Jonathan M. Siner

Circulating Monocytes from Systemic Sclerosis Patients with Interstitial Lung Disease Show an Enhanced Profibrotic Phenotype

Profibrotic cells derived from circulating CD14+ monocytes include fibrocytes and alternatively activated macrophages. These cells are associated with interstitial lung disease (ILD) and are implicated in the pathogenesis of systemic sclerosis (SSc); however, the simultaneous presence of profibrotic cells and their associated mediators in the circulation of these patients has not been defined. We hypothesized that monocytes from patients with SSc-related ILD (SSc-ILD) would show profibrotic characteristics when compared with normal controls. We recruited patients with SSc-ILD (n=12) and normal controls (n=27) and quantified circulating collagen-producing cells by flow cytometry for CD45 and pro-collagen I. The in vitro activation potential of CD14+ monocytes in response to lipopolysaccharide was assessed using flow cytometry for CD163, and by ELISA for CCL18 and IL-10 secretion. Profibrotic mediators in plasma were quantified using Luminex-based assays. The concentration of circulating collagen-producing cells was increased in the SSc-ILD patients when compared with controls. These cells were composed of both CD34+ fibrocytes and a population of CD34+CD14+ cells. Cultured CD14+ monocytes from SSc-ILD patients revealed a profibrotic phenotype characterized by expression of CD163 and by enhanced secretion of CCL18 and IL-10 in response to proinflammatory activation. Plasma levels of IL-10, MCP-1, IL-1RA, and TNF levels were significantly elevated in the plasma of the SSc-ILD cohort. Subgroup analysis of the normal controls revealed that unlike the subjects ≤35 years, subjects ≥60 years old showed higher levels of circulating CD34+CD14+ cells, collagen-producing CD14+ monocytes, CD163+ monocytes, IL-4, IL-10, IL-13, MCP-1, and CCL18. These data indicate that the blood of patients with SSc-ILD and of healthy aged controls is enriched for fibrocytes, profibrotic monocytes, and fibrosis-associated mediators. Investigations defining the factors responsible for this peripheral blood profile may provide new insight into SSc-ILD as well as the pathophysiology of aging.

Elevated serum angiopoietin 2 levels are associated with increased mortality in sepsis.

The vascular growth factor angiopoietin 2 (Ang-2) is known to promote inflammation and endothelial dysfunction, but its prognostic capacity and relationship to outcomes in human sepsis are unknown. This is a prospective observational cohort study of 66 patients newly admitted to a tertiary care medical intensive care unit (ICU), which included ICU patients with no sepsis (n = 20) as well as those with sepsis (n = 10), severe sepsis (n = 12), and septic shock (n = 24). Clinical data were collected until hospital discharge, and Ang-2 and IL-6 levels were determined on specimens obtained after ICU admission. Serum Ang-2 correlated with IL-6 and severity-of-illness scores. In the septic cohort, circulating Ang-2 levels were significantly higher (P = 0.01) in those who died (24.9 ng/mL; interquartile range, 21.5-38.0 ng/mL) compared with those who survived (13.5 ng/mL; interquartile range, 8.1-21.6 ng/mL). Elevated circulating serum Ang-2 levels are associated with increased hospital mortality in patients with sepsis.

Structure, process, and annual ICU mortality across 69 centers: United States critical illness and injury trials group critical illness outcomes study

Objective:Hospital-level variations in structure and process may affect clinical outcomes in ICUs. We sought to characterize the organizational structure, processes of care, use of protocols, and standardized outcomes in a large sample of U.S. ICUs. Design:We surveyed 69 ICUs about organization, size, volume, staffing, processes of care, use of protocols, and annual ICU mortality. Setting:ICUs participating in the United States Critical Illness and Injury Trials Group Critical Illness Outcomes Study. Subjects:Sixty-nine intensivists completed the survey. Measurements and Main Results:We characterized structure and process variables across ICUs, investigated relationships between these variables and annual ICU mortality, and adjusted for illness severity using Acute Physiology and Chronic Health Evaluation II. Ninety-four ICU directors were invited to participate in the study and 69 ICUs (73%) were enrolled, of which 25 (36%) were medical, 24 (35%) were surgical, and 20 (29%) were of mixed type, and 64 (93%) were located in teaching hospitals with a median number of five trainees per ICU. Average annual ICU mortality was 10.8%, average Acute Physiology and Chronic Health Evaluation II score was 19.3, 58% were closed units, and 41% had a 24-hour in-house intensivist. In multivariable linear regression adjusted for Acute Physiology and Chronic Health Evaluation II and multiple ICU structure and process factors, annual ICU mortality was lower in surgical ICUs than in medical ICUs (5.6% lower [95% CI, 2.4–8.8%]) or mixed ICUs (4.5% lower [95% CI, 0.4–8.7%]). We also found a lower annual ICU mortality among ICUs that had a daily plan of care review (5.8% lower [95% CI, 1.6–10.0%]) and a lower bed-to-nurse ratio (1.8% lower when the ratio decreased from 2:1 to 1.5:1 [95% CI, 0.25–3.4%]). In contrast, 24-hour intensivist coverage (p = 0.89) and closed ICU status (p = 0.16) were not associated with a lower annual ICU mortality. Conclusions:In a sample of 69 ICUs, a daily plan of care review and a lower bed-to-nurse ratio were both associated with a lower annual ICU mortality. In contrast to 24-hour intensivist staffing, improvement in team communication is a low-cost, process-targeted intervention strategy that may improve clinical outcomes in ICU patients.

VEGF-induced heme oxygenase-1 confers cytoprotection from lethal hyperoxia in vivo

Prolonged exposure to hyperoxia results in hyperoxic acute lung injury (HALI). Vascular endothelial growth factor (VEGF) has been shown to have cytoprotective effects and prolong survival in an in vivo model of HALI. Heme oxygenase‐1 (HO‐1) has protective effects in hyperoxia; therefore, we hypothesized that induction of HO‐1 would be an important contributor to VEGF‐induced cytoprotection. Using inducible, lung‐specific VEGF overexpressing transgenic mice, we demonstrated that VEGF is a potent inducer of HO‐1 mRNA and protein in mouse lung. To evaluate the effect of inhibition of HO‐1 on injury, VEGF transgenic mice were treated with HO‐1 short interfering RNA (HO‐1 siRNA) and exposed to hyperoxia. Total lung lavage protein concentration, TUNEL staining, lipid peroxidation, and wet‐to‐dry ratio were all increased, consistent with increased injury. These findings were corroborated by survival studies in which inhibition of HO‐1 function using tin‐protoporphryin or silencing of HO‐1 with lentiviral HO‐1 short hairpin RNA (ShRNA) significantly decreased survival in hyperoxia. We conclude from these data that VEGF‐induced HO‐1 is an important contributor to cytoprotection in this in vivo model of acute lung injury and that alterations in VEGF function in the lung are likely to be important determinants of the outcome of acute lung injury.—Siner, J. M., Jiang, G., Cohen, Z. I., Shan, P., Zhang, X., Lee, C. G., Elias, J. A., Lee, P. J. VEGF‐induced heme oxygenase‐1 confers cytoprotection from lethal hyper‐oxia in vivo. FASEB J. 21, 1422–1432 (2007)

Role of semaphorin 7a signaling in transforming growth factor β1-induced lung fibrosis and scleroderma-related interstitial lung disease.

OBJECTIVE Semaphorin 7a regulates transforming growth factor β1 (TGFβ1)-induced fibrosis. This study was undertaken to test the hypothesis that semaphorin 7a exerts its profibrotic effects in part by promoting the tissue accumulation of CD45+ fibrocytes. METHODS A murine model of pulmonary fibrosis in which an inducible, bioactive form of the human TGFβ1 gene is overexpressed in the lung was used. Fibrosis and fibrocytes were evaluated in TGFβ1-transgenic mice in which the semaphorin 7a locus had been disrupted. The effect of replacement or deletion of semaphorin 7a on bone marrow-derived cells was ascertained using bone marrow transplantation. The role of the semaphorin 7a receptor β1 integrin was assessed using neutralizing antibodies. The applicability of these findings to TGFβ1-driven fibrosis in humans was examined in patients with scleroderma-related interstitial lung disease (ILD). RESULTS The appearance of fibrocytes in the lungs of TGFβ1-transgenic mice required semaphorin 7a. Replacement of semaphorin 7a on bone marrow-derived cells restored lung fibrosis and fibrocytes. Immunoneutralization of β1 integrin reduced pulmonary fibrocytes and fibrosis. Peripheral blood mononuclear cells (PBMCs) from patients with scleroderma-related ILD showed increased levels of messenger RNA for semaphorin 7a and its receptors, with semaphorin 7a located on collagen-producing fibrocytes and CD19+ lymphocytes. Peripheral blood fibrocyte outgrowth was enhanced in these patients. Stimulation of normal human PBMCs with recombinant semaphorin 7a enhanced fibrocyte differentiation; these effects were attenuated by β1 integrin neutralization. CONCLUSION Our findings indicate that interventions that reduce semaphorin 7a expression or prevent the semaphorin 7a-β1 integrin interaction may ameliorate TGFβ1-driven or fibrocyte-associated autoimmune fibroses.

Protocols and hospital mortality in critically ill patients: The United States Critical Illness and Injury Trials Group Critical Illness Outcomes Study

Objective:Clinical protocols may decrease unnecessary variation in care and improve compliance with desirable therapies. We evaluated whether highly protocolized ICUs have superior patient outcomes compared with less highly protocolized ICUs. Design:Observational study in which participating ICUs completed a general assessment and enrolled new patients 1 day each week. Patients:A total of 6,179 critically ill patients. Setting:Fifty-nine ICUs in the United States Critical Illness and Injury Trials Group Critical Illness Outcomes Study. Interventions:None. Measurements and Main Results:The primary exposure was the number of ICU protocols; the primary outcome was hospital mortality. A total of 5,809 participants were followed prospectively, and 5,454 patients in 57 ICUs had complete outcome data. The median number of protocols per ICU was 19 (interquartile range, 15–21.5). In single-variable analyses, there were no differences in ICU and hospital mortality, length of stay, use of mechanical ventilation, vasopressors, or continuous sedation among individuals in ICUs with a high versus low number of protocols. The lack of association was confirmed in adjusted multivariable analysis (p = 0.70). Protocol compliance with two ventilator management protocols was moderate and did not differ between ICUs with high versus low numbers of protocols for lung protective ventilation in acute respiratory distress syndrome (47% vs 52%; p = 0.28) and for spontaneous breathing trials (55% vs 51%; p = 0.27). Conclusions:Clinical protocols are highly prevalent in U.S. ICUs. The presence of a greater number of protocols was not associated with protocol compliance or patient mortality.

A tale of two ligands: angiopoietins, the endothelium, and outcomes

Angiopoietins signal via the Tie-2 receptor and are essential molecules for vasculogenesis during development and in the adult state play roles in vascular stability as well as inflammation and appear to be involved in the dysregulation of the endothelium in illness. Angiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2) are, respectively, agonists and competitive partial agonists, which have been found to undergo alterations in individuals with sepsis. In sepsis, Ang-2 levels are elevated and Ang-1 is decreased. In the previous issue of Critical Care, Fiusa and colleagues measure circulating Ang-1 and Ang-2 along with other growth factors in humans with febrile neutropenia. The authors found that an increased Ang-2/Ang-1 ratio, or an elevated Ang-2 level, at the time of an initial fever, is associated with subsequent development of septic shock and death. These findings validate that the Ang-2/Ang-1 balance, which is thought to reflect overall signaling via the Tie-2 receptor, is relevant to outcomes in patients with sepsis. Importantly, the specimens were obtained far in advance of the development of septic shock, suggesting that detectable alterations in this pathway may provide early clues regarding outcomes. This study adds to the evidence that angiopoietins are early markers of endothelial dysfunction in sepsis and provide prognostic information regarding outcomes.

Attitudes of Pulmonary and Critical Care Training Program Directors toward Quality Improvement Education

RATIONALE Quality improvement (QI) is a required component of fellowship training in pulmonary, critical care, and sleep medicine. However, little is known about how training programs approach QI education. OBJECTIVES We sought to understand the perceptions of pulmonary, critical care, and sleep medicine training program directors toward QI education. METHODS We developed and fielded an internet survey of pulmonary, critical care, and sleep medicine training program directors during 2013. Survey domains included program characteristics, the extent of trainee and faculty involvement in QI, attitudes toward QI education, and barriers to successful QI education in their programs. MEASUREMENTS AND MAIN RESULTS A total of 75 program directors completed the survey (response rate = 45.2%). Respondents represented both adult (n = 43, 57.3%) and pediatric (n = 32, 42.7%) programs. Although the majority of directors (n = 60, 80.0%) reported substantial fellow involvement in QI, only 19 (26.0%) reported having a formal QI education curriculum. QI education was primarily based around faculty mentoring (n = 46, 61.3%) and lectures (n = 38, 50.7%). Most directors agreed it is an important part of fellowship training (n = 63, 84.0%). However, fewer reported fellows were well integrated into ongoing QI activities (n = 45, 60.0%) or graduating fellows were capable of carrying out independent QI (n = 28, 50.7%). Key barriers to effective QI education included lack of qualified faculty, lack of interest among fellows, and lack of time. CONCLUSIONS Training program directors in pulmonary, critical care, and sleep medicine value QI education but face substantial challenges to integrating it into fellowship training.

Adverse Event Reporting and Quality Improvement in the Intensive Care Unit

Patients in the intensive care unit are at high risk for experiencing adverse events and errors. The high-acuity health care needs of these vulnerable patients expose them to numerous medications, procedures, and health care providers. The occurrence of adverse events is associated with detriments to patient outcomes including increased mortality. Adverse event reporting is the most commonly used event-detection tool, but it should also be complimented with other tools such as trigger tools, chart review, and direct observation. Although adverse event reporting is essential for continuous improvement processes and is associated with improvements in safety culture, it remains significantly underutilized.

Protocol-Based Care versus Individualized Management of Patients in the Intensive Care Unit.

The delivery of evidence-based care in the high-acuity environment of the intensive care unit can be challenging. In an effort to help turn guidelines and standards of care into consistent and uniform practice, physicians and hospitals turn toward protocol-based medical care. A protocol can help guide a practitioner to make correct interventions, at the right time, and in the proper order when managing a given disease. But to be considered a success, a protocol must meet several standards. A protocol must facilitate consistent practice, guiding the practitioner to deliver care more consistently than without the protocol. A good protocol must also be in alignment with the providers general practice and beliefs to assure wide adoption and complete penetrance. Finally, the protocol must deliver the most medically correct care-neither simplifying nor overcomplicating health care delivery. In addition to the care the protocol delivers, it must overcome other barriers to gain acceptance. These include concerns about protocol usage among medical trainees, physician concern regarding loss of autonomy, and the ceiling effect protocol-driven care places on expert practitioners, among other concerns. The aim of this article is to critically appraise what it means for a protocol to be considered successful with an aim toward improving protocol design and implementation in the future.