Sushma K. Cribbs

Stem cells in sepsis and acute lung injury.

Objective:Sepsis and acute lung injury continue to be major causes of morbidity and mortality worldwide despite advances in our understanding of pathophysiology and the discovery of new management strategies. Recent investigations show that stem cells may be beneficial as prognostic biomarkers and novel therapeutic strategies in these syndromes. This article reviews the potential use of endogenous adult tissue-derived stem cells in sepsis and acute lung injury as prognostic markers and also as exogenous cell-based therapy. Data Sources:A directed systematic search of the medical literature using PubMed and OVID, with particular emphasis on the time period after 2002, was done to evaluate topics related to 1) the epidemiology and pathophysiology of sepsis and acute lung injury; and 2) the definition, characterization, and potential use of stem cells in these diseases. Data Synthesis and Findings:When available, preferential consideration was given to prospective nonrandomized clinical and preclinical studies. Conclusions:Stem cells have shown significant promise in the field of critical care both for 1) prognostic value and 2) treatment strategies. Although several recent studies have identified the potential benefit of stem cells in sepsis and acute lung injury, further investigations are needed to more completely understand stem cells and their potential prognostic and therapeutic value.

Correlation of the lung microbiota with metabolic profiles in bronchoalveolar lavage fluid in HIV infection

BackgroundWhile 16S ribosomal RNA (rRNA) sequencing has been used to characterize the lung’s bacterial microbiota in human immunodeficiency virus (HIV)-infected individuals, taxonomic studies provide limited information on bacterial function and impact on the host. Metabolic profiles can provide functional information on host-microbe interactions in the lungs. We investigated the relationship between the respiratory microbiota and metabolic profiles in the bronchoalveolar lavage fluid of HIV-infected and HIV-uninfected outpatients.ResultsTargeted sequencing of the 16S rRNA gene was used to analyze the bacterial community structure and liquid chromatography-high-resolution mass spectrometry was used to detect features in bronchoalveolar lavage fluid. Global integration of all metabolic features with microbial species was done using sparse partial least squares regression. Thirty-nine HIV-infected subjects and 20 HIV-uninfected controls without acute respiratory symptoms were enrolled. Twelve mass-to-charge ratio (m/z) features from C18 analysis were significantly different between HIV-infected individuals and controls (false discovery rate (FDR) = 0.2); another 79 features were identified by network analysis. Further metabolite analysis demonstrated that four features were significantly overrepresented in the bronchoalveolar lavage (BAL) fluid of HIV-infected individuals compared to HIV-uninfected, including cystine, two complex carbohydrates, and 3,5-dibromo-l-tyrosine. There were 231 m/z features significantly associated with peripheral blood CD4 cell counts identified using sparse partial least squares regression (sPLS) at a variable importance on projection (VIP) threshold of 2. Twenty-five percent of these 91 m/z features were associated with various microbial species. Bacteria from families Caulobacteraceae, Staphylococcaceae, Nocardioidaceae, and genus Streptococcus were associated with the greatest number of features. Glycerophospholipid and lineolate pathways correlated with these bacteria.ConclusionsIn bronchoalveolar lavage fluid, specific metabolic profiles correlated with bacterial organisms known to play a role in the pathogenesis of pneumonia in HIV-infected individuals. These findings suggest that microbial communities and their interactions with the host may have functional metabolic impact in the lung.

Stem cells in sepsis and acute lung injury

Introduction:Critical illnesses continue to be major causes of morbidity and mortality worldwide. Recent investigations show that stem cells may be beneficial as prognostic biomarkers and novel therapeutic strategies in these syndromes. This article reviews the use of stem cells in sepsis and acute lung injury as prognostic biomarkers and also as a potential for exogenous cell-based therapy. Methods:A directed search of the medical literature was done using PubMed and OVID to evaluate topics related to pathophysiology of sepsis and acute lung injury, in addition to the characterization and utilization of stem cells in these diseases. Conclusions:Stem cells have shown significant promise in the field of critical care medicine both for prognostication and treatment strategies. Although recent studies have been done to describe the mechanistic pathways of stem cells in critical illness, further investigation is necessary to fully delineate the mechanisms behind a stem cells immunomodulatory characteristics and its ability to mobilize and engraft in tissues.

Monitoring of endothelial dysfunction in critically ill patients: the role of endothelial progenitor cells

Purpose of reviewThis review provides an overview of sepsis as a prototypical critical illness and discusses the role of the endothelium in the pathophysiology of sepsis and sepsis-related organ dysfunction, the characterization and functions of endothelial progenitor cells, and investigates these cells both as a prognostic and therapeutic strategy in critically ill patients. Recent findingsSepsis continues to be a major cause of morbidity and mortality worldwide. Preclinical and clinical sepsis studies have shown that the acute systemic inflammatory and procoagulant response results in structural and functional alterations in the endothelium, which may lead to organ failure and ultimately, death. In the last decade, the concept of postnatal vasculogenesis has been revolutionized to include angiogenesis by mature endothelial cells and vasculogenesis by endothelial progenitor cells. These cells are recruited from the bone marrow to areas of endothelial injury, at which point they differentiate and promote revascularization of the endothelium, which has been shown to have significant prognostic and therapeutic implications in a variety of ischemic vascular disorders. SummaryCirculating endothelial progenitor cells may be an important mechanism of vascular repair, and thus shows significant promise for prognostic and therapeutic strategies in critical illness, namely sepsis and sepsis-related organ dysfunction.

A deep breath bronchoconstricts obese asthmatics.

Background: Asthma is characterized by the loss of a deep breath (DB)-induced bronchodilation and bronchoprotection. Obesity causes lung restriction and increases airway resistance, which may further worsen the capacity of a DB to induce bronchodilation; however, whether increasing BMI impairs the bronchodilatory response to a DB in asthmatics is unknown. Methods: The population consisted of 99 subjects, 87 with moderate to severe persistent asthma and 12 obese control subjects. Using transfer impedance we derived airway resistance (Raw). Participants breathed for 1 minute and took a slow DB followed by passive exhalation to functional residual capacity (FRC) and tidal breathing for another minute. Results: After a DB, obese asthmatics had the largest percent increase in Raw (median 9.8% interquartile range [IQR] 3.1–15.1), compared with overweight (6.5% IQR −1.3, 12.1) and lean (0.7% IQR −3, 7.9) asthmatics and obese controls (2.5% IQR –.6, 11) (p for trend = 0.008). The association between the percent increase in Raw after a DB and BMI as a continuous variable was significant (p = 0.02). Conclusions: In obese, moderate to severe and poorly controlled asthmatics, a DB results in increased Raw. This phenomenon was not observed in leaner asthmatics of similar severity or in obese control subjects.

Anti-Retroviral Therapy Is Associated with Decreased Alveolar Glutathione Levels Even in Healthy HIV-Infected Individuals

Objective Lung infections are a leading cause of death in HIV-infected individuals. Measuring redox in HIV-infected individuals may identify those with chronic oxidative stress who are at increased risk for lung infection. We sought to estimate the association between HIV infection and oxidative stress in the lung, as reflected by decreased levels of glutathione and cysteine in the epithelial lining fluid. Methods Bronchoalveolar lavage (BAL) fluid was collected from healthy HIV-infected subjects and controls. Individuals were excluded if they had evidence of major medical co-morbidities, were malnourished or smoked cigarettes. Results We enrolled 22 otherwise healthy HIV and 21 non-HIV subjects. Among the HIV-infected subjects, 72.7% were on anti-retroviral therapy (ART) with a median CD4 count of 438 (279.8–599) and viral load of 0 (0–1.0) log copies/mL. There were no significant differences in median BAL fluid glutathione and cysteine levels between HIV and HIV-uninfected subjects. However, BAL glutathione was significantly higher in HIV-infected subjects on anti-retroviral therapy (ART) compared to those not on ART [367.4 (102–965.3) nM vs. 30.8 (1.0–112.1) nM, p = 0.008]. Further, HIV infection with ART was associated with an OR of 2.02 for increased BAL glutathione when adjusted for age and body mass index, whereas HIV infection without ART was associated with an OR of 2.17 for decreased BAL glutathione. Conclusion HIV infection without ART was associated with increased oxidative stress, as reflected by decreased alveolar glutathione levels, in otherwise healthy HIV-infected individuals. Further study needs to be done identify predictors of lung health in HIV and to address the role of ART in improving lung immunity.

Biomarkers in acute lung injury: Are we making progress?

Acute lung injury (ALI) and its severe form, acute respiratory distress syndrome (ARDS), continue to be significant challenges to the critical care physician. First described in 1967, ALI/ARDS is characterized by the onset of clinically significant hypoxemia and diffuse bilateral pulmonary infiltrates. A clinically devastating and life threatening syndrome, it continues to carry a mortality of 40% – 50%, and is an important cause of pulmonary and non-pulmonary morbidity in patients who survive hospitalization. (1) For four decades, the search has continued for useful diagnostic and prognostic biomarkers that will guide us as critical care physicians to precisely distinguish ALI/ARDS from other disorders and to portend disease progression. The identification of such a biomarker would allow for improved clinical decision-making, knowledgeable family discussions, and better utilization of healthcare resources. Unfortunately, this search has been hindered by the inherent heterogeneity of the disease along with the consistent lack of correlation between biochemical markers, pathophysiologic variables and clinical outcomes. ALI/ARDS instigates a myriad of cellular and molecular cascades that result in circulating inflammatory and prothrombotic mediators; pathophysiologic disturbances that may be important determinants of mortality. With improved understanding of pathophysiology, many biomarkers have been assessed for diagnostic or prognostic capability, such as inflammatory mediators such as interleukin-1β [IL-1β] (2,3) and tumor necrosis factor-α [TNF-α] (4), which can be detected in the distal airspaces of the lung in ALI/ARDS patients. Most recently investigators have documented the influence of the coagulation system in ALI/ARDS, with levels of IL-8, ICAM-8, plasminogen activator inhibitor-1 and protein C being predictive of clinical outcomes. (5,6) We have also evaluated markers of endothelial injury (von Willebrand factor), (7,8) epithelial injury, (receptor for advanced glycation end-products [RAGE] (9) and surfactant protein-D [SP-D]), (10) stem cells, (11) and physiologic measures such as pulmonary dead space fraction (12) or extravascular lung water. (13,14) This issue of Critical Care Medicine includes an important hypothesis-generating article by Mauri and his colleagues (15). The authors report the results of an observational study of pentraxin 3 (PTX3) as a marker of severity and as an outcome predictor in ALI/ARDS patients. They enrolled 21 patients with ALI/ARDS, measured plasma PTX3, C-reactive protein (CRP), and other inflammatory markers at various time points, and correlated these results to multiple measures of disease severity and organ dysfunction including lung injury score (LIS), sequential organ failure assessment (SOFA), and simplified acute physiology score II (SAPS II). The authors made several novel observations: 1) Plasma PTX3 levels were elevated in patients with ALI/ARDS for the first week, which then decreased and stabilized until ICU discharge. In contrast, CRP levels remained consistently elevated throughout the ICU stay; 2) PTX3 level was the only parameter examined that was consistently and significantly different between survivors and non-survivors; 3) PTX3 levels correlated with parameters of lung injury and organ dysfunction; 4) PTX3 levels were elevated in either blood or bronchoalveolar lavage fluid for patients with a documented infection. Using analytical tools to assess biological parameters can provide researchers with an opportunity to gain a mechanistic understanding of disease processes. In 2001, the NIH adopted the definition of a biomarker as “…an indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention.” (16) The authors of this study have begun to study an interesting idea will PTX3 levels help predict which ALI/ARDS patients will die? PTX3, a newly discovered acute phase protein, is expressed locally in response to a variety of infectious and inflammatory stimuli and plays a key role in innate immunity (17,18). Unlike its cousin, CRP, PTX3 gene expression is induced by TNF-α and IL-1β in an assortment of human tissue cells, including fibroblasts and epithelial cells (17). Increased levels of PTX3 have been found in a number of sepsis and ALI animal models, correlating with lung injury severity (19), and in some cases mortality (20), suggesting that PTX3 may play a role in the pathogenesis of ARDS. A biomarker that indicates pathogenic processes and is involved in molecular pathways will guide researchers in further understanding intricate disease mechanisms, so that novel therapeutic interventions may be developed. Applying criteria publicized by the McMaster group (21), we can assess the value of PTX3 as a biomarker in ALI/ARDS. Accordingly, there was a representative inception cohort of ALI/ARDS patients, with the primary cause being pneumonia; however, the small sample from a single ICU setting limits generalizability. Objective outcome criteria were used and included standards for measuring organ dysfunction (LIS, SOFA, SAPS II) and survival, although adjustment for extraneous prognostic factors was not performed. Despite PTX3 being the only parameter statistically different between survivors and non-survivors, it is likely that other parameters would also differ with a larger study population. In addition, the numerical differences seen with age, SOFA and SAPS II scores may be clinically (if not statistically) significant. Because of these limitations, the different PTX3 levels seen between ALI/ARDS survivors and non-survivors should be interpreted with caution. Nevertheless, despite these limitations, this work on PTX3 represents an important development in our understanding of ALI/ARDS the exploration of a novel prognostic and potentially pathophysiologic biomarker in a patient population that continues to suffer a high mortality. Because PTX3 may play an important role in host defense and contribute to the pathogenesis of ALI/ARDS, it may be a critical biochemical marker to improve our understanding of ALI/ARDS pathophysiology, to help us accurately identify ALI/ARDS patients, and to predict outcomes. Further study is needed to corroborate these hypotheses, with sufficient numbers of patients to account for both relevant biomarker parameters as well as clinical data that is available at the bedside for prognostic purposes (such as organ dysfunctions or severity of illness scores). While biomarker exploration may have scientific value in isolation, the combination of biological data with clinical information is necessary for biomarkers to have clinical utility. This combined approach is the standard for future biomarker studies. With our recent advances in understanding both pathophysiology of ALI/ARDS and technological advances in biomarker identification, we are optimistic that a clinically and scientifically useful biomarker is not far over the horizon.

Navigating the institutional review board approval process in a multicenter observational critical care study.

Objective:To characterize variation in the institutional review board application process of a multicenter, observational critical care study. Design, Setting, and Subjects:Survey analysis of 36 investigators who applied for participation in the United States Critical Illness and Injury Trials Group: Critical Illness and Outcomes Study, an observational study of 69 adult ICUs. Interventions:None. Measurements and Main Results:Analysis of investigator-specific characteristics, institutional review board process, application and approval dates, and level of difficulty in obtaining approval. Surveys were analyzed from 36 sites (95%) that applied for institutional review board approval. Level of review ranged from full board, expedited, to exempt. Seventy-five percent of applications were submitted by an experienced investigator while 25% were submitted by a less experienced investigator. Median time to institutional review board approval was 30 days (interquartile range, 14–54) and ranged from 5 days to 5.5 months. Time to approval was 29 days (interquartile range, 17–48) for applications submitted by an experienced investigator compared with 97 days (interquartile range, 25–159) for those submitted by a less experienced investigator (p = 0.08). Subjective level of difficulty was significantly higher for less experienced investigators (4 of 10; interquartile range, 2–8) vs experienced investigators (2 of 10; interquartile range, 1–3) (p = 0.04). Four sites cited institutional review board concern regarding waiver of consent as a major barrier to approval and were required to perform revisions or participate in board meetings regarding this concern. Conclusions:In a multicenter, observational critical care study, significant variation was observed between sites in all aspects of the institutional review board evaluation and approval process. The level of difficulty was significantly higher for less experienced investigators with a trend toward longer time to institutional review board approval. Variation in institutional review board interpretation of waiver of informed consent regulations was cited as a major barrier to approval.

Fluid balance and colloid osmotic pressure in acute respiratory failure: optimizing therapy

Acute lung injury and acute respiratory distress syndrome continue to be major causes of morbidity and mortality in the intensive care unit due to a lack of specific effective therapy. Affecting nearly 200,000 people every year in the USA alone, patients with this syndrome often require extensive intensive care unit and hospital care, leading to enormous utilization of healthcare resources and significant expenditures, and ultimately leaving survivors with a reduced quality of life. A disease of altered capillary permeability, acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is characterized by significant fluid imbalances and oncotic pressure changes. Although investigations directed at these abnormalities may improve patient-centered outcomes, fluid management in ALI/ARDS continues to be a source of great controversy. In this review, we discuss fluid balance and the colloid osmotic pressure gradients in ALI/ARDS, followed by a review of the prognostic implications of increasing extravascular lung water, and conclude with contemporary approaches to optimizing therapy in this condition, including the role of albumin and diuretic therapy.

Safety of research bronchoscopy in critically ill patients

OBJECTIVE Bronchoscopy and bronchoalveolar lavage (BAL) are common procedures in intensive care units; however, no contemporaneous safety and outcomes data have been reported, particularly for critically ill patients. DESIGN This is a retrospective analysis of prospectively collected data from teaching hospital adult intensive care units. INTERVENTIONS One hundred mechanically ventilated patients with severe sepsis, septic shock, acute lung injury (ALI), and/or acute respiratory distress syndrome underwent bronchoscopy with unilateral BAL. Data collected included demographics, presence of sepsis or ALI, Pao2 to Fio2 ratio, positive end-expiratory pressure, Acute Physiology and Chronic Health Evaluation score, Sequential Organ Failure Assessment score, and peri- or postprocedural complications. RESULTS Men comprised 51% of the patients; 81% of the patients were black, and 15% were white. The mean age was 52 (SD, ±16) years. The mean Acute Physiology and Chronic Health Evaluation score was 22 (±7.5), whereas the median Sequential Organ Failure Assessment score was 9 (interquartile range, 5-12). Ten patients (10%) had complications during or immediately after the procedure. Hypoxemia during or immediately after the BAL was the most common complication. Ninety percent of the complications were related to transient hypoxemia, whereas bradycardia and hypotension each occurred in 1 patient. Age, female sex, and higher positive end-expiratory pressure were associated with complications. CONCLUSIONS Bronchoscopy with BAL in critically ill patients with sepsis and ALI is well tolerated with low risk of complications, primarily related to manageable hypoxemia.