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OBJECTIVE: : To determine the association between excess weight and processes of care and outcomes for critically ill adults. DESIGN: : Prospective cohort study. SETTING: : Three medical intensive care units at two hospitals. PATIENTS: : Five hundred eighty mechanically ventilated adult patients admitted between February 1, 2006 and January 31, 2008. INTERVENTIONS: : None. MEASUREMENTS AND MAIN RESULTS: : After adjusting weight based on the recorded fluid balance before enrollment, 21.9% of subjects were categorized into different body mass index categories than without this adjustment. We used a competing risk analysis with events of interest considered death during hospitalization and successful liberation from mechanical ventilation. We found no statistically significant difference between body mass index categories (<25 kg/m vs. 25 to <30 kg/m vs. >=30 kg/m) in the competing risks analyses when the results were unadjusted or adjusted for severity of illness and comorbidities. When the analyses were adjusted for the use of continuous infusions of opioids and/or sedatives and ventilator parameters (tidal volume per ideal body weight, positive end-expiratory pressure, and airway pressure), subjects with an overweight fluid-balance-adjusted body mass index had significantly lower hazard ratios for dying while hospitalized (adjusted hazard ratio 0.68 [95% confidence interval 0.47-0.99], p = .044), and those with an obese fluid-adjusted body mass index had significantly higher hazard ratios for successful extubation (adjusted hazard ratio 1.53 [95% confidence interval 1.14-2.06], p = .005). An analysis of longer-term mortality found lower adjusted hazard ratios for subjects with overweight (adjusted hazard ratio 0.74 [95% confidence interval 0.56-0.96]) and obese (adjusted hazard ratio 0.74 [95% confidence interval 0.59-0.94]) fluid-balance-adjusted body mass indices. CONCLUSIONS: : Processes of provided care may affect the observed association between excess weight and outcomes for critically ill adults and should be considered when making inferences about observed results. It is unknown if disparities in processes of care are due to clinically justified reasons for variation, bias against heavier patients, or other reasons. [ABSTRACT FROM AUTHOR]

RATIONALE: Little is known about the consequences of intensivists' work schedules, or intensivist continuity of care. OBJECTIVES: To assess the impact of weekend respite for intensivists, with consequent reduction in continuity of care, on them and their patients. METHODS: In five medical intensive care units (ICUs) in four academic hospitals we performed a prospective, cluster-randomized, alternating trial of two intensivist staffing schedules. Daily coverage by a single intensivist in half-month rotations (continuous schedule) was compared with weekday coverage by a single intensivist, with weekend cross-coverage by colleagues (interrupted schedule). We studied consecutive patients admitted to study units, and the intensivists working in four of the participating units. MEASUREMENTS AND MAIN RESULTS: The primary patient outcome was ICU length of stay (LOS);we also assessed hospital LOS and mortality rates. The primary intensivist outcome was physician burnout. Analysis was by multivariable regression. A total of 45 intensivists and 1,900 patients participated in the study. Continuity of care differed between schedules (patients with multiple intensivists = 28% under continuous schedule vs. 62% under interrupted scheduling; P < 0.0001). LOS and mortality were nonsignificantly higher under continuous scheduling ([Delta]ICU LOS 0.36 d, P = 0.20; [Delta]hospital LOS 0.34 d, P = 0.71; ICU mortality, odds ratio = 1.43, P = 0.12; hospital mortality, odds ratio = 1.17,P = 0.41). Intensivists experienced significantly higher burnout, work-home life imbalance, and job distress working under the continuous schedule. CONCLUSIONS: Work schedules where intensivists received weekend breaks were better for the physicians and, despite lower continuity of intensivist care, did not worsen outcomes for medical ICU patients. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To determine the association between alcohol dependence (alcoholism not in remission and/or alcohol withdrawal) and sepsis, septic shock, and hospital mortality among intensive care unit (ICU) patients. DESIGN: Retrospective cohort study. SETTING: Two ICUs in an urban hospital. PATIENTS: Patients included 11,651 adult admissions to Denver Health Medical Center from January 1, 1999, to December 31, 2004, with >or=1 ICU day. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of first admissions appearing in the data set (n=9,981), 1,222 (12.2%) had a diagnosis consistent with alcohol dependence. These patients had higher rates of sepsis (12.9% vs. 7.6%, p<.001), organ failure (67.3% vs. 45.8%, p<.001), septic shock (3.6% vs. 2.1%, p=.001), and hospital mortality (9.4% vs. 7.5%, p=.022) on unadjusted analyses. Patients with alcohol dependence also had fewer hospital-free days. After adjustment for factors with known association with sepsis, alcohol dependence was associated with sepsis. This association was modified if the patient received (adjusted odds ratio, 0.92; 95% confidence interval, 0.65-1.31) or did not receive (adjusted odds ratio, 1.91; 95% confidence interval, 1.49-2.44) red cell transfusions. A general predisposition to infections mediated some, but not all, of this association. Results were similar when repeat admissions were included in the analysis. Alcohol dependence was also associated with septic shock and hospital mortality in multivariable analyses. Among those with liver disease and sepsis, alcohol dependence was associated with more than two-fold increased risk-adjusted odds of hospital mortality (adjusted odds ration, 2.31; 95% confidence interval, 1.26-4.24). Similarly, sepsis and liver disease carried higher odds of death for alcohol-dependent patients than for those without alcohol dependence. CONCLUSIONS: Alcohol dependence is independently associated with sepsis, septic shock, and hospital mortality among ICU patients. The underlying mechanisms of this association require exploration, as an increased rate of infections mediated some, but not all, of this association. [ABSTRACT FROM AUTHOR]

Objective: To determine the association between body mass index (BMI) and hospital mortality for critically ill adults.Design: Retrospective cohort study.Setting: One-hundred six intensive care units (ICUs) in 84 hospitals.Patients: Mechanically ventilated adults (n=1,488) with acute lung injury (ALI) included in the Project IMPACT database between December 1995 and September 2001.Interventions: None.Measurements and Main Results: Over half of the cohort had a BMI above the normal range. Unadjusted analyses showed that BMI was higher among subjects who survived to hospital discharge vs. those who did not (p<.0001). ICU and hospital mortality rates were lower in higher BMI categories. After risk-adjustment, BMI was independently associated with hospital mortality (p<.0001) when modeled as a continuous variable. The adjusted odds were highest at the lowest BMIs and then declined to a minimum between 35 and 40 kg/m2. Odds increased after the nadir but remained below those seen at low BMIs. With use of a categorical designation, BMI was also independently associated with hospital mortality (p=.0055). The adjusted odds were highest for the underweight BMI group (adjusted odds ratio [OR], 1.94; 95% confidence interval [CI], 1.05-3.60) relative to the normal BMI group. As in the analysis using the continuous BMI variable, the odds of hospital mortality were decreased for the groups with higher BMIs (overweight adjusted OR, 0.72; 95% CI, 0.51-1.02; obese adjusted OR, 0.67; 95% CI, 0.46-0.97; severely obese adjusted OR, 0.78; 95% CI, 0.44-1.38). Differences in the use of heparin prophylaxis mediated some of the protective effect of severe obesity.Conclusions: BMI was associated with risk-adjusted hospital mortality among mechanically ventilated adults with ALI. Lower BMIs were associated with higher odds of death, whereas overweight and obese BMIs were associated with lower odds. [ABSTRACT FROM AUTHOR]

Background: Despite an epidemic of obesity among adults, the effect of excess body weight on outcome from critical illness is not well studied.Objective: To examine the association between excess body weight and outcome in mechanically ventilated patients with acute lung injury.Design: Secondary analysis of participants in trials of therapy for acute lung injury.Setting: 10 U.S. medical centers that participate in the National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome Network.Patients: 902 mechanically ventilated patients who were enrolled in randomized, controlled trials of therapy for acute lung injury.Intervention: Assignment to higher (12 mL/kg of predicted weight) or lower (6 mL/kg of predicted weight) tidal volume ventilation strategies with specified weaning protocols. Some patients also received ketoconazole, lisofylline, or placebo by factorial design.Measurements: Mortality rate, rate of unassisted ventilation by day 28, and number of ventilator-free days.Results: Indirect causes of lung injury, including trauma, were more common in obese patients. Overweight and obese patients had higher peak and plateau airway pressures before enrollment because of higher set tidal volumes. After risk adjustment, excess body weight was not associated with death, achievement of unassisted ventilation, or number of ventilator-free days. This lack of effect persisted with categorical or continuous measures of body mass index (BMI). We found no significant interaction between ventilator protocol assignment and BMI category.Conclusions: After risk adjustment, overweight and obese patients with acute lung injury have outcomes similar to those of patients with normal BMI. The lack of interaction between ventilator protocol assignment and BMI suggests that patients with normal, overweight, or obese BMI benefit from lower tidal volume ventilation for acute lung injury. [ABSTRACT FROM AUTHOR]

Objectives: To review human models of endotoxemia with an emphasis on the inflammatory and coagulopathic effects of lipopolysaccharide to describe the possible mechanisms of clinical benefit of recombinant human activated protein C (drotrecogin alfa [activated]) in severe sepsis.Data Source: A selected review of published literature in English on human endotoxemia models with special attention to studies using drotrecogin alfa (activated) in concert with endotoxemia.Data Extraction and Synthesis: After intravenous administration of purified lipopolysaccharide, subjects report constitutional influenza-like symptoms associated with an increase in temperature. Within 1 hr of lipopolysaccharide infusion, total leukocyte counts decline. Sustained leukocytosis, due to an increase in neutrophils counts, follows. An increase in markers of neutrophil activation (e.g., serum elastase) accompanies this leukocytosis. Production of tumor necrosis factor-alpha, interleukin-6, and interleukin-8 is also increased. In association with an inflammatory response, lipopolysaccharide administration also activates the coagulation system. Lipopolysaccharide infusion generates thrombin and initially activates fibrinolysis but subsequently generates inhibitors of the fibrinolytic system. Serum levels of endogenous inhibitors of coagulation (e.g., antithrombin, protein C, tissue factor pathway inhibitor) are not affected. Data are available for 40 subjects who have participated in placebo-controlled studies of drotrecogin alfa (activated) infusion before an intravenous dose of lipopolysaccharide. In these subjects, drotrecogin alfa (activated) has minimal effects on measured variables, including physiologic variables, markers of inflammation, and measures of sepsis-induced coagulopathy.Conclusion: Human endotoxemia is, at best, an incomplete model of human sepsis. In two studies using recombinant human activated protein C in the setting of human endotoxemia, there were minimal effects on hemodynamics, inflammation, thrombin generation, fibrinolysis, and markers of cellular activation. Other putative mechanisms of recombinant human activated protein C, such as inhibition of apoptosis and leukocyte recruitment, remain to be studied. [ABSTRACT FROM AUTHOR]

Objectives: Although critical care physicians view obesity as an independent poor prognostic marker, growing evidence suggests that obesity is, instead, associated with improved mortality following ICU admission. However, this prior empirical work may be biased by preferential admission of obese patients to ICUs, and little is known about other patient-centered outcomes following critical illness. We sought to determine whether 1-year mortality, healthcare utilization, and functional outcomes following a severe sepsis hospitalization differ by body mass index., Design: Observational cohort study., Setting: U.S. hospitals., Patients: We analyzed 1,404 severe sepsis hospitalizations (1999-2005) among Medicare beneficiaries enrolled in the nationally representative Health and Retirement Study, of which 597 (42.5%) were normal weight, 473 (33.7%) were overweight, and 334 (23.8%) were obese or severely obese, as assessed at their survey prior to acute illness. Underweight patients were excluded a priori., Interventions: None., Measurements and Main Results: Using Medicare claims, we identified severe sepsis hospitalizations and measured inpatient healthcare facility use and calculated total and itemized Medicare spending in the year following hospital discharge. Using the National Death Index, we determined mortality. We ascertained pre- and postmorbid functional status from survey data. Patients with greater body mass indexes experienced lower 1-year mortality compared with nonobese patients, and there was a dose-response relationship such that obese (odds ratio = 0.59; 95% CI, 0.39-0.88) and severely obese patients (odds ratio = 0.46; 95% CI, 0.26-0.80) had the lowest mortality. Total days in a healthcare facility and Medicare expenditures were greater for obese patients (p < 0.01 for both comparisons), but average daily utilization (p = 0.44) and Medicare spending were similar (p = 0.65) among normal, overweight, and obese survivors. Total function limitations following severe sepsis did not differ by body mass index category (p = 0.64)., Conclusions: Obesity is associated with improved mortality among severe sepsis patients. Due to longer survival, obese sepsis survivors use more healthcare and result in higher Medicare spending in the year following hospitalization. Median daily healthcare utilization was similar across body mass index categories.

As health care expenditures increase, payers, including the Centers for Medicare and Medicaid Services, are moving away from reimbursement based on types and volume of services to an emphasis on quality of provided care, an approach called value-based purchasing (VBP). Because it is tied to reimbursement, VBP creates economic motivation to measure and improve care. VBP is proceeding without high-level evidence supporting its effectiveness in improving health care quality. Rising health care costs, however, make VBP an attractive approach for curtailing costs and emphasizing improved quality, and VBP is likely to become a more prevalent mechanism of reimbursement for providers and facilities., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Introduction: Socio-demographic and clinical factors associated with increased sepsis risk, including older age, non-white race and specific co-morbidities, are more common among patients with Medicare or Medicaid or no health insurance. We hypothesized that patients with Medicare and/or Medicaid or without health insurance have a higher risk of sepsis-associated hospitalization or sepsis-associated death than those with private health insurance., Methods: We performed a retrospective cohort study of records from the 2003 Nationwide Inpatient Sample. We stratified the study cohort by Medicare age-qualification (18 to 64 and 65+ years old). We examined the association between insurance category and sepsis diagnosis and death among admissions involving sepsis. We used validated diagnostic codes to determine the presence of sepsis, co-morbidities and organ dysfunction and to provide risk-adjustment., Results: Among patients 18 to 64 years old, those with Medicaid (adjusted odds ratio (AOR) 1.50), Medicare (AOR 1.96), Medicaid + Medicare (AOR 2.22) and the uninsured (AOR 1.18) had significantly higher risk-adjusted odds of a sepsis-associated admission than those with private insurance (all P < 0.0001). Those with Medicaid (AOR 1.17, P < 0.001) and those without insurance (AOR 1.45, P < 0.001) also had significantly higher adjusted odds of sepsis-associated hospital mortality than those with private insurance. Among those 65+ years old, those with Medicaid (AOR 1.43), Medicare alone (AOR 1.13) or Medicaid + Medicare (AOR 1.62) had significantly higher risk-adjusted odds of sepsis-associated admission than those with private insurance and Medicare (all P < 0.0001). Among sepsis patients 65+, uninsured patients had significantly higher risk-adjusted odds (AOR 1.45, P = 0.0048) and those with Medicare alone had significantly lower risk-adjusted odds (AOR 0.92, P = 0.0072) of hospital mortality than those with private insurance and Medicare. Lack of health insurance remained associated with sepsis-associated mortality after stratification of hospitals into quartiles based on rates of sepsis-associated admissions or mortality in both age strata., Conclusions: Risks of sepsis-associated hospitalization and sepsis-associated death vary by insurance. These increased risks were not fully explained by the available socio-demographic factors, co-morbidities or hospital rates of sepsis-related admissions or deaths.

Purpose: We sought to evaluate factors associated with choices about provided care for patients with septic shock, including the use of drotrecogin α (activated) (DAA)., Materials and Methods: We administered a mail-based survey to a random sample of intensivists. Study vignettes presented patients with septic shock with identical severity of illness scores but different ages, body mass indices, and comorbidities. Respondents estimated outcomes and selected care beyond standardized initial care (eg, antibiotics) for each hypothetical patient., Results: For most vignettes (99.1%), respondents added care, most commonly low tidal volume ventilation (87.6%) and enteral nutrition (73.3%). Choosing to administer DAA was not associated with predictions about mortality or bleeding. Vignettes with early-stage lung cancer were less likely to receive DAA. Time since medical school graduation was also associated with lower odds of selecting DAA. Most respondents (52.6%) chose identical care for all 4 completed vignettes., Conclusions: There was wide variability in the therapeutic choices of respondents. The use of DAA was not associated with perceived risk of mortality or bleeding, as recommended by consensus guidelines. Physicians appear to base treatment decisions in septic shock on a consistent pattern of practice rather than estimates of patient outcome., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS) are common indications for ICU admission and mechanical ventilation. ALI/ARDS also consumes significant health care resources and is a common cause of death in ICU patients. Obesity produces changes in respiratory system physiology that could affect outcomes for ALI/ARDS patients and their response to treatment. Additionally, the biochemical alterations seen in obese patients, such as increased inflammation and altered metabolism, could affect the risk of developing ALI/ARDS in patients with another risk factor (eg, sepsis). The few studies that have examined the influence of obesity on the outcomes from ALI/ARDS are inconclusive. Furthermore, observed results could be biased by disparities in provided care.

Background: Physicians are slow to adopt novel therapies, and the reasons for this are poorly understood. The authors sought to determine if the size of the treatment effect of a novel therapy influences willingness to adopt it., Methods: We developed 2 experimental vignette pairs describing a trial of a therapy for a hypothetical disease that showed a statistically significant mortality benefit. The size of the mortality effect was varied in vignettes of a pair (3% v. 10%). The 2 experimental vignette pairs differed in whether study enrollment was reported. Vignettes were mailed to a random sample of physicians using an intersubject design. The main study outcome was respondents' willingness to adopt the hypothetical therapy, based on the results of the hypothetical trial., Results: There were 124 and 89 respondents to vignette pairs 1 and 2, respectively. In vignette pair 1, 91% versus 71% of respondents adopted the therapy when it reduced mortality by 10% and 3%, respectively (P = 0.0058). For vignette pair 2, 88% versus 51% of respondents adopted the therapy when it reduced mortality by 10% and 3%, respectively (P = 0.0002). In both vignette pairs, nonadopters were more likely than adopters to report side effects of the therapy as a principal reason for their decision., Conclusions: In this study, respondents were less likely to adopt a lifesaving therapy if its associated mortality reduction was 3% compared to 10%. Because most therapies for major medical conditions reduce mortality within or below this range, and because there were no opportunity costs associated with the adoption of the therapy, we believe that this effect represents a bias. Further investigation will be required to determine its prevalence and mechanism.

Medical practice is increasingly informed by the evidence from randomized controlled trials. When such evidence is not available, clinical hypotheses based on pathophysiological reasoning and common sense guide clinical decision making. One commonly utilized general clinical hypothesis is the assumption that normalizing abnormal laboratory values and physiological parameters will lead to improved patient outcomes. We refer to the general use of this clinical hypothesis to guide medical therapeutics as the "normalization heuristic". In this paper, we operationally define this heuristic and discuss its limitations as a rule of thumb for clinical decision making. We review historical and contemporaneous examples of normalization practices as empirical evidence for the normalization heuristic and to highlight its frailty as a guide for clinical decision making.

Introduction: Critically ill patients and families rely upon physicians to provide estimates of prognosis and recommendations for care. Little is known about patient and clinician factors which influence these predictions. The association between these predictions and recommendations for continued aggressive care is also understudied., Methods: We administered a mail-based survey with simulated clinical vignettes to a random sample of the Critical Care Assembly of the American Thoracic Society. Vignettes represented a patient with septic shock with multi-organ failure with identical APACHE II scores and sepsis-associated organ failures. Vignettes varied by age (50 or 70 years old), body mass index (BMI) (normal or obese) and co-morbidities (none or recently diagnosed stage IIA lung cancer). All subjects received the vignettes with the highest and lowest mortality predictions from pilot testing and two additional, randomly selected vignettes. Respondents estimated outcomes and selected care for each hypothetical patient., Results: Despite identical severity of illness, the range of estimates for hospital mortality (5th to 95th percentile range, 17% to 78%) and for problems with self-care (5th to 95th percentile range, 2% to 74%) was wide. Similar variation was observed when clinical factors (age, BMI, and co-morbidities) were identical. Estimates of hospital mortality and problems with self-care among survivors were significantly higher in vignettes with obese BMIs (4.3% and 5.3% higher, respectively), older age (8.2% and 11.6% higher, respectively), and cancer diagnosis (5.9% and 6.9% higher, respectively). Higher estimates of mortality (adjusted odds ratio 1.29 per 10% increase in predicted mortality), perceived problems with self-care (adjusted odds ratio 1.26 per 10% increase in predicted problems with self-care), and early-stage lung cancer (adjusted odds ratio 5.82) were independently associated with recommendations to limit care., Conclusions: The studied clinical factors were consistently associated with poorer outcome predictions but did not explain the variation in prognoses offered by experienced physicians. These observations raise concern that provided information and the resulting decisions about continued aggressive care may be influenced by individual physician perception. To provide more reliable and accurate estimates of outcomes, tools are needed which incorporate patient characteristics and preferences with physician predictions and practices.

Rationale: ICU-acquired paresis (ICUAP) is common in survivors of critical illness. There is significant associated morbidity, including prolonged time on the ventilator and longer hospital stay. However, it is unclear whether ICUAP is independently associated with mortality, as sicker patients are more prone and existing studies have not adjusted for this., Objectives: To test the hypothesis that ICUAP is independently associated with increased mortality. Secondarily, to determine if handgrip dynamometry is a concise measure of global strength and is independently associated with mortality., Methods: A prospective multicenter cohort study was conducted in intensive care units (ICU) of five academic medical centers. Adults requiring at least 5 days of mechanical ventilation without evidence of preexisting neuromuscular disease were followed until awakening and were then examined for strength., Measurements and Main Results: We measured global strength and handgrip dynamometry. The primary outcome was in-hospital mortality and secondary outcomes were hospital and ICU-free days, ICU readmission, and recurrent respiratory failure. Subjects with ICUAP (average MRC score of < 4) had longer hospital stays and required mechanical ventilation longer. Handgrip strength was lower in subjects with ICUAP and had good test performance for diagnosing ICUAP. After adjustment for severity of illness, ICUAP was independently associated with hospital mortality (odds ratio [OR], 7.8; 95% confidence interval [CI], 2.4-25.3; P = 0.001). Separately, handgrip strength was independently associated with hospital mortality (OR, 4.5; 95% CI, 1.5-13.6; P = 0.007)., Conclusions: ICUAP is independently associated with increased hospital mortality. Handgrip strength is also independently associated with poor hospital outcome and may serve as a simple test to identify ICUAP. Clinical trial registered with www.clinicaltrials.gov (NCT00106665).

Objective: Treatment and prevention of hyperglycemia has been advocated for subjects with sepsis. Glucose variability, rather than the glucose level, has also been shown to be an important factor associated with in-hospital mortality, in general, critically ill patients. Our objective was to determine the association between glucose variability and hospital mortality in septic patients and the expression of glucose variability that best reflects this risk., Design: Retrospective, single-center cohort study., Setting: Academic, tertiary care hospital., Patients: Adult subjects hospitalized for >1 day, with a diagnosis of sepsis were included., Interventions: None., Measurements: Glucose variability was calculated for all subjects as the average and standard deviation of glucose, the mean amplitude of glycemic excursions, and the glycemic lability index. Hospital mortality was the primary outcome variable. Logistic regression was used to determine the odds of hospital death in relation to measures of glucose variability after adjustment for important covariates., Main Results: Of the methods used to measure glucose variability, the glycemic lability index had the best discrimination for mortality (area under the curve = 0.67, p < 0.001). After adjustment for confounders, including the number of organ failures and the occurrence of hypoglycemia, there was a significant interaction between glycemic lability index and average glucose level, and the odds of hospital mortality. Higher glycemic lability index was not independently associated with mortality among subjects with average glucose levels above the median for the cohort. However, subjects with increased glycemic lability index, but lower average glucose values had almost five-fold increased odds of hospital mortality (odds ratio = 4.73, 95% confidence interval = 2.6-8.7) compared with those with lower glycemic lability index., Conclusions: Glucose variability is independently associated with hospital mortality in septic patients. Strategies to reduce glucose variability should be studied to determine whether they improve the outcomes of septic patients.

Several research papers published in Critical Care throughout 2007 examined the pathogenesis, diagnosis, treatment and prognosis of sepsis and multiorgan failure. The present review summarizes the findings and implications of the papers published on sepsis and multiorgan failure and places the research in the context of other work in the field.

Sepsis is a clinical syndrome defined by a systemic response to infection. With progression to sepsis-associated organ failure (ie, severe sepsis) or hypotension (ie, septic shock) mortality increases. Sepsis is a cause of considerable mortality, morbidity, cost, and health care utilization. Abnormalities in the inflammation, immune, coagulation, oxygen delivery, and utilization pathways play a role in organ dysfunction and death. Early identification of septic patients allows for evidence-based interventions, such as prompt antibiotics, goal-directed resuscitation, and activated protein C. Appropriate care for sepsis may be more easily delivered by dividing this clinical entity into various stages and with changes in structures of delivery that extend across traditional boundaries. Better description of the molecular basis of the disease process also will allow for more targeted therapies.

Rationale: An increase in the number of mononuclear phagocytes in lung biopsies from patients with idiopathic pulmonary fibrosis (IPF) worsens prognosis. Chemokines that recruit mononuclear phagocytes, such as CC chemokine ligand 2 (CCL2), are elevated in bronchoalveolar lavage (BAL) fluid (BALF) from patients with IPF. However, little attention is given to the role of the mononuclear phagocyte survival and recruitment factor, macrophage colony-stimulating factor (M-CSF), in pulmonary fibrosis., Objectives: To investigate the role of mononuclear phagocytes and M-CSF in pulmonary fibrosis., Methods: Wild-type, M-CSF-/-, or CCL2-/- mice received intraperitoneal bleomycin. Lung inflammation and fibrosis were measured by immunohistochemistry, ELISA, collagen assay, BAL differentials, real-time polymerase chain reaction, and Western blot analysis. Human and mouse macrophages were stimulated with M-CSF for CCL2 expression. BALF from patients with IPF was examined for M-CSF and CCL2., Measurements and Main Results: M-CSF-/- and CCL2-/- mice had less lung fibrosis, mononuclear phagocyte recruitment, collagen deposition, and connective tissue growth factor (CTGF) expression after bleomycin administration than wild-type littermates. Human and mouse macrophages stimulated with M-CSF had increased CCL2 production, and intratracheal administration of M-CSF in mice induced CCL2 production in BALF. Finally, BALF from patients with IPF contained significantly more M-CSF and CCL2 than BALF from normal volunteers. Elevated levels of M-CSF were associated with elevated CCL2 in BALF and the diagnosis of IPF., Conclusions: These data suggest that M-CSF contributes to the pathogenesis of pulmonary fibrosis in mice and in patients with IPF through the involvement of mononuclear phagocytes and CCL2 production.

Laboratory testing is ubiquitous among hospitalized patients and is more common among patients in the intensive care unit (ICU). Despite its high cost and prevalence, there are few data to support the current practice of laboratory testing in most ICUs. Although testing offers considerable potential benefits, it is not without risk, including misleading results, iatrogenic anemia, and therapeutic actions of uncertain benefit. Laboratory testing should be conducted as part of a therapeutic approach to a clinical problem, mindful of pretest probability of disease, the performance of the selected test, and the relative benefits and risks of testing. Considering the indication for a particular test can lead to a more rational approach to laboratory testing and better use of available tests.

Background: Hyperglycemia is often observed in medically ill patients. Previous studies have shown that patients with hyperglycemia during induction therapy for acute lymphoblastic leukemia develop more infections and have shorter disease-free survival. The authors hypothesized that hyperglycemia may be associated with adverse outcomes in patients with acute myeloid leukemia (AML) and sought to determine whether this association exists in this population., Methods: The authors performed a retrospective cohort study to examine the relation between hyperglycemia and hospital mortality in patients with the diagnosis of AML. Two hundred eighty-three adult patients were treated over a 3-year period. All hospitalizations were reviewed during the study period, and glucose exposure and outcomes were quantified., Results: Hyperglycemia during a patient's hospitalization was associated with increased hospital mortality (OR, 1.38; 95% CI, 1.23-1.55; P < .001) after adjusting for covariates, including disease state, treatment type, and response. The rise in mortality was evident at even mild levels (110-150 mg/dL) of glucose elevation. Although the odds of developing severe sepsis (OR, 1.24; 95% CI, 1.13.-1.38; P < .001) or severe sepsis with respiratory failure (OR, 2.04; 95% CI, 1.44-2.91; P < .001) were increased with hyperglycemia, sepsis did not appear to be the main factor responsible for the negative impact of hyperglycemia on hospital mortality., Conclusions: This study demonstrated an association between hospital mortality and even modest levels of hyperglycemia in AML patients. Prospective studies are needed to confirm this association and to discern causal pathways that mediate this effect., (Copyright (c) 2007 American Cancer Society.)

The clinical spectrum of sepsis, severe sepsis, and septic shock is responsible for a growing number of deaths and excessive health care expenditures. Until recently, despite multiple clinical trials, no intervention provided a beneficial outcome in septic patients. Within the last 2 years, studies that involved drotrecogin alfa (activated), corticosteroid therapy, and early goal-directed therapy showed efficacy in those with severe sepsis and septic shock. These results have provided optimism for reducing sepsis-related mortality.

IL-1 beta is a proinflammatory cytokine secreted chiefly by monocytes and macrophages. Currently, much of its mechanism of processing and secretion is poorly understood, but there is increasing evidence that the microtubule system may be involved. For example, it is known that taxol and colchicine, two drugs that affect microtubule structure and function, increase LPS-induced IL-1 beta release. However, it is not known whether these drugs affect the synthesis of the 31-kDa precursor (pro-IL-1 beta) or the processing and release of mature IL-1 beta. To test this, an assay was used that allowed for the temporal separation of IL-1 beta synthesis and release. The addition of taxol or colchicine to the secretory phase of the assay resulted in no significant change in IL-1 beta release. However, when these drugs were added to the stimulus for IL-1 beta production, there was a significant increase in both IL-1 beta release and total IL-1 beta production, as measured by ELISA. These findings indicate that taxol and colchicine increase LPS-induced IL-1 beta release by an increase in the production of the precursor molecule. Thus, it is unlikely that microtubules are involved in the IL-1 beta secretory machinery in any significant manner, but they do play a role in the regulation of pro-IL-1 beta production.

L-Proline dehydrogenase catalyzes the oxidation of L-proline to delta 1-pyrroline-5-carboxylate, a reaction that is an important step in the utilization of proline as a carbon or nitrogen source by bacteria. A mutant of Escherichia coli K-12 lacking L-leucyl-tRNA:protein transferase had been found previously to contain about five times as much proline dehydrogenase activity as its parent strain. This difference has now been shown to be due to the presence in the parent strain of a previously unrecognized mutation. This mutation, which has been designated put-4977, specifically affects proline dehydrogenase rather than proline uptake. Although proline dehydrogenase remains inducible by L-proline in strains carrying the mutation, there is a premature cessation of differential synthesis during induction that results in a lower specific activity. The mutation shows about 50% P1-mediated cotransduction with pyrC and is therefore located at about 22 min on the E. coli chromosome. Merodiploids containing a normal F' factor still exhibit decreased enzyme activity, indicating that the put-4977 mutation is trans-dominant. The mutation cannot be detected in present stocks of the transferase-deficient mutant, suggesting that this mutant is a revertant for put-4977.