophageal reflux disease (GERD) on pH-monitoring (n = 8 and n = 12, respectively), and after treatment of GERD by LARS (n = 19). Time to the development of bronchiolitis obliterans syndrome was contrasted between groups based on GERD status or the presence of pepsin in the BALF.
We found that lung transplant patients with GERD had more pepsin in their BALF than lung transplant patients who underwent LARS (P = .029), and that pepsin was undetectable in the BALF of controls. Moreover, those with more pepsin had quicker progression to BOS and more acute rejection episodes.
This study compared pepsin in the BALF from lung transplant patients with and without LARS. Our data show that: (1) the detection of pepsin in the BALF proves aspiration because it is not present in healthy volunteers, and (2) LARS appears effective as a measure to prevent the aspiration of gastroesophageal refluxate in the lung transplant population. We believe that these findings provide a mechanism for those studies suggesting that LARS may prevent nonallogenic injury to the transplanted lungs from aspiration of gastroesophageal contents.
To determine whether the CXC chemokine receptor (CXCR) 4 ligands ubiquitin and stromal cell-derived factor (SDF)-1α are detectable in bronchoalveolar lavage fluid (BALF) after burn and inhalation injury and whether their concentrations in BALF are associated with injury severity, physiological variables or clinical outcomes.
BALF was obtained on hospital admission from 51 patients (48±18 years) with burn (TBSA: 23±24%) and inhalation injury (controls: 10 healthy volunteers, 42±8 years). BALF was analyzed for total protein and for ubiquitin and SDF-1α by ELISA. Ubiquitin/SDF-1α levels were normalized to total BALF protein content. The extent of inhalation injury was determined during bronchoscopy using a standardized scoring system. Percent TBSA, Baux scores, revised Baux scores and clinical variables were documented.
Ubiquitin and SDF-1α were detectable in 40% of normal BALF specimens. After injury, ubiquitin was detectable in 90% (p<0.01 vs. control) and SDF-1α in 10% of the specimens (p<0.05 vs. control), respectively. While SDF-1α levels were reduced in patients (p<0.01), ubiquitin levels were increased (p<0.01). Ubiquitin concentrations correlated inversely with grade of inhalation injury, revised Baux scores and resuscitation fluid requirements (Spearman correlation coefficients (r): -0.3, -0.33 and -0.45, respectively). Ubiquitin levels correlated positively with arterial oxygenation at the time of bronchoscopy (r: 0.35).
BALF levels of CXCR4 agonists are differentially regulated after burn and inhalation injury. Increases in BALF ubiquitin after inhalation injury may maintain CXCR4 mediated lung protection and repair processes. The finding that BALF ubiquitin decreased with higher grades of inhalation injury may provide a biological correlate for an insufficient local inflammatory response after severe inhalation injury.
Extracellular ubiquitin; chemokine (CXC motif) ligand 12; CXC chemokine receptor 4; fusin; CD184; bronchoscopy
To determine if the graded severity of smoke inhalation is reflected by the acute pulmonary inflammatory response to injury.
In a prospective observational study we assessed the bronchoalveolar lavage fluid (BALF) for both leukocyte differential and concentration of 28 cytokines, chemokines, and growth factors. Results were then compared to the graded severity of inhalation injury as determined by Abbreviated Injury Score criteria (0: None, 1: Mild, 2: Moderate, 3: Severe, 4: Massive).
All patients were enrolled at a single tertiary burn center.
The BALF was obtained from 60 patients within 14 hours of burn injury who underwent bronchoscopy for suspected smoke inhalation.
Measurements and Main Results
Those who presented with worse grades of inhalation injury had higher plasma levels of carboxyhemoglobin and enhanced airway neutrophilia. Patients with the most severe inhalation injuries also had a greater requirement for tracheostomy, longer time on the ventilator, and a prolonged stay in the intensive care unit. Of the 28 inflammatory mediators assessed in the BALF, 21 were at their highest in those with the worst inhalation injury scores (Grades 3 and 4), the greatest of which was interleukin (IL)-8 (92,940 pg/ml, Grade 4). When compared in terms of low inhalation injury (Grades 1–2) versus high inhalation injury (Grades 3–4), we found significant differences between groups for IL-4, IL-6, IL-9, IL-15, interferon-γ, granulocyte-macrophage colony-stimulating factor, and monocyte chemotactic protein-1 (p<0.05 for all).
These data reveal that the degree of inhalation injury: 1) has basic and profound effects on burn patient morbidity; 2) evokes complex changes of multiple alveolar inflammatory proteins; and 3) is a determinant of the pulmonary inflammatory response to smoke inhalation. Accordingly, future investigations should consider inhalation injury to be a graded phenomenon.
Burn; Inhalation Injury; Inflammation; Cytokine; Chemokine; Growth Factor
Unhealthy alcohol use predisposes to multiple conditions that frequently result in critical illness and is present in up to one-third of patients admitted to a medical intensive care unit (ICU). We sought to determine the baseline readiness to change in medical ICU patients with unhealthy alcohol use and hypothesized that the severity of acute illness would be independently associated with higher scores on readiness to change scales. We further sought to determine whether this effect is modified by the severity of unhealthy alcohol use.
Materials and Methods
We performed a cross-sectional observational study of current regular drinkers in three medical ICUs. The Alcohol Use Disorders Identification Test was used to differentiate low risk and unhealthy alcohol use and further categorize patients into risky alcohol use or an alcohol use disorder. The severity of a patient’s acute illness was assessed by calculating the Acute Physiology and Chronic Healthy Evaluation II score at the time of admission to the medical ICU. Readiness to change was assessed using standardized questionnaires.
Of 101 medical ICU patients who were enrolled, 65 met the criteria for unhealthy alcohol use. The association between the severity of acute illness and readiness to change depended on the instrument used. A higher severity of illness measured by APACHEII score was an independent predictor of readiness to change as assessed by the Stages of Change Readiness and Treatment Eagerness Scale (Taking Action scale) (p< 0.01). When a visual analog scale was used to assess readiness to change, there was a significant association with severity of acute illness (p < 0.01) that was modified by the severity of unhealthy alcohol use (p = 0.04 for interaction term).
Medical ICU patients represent a population where brief interventions require further study. Studies of brief intervention should account for the severity of acute illness and the severity of unhealthy alcohol use as potential effect modifiers.
Despite recent advances in critical care and ventilator management, acute lung injury (ALI) and the Acute Respiratory Distress Syndrome (ARDS) continue to cause significant morbidity and mortality. Granulocyte-macrophage colony stimulating factor (GM-CSF) may be beneficial for patients with ARDS.
To determine whether intravenous infusion of GM-CSF would improve clinical outcomes for patients with ALI/ARDS.
A randomized, double-blind, placebo-controlled clinical trial of human recombinant GM-CSF vs. placebo. The primary outcome was days alive and breathing without mechanical ventilatory support within the first 28 days after randomization. Secondary outcomes included mortality and organ failure free days.
Medical and Surgical Intensive Care Units at three academic medical centers.
One hundred-thirty individuals with ALI of at least three days duration were enrolled, out of a planned cohort of 200 subjects.
Patients were randomized to receive human recombinant GM-CSF (64 subjects, 250 μg/M2) or placebo (66 subjects) by intravenous infusion daily for 14 days. Patients received mechanical ventilation using a lung protective protocol.
Measurements and Main Results
There was no difference in ventilator-free days between groups (10.7 ± 10.3 days placebo vs. 10.8 ± 10.5 days GM-CSF, p=0.82). Differences in 28-day mortality (23% in placebo vs. 17% in patients receiving GM-CSF (p=0.31)) and organ failure free days (12.8 ± 11.3 days placebo vs. 15.7 ± 11.9 days GM-CSF, p=0.16) were not statistically significant. There were similar numbers of serious adverse events in each group.
In a randomized phase II trial, GM-CSF treatment did not increase the number of ventilator free days in patients with ALI/ARDS. A larger trial would be required to determine whether treatment with GM-CSF might alter important clinical outcomes such as mortality or multiorgan failure. (ClinicalTrials.gov number, NCT00201409 [ClinicalTrials.gov])
Acute Respiratory Distress Syndrome; growth factors; sepsis; innate immunity
Alcohol abuse increases the risk for acute respiratory distress syndrome (ARDS). Efferocytosis, the clearance of apoptotic cells, is important in the resolution of inflammation and is regulated by RhoA and rho kinase (ROCK) activation. The effects of alcohol on pulmonary Rho pathway activation and efferocytosis have not been determined. We hypothesize that acute and chronic alcohol exposure impair pulmonary efferocytosis, leading to heightened inflammation during ARDS.
For in vivo experiments, C57BL/6 mice received either a single, intraperitoneal injection of alcohol or chronic ethanol-in-water for 8 weeks prior to intratracheal instillation of apoptotic cells or lipopolysaccharide (LPS). Bronchoalveolar lavage (BAL) was performed for cells counts, calculation of the phagocytic index (PI), and Rho activity measurements. For in vitro studies, primary alveolar macrophages were cultured in alcohol (25-100mM) and then co-cultured with apoptotic cells. RhoA activity was determined following alcohol exposure, and the PI was determined before and after treatment with the ROCK inhibitor, Y27632.
Acute alcohol exposure was associated with impaired efferocytosis. Following LPS exposure, acute alcohol exposure was also associated with increased BAL neutrophils. Chronic alcohol exposure alone did not alter efferocytosis. However, following exposure to LPS, chronic alcohol exposure was associated with both impaired efferocytosis and increased BAL neutrophils. In vitro alcohol exposure caused a dose-dependent decrease in efferocytosis. Despite the fact that RhoA activity was decreased by alcohol exposure and RhoA inhibition did not alter the effects of alcohol on efferocytosis, treatment with the Rho kinase inhibitor, Y27632, reversed the effects of alcohol on efferocytosis.
Acute alcohol exposure impairs pulmonary efferocytosis, while exposure to chronic alcohol is only associated with impaired efferocytosis following LPS-induced lung injury. Both forms of alcohol exposure are associated with increased alveolar neutrophil numbers in response to LPS. The acute effects of alcohol on efferocytosis appear to be mediated, at least in part, by RhoA-independent activation of ROCK. Further studies are needed to dissect the differences between the effects of acute and chronic alcohol exposure on efferocytosis and to determine the effects of alcohol on alternative activators of ROCK.
Alcohol; ARDS; Efferocytosis; RhoA; Rho kinase
Dysphagia is common among survivors of critical illness who required mechanical ventilation during treatment. The risk factors associated with the development of postextubation dysphagia, and the effects of dysphagia on patient outcomes, have been relatively unexplored.
We conducted a retrospective, observational cohort study from 2008 to 2010 of all patients over 17 years of age admitted to a university hospital ICU who required mechanical ventilation and subsequently received a bedside swallow evaluation (BSE) by a speech pathologist.
A BSE was performed after mechanical ventilation in 25% (630 of 2,484) of all patients. After we excluded patients with stroke and/or neuromuscular disease, our study sample size was 446 patients. We found that dysphagia was present in 84% of patients (n = 374) and classified dysphagia as absent, mild, moderate or severe in 16% (n = 72), 44% (n = 195), 23% (n = 103) and 17% (n = 76), respectively. In univariate analyses, we found that statistically significant risk factors for severe dysphagia included long duration of mechanical ventilation and reintubation. In multivariate analysis, after adjusting for age, gender and severity of illness, we found that mechanical ventilation for more than seven days remained independently associated with moderate or severe dysphagia (adjusted odds ratio (AOR) = 2.84 [interquartile range (IQR) = 1.78 to 4.56]; P < 0.01). The presence of severe postextubation dysphagia was significantly associated with poor patient outcomes, including pneumonia, reintubation, in-hospital mortality, hospital length of stay, discharge status and surgical placement of feeding tubes. In multivariate analysis, we found that the presence of moderate or severe dysphagia was independently associated with the composite outcome of pneumonia, reintubation and death (AOR = 3.31 [IQR = 1.89 to 5.90]; P < 0.01).
In a large cohort of critically ill patients, long duration of mechanical ventilation was independently associated with postextubation dysphagia, and the development of postextubation dysphagia was independently associated with poor patient outcomes.
Aims: Our overall objective was to examine whether characteristics of epithelial lining fluid (ELF) from subjects with alcohol use disorders (AUDs) obtained via bronchoalveolar lavage (BAL) contribute to their predisposition to pneumococcal pneumonia. We sought to compare the anti-pneumococcal activity of acellular human BAL from subjects with AUDs to matched controls. Further, differences in BAL lysozyme activity and lactoferrin concentrations between these two groups were examined to determine the effect of AUDs on these antimicrobial proteins. Methods: BAL was performed in subjects with AUDs and matched controls. Acellular BAL was used at varying concentrations in an in vitro killing assay of Streptococcus pneumoniae, type 2, and the percent kill of organisms per microgram per milliliter total BAL protein was ascertained. Lysozyme activity and lactoferrin concentrations were measured in BAL from subjects and controls at measured concentrations of BAL protein. Results: AUD subjects (n = 15) and controls (n = 10) were enrolled in these investigations who were balanced in terms of smoking history. Using a mixed effect model, across the range of BAL protein concentrations, killing of pneumococcus tended to be less potent with BAL fluid from AUD subjects. Additionally, lysozyme activity and lactoferrin concentrations were significantly lower in the AUD group. Conclusions: The predisposition for pneumococcal pneumonia among those with AUDs may be in part mediated through effects of alcohol on substances within ELF that include antimicrobial proteins. Clarifying the composition and activity of ELF antimicrobial proteins in the setting of AUDs via investigations with human BAL fluid can help establish their contribution to the susceptibility for pulmonary infections in these individuals.
To determine whether post-traumatic stress disorder (PTSD) and burnout syndrome (BOS) are common in nurses, and whether the co-existence of PTSD and BOS is associated with altered perceptions of work and non-work related activities.
University hospital Nurses were administered four validated psychological questionnaires.
The response rate was 41% (332/810). Twenty two percent (73/332) had symptoms of PTSD, 18% (61/332) met diagnostic criteria for PTSD, and 86% (277/323) met criteria for BOS. Ninety eight percent (59/60) of those fulfilling diagnostic criteria for PTSD were positive for BOS. When grouped into three categories: positive for PTSD and BOS (n=59), positive for BOS and negative for PTSD (n=217), and negative for both BOS and PTSD (n=46), there were significant differences in the years of employment as a nurse (p < 0.0001), perceptions of collaborative nursing care (p = 0.006), confidence in physicians (p = 0.01), and perception that their work impacted patient outcomes (p = 0.01). Nurses with BOS and PTSD were significantly more likely to have difficulty in their life outside of the work environment when compared to those with BOS alone.
We identified that PTSD and BOS are common in nurses and those with PTSD will almost uniformly have symptoms of BOS. Co-existence of PTSD and BOS has a dramatic effect on work and non-work related activities and perceptions.
Burnout Syndrome; Post Traumatic Stress Disorder; and Nursing
Aims: Alcohol abuse is associated with the development of the acute respiratory distress syndrome, a disorder characterized by abnormal alveolar-capillary permeability. We hypothesized that individuals with a history of alcohol abuse would have clinical evidence of abnormal alveolar-capillary permeability even in the absence of symptoms. This could contribute to their propensity for the development of this disorder. Methods: Thirty-three subjects with a history of alcohol abuse, but no other medical problems, and 13 age- and smoking-matched controls inhaled 99mTc–DTPA (technetium-labeled diethylenetriamine penta-acetate; an isotope used to measure lung permeability) for a 3-min period, and washout of this isotope was measured for a 90-min period. The rate at which it was cleared from the lungs was assessed and compared between subjects and controls. Results: The half-life of 99mTc–DTPA in the lungs of subjects with alcohol abuse was significantly shorter than that observed in matched controls, even when correcting for the effects of concomitant tobacco use. When the half-life of the isotope for smoking alcohol-abusing subjects and smoking controls were compared separately, there was a trend for the alcohol-abusing subjects to have a shorter half-life of the isotope present in the lungs. This was also true when non-smokers were compared. Conclusions: These observations provide further evidence that alcohol abuse affects the normal permeability of the alveolar-capillary barrier and thereby may contribute to the development of the acute respiratory distress syndrome in individuals with alcohol abuse.
Chronic alcoholism is associated with an elevated risk for pulmonary infection and a 3-fold chance for incidence and mortality of acute respiratory distress syndrome with critical injury. Limited sampling of the alveolar lining fluid has restricted clinical studies of the role of glutathione (GSH) redox balance in pulmonary function and diseased states. Non-invasive sampling in the exhaled breath condensate (EBC) to monitor alveolar GSH would facilitate research in pulmonary oxidative stress.
EBC was collected from otherwise healthy subjects with and without a history of alcohol abuse. Reduced and oxidized EBC glutathione (GSH and GSSG, respectively), pH, and hydrogen peroxide were measured.
GSH was statistically decreased in alcohol abusers only when normalized to protein (4.7 nmol/mg protein [0.75, 11.4] vs 13.4 [7.8, 26.4], p=0.03). In contrast, GSSG was significantly elevated in the EBC from alcohol abusers when compared to controls, 5.62 [0.45. 8.94] vs 0.50 nM [0.38, 0.80], p= 0.03. Thus, a greater percentage was in the oxidized GSSG form when subjects abused alcohol, 35.3% [11.8, 58.1] vs 5.2 [3.6, 6.1], p<0.001). These concentrations represented a 40 mV shift in GSH redox state towards a more oxidized state.
Proper sample preparation was essential to prevent GSH loss and artificial oxidation. The shift in redox potential or %GSSG, which were not affected by dilution, may serve as better markers of pulmonary oxidative stress. Furthermore, these data suggested that the oxidant stress observed in the lavage fluid of otherwise healthy alcoholics could be measured non-invasively in the EBC.
EBC; GSH; Alcoholism; Redox potential
Rationale: Previous studies have linked the development and severity of acute respiratory distress syndrome with a history of alcohol abuse. In clinical studies, this association has been centered on depletion of pulmonary glutathione and subsequent chronic oxidant stress.
Objectives: The impact on redox potential of the plasma or pulmonary pools, however, has never been reported.
Methods: Plasma and bronchoalveolar lavage fluid were collected from otherwise healthy alcohol-dependent subjects and control subjects matched by age, sex, and smoking history.
Measurements and Main Results: Redox potential was calculated from measured reduced and oxidized glutathione in plasma and lavage. Among subjects who did and did not smoke, lavage fluid glutathione redox potential was more oxidized in alcohol abusers by approximately 40 mV, which was not altered by dilution. This oxidation of the airway lining fluid associated with chronic alcohol abuse was independent of smoking history. A shift by 20 mV in plasma glutathione redox potential, however, was noted only in subjects who both abused alcohol and smoked.
Conclusions: Chronic alcoholism was associated with alveolar oxidation and, with smoking, systemic oxidation. However, systemic oxidation did not accurately reflect the dramatic alcohol-induced oxidant stress in the alveolar space. Although there was compensation for the oxidant stress caused by smoking in control groups, the capacity to maintain a reduced environment in the alveolar space was overwhelmed in those who abused alcohol. The significant alcohol-induced chronic oxidant stress in the alveolar space and the subsequent ramifications may be an important modulator of the increased incidence and severity of acute respiratory distress syndrome in this vulnerable population.
glutathione; alcoholism; oxidative stress; pulmonary
We sought to determine whether higher levels of the novel biomarker growth differentiation factor-15 (GDF-15) are associated with poor outcomes and the presence of pulmonary vascular dysfunction (PVD) in patients with acute respiratory distress syndrome (ARDS).
We conducted a retrospective cohort study in patients enrolled in the Acute Respiratory Distress Syndrome Network Fluid and Catheter Treatment (FACT) Trial. Patients enrolled in the FACT Trial who received a pulmonary artery catheter (PAC), had plasma available from the same study day and sufficient hemodynamic data to determine the presence of PVD were included. Logistic regression was used to determine the association between GDF-15 level and 60-day mortality.
Of the 513 patients enrolled in the FACT Trial assigned to receive a PAC, 400 were included in this analysis. Mortality at 60 days was significantly higher in patients whose GDF-15 levels were in the third (28%) or fourth (49%) quartile when compared to patients with GDF-15 levels in the first quartile (12%) (P <0.001). Adjusting for severity of illness measured by APACHE III score, the odds of death for patients with GDF-15 levels in the fourth quartile when compared to the first quartile was 4.26 (95% CI 2.18, 10.92, P <0.001). When added to APACHE III alone for prediction of 60-day mortality, GDF-15 levels increased the area under the receiver operating characteristic curve from 0.72 to 0.77. At an optimal cutoff of 8,103 pg/mL, the sensitivity and specificity of GDF-15 for predicting 60-day mortality were 62% (95% CI 53%, 71%) and 76% (95% CI 71%, 81%), respectively. Levels of GDF-15 were not useful in identifying the presence of PVD, as defined by hemodynamic measurements obtained by a PAC.
In patients with ARDS, higher levels of GDF-15 are significantly associated with poor outcome but not PVD.
Acute respiratory distress syndrome; pulmonary vascular dysfunction; risk prediction; growth differentiation factor-15
Acute respiratory distress syndrome (ARDS) is a poorly understood condition with greater than 30% mortality. Massive recruitment of neutrophils to the lung occurs in the initial stages of the ARDS. Significant variability in the severity and duration of ARDS-associated pulmonary inflammation could be linked to heterogeneity in the inflammatory capacity of neutrophils. Interferon-stimulated genes (ISGs) are a broad gene family induced by Type I interferons. While ISGs are central to anti-viral immunity, the potential exists for these genes to evoke extensive modification in cellular response in other clinical settings. In this prospective study, we sought to determine if ISG expression in circulating neutrophils from ARDS patients is associated with changes in neutrophil function. Circulating neutrophil RNA was isolated, and hierarchical clustering ranked patients' expression of three ISGs. Neutrophil response to pathogenic bacteria was compared between normal and high ISG-expressing neutrophils. High neutrophil ISG expression was found in 25 of 95 (26%) of ARDS patients and was associated with reduced migration toward interleukin-8, and altered responses to Staphylococcus aureus, but not Pseudomonas aeruginosa, which included decreased p38 MAP kinase phosphorylation, superoxide anion release, interleukin-8 release, and a shift from necrotic to apoptotic cell death. These alterations in response were reflected in a decreased capacity to kill S. aureus, but not P. aeruginosa. Therefore, the ISG expression signature is associated with an altered circulating neutrophil response phenotype in ARDS that may predispose a large subgroup of patients to increased risk of specific bacterial infections.