Although obesity is implicated in numerous health complications leading to increased mortality, the relationship between obesity and outcomes for critically ill patients appears paradoxical. Recent studies have reported better outcomes and lower levels of inflammatory cytokines in obese patients with acute lung injury (ALI)/acute respiratory distress syndrome, suggesting that obesity may ameliorate the effects of this disease. We investigated the effects of obesity in leptin-resistant db/db obese and diet-induced obese mice using an inhaled LPS model of ALI. Obesity-associated effects on neutrophil chemoattractant response were examined in bone marrow neutrophils using chemotaxis and adoptive transfer; neutrophil surface levels of chemokine receptor CXCR2 were determined by flow cytometry. Airspace neutrophilia, capillary leak, and plasma IL-6 were all decreased in obese relative to lean mice in established lung injury (24 h). No difference in airspace inflammatory cytokine levels was found between obese and lean mice in both obesity models during the early phase of neutrophil recruitment (2-6 h), but early airspace neutrophilia was reduced in db/db obese mice. Neutrophils from uninjured obese mice demonstrated diminished chemotaxis to the chemokine keratinocyte cytokine compared with lean control mice, and adoptive transfer of obese mouse neutrophils into injured lean mice revealed a defect in airspace migration of these cells. Possibly contributing to this defect, neutrophil CXCR2 expression was significantly lower in obese db/db mice, and a similar but nonsignificant decrease was seen in diet-induced obese mice. ALI is attenuated in obese mice, and this blunted response is in part attributable to an obesity-associated abnormal neutrophil chemoattractant response.Keywords: adult respiratory distress syndrome; chemotaxis; cytokines; innate immunity Acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS) are characterized by persistent, uncontrolled pulmonary inflammation that occurs in response to a wide range of insults, including pneumonia, sepsis, and trauma (1, 2). Alveolar recruitment of neutrophils is thought to be a central factor in the onset and progression of this syndrome (3, 4), and increases in airspace neutrophilia and plasma neutrophilic cytokine levels, including TNF-a, IL-1b, IL-6, and IL-8, are associated with increased morbidity and mortality from this disease (4-6). It is increasingly recognized that ALI pathogenesis and outcome are strongly influenced by host factors, including genetic polymorphisms and comorbid conditions (1, 2). Preliminary clinical evidence suggests that obesity may have an ameliorative effect on ALI outcome (7). Although ambiguity exists in smaller studies (8, 9), recent large cohort studies from our group and others, as well as several metaanalyses, have shown a reduction in mortality with rising body mass index in ALI and critical illness in general (7,(10)(11)(12)(13)(14)(15)(16). Such an association, though tentative, is surprising because obesity...

The authors have no financial or intellectual conflicts of interest relevant to this research. The research was not supported by external funding.HYPOTHESIS: Institution of a rapid response team (RRT) improves patients' quality of death (QOD). SETTING: A 425-bed community teaching hospital. PATIENTS: All medical-surgical patients whose end-of-life care was initiated on the hospital wards during the 8 months before (pre-RRT) and after (post-RRT) actuation.STUDY DESIGN: Retrospective cohort study. METHODS: Medical records of all patients were reviewed using a uniform data abstraction tool. Demographic information, diagnoses, physiologic and laboratory data, and outcomes were recorded. RESULTS:A total of 197 patients died in both the pre-RRT and post-RRT periods. There were no differences in age, sex, advance directives, ethnicity, or religion between groups. Restorative outcomes, including in-hospital mortality (27 vs. 30/ 1000 admissions), unexpected transfers to intensive care (17 vs. 19/1000 admissions) and cardiac arrests (3 vs. 2.5/1000 admissions) were similar during the 2 periods. Outcomes, including formal comfort care only orders (68 vs. 46%), administration of opioids (68 vs. 43%), pain scores (3.0 AE 3.5 vs. 3.7 AE 3.2), patient distress (26 vs. 62%), and chaplain visits (72 vs. 60%), were significantly better in the post-RRT period compared to the pre-RRT period (all P < 0.05). During the post-RRT period, 61 patients died with RRT care and 136 died without RRT care. End-of-life care outcomes were similar for these groups except more RRT patients had chaplain visits proximate to their deaths (80% vs. 68%; P ¼ 0.0001). CONCLUSIONS:Institution of an RRT in our hospital had negligible impact on outcomes of patients whose goal was restorative care. Deployment of the RRT was associated with generally improved end-of-life pain management and psychosocial care.

Mounting evidence suggests that obesity and the metabolic syndrome have significant but often divergent effects on the innate immune system. These effects have been best established in monocytes and macrophages, particularly as a consequence of the hypercholesterolemic state. We have recently described defects in neutrophil function in the setting of both obesity and hypercholesterolemia, and hypothesized that exposure to elevated levels of lipoproteins, particularly LDL its oxidized forms, contributed to these defects. As a model of chronic cholesterol exposure, we examined functional responses of bone marrow neutrophils isolated from nonobese mice with diet-induced hypercholesterolemia compared to normal cholesterol controls. Chemotaxis, calcium flux, CD11b display, and F-actin polymerization were assayed in response to several chemoattractants, while neutrophil cytokine transcriptional response was determined to LPS. Following this, the acute effects of isolated LDL and its oxidized forms on normal neutrophils was assayed using the same functional assays. We found that neutrophils from nonobese hypercholesterolemic mice had blunted chemotaxis, altered calcium flux, and normal to augmented CD11b display with prolonged actin polymerization in response to stimuli. In response to acute exposure to lipoproteins, neutrophils showed chemotaxis to LDL which increased with the degree of LDL oxidation. Paradoxically, LDL oxidation yielded the opposite effect on LDL-induced CD11b display and actin polymerization, and both native and oxidized LDL were found to induce neutrophil transcription of the monocyte chemoattractant MCP-1. Together these findings suggest that chronic hypercholesterolemia impairs neutrophil functional responses, and these defects may be in part due to protracted signaling responses to LDL and its oxidized forms.

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