Ellen L. Burnham

Chronic alcohol abuse is associated with an increased incidence of acute respiratory distress syndrome and severity of multiple organ dysfunction in patients with septic shock.

ObjectiveAlcohol is one of the most commonly used drugs in the world and causes dysfunction in many vital organs. However, the effects of chronic alcohol abuse on acute lung injury and nonpulmonary organ dysfunction are relatively unexplored. The goal of this study was to determine the effects of chronic alcohol abuse on the incidence and severity of the acute respiratory distress syndrome and multiple organ dysfunction syndrome in patients with septic shock. DesignMulticenter prospective epidemiologic study. SettingIntensive care units of four university urban hospitals. PatientsA total of 220 critically ill patients with septic shock. Measurements and Main FindingsThirty percent of the patients (66 of 220) were identified as having a history of chronic alcohol abuse based on a positive response to an alcohol screening questionnaire. The incidence of acute respiratory distress syndrome in patients with a positive history of chronic alcohol abuse was 70% (46 of 66), compared with 31% (47 of 154) in individuals without a history of chronic alcohol abuse (p < .001). After adjusting for differences in the source of infection, sex, age, chronic hepatic dysfunction, diabetes, severity of illness, nutritional status, and smoking status, the effects of chronic alcohol abuse on the incidence of acute respiratory distress syndrome remained significant (p < .001; odds ratio, 3.70; 95% confidence interval, 1.83–7.71). The effect of the source of infection (pulmonary vs. nonpulmonary) on the development of acute respiratory distress syndrome also remained significant in this multivariable analysis (p < .001; odds ratio, 3.68; 95% confidence interval, 1.95–7.18). Based on the highest daily Sequential Organ Failure Assessment score, patients with a history of chronic alcohol abuse had more severe nonpulmonary organ dysfunction when compared with nonalcoholics (9.42 ± 3.89 vs. 8.05 ± 4.10, p = .01). After adjusting for source of infection, sex, age, nutritional status, history of diabetes, and smoking status, the effects of chronic alcohol abuse on the incidence of nonpulmonary organ dysfunction also remained significant (p = .03; odds ratio, 2.07; 95% confidence interval, 1.09–3.97). ConclusionsWe conclude that chronic alcohol abuse is an independent risk factor for acute respiratory distress syndrome and increases the severity of nonpulmonary organ dysfunction in patients with septic shock.

Postextubation dysphagia is persistent and associated with poor outcomes in survivors of critical illness

IntroductionDysphagia 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.MethodsWe 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.ResultsA 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).ConclusionsIn 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.

Chronic alcohol abuse, acute respiratory distress syndrome, and multiple organ dysfunction

ObjectiveTo review the effects of chronic alcohol abuse on the incidence, severity, and pathogenesis of acute respiratory distress syndrome (ARDS) and multiple organ dysfunction. Data SourcesA summary of published medical literature from MEDLINE search files and other reviews published concerning chronic alcohol abuse and critical illness. Data SummaryA history of chronic alcohol abuse is associated with an increased incidence and severity of ARDS in critically ill patients. In two separate epidemiologic studies, involving 571 intensive care patients, chronic alcohol abuse was a significant comorbid variable that increased the incidence of ARDS by nearly three-fold and was associated with more severe nonpulmonary organ dysfunction. In addition, nearly 50% of all ARDS patients had a significant history of chronic alcohol abuse, making the association between chronic alcohol abuse and ARDS a common scenario in the intensive care unit. By using animal models of chronic ethanol ingestion, researchers have identified alcohol-mediated alterations in epithelial and endothelial cell function, surfactant synthesis and secretion, alveolar-capillary barrier function, and lung matrix content and composition. More importantly, similar changes have been reported in humans with a history of chronic alcohol abuse. Individuals with a history of chronic alcohol abuse have decreased concentrations of glutathione in the epithelial lining fluid of the lung, which do not significantly increase after 1 wk of abstinence from alcohol. The total protein concentration in the epithelial lining fluid also is increased in these individuals with a history of chronic alcohol abuse compared with healthy controls, suggesting alterations in alveolar-capillary barrier function. ConclusionsChronic alcohol abuse is associated with an increased incidence of ARDS and the severity of multiple organ dysfunction. This research has implications in understanding the diagnosis of, and prognosis for, critically ill patients who are at risk of developing ARDS. It also may lead to the development of novel therapies for those patients at greatest risk of acute lung injury as a consequence of chronic alcohol abuse.

Adult lung side population cells have mesenchymal stem cell potential

BACKGROUND The development of stem cell therapy for pulmonary diseases remains a challenge. Many diverse cell types reside within the lung and a common stem cell has not yet been identified. A basic understanding of lung stem cell fate during disease may prove important for drug intervention as well as autologous therapies. Niches for resident mesenchymal stem cells (MSC) have been identified in many adult tissues and more recently in the lung. We present data to confirm the observation that non-hematopoietic CD45(neg) lung side population (SP) cells contain MSC, single cells capable of multilineage differentiation. METHODS We carried these observations forward by analyzing the MSC potential of single-cell clones, as well as their chromosomal stability and telomerase activity. RESULTS The expression of MSC markers was characterized in mouse CD45(neg) lung SP by flow cytometry on freshly isolated or cultured clonal populations. The karyotype of these cells was subsequently assayed by banding analysis, and telomerase activity was assessed using quantitative polymerase chain reaction. MSC differentiation potential was confirmed by the characteristic ability of single-cell clones to differentiate into cells of three mesenchymal lineages, chondrocytes, adipocytes and osteocytes. Differentiation was confirmed by histochemical analysis. All analyzed populations of CD45(neg) lung SP expressed mesenchymal markers (CD44, CD90, CD105, CD106, CD73 and Sca-I) and lacked hematopoietic markers (CD45, c-kit, CD11b, CD34 and CD14). The cultured and clonal CD45(neg) lung SP had normal chromosomal structures and expressed high levels of telomerase. After being expanded and cultured in differentiation medium, all populations of CD45(neg) lung SP demonstrated adipogenic, osteogenic and chrondrogenic potential. Adult CD45(neg) lung SP cells are a source of MSC. DISCUSSION In defining this tissue-specific stem cell population in the lung, we are now better able to clarify a potential role for them in lung diseases.

A randomized trial of recombinant human granulocyte-macrophage colony stimulating factor for patients with acute lung injury*

Rationale:Despite recent advances in critical care and ventilator management, acute lung injury and acute respiratory distress syndrome continue to cause significant morbidity and mortality. Granulocyte-macrophage colony stimulating factor may be beneficial for patients with acute respiratory distress syndrome. Objectives:To determine whether intravenous infusion of granulocyte-macrophage colony stimulating factor would improve clinical outcomes for patients with acute lung injury/acute respiratory distress syndrome. Design:A randomized, double-blind, placebo-controlled clinical trial of human recombinant granulocyte-macrophage colony stimulating factor 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. Setting:Medical and surgical intensive care units at three academic medical centers. Patients:One hundred thirty individuals with acute lung injury of at least 3 days duration were enrolled, out of a planned cohort of 200 subjects. Interventions:Patients were randomized to receive human recombinant granulocyte-macrophage colony stimulating factor (64 subjects, 250 &mgr;g/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 granulocyte-macrophage colony stimulating factor, p = .82). Differences in 28-day mortality (23% in placebo vs. 17% in patients receiving granulocyte-macrophage colony stimulating factor (p = .31) and organ failure-free days (12.8 ± 11.3 days placebo vs. 15.7 ± 11.9 days granulocyte-macrophage colony stimulating factor, p = .16) were not statistically significant. There were similar numbers of serious adverse events in each group. Conclusions:In a randomized phase II trial, granulocyte-macrophage colony stimulating factor treatment did not increase the number of ventilator-free days in patients with acute lung injury/acute respiratory distress syndrome. A larger trial would be required to determine whether treatment with granulocyte-macrophage colony stimulating factor might alter important clinical outcomes, such as mortality or multiorgan failure. (ClinicalTrials.gov number, NCT00201409 [ClinicalTrials.gov]).

Alcohol abuse in the critically ill patient

Alcohol abuse and dependence disorders are common in the 10% of hospitalised patients who need admission to the intensive care unit (ICU), but these disorders are often undiagnosed. The systemic effects from the excessive use of alcohol increase susceptibility to, or directly cause various important disorders in the critically ill. Early recognition of alcohol abuse and dependence is necessary and should prompt consideration of several alcohol-specific diagnoses that have important prognostic and therapeutic implications for these patients. We discuss the use of screening tests to improve the identification of alcohol abuse and dependence disorders, the epidemiology and pathogenesis of important alcohol-related disorders, differences in the presentation of several common alcohol-related diagnoses in the ICU, and important alcohol-specific therapies.

Training Mentors of Clinical and Translational Research Scholars: A Randomized Controlled Trial

Purpose To determine whether a structured mentoring curriculum improves research mentoring skills. Method The authors conducted a randomized controlled trial (RCT) at 16 academic health centers (June 2010 to July 2011). Faculty mentors of trainees who were conducting clinical/translational research ≥50% of the time were eligible. The intervention was an eight-hour, case-based curriculum focused on six mentoring competencies. The primary outcome was the change in mentors’ self-reported pretest to posttest composite scores on the Mentoring Competency Assessment (MCA). Secondary outcomes included changes in the following: mentors’ awareness as measured by their self-reported retrospective change in MCA scores, mentees’ ratings of their mentors’ competency as measured by MCA scores, and mentoring behaviors as reported by mentors and their mentees. Results A total of 283 mentor–mentee pairs were enrolled: 144 mentors were randomized to the intervention; 139 to the control condition. Self-reported pre-/posttest change in MCA composite scores was higher for mentors in the intervention group compared with controls (P < .001). Retrospective changes in MCA composite scores between the two groups were even greater, and extended to all six subscale scores (P < .001). More intervention-group mentors reported changes in their mentoring practices than control mentors (P < .001). Mentees working with intervention-group mentors reported larger changes in retrospective MCA pre-/posttest scores (P = .003) and more changes in their mentors’ behavior (P = .002) than those paired with control mentors. Conclusions This RCT demonstrates that a competency-based research mentor training program can improve mentors’ skills.

The fibroproliferative response in acute respiratory distress syndrome: mechanisms and clinical significance

Acute respiratory distress syndrome (ARDS) continues to be a major healthcare problem, affecting >190 000 people in the USA annually, with a mortality of 27–45%, depending on the severity of the illness and comorbidities. Despite advances in clinical care, particularly lung protective strategies of mechanical ventilation, most survivors experience impaired health-related quality of life for years after the acute illness. While most patients survive the acute illness, a subset of ARDS survivors develops a fibroproliferative response characterised by fibroblast accumulation and deposition of collagen and other extracellular matrix components in the lung. Historically, the development of severe fibroproliferative lung disease has been associated with a poor prognosis with high mortality and/or prolonged ventilator dependence. More recent studies also support a relationship between the magnitude of the fibroproliferative response and long-term health-related quality of life. The factors that determine which patients develop fibroproliferative ARDS and the cellular mechanisms responsible for this pathological response are not well understood. This article reviews our current understanding of the contribution of pulmonary dysfunction to mortality and to quality of life in survivors of ARDS, the mechanisms driving pathological fibroproliferation and potential therapeutic approaches to prevent or attenuate fibroproliferative lung disease. Despite protective ventilation, a subset of ARDS survivors develop lung fibrosis contributing to poor quality of life http://ow.ly/q8xCo

The acute pulmonary inflammatory response to the graded severity of smoke inhalation injury.

Objectives:To determine whether the graded severity of smoke inhalation is reflected by the acute pulmonary inflammatory response to injury. Design:In a prospective observational study, we assessed the bronchoalveolar lavage fluid 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). Setting:All patients were enrolled at a single tertiary burn center. Patients:The bronchoalveolar lavage fluid was obtained from 60 patients within 14 hrs of burn injury who underwent bronchoscopy for suspected smoke inhalation. Interventions:None. 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 bronchoalveolar lavage fluid, 21 were at their highest in those with the worst inhalation injury scores (grades 3 and 4), the greatest of which was interleukin-8 (92,940 pg/mL, grade 4). When compared in terms of low inhalation injury (grades 1–2) vs. high inhalation injury (grades 3–4), we found significant differences between groups for interleukin-4, interleukin-6, interleukin-9, interleukin-15, interferon-&ggr;, granulocyte-macrophage colony-stimulating factor, and monocyte chemotactic protein-1 (p < .05 for all). Conclusions:These data reveal that the degree of inhalation injury has basic and profound effects on burn patient morbidity, evokes complex changes of multiple alveolar inflammatory proteins, and is a determinant of the pulmonary inflammatory response to smoke inhalation. Accordingly, future investigations should consider inhalation injury to be a graded phenomenon. (Crit Care Med 2012; 40:–1121)

The protective role of laparoscopic antireflux surgery against aspiration of pepsin after lung transplantation.

BACKGROUND 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). METHODS 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. RESULTS 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. CONCLUSION 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.