Plasma receptor for advanced glycation end products and clinical outcomes in acute lung injury.

OBJECTIVES: To determine whether baseline plasma levels of the receptor for advanced glycation end products (RAGE), a novel marker of alveolar type I cell injury, are associated with the severity and outcomes of acute lung injury, and whether plasma RAGE levels are affected by lower tidal volume ventilation. DESIGN, SETTING AND PARTICIPANTS: Measurement of plasma RAGE levels from 676 subjects enrolled in a large randomised controlled trial of lower tidal volume ventilation in acute lung injury. MEASUREMENTS AND MAIN RESULTS: Higher baseline plasma RAGE was associated with increased severity of lung injury. In addition, higher baseline RAGE was associated with increased mortality (OR for death 1.38 (95% CI 1.13 to 1.68) per 1 log increment in RAGE; p = 0.002) and fewer ventilator free and organ failure free days in patients randomised to higher tidal volumes. These associations persisted in multivariable models that adjusted for age, gender, severity of illness and the presence of sepsis or trauma. Plasma RAGE was not associated with outcomes in the lower tidal volume group (p = 0.09 for interaction in unadjusted analysis). In both tidal volume groups, plasma RAGE levels declined over the first 3 days; however, the decline was 15% greater in the lower tidal volume group (p = 0.02; 95% CI 2.4% to 25.0%). CONCLUSIONS: Baseline plasma RAGE levels are strongly associated with clinical outcomes in patients with acute lung injury ventilated with higher tidal volumes. Lower tidal volume ventilation may be beneficial in part by decreasing injury to the alveolar epithelium.

Clinicians' approaches to mechanical ventilation in acute lung injury and ARDS.

STUDY OBJECTIVES: To examine clinicians' approaches to mechanical ventilation in patients with acute lung injury (ALI; PaO(2)/fraction of inspired oxygen [FIO(2)] 35 cm H(2)O in 26% of patients. Seventy-eight percent of patients with ARDS received

Mediators and mechanisms of acute lung injury.

Since last reviewed in this forum, there have been remarkable advances in our understanding of the acute inflammatory process and how it contributes to the development of ALI. As stated in the beginning of this article, it is not possible to even begin to review all the specific advances that have been made. Instead, the author has focused on concepts that have emerged and improved our ability to study the pathogenesis of ARDS. These include the recognition that patients at risk for and with ARDS represent a heterogeneous population, that mediators or markers of inflammation cannot be considered in isolation, that a balance between proinflammatory mediators and inflammatory modulators may be important, and that there are several genetic factors that could contribute to the susceptibility for the development of ARDS. Hopefully these concepts can be expanded and clarified so that the next review of this topic can report on successful therapeutic interventions for the prevention and the treatment of ARDS.

Diabetic patients have a decreased incidence of acute respiratory distress syndrome.

OBJECTIVE: Our ability to predict which critically ill patients will develop acute respiratory distress syndrome (ARDS) is imprecise. Based on the effects of diabetes mellitus on the inflammatory cascade, we hypothesized that a history of diabetes might alter the incidence of ARDS. DESIGN: A prospective multicenter study. SETTING: Intensive care units at four university medical centers. PATIENTS: One hundred thirteen consecutive patients with septic shock. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: All patients were prospectively followed during their intensive care course for the development of ARDS. A history of diabetes was identified in 28% (32/113) of the patients. In this study, nondiabetics were more likely to develop septic shock from a pulmonary source (48%, 39/81) compared with diabetics (25%, 8/32) (p = .02). Forty-one percent (46/113) of the patients with septic shock developed ARDS. Forty-seven percent of the nondiabetic patients developed ARDS compared with only 25% of those with diabetes (p = .03, relative risk = 0.53, 95% confidence interval = 0.28-0.98). In a multivariate logistic regression analysis, when we adjusted for several variables including source of infection, the effect of diabetes on the incidence of ARDS remained significant (p = .03, odds ratio = 0.33, 95% confidence interval = 0.12-0.90). CONCLUSIONS: In patients with septic shock, a history of diabetes is associated with a lower risk of developing ARDS compared with nondiabetics.

The association between health care coverage and the use of cancer screening tests. Results from the 1992 National Health Interview Survey.

OBJECTIVES: The authors investigated whether utilization of six different cancer screening tests (mammography, clinical breast exam, Pap smear, Fecal Occult Blood Test, and Digital rectal exam) varied according to type of health care coverage. METHODS: Data on the use of cancer screening tests and coverage in two age groups from a 1992 nationally representative cross-sectional survey of approximately 9,400 adults were analyzed. Multiple logistic regression analysis was used to estimate proportions of persons screened according to type and extent of coverage, adjusted for socioeconomic, demographic, and health status characteristics. RESULTS: Persons aged 40 to 64 years with Medicaid coverage were equally as likely to receive five of six cancer screening tests as those with private fee-for-service coverage, and both groups were much more likely to be screened (70% higher for all six tests) than those who had no coverage. In contrast, persons aged 65 years and older who had supplemental private fee-for-service insurance in addition to Medicare were more likely to receive five of six tests than those with Medicare and Medicaid or those with Medicare only. For all six screening tests, managed care enrollees at all ages were approximately 10% more likely to be screened than persons enrolled in private fee-for-service plans. Fecal Occult Blood Test (25% versus 20%) and digital rectal exams (44% versus 38%) in persons aged 40 to 64 years and mammography (59% versus 48%) and Fecal Occult Blood Test screening (38% versus 30%) in the elderly were significantly more frequent for persons in managed care plans. CONCLUSIONS: The extent of fee-for-service insurance coverage in the traditional indemnity US health care system was positively associated with the use of cancer screening tests. The authors found less difference in use of cancer screening between managed care and fee-for-service care in 1992 than we expected based on earlier research comparing use of preventive services in health maintenance organizations with fee-for-service care.

Access to health care. Part 3: Older adults.

OBJECTIVES: This report examines access to health care for older adults, 65 years of age and over. In the United States for 1993. Access indicators include having a regular source of care, place of care, main reason for no regular source of care, unmet health care needs, and use of clinical and preventive services. Sociodemographic characteristics include sex, age, race, income, health status, and health insurance coverage. METHODS: Data are from the 1993 Access to Care, Health insurance, and Year 2000 Surveys of the National Health interview Survey (NHIS), a continuing household survey of the civilian noninstitutionalized population of the United States. The sample for the Access to Care and Health insurance surveys contained 61,287 persons in 24,071 households. The sample for the Year 2000 survey was 21,028 persons. RESULTS: Persons with Medicare and private or Medicare and public coverage were more likely to have a regular source of medical care than elderly persons with Medicare only. Over 3.3 million elderly persons had at least one unmet need in 1993. Older adults on Medicare and public or Medicare only coverage were twice as likely to have unmet medical needs than those with Medicare and private coverage. Persons with Medicare and private coverage were more likely to receive immunizations than elderly persons with Medicare and public coverage or Medicare only. CONCLUSIONS: Although the majority of older adults have Medicare, this only provides a basic level of access to the health care system. Older adults who do not supplement Medicare with private coverage are at the greatest risk of having unmet health care needs.

Access to health care. Part 1: Children.

OBJECTIVES: This report presents national estimates of access to medical care and unmet health care needs for children through 17 years of age by selected sociodemographic variables including sex, age, race and/or ethnicity, family income, family structure, place of residence, and health status. In addition, the impact of children's health insurance status on access to care is described. METHODS: Data from the 1993 Access to Care and Health Insurance questionnaires of the National Health Interview Survey (NHIS) are analyzed to examine access indicators. The NHIS is a continuing household survey of the civilian noninstitutionalized population of the United States. The sample included 16,907 children from infants through 17 years of age from 24,071 households. RESULTS: In 1993, over 7.3 million U.S. children had at least one unmet health care need or had medical care delayed because of worry about the cost of care. These health care needs included medical care, dental care, prescription medicine, glasses, and mental health care. In addition, almost 4.2 million children lacked a regular source of health care. Factors related to access indicators included health insurance, family income, race and/or ethnicity, family structure, and place of residence. The lack of health insurance or inability to afford care was the main reason given by respondents for children lacking a regular source of medical care. CONCLUSIONS: In the United States, millions of children do not receive needed health care services. Uninsured children and those in families with low income are at the greatest risk of having unmet health needs.

Access to health care. Part 2: Working-age adults.

OBJECTIVES: This report presents data on access to health care for U.S. working-age adults, 18-64 years old. Access indicators are examined by selected sociodemographic characteristics including sex, age, race and/or ethnicity, place of residence, employment status, income, health status, and health insurance status. METHODS: Data are from the 1993 Access to Care and 1993 Health Insurance Surveys of the National Health Interview Survey (NHIS), a continuing household survey of the civilian noninstitutionalized population of the United States. The sample contained 61,287 persons in 24,071 households. RESULTS: In 1993, approximately 3 out of 4 working-age adults had a regular source of medical care. Nine out of 10 adults with health insurance had a regular source of care compared with 6 out of 10 adults without health insurance. For adults with a regular source of care, 86 percent received care in a private doctor's office, 9 percent in a clinic, and 2 percent in a hospital emergency room. The two main reasons given for not having a regular source of care were "do not need a doctor" (49 percent), and "no insurance can't afford it" (22 percent). Persons in the highest income group were more likely to report no need for a doctor (59 percent) than persons in the lowest income group (35 percent). About 40 percent of uninsured persons and 16 percent of insured persons reported an unmet medical need. CONCLUSIONS: Health insurance plays a key role in the access to medical care services. Persons who are uninsured or have low incomes are at the greatest risk of having unmet medical needs.

Circulating IL-1ra and IL-10 levels are increased but do not predict the development of acute respiratory distress syndrome in at-risk patients.

Although numerous cytokines, including interleukin (IL)-1, IL-8, and tumor necrosis factor, circulate in critically ill patients at risk for acute respiratory distress syndrome (ARDS), none clearly predict the development of the syndrome. We hypothesized that cytokines, such as IL-1ra, IL-10, and IL-4, which modulate inflammation, might contribute to or reflect the development of acute lung injury. Accordingly, serial levels of IL-1ra and IL-10 were measured in 77 patients who were identifed as being at risk for the development of ARDS. Initial IL-1ra levels were significantly higher (p < 0.0001) in the patients (7.82 [2.29-38.01] ng/ml) than in normal control subjects (0.24 [0.24-0.34] ng/ml) but did not predict the development of ARDS. Initial IL-1ra levels, however, were greater (p = 0.038) in the patients who died (31.95 [3.02-65.06] ng/ml) compared with survivors (6.61 [1.86-29.33] ng/ml). Similarly, IL-10 levels were increased in patients (155 [53.75-318.75] ng/ml) compared with normal control subjects (0 ng/ml) but did not predict the development of ARDS. Like IL-1ra levels, initial IL-10 levels were significantly higher (p = 0.005) in patients who died compared with survivors. IL-4 was not detectable in any of the patient plasma samples measured. Thus, modulators of inflammation are increased in patients at risk for ARDS who die, but do not predict the development of the syndrome.

Serum ferritin as a predictor of the acute respiratory distress syndrome.

We investigated serum ferritin levels as a predictor of the acute respiratory distress syndrome (ARDS) because: (1) proinflammatory cytokines, which are implicated in ARDS, increase ferritin synthesis; and (2) oxidative stress in patients at risk for ARDS might liberate iron from ferritin, accelerating toxic hydroxyl radical (.OH) formation. Serum ferritin levels measured by radioimmunoassay (RIA) were greater in 75 patients at risk for ARDS (women, p < 0.0001; men, p < 0.0001) and 8 patients with ARDS (women, p = 0.001; men, p = 0.0009) than in healthy control subjects. Serum ferritin levels were also greater in female (p = 0.003) and male (p = 0.003) at-risk patients who developed ARDS than in patients who did not develop ARDS. In women, a value exceeding 270 ng/ml predicted ARDS with an 83% sensitivity, 71% specificity, 67% positive, and 86% negative predictive value. In men, a value exceeding 680 ng/ml predicted ARDS with a 60% sensitivity, 90% specificity, 75% positive, and 82% negative predictive value. Serum ferritin levels did not correlate with C-reactive protein levels, were not different in medical or surgical at-risk patients, and were not accounted for by liver disease. Evaluating serum ferritin levels in at-risk patients may help predict the development of ARDS and thereby improve study and treatment of ARDS. Elevated serum ferritin levels may also regulate the participation of iron in the oxidative responses that contribute to ARDS.

Endothelial cell activity varies in patients at risk for the adult respiratory distress syndrome.

OBJECTIVE: The endothelial cell produces many bioactive compounds that are presumed to play important roles in the pathogenesis of the adult respiratory distress syndrome (ARDS). We postulated that individuals with sepsis and trauma-two at-risk diagnoses for the development of ARDS--might demonstrate differences in the degree of endothelial cell activity. DESIGN: Prospective cohort study. SETTING: Intensive care unit patients in a tertiary, university-affiliated, city hospital. PATIENTS: Fifty-five intensive care unit patients (19 with sepsis and 36 trauma patients). INTERVENTIONS: Plasma measurements of three endothelial cell products--von Willebrand factor antigen, soluble intercellular adhesion molecule-1 (ICAM-1), and soluble E-selectin-were performed within 8 hrs of patients meeting our inclusion criteria, and at the clinical onset of ARDS. MEASUREMENTS AND MAIN RESULTS: Twenty-six percent of the septic patients and 25% of the trauma patients developed ARDS. The median (and 25% to 75% quartiles) concentrations of all three mediators measured in the sepsis patients (von Willebrand factor antigen 399% [375% to 452%], ICAM-1 573 ng/mL [470 to 980], and soluble E-selectin 180 ng/mL [81 to 340]) were significantly higher (p < .001 for each individual analysis) than in the trauma patients (von Willebrand factor antigen 256% [217% to 310%], ICAM-1 148 ng/mL [113 to 210], and soluble E-selectin 42 ng/mL [31 to 65 ng/ mL]). In addition, neither the ICAM-1 nor soluble E-selectin concentrations measured in the trauma patients were different (p = .17 and p = .24, respectively) from normal controls. In those patients who developed ARDS, the differences in the concentrations of all three endothelial cell mediators between the sepsis and trauma patients persisted (p = .008 for von Willebrand factor antigen, p = .003 for ICAM-1, and p = .003 for E-selectin). CONCLUSION: These findings suggest that differences in endothelial cell activity exist between sepsis and trauma patients who are at risk for the development of ARDS.

Early detection and markers of sepsis.

In vitro and animal models of sepsis have provided a template for studies of the pathogenesis of sepsis in patients at risk for and with the syndrome. Numerous potential markers have been identified in these models and then looked for in patients. No single marker or combination of markers convincingly identifies sepsis, predicts the development of sepsis, predicts the development of complications of sepsis, or predicts mortality. As discussed, the clinical studies have been complicated by many confounding variables, including the lack of adherence to rigorous definitions, differences in assay methods, differences in timing of the studies, and differences in outcome variables analyzed. In spite of the limitations, the studies have been critical in helping determine the pathogenesis of sepsis in humans. As new mediators and modulators of inflammation are identified, it will be important to study their role as markers, individually and in combination, in human disease.

The role of chronic alcohol abuse in the development of acute respiratory distress syndrome in adults.

OBJECTIVE: To determine the effect of a history of chronic alcohol abuse on the incidence of acute respiratory distress syndrome (ARDS) and in-hospital mortality. DESIGN: Prospective cohort study. PATIENTS: A total of 351 medical and surgical intensive care unit patients with one of seven at-risk diagnoses for the development of ARDS. MAIN OUTCOME MEASURES: The development of ARDS and in-hospital mortality. RESULTS: Of the 351 patients enrolled in the study, the incidence of ARDS in patients with a history of alcohol abuse was significantly higher than in patients without a history of alcohol abuse (43% vs 22%) (P < .001; relative risk [RR], 1.98; 95% confidence interval [Cl], 1.32 to 2.85). In patients with sepsis, ARDS developed in 52% of the patients with a prior history of alcohol abuse compared with only 20% in patients without a history of alcohol abuse (P < .001; RR, 2.59; 95% Cl, 1.29 to 5.12). Fifty-one percent (52/102) of the patients who developed ARDS died compared with only 14% (36/249) of patients who did not develop ARDS (P < .001). In the subset of patients who developed ARDS, the in-hospital mortality rate was 65% in patients with a prior history of alcohol abuse. This mortality rate was significantly higher (P = .003) than the mortality rate in patients without a history of alcohol abuse (36%). CONCLUSIONS: A prior history of chronic alcohol abuse significantly increases the risk of developing ARDS in critically ill patients with an identified at-risk diagnosis. Our results may be useful in the earlier and more accurate identification of patients at high risk for developing ARDS.

Income, social stratification, class, and private health insurance: a study of the Baltimore metropolitan area.

Most studies of inequalities and access to health care have used income as the sole indicator of social stratification. Despite the significance of social theory in health insurance research, there are no empirical studies comparing the ability of different models of social stratification to predict health insurance coverage. The aim of this study is to provide a comparative analysis using a variety of theory-driven indicators of social stratification and assess the relative strength of the association between these indicators and private health insurance. Data were collected in a 1993 telephone interview of a random digit dialing sample of the white population in the Baltimore Metropolitan Statistical Area. Indicators of social stratification included employment status, full-time work, education, occupation, industry, household income, firm size, and three types of assets: ownership, organizational, and skill/credential. The association between social stratification and private health insurance was strongest for those having higher household incomes, having attained at least a bachelor's degree, and working in a firm with more than 50 employees, followed by being an owner or manager, and by being employed. The addition of education and firm size improved the prediction of the household income model. The authors conclude that studies of inequalities in health insurance coverage can benefit from the inclusion of theory-driven indicators of social stratification such as human capital, labor market segmentation, and control over productive assets.

Racial differences in health: not just black and white, but shades of gray.

Explanations for racial/ethnic disparities in health are varied and complex. This paper reviews the literature to assess the extent to which current disparities are a consequence of racial differences in the social class composition of the US population. We focus this review on African Americans and examine studies that provide information on the effect of race on four outcome measures: infant mortality, hypertension, substance use, and mortality from all-causes. Twenty-three studies were identified that met criteria for inclusion in this review. As expected, most studies provide evidence that socioeconomic conditions are a major factor explaining racial differences in health. Findings, however, vary for the different health indices. Research in the area of substance abuse provides the most consistent evidence that socioeconomic conditions account for observed racial differences. In contrast, studies on infant mortality and hypertension provide a compelling case that the effects of socioeconomic status are important, but not sufficient to explain racial differences. Evidence on mortality from all-causes is equally divided between studies showing no significant race effect and those in which racial differences persist after adjusting for social class. The paper offers possible explanations for the seemingly divergent results and identifies conceptual and methodologic issues for future research seeking to disentangle the complex relations between race, social class, and health.