Lipoprotein(a) associated with coronary artery disease in older women: age and gender analysis.

BACKGROUND: Lipoprotein (a) has been associated with increased coronary artery disease (CAD) risk in men, but relatively little data exists in women. While age influences the cardiovascular risk associated with Lp(a) in men, little is known about this phenomenon in women. The impact of gender on Lp(a) has not been fully studied in an ongoing clinical practice. METHODS AND RESULTS: Baseline Lp(a) values were measured in 918 CAD and 829 non-CAD patients (603 females, 1144 males) entering an outpatient prevention clinic. The age-specific association of elevated Lp(a) (> 30 mg/dl) with CAD was examined after adjustment for traditional risk factors. Lp(a) was a significant risk factor (OR = 1.9, CI, 1.4-2.6) in men and women (OR = 1.9, CI 1.3-2.9). In men age < or = 55 years the odds ratio for increased cardiovascular risk in high vs low Lp(a) was 2.5 (CI 1.6-3.9). In men < or = 55, CAD increased from 32 to 61% as Lp(a) progressively rose from < or = 5 to > or = 45 mg/dl (P value for trend < 0.001). No significant increase was observed in men > 55 years (OR = 1.3, CI 0.9-2.1). In women < or = 55 years, the risk of CAD increased from 22 to 35% (OR 1.6, CI 0.8-3.2), and increased from 38 to 63% in women > 55 (OR 2.1, CI 1.3-3.5). Further, of high-risk patients (men < or = 55 and women > 55 years) with an Lp(a) in the range of 20-44 mg/dl (third quartile), younger men showed a greater incidence of CAD (51%) than older women (43%). Both genders revealed substantial risk when the Lp(a) values were above 45 mg/dl. (OR = 3.7, CI = 2.0-6.8 in younger men; OR = 3.3, CI = 1.6-6.6 in older women). CONCLUSIONS: In this cross sectional study of both men and women, elevated Lp(a) was associated with a significantly increased risk of CAD in men and women. While we corroborate previous reports on the lack of association in older men, the determination of an enhanced Lp(a)-related risk in older women was new and unanticipated. Further, in this population of high risk patients, substantial cardiovascular risk appeared to be represented by higher concentrations of Lp(a) in women than observed in men.

Improved survival of patients with acute respiratory distress syndrome (ARDS): 1983-1993.

OBJECTIVE: To analyze temporal trends in acute respiratory distress syndrome (ARDS) fatality rates since 1983 at one institution. DESIGN: Cohort. SETTING: Intensive care units of a large county hospital. PATIENTS: Consecutive adult patients (> or = 18 years of age) meeting ARDS criteria were identified through daily surveillance of intensive care units (N = 918 from 1983 through 1993). The major causes were sepsis syndrome in 37% and major trauma in 25%; 37% had other risks. Sixty-five percent were male. The median age was 45 years (range, 18 to 92 years); 70% were younger than 60 years. MAIN OUTCOME MEASURE: Hospital mortality. RESULTS: Overall fatality rates showed no trend from 1983 to 1987, declined slightly in 1988 and 1989, and decreased to a low of 36% in 1993 (95% confidence interval, 25% to 46%). The crude rates were largely unchanged after adjustment for age, ARDS risk, and gender distribution. While patients both younger than 60 years and 60 years or older experienced declines in fatality rate, the larger decrease occurred in the younger cohort. In sepsis patients, ARDS fatality rates declined steadily, from 67% in 1990 to 40% in 1993 (95% confidence interval, 23% to 57%). The decline in sepsis-related ARDS fatality was confined largely to patients less than 60 years of age. Trauma patients and all other patients also experienced declines in fatality rates after 1987, although these trends were not as strong and consistent as in the sepsis population. CONCLUSIONS: In this large series, we observed a significant decrease in fatality rates occurring largely in patients younger than 60 years and in those with sepsis syndrome as their risk for ARDS. We are unable to determine the extent to which experimental therapies or other changes in treatment have contributed to the observed decline in the ARDS fatality rate. Institution-specific rates and temporal trends in ARDS fatality rates should be considered in clinical trials designed to prevent ARDS and the high mortality associated with this syndrome.

Type III procollagen peptide in the adult respiratory distress syndrome. Association of increased peptide levels in bronchoalveolar lavage fluid with increased risk for death.

OBJECTIVE: To determine whether bronchoalveolar lavage fluid levels of the N-terminal peptide of type III procollagen (procollagen III) are increased in patients with the adult respiratory distress syndrome and, if so, whether increased procollagen III levels in lavage fluid are associated with increased fatality rates. DESIGN: Prospective cohort study. SETTING: Intensive care units of a tertiary care hospital affiliated with a medical school. PATIENTS: 117 consecutive patients with the adult respiratory distress syndrome prospectively identified on admission; 6 healthy volunteers served as controls. MEASUREMENTS: Bronchoalveolar lavage fluid procollagen III levels in 117 patients at 3, 7, and 14 days after onset of the adult respiratory distress syndrome (total of 196 lavage samples). RESULTS: The median procollagen III level was 1.75 U/mL (range, 0 to 13.4 U/mL) in lavage fluid obtained from patients with the adult respiratory distress syndrome. We detected procollagen III levels in lavage fluid from 80% of patients (94 of 117) but not in 6 normal volunteers. The overall fatality rate was 41% (48 of 117 patients). In a univariate analysis, the relative risk (RR) for death was increased in patients with procollagen III levels of 1.75 U/mL or more obtained on day 3 (RR, 2.4; 95% CI, 1.3 to 4.3), day 7 (RR, 2.7; CI, 1.4 to 5.4), and day 14 (RR, 2.7; CI, 1.1 to 6.3). Inclusion of other variables in a multivariate model only minimally decreased the risk associated with increased procollagen III levels. CONCLUSION: Increased levels of type III procollagen in bronchoalveolar lavage fluid are frequently detected in patients with the adult respiratory distress syndrome and are strongly associated with increased risk for fatal outcome independent of other variables related to fatality in patients with the syndrome.

Clinical risks for development of the acute respiratory distress syndrome.

To further understanding of the epidemiology of acute respiratory distress syndrome (ARDS), we prospectively identified 695 patients admitted to our intensive care units from 1983 through 1985 meeting criteria for seven clinical risks, and followed them for development of ARDS and eventual outcome. ARDS occurred in 179 of the 695 patients (26%). The highest incidence of ARDS occurred in patients with sepsis syndrome (75 of 176; 43%) and those with multiple emergency transfusions (> or = 15 units in 24 h) (46 of 115; 40%). Of patients with multiple trauma, 69 of 271 (25%) developed ARDS. If any two clinical risks for trauma were present, the incidence of ARDS was 23 of 57, or 40%. During the study period, we identified 48 patients with ARDS who did not have one of the defined clinical risks, yielding a sensitivity of 79% (179 of 227). Secondary factors associated with increased risk for ARDS in clinical risk subgroups include an elevated Acute Physiologic and Chronic Health Evaluation II (APACHE II) score in patients with sepsis and increased APACHE II and Injury Severity Scores (ISS) in trauma victims. Mortality was threefold higher when ARDS was present (62%) than among patients with clinical risks who did not develop ARDS (19%; p < 0.05). The difference in mortality if ARDS developed was particularly striking in patients with trauma (56% versus 13%), but less in those with sepsis (69% versus 49%). The mortality data should be interpreted with caution, since the fatality rate in ARDS patients appears to have decreased in our institution from the time that these data were collected.(ABSTRACT TRUNCATED AT 250 WORDS)

Evolution of bronchoalveolar cell populations in the adult respiratory distress syndrome.

To characterize the evolution of inflammation in the adult respiratory distress syndrome (ARDS) and test the hypothesis that sustained alveolar inflammation is associated with a poor outcome in patients with ARDS, we performed fiberoptic bronchoscopy and bronchoalveolar lavage (BAL) in 125 patients and compared BAL cells and protein concentrations in survivors and nonsurvivors. ARDS followed sepsis syndrome in 35 patients, major trauma in 41, and other causes in 49. When possible, BAL was performed on Days 3, 7, and 14 after the onset of ARDS. Sixty-five patients (52%) had more than one BAL. We first performed analyses on each BAL day using information from all 212 BAL in the 125 patients (cross-sectional analysis). All patients had increased leukocytes and total protein in the first BAL (Day 3 after onset of ARDS). In patients with ARDS following sepsis, the percentage of BAL polymorphonuclear leukocytes (PMN) was higher on Day 7 (p = 0.11) and particularly Day 14 (p = 0.02) in patients who died; there was a consistent trend of a higher PMN concentration on all days in patients who died then in those who lived. In patients with ARDS following trauma and other risks, however, BAL PMN measures did not distinguish survivors from patients who died. Analysis of serial data from the patients with more than one BAL showed that alveolar macrophages (AM) increased in survivors of ARDS, both in absolute numbers and as a percentage of total cells; this pattern was most pronounced in the sepsis patients. The cross-sectional data analysis suggests that sustained alveolar inflammation occurs frequently in patients with ARDS following sepsis and is associated with a high mortality.

Recovery of function in survivors of the acute respiratory distress syndrome.

We performed a prospective cohort analysis to determine the rate and extent of improvement in pulmonary function abnormalities and self-perceived health for 1 yr after surviving an episode of the acute respiratory distress syndrome (ARDS). We also examined the effect of ARDS severity and etiology, age, and sex on functional recovery. Patients were recruited from the intensive care units of one hospital and followed at regular time intervals from extubation to 1 yr. Fifty-two of 82 eligible adult survivors (63%) consented to participate; 37 of 82 (45%) had at least two examinations, and 20 (24%) had complete follow-up. Risk factors for ARDS included sepsis (n = 12), trauma (n = 15), and other (n = 10). Pulmonary function and self-perceived health scores improved considerably in the first 3 mo after extubation, with only slight additional improvement at 6 mo. No further changes were evident at 1 yr. Patients with more severe ARDS had significantly lower pulmonary function tests than did other survivors throughout follow-up. These observations should be useful for clinical follow-up of ARDS survivors and provide specific information concerning the expected rate of functional recovery in these patients.

Safety of bronchoalveolar lavage in patients with adult respiratory distress syndrome.

Although shown to be safe in many other lung disorders, the safety of fiberoptic bronchoscopy (FOB) with bronchoalveolar lavage (BAL) in critically ill patients with adult respiratory distress syndrome (ARDS) remains unproven. We conducted a prospective study to evaluate the safety of BAL in patients with ARDS. There were 438 patients with ARDS at our institution during the study period. Of these, 110 underwent FOB and BAL for either research or clinical purposes. Data were collected at baseline, at 5-min intervals during the procedure, and 1 h after the procedure. We did not detect any statistically or clinically significant changes in PaO2/FlO2, mean arterial pressure, heart rate, peak inspiratory pressure, or static thoracic compliance after the procedure. A small decrease in SaO2 occurred after BAL. Although this change was statistically significant, the magnitude was not of clinical importance. Five patients (4.5%) had transient arterial oxygen desaturation to < 90% during FOB and one patient (0.9%) experienced desaturation to < 80%. There were no prolonged episodes of severe hypoxemia. No serious bleeding occurred. One pneumothorax developed during the procedure. No deaths occurred that were related to the procedure. We conclude that FOB and BAL can be performed safely and are reasonably well-tolerated in patients with ARDS.

Pulmonary infection during the acute respiratory distress syndrome.

Pulmonary infection is thought to be a common complication of ARDS. We undertook this prospective study to determine the incidence of pulmonary infection in patients with ARDS, and to evaluate the impact of nosocomial pneumonia on severity of ARDS and on survival. Two hundred one bronchoscopies were performed in 105 patients with ARDS with retrieval of distal airway secretions by bronchoalveolar lavage (BAL) and protected specimen brush (PSB). Whenever possible, bronchoscopy was performed at predetermined times: Day 3, Day 7, Day 14, and Day 21 after the onset of ARDS. The majority of patients were receiving antibiotics at the time of study. Changes in bacterial flora over time were determined by quantitative cultures of BAL and PSB. Bacterial growth was common, but usually at small concentrations. Only 16 patients met quantitative culture criteria for pneumonia (PSB > or = 10(3) cfu/ml or BAL > or = 10(4) cfu/ml). Correlation was poor between clinical evidence of pneumonia and pneumonia by quantitative culture criteria: clinical criteria had a very low sensitivity (24%) for predicting positive quantitative culture results, and a low specificity (77%) for predicting negative quantitative culture results. There was no correlation between total colony counts on BAL or PSB and severity of ARDS as judged by Pao2/FIo2 ratios, days receiving ventilation, or compliance. Furthermore, there was no correlation between bacterial growth and survival. We conclude that pneumonia defined by quantitative bacteriology is uncommon in ARDS. The potentially confounding role of broad-spectrum antibiotics should be studied further.

The frequency of breech presentation by gestational age at birth: a large population-based study.

From a study of birth records, breech presentation at delivery for each gestational age was found to be less frequent as compared with other reports about antenatal ultrasonographic examination. Selection bias or the effect of labor may account for the observed difference.

Homocysteine and lipoprotein(a) interact to increase CAD risk in young men and women.

A biochemical link between homocysteine (tHcy) and lipoprotein(a) [Lp(a)] related to fibrin binding has been proposed. This hypothesis has not been specifically examined in human subjects. We sought to determine in a clinical setting whether these risk factors would interact to increase coronary artery disease (CAD) risk. We performed a cross-sectional analysis of 750 men and 403 women referred to a preventive cardiology clinic at the Cleveland Clinic Foundation, in whom baseline tHcy and Lp(a) data were available. Logistic regression after adjusting for standard cardiovascular risk factors was used to estimate the relative risk of CAD in patients with an Lp(a) >/=30 mg/dL and a tHcy >/=17 micromol/L. Neither isolated high tHcy (odds ratio [OR]=1.06, P=0.89) nor isolated high Lp(a) (OR=1.15, P=0.60) appeared to be associated with CAD in women. However, strong evidence of an association was seen when both risk factors were present (OR=4.83, P=0.003). Moreover, this increased risk showed evidence of an interactive effect beyond that attributable to either additive or multiplicative effects of tHcy and Lp(a) (P=0.03). In contrast, both elevated tHcy (OR=1.93, P=0. 05) and elevated Lp(a) (OR=1.87, P=0.01) showed evidence of being independent risk factors for CAD in men. The presence of both risk factors in men did not appear to confer additional risk (OR=2.00, P=0.09), even though ORs as high as 12.4 were observed within specific age intervals. Consistent with prior studies, tHcy and Lp(a) are risk factors, either independently or in concert, for CAD in this clinical population. More significantly, we found evidence that when both risk factors were present in women, the associated risk was greater than what would be expected if the 2 risks were simply acting independently. The absence of such an interactive effect in men may be due to the confounding effects of age manifested as "survivor bias." These clinical findings provide insights into the potential roles of both tHcy and Lp(a) in the pathogenesis of atherosclerosis.

Elevated transforming growth factor-alpha levels in bronchoalveolar lavage fluid of patients with acute respiratory distress syndrome.

The acute respiratory distress syndrome (ARDS) frequently results in a fibroproliferative response that precludes effective alveolar repair. Transforming growth factor-alpha (TGF-alpha), a potent epithelial and mesenchymal cell mitogen, may modulate the response to lung injury. In this study, we determined whether bronchoalveolar lavage fluid (BALF) concentrations of TGF-alpha are increased during the first 2 wk after the onset of ARDS and, if so, whether increased TGF-alpha levels in lavage fluid are associated with increased levels of procollagen peptide III (PCP III), a biological marker of fibroproliferation, and with increased fatality rates. We enrolled 74 consecutive patients with ARDS prospectively identified on admission to the intensive care unit of a tertiary care hospital, and 11 patients with chronic interstitial lung disease. Thirteen healthy volunteers served as control subjects. TGF-alpha concentrations were measured in BALF recovered on Days 3, 7, and 14 after the onset of ARDS (total of 130 lavage samples). TGF-alpha was detected in the lavage fluid of 90% of patients with ARDS (67 of 74), and in 100% of patients with idiopathic pulmonary fibrosis (IPF) (10 of 10), but in none of 13 normal volunteers. At each day tested, the median lavage TGF-alpha level of patients with ARDS was significantly higher than that of normals. The overall fatality rate was 45% (33 of 74 patients). In a univariate analysis, the median TGF-alpha levels in nonsurvivors were 1.5-fold higher at Day 7 (p = 0.06) and 1.8-fold higher at Day 14 (p = 0.048). The fatality rate was 4 times higher (CI 1.6, 17.5) for patients with both increased lavage TGF-alpha and PCP III concentrations at Day 7 than for patients with low TGF-alpha and PCP III values, indicating a synergistic relationship between TGF-alpha and PCP III. We conclude that increased levels of TGF-alpha in BALF are common in patients with ARDS and that lavage TGF-alpha is associated with a marker of the fibroproliferative response in sustained ARDS.

Inflammatory cytokines in patients with persistence of the acute respiratory distress syndrome.

To determine the relationship between airspace cytokines and cellular inflammatory responses in patients with the acute respiratory distress syndrome (ARDS), we performed bronchoalveolar lavage (BAL) in 82 prospectively identified, mechanically ventilated patients on Days 3, 7, 14, and/or 21 after the onset of ARDS. We studied the relationships between bronchoalveolar lavage fluid (BALF) cell populations and the concentrations of two potent neutrophil (PMN) chemoattractants, interleukin-8 (IL-8) and epithelial cell-derived neutrophil activator-78 (ENA-78); two potent monocyte chemoattractants, monocyte chemotactic peptide-1 (MCP-1) and macrophage inflammatory peptide-1 alpha (MIP-1 alpha); and the early response cytokine interleukin-1 beta (IL-1 beta) and its naturally occurring antagonist, IL-1 receptor antagonist protein (IRAP). We found that all of these cytokines were significantly increased regardless of the duration of ARDS. IL-8 and ENA-78 were the cytokines most strongly and consistently correlated with PMN concentrations in the lung fluids of patients with ARDS, and the correlations were independent of the other cytokines or coexisting lung infection. None of the cytokines tested correlated with macrophage concentrations. MCP-1 was directly correlated with lung injury score on Days 7, 14, and 21. Although neither IL-8 nor ENA-78 was associated with outcome, levels of IL-1 beta measured on Day 7 were associated with an increased risk of death (odds ratio [OR] = 2.8; 95% confidence interval [CI] = 1.1 to 7.4). These data demonstrate potential molecular mechanisms of the persistent inflammatory process in the lungs of patients with ARDS.