Effects of acute and chronic low density lipoprotein exposure on neutrophil function.

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 non-obese 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 were assayed using the same functional assays. We found that neutrophils from non-obese 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.

Obesity is associated with neutrophil dysfunction and attenuation of murine acute lung injury.

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.

Enhanced end-of-life care associated with deploying a rapid response team: a pilot study.

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 +/- 3.5 vs. 3.7 +/- 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 = 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.

Outcomes of cardiopulmonary resuscitation for patients on vasopressors or inotropes: a pilot study.

HYPOTHESIS: Outcomes of critically ill patients who receive cardiopulmonary resuscitation (CPR) are poor, and the subgroup on vasopressors or inotropes before cardiopulmonary arrest (CPA) rarely survives. SETTING: The setting of the study was a critical care unit of a 350-bed community teaching hospital. STUDY DESIGN: This was a retrospective, cohort study. METHODS: A retrospective review was performed of medical records of all patients, identified through medical billing and hospital committee records, who received CPR for CPA in a critical care unit. RESULTS: Of 83 patients, with an average age of 66 years, 14 (17%) survived to hospital discharge. Patients with pulseless electrical activity and asystole were significantly less likely to survive (9% and none, respectively; P = .0001). Only 2 (4%) of 55 critically ill patients receiving vasopressors before CPR survived, whereas 12 of 28 patients not on vasopressors survived (P < .0001). Although mechanical ventilation just before CPR was highly associated with administration of vasopressors, ventilation was not significantly associated with mortality (P = .13). Mortality of patients on vasopressors was higher for both mechanically ventilated (95% vs 33%, P < .001) and spontaneously breathing (100% vs 64%, P = .02) patients. In multiple logistic regression analyses, administration of vasopressors was the only variable independently associated with in-hospital mortality (odds ratio, 35.1; 95% confidence interval = 4.1-304.3). CONCLUSIONS: Survival of patients requiring CPR during critical care admission was 17%. Very few patients survived who required vasopressors or inotropes immediately before CPA. This study is limited significantly by its retrospective design and small cohort, and so this question should be reexamined in a larger study.