ABSTRACT
AIMS: To analyse the impact of overtime and extended working hours on the risk of occupational injuries and illnesses among a nationally representative sample of working adults from the United States. METHODS: Responses from 10,793 Americans participating in the National Longitudinal Survey of Youth (NLSY) were used to evaluate workers' job histories, work schedules, and occurrence of occupational injury and illness between 1987 and 2000. A total of 110,236 job records were analysed, encompassing 89,729 person-years of accumulated working time. Aggregated incidence rates in each of five exposure categories were calculated for each NLSY survey period. Multivariate analytical techniques were used to estimate the relative risk of long working hours per day, extended hours per week, long commute times, and overtime schedules on reporting a work related injury or illness, after adjusting for age, gender, occupation, industry, and region. RESULTS: After adjusting for those factors, working in jobs with overtime schedules was associated with a 61% higher injury hazard rate compared to jobs without overtime. Working at least 12 hours per day was associated with a 37% increased hazard rate and working at least 60 hours per week was associated with a 23% increased hazard rate. A strong dose-response effect was observed, with the injury rate (per 100 accumulated worker-years in a particular schedule) increasing in correspondence to the number of hours per day (or per week) in the workers' customary schedule. CONCLUSIONS: Results suggest that job schedules with long working hours are not more risky merely because they are concentrated in inherently hazardous industries or occupations, or because people working long hours spend more total time "at risk" for a work injury. Strategies to prevent work injuries should consider changes in scheduling practices, job redesign, and health protection programmes for people working in jobs involving overtime and extended hours.
Subject(s)
Accidents, Occupational/statistics & numerical data , Occupational Diseases/epidemiology , Work Schedule Tolerance , Wounds and Injuries/epidemiology , Adult , Epidemiologic Methods , Female , Humans , Male , Occupational Diseases/etiology , Time Factors , United States/epidemiology , Wounds and Injuries/etiologyABSTRACT
We investigated whether decreases in circulating polymorphonuclear neutrophils (PMN) during lethal Escherichia coli (E. coli) sepsis in canines are related to insufficient host granulocyte colony-stimulating factor (G-CSF). Two-year-old purpose-bred beagles had intraperitoneal E. coli-infected or -noninfected fibrin clots surgically placed. By 10 to 12 h following clot, both infected survivors and nonsurvivors had marked increases (P = 0.001) in serum G-CSF levels (mean peak G-CSF ng/ml +/- SE, 1,931 +/- 364 and 2,779 +/- 681, respectively) compared with noninfected controls (134 +/- 79), which decreased at 24 to 48 h. Despite increases in G-CSF, infected clot placement caused delayed (P = 0.06) increases in PMN (mean +/- SE change from baseline in cells x 10(3)/mm(3) at 24 and 48 h) in survivors (+3.9 +/- 3.9 and +13.8 +/- 3.6) compared with noninfected controls (+13.1 +/- 2.8 and +9.1 +/- 2.5). Furthermore, infected nonsurvivors had decreases in PMN (-1.4 +/- 1.0 and -1.1 +/- 2.3, P = 0.006 compared with the other groups). We next investigated whether administration of G-CSF immediately after clot placement and continued for 96 h to produce more rapid and prolonged high levels of G-CSF after infection would alter PMN levels. Although G-CSF caused large increases in PMN compared with control protein from 2 to 48 h following clot in noninfected controls, it caused much smaller increases in infected survivors and decreases in infected nonsurvivors (P = 0.03 for the ordered effect of G-CSF comparing the three groups). Thus insufficient host G-CSF is unlikely the cause of decreased circulating PMN in this canine model of sepsis. Other factors associated with sepsis either alone or in combination with G-CSF itself may reduce increases or cause decreases in circulating PMN.
Subject(s)
Escherichia coli Infections/drug therapy , Granulocyte Colony-Stimulating Factor/therapeutic use , Sepsis/drug therapy , Animals , Blood Pressure/drug effects , Bronchoalveolar Lavage Fluid/cytology , Cell Count , Disease Models, Animal , Disease Progression , Dogs , Escherichia coli Infections/pathology , Granulocyte Colony-Stimulating Factor/adverse effects , Granulocyte Colony-Stimulating Factor/blood , Heart Function Tests/drug effects , Myocardium/metabolism , Neutrophils/pathology , Recombinant Proteins/adverse effects , Recombinant Proteins/therapeutic use , Sepsis/pathology , Survival Rate , Treatment FailureABSTRACT
The ethic of fairness in program evaluation requires that measures of behavioral health agency performance be sensitive to differences in those agencies' caseload composition. The authors describe two traditional approaches to the statistical risk adjustment of outcome measures (stratification weighting and pre-post measurement) that are designed to account for differences in caseload composition and introduce a method that incorporates the strengths of both approaches. Procedures for deriving each of these measures are described in detail and demonstrated in the evaluation of a statewide system of community-based behavioral health care programs. This evaluation examines the degree to which service recipients get into trouble with the law after treatment. Three measures are recommended for inclusion in outcome-oriented "report cards," and the interpretation of each measure is discussed. Finally, the authors suggest formats for graphic and tabular presentation of the risk-adjusted evaluation for sharing findings with diverse stakeholder groups.
Subject(s)
Community Mental Health Services/standards , Crime/statistics & numerical data , Outcome Assessment, Health Care/methods , Public Health Administration/standards , Risk Adjustment , Adult , Community Mental Health Services/statistics & numerical data , Female , Humans , Male , Middle Aged , Models, Statistical , Program Evaluation , Quality Indicators, Health Care , Retrospective Studies , Sampling Studies , Vermont/epidemiologyABSTRACT
To evaluate the effects of endotoxemia on respiratory controller function, 12 subjects were randomized to receive endotoxin or saline; six also received ibuprofen, a cyclooxygenase inhibitor, and six received placebo. Administration of endotoxin produced fever, increased respiratory frequency, decreased inspiratory time, and widened alveolar-arterial oxygen tension gradient (all p < or = 0.001); these responses were blocked by ibuprofen. Independent of ibuprofen, endotoxin produced dyspnea, and it increased fractional inspiratory time, minute ventilation, and mean inspiratory flow (all p < or = 0.025). Endotoxin altered the autocorrelative behavior of respiratory frequency by increasing its autocorrelation coefficient at a lag of one breath, the number of breath lags with significant serial correlations, and its correlated fraction (all p < 0.05); these responses were blocked by ibuprofen. Changes in correlated behavior of respiratory frequency were related to changes in arterial carbon dioxide tension (r = 0.86; p < 0.03). Endotoxin decreased the oscillatory fraction of inspiratory time in both the placebo (p < 0.05) and ibuprofen groups (p = 0.06). In conclusion, endotoxin produced increases in respiratory motor output and dyspnea independent of fever and symptoms, and it curtailed the freedom to vary respiratory timing-a response that appears to be mediated by the cyclooxygenase pathway.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Dyspnea/immunology , Dyspnea/physiopathology , Endotoxemia/immunology , Endotoxemia/physiopathology , Endotoxins/adverse effects , Ibuprofen/therapeutic use , Prostaglandin-Endoperoxide Synthases/drug effects , Prostaglandin-Endoperoxide Synthases/immunology , Pulmonary Ventilation/drug effects , Pulmonary Ventilation/immunology , Sepsis/immunology , Sepsis/physiopathology , Adult , Anti-Inflammatory Agents, Non-Steroidal/immunology , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Blood Gas Analysis , Carbon Dioxide/blood , Dyspnea/drug therapy , Dyspnea/metabolism , Endotoxemia/drug therapy , Endotoxemia/metabolism , Female , Fever/drug therapy , Fever/immunology , Fever/metabolism , Fever/physiopathology , Humans , Ibuprofen/immunology , Ibuprofen/pharmacology , Inflammation , Male , Respiratory Muscles/drug effects , Respiratory Muscles/immunology , Respiratory Muscles/physiopathology , Sepsis/drug therapy , Sepsis/metabolism , Single-Blind MethodSubject(s)
Clinical Trials as Topic/standards , Critical Illness/mortality , Critical Illness/therapy , Aspirin/analogs & derivatives , Aspirin/therapeutic use , Blood Substitutes/therapeutic use , Hemoglobins/therapeutic use , Human Growth Hormone/therapeutic use , Humans , Shock, Hemorrhagic/drug therapy , Shock, Septic/drug therapy , omega-N-Methylarginine/therapeutic useABSTRACT
To study local lung inflammation, 34 subjects had endotoxin (1-4 ng/kg) instilled into a lung segment and saline instilled into a contralateral segment followed by bronchoalveolar lavage (BAL) at 2 h, 6 h, 24 h, or 48 h. Endotoxin instillation resulted in a focal inflammatory response with a distinct time course. An early phase (2 h to 6 h) revealed an increase in neutrophils (p = 0.0001) with elevated cytokines (tumor necrosis factor [TNF]-alpha, TNF receptors [TNFR], interleukin [IL]-1beta, IL-1 receptor antagonist, IL-6, granulocyte-colony-stimulating factor [G-CSF], all p < or = 0.002, but no change in IL-10) and chemokines (IL-8, epithelial neutrophil activating protein-78, monocyte chemotactic protein-1, macrophage inflammatory protein [MIP]-1alpha, MIP-1beta, all p < or = 0.001, but no change in growth-regulated peptide-alpha). A later phase (24 h to 48 h) showed increased neutrophils, macrophages, monocytes, and lymphocytes (all p < or = 0.02), and a return to basal levels of most mediators. Elevated levels of inflammatory markers (TNFR(1), TNFR(2), L-selectin, lactoferrin, and myeloperoxidase) persisted in the BAL at 48 h (p < or = 0.001). Increased permeability to albumin occurred throughout both phases (p = 0.001). Blood C-reactive protein, serum amyloid A, IL-6, IL-1ra, G-CSF, but not TNF-alpha increased by 8 h (all p < or = 0.008). The local pulmonary inflammatory response to endotoxin has a unique qualitative and temporal profile of inflammation compared with previous reports of intravenous endotoxin challenges. This model provides a means to investigate factors that initiate, amplify, and resolve local lung inflammation.
Subject(s)
Endotoxins/pharmacology , Inflammation Mediators/metabolism , Lung/drug effects , Adult , Bronchoalveolar Lavage Fluid/chemistry , Bronchoalveolar Lavage Fluid/cytology , Bronchoscopy , Chemokines/metabolism , Cytokines/metabolism , Endotoxins/administration & dosage , Escherichia coli , Female , Humans , Inflammation/metabolism , Instillation, Drug , Lung/metabolism , Lung/pathology , Male , Neutrophils , Pilot ProjectsABSTRACT
Probabilistic population estimation is a statistical procedure for deriving unduplicated counts of the number of people represented in data sets that do not include unique person identifiers and the number of people shared by data sets that do not share personal identifiers. Because the procedure relies on anonymous data sets, the personal privacy of individuals and the confidentiality of medical records is protected. This paper describes the mathematics of probabilistic population estimation, and applies the procedure to an important contemporary public policy issue.
Subject(s)
Computer Simulation , Data Interpretation, Statistical , Databases, Factual , Models, Statistical , Population Dynamics , Age Factors , Confidentiality , Female , Humans , Male , Models, Biological , Public PolicyABSTRACT
Consumer satisfaction is increasingly used to measure community mental health program performance. Understanding the relationship between consumer satisfaction and treatment outcomes is only beginning. This article adds to this understanding by reporting on an assessment of the relationship between consumer evaluation of community mental health services and incarceration after treatment in a statewide system of care. Results indicate that satisfaction with services is related to incarceration after treatment, with satisfied consumers having lower incarceration rates. These results support the use of self-reported consumer satisfaction as a measure of mental health program performance.
Subject(s)
Commitment of Mentally Ill/statistics & numerical data , Community Mental Health Services/standards , Institutionalization/statistics & numerical data , Mental Disorders/therapy , Outcome Assessment, Health Care/methods , Patient Satisfaction , Adult , Chronic Disease , Female , Health Care Surveys , Humans , Male , VermontABSTRACT
The idea that the deinstitutionalization of state psychiatric centers has resulted in increased utilization of general hospitals and correctional facilities by people with severe and persistent mental illness is widely held. This hypothesis of trans-institutionalization was tested by examining hospitalization and incarceration rates of people who had been or would be institutionalized in state psychiatric centers in 16 upstate New York counties. The results do not support the hypothesis of trans-institutionalization. Assumptions underlying the hypothesis are examined, potential explanations for the observed patterns are discussed, and areas for further research are suggested.
Subject(s)
Deinstitutionalization/trends , Hospitals, General/statistics & numerical data , Hospitals, Psychiatric/statistics & numerical data , Prisons/statistics & numerical data , Cohort Studies , Commitment of Mentally Ill/trends , Female , Hospitals, State/statistics & numerical data , Humans , Institutionalization/trends , Male , New York , Outcome and Process Assessment, Health Care , Retrospective StudiesABSTRACT
AIMS: This study is designed to determine the relative risk of mortality for white male problem drinkers compared to white males in the general population, and to identify any variation in relative risk of problem drinking in three age groups (18-29, 30-49 and 50-79 years). DESIGN: The research design is prospective, using historical administrative datasets from treatment programs in conjunction with vital records datasets. PARTICIPANTS: Participants include all white men aged 18-79 treated for alcohol-related problems in community mental health substance abuse programs in Vermont during 1991. The treatment group includes 1853 service recipients; the comparison group includes 196,443 adult white male residents of Vermont. MEASUREMENT: Measurement of mortality rates for problem drinkers was based on probabilistic determination of overlap between treatment and vital record datasets. FINDINGS: Mortality for problem drinkers is greater than the general population in all three age groups. The estimated relative risk of mortality in the oldest age group was lower than the other groups, but substantially higher than found in recently published research. The estimated relative risk of mortality in the youngest age group, which has rarely been addressed in previous research, was higher than the relative risk in the middle age group. CONCLUSION: The application of a public health research model in which problem drinkers are compared to the general population has potential to inform public policy. In this case, the public health approach identified an elevated risk of mortality associated with problem drinking among older adults that had not been evident in the previous research.
Subject(s)
Alcohol-Related Disorders/mortality , Alcoholism/mortality , White People/statistics & numerical data , Adolescent , Adult , Age Distribution , Aged , Databases, Factual , Health Services Research , Humans , Male , Middle Aged , Prospective Studies , Risk , Vermont/epidemiologyABSTRACT
The heads of 137 white-tailed deer (Odocoileus virginianus) were collected on the opening day of the 1996 Missouri (USA) fire-arms deer season and surveyed for the presence of meningeal worm (Parelaphostrongylus tenuis). Eighteen percent of the deer examined were infected. Mean intensity of infection was 2.0 (range 1-7). There were no significant differences of infection or mean intensity when deer were classified and compared according to sex or age class.
Subject(s)
Deer/parasitology , Metastrongyloidea/isolation & purification , Strongylida Infections/veterinary , Age Distribution , Animals , Female , Head/parasitology , Male , Missouri/epidemiology , Prevalence , Sex Distribution , Strongylida Infections/epidemiology , Strongylida Infections/parasitologyABSTRACT
OBJECTIVE: Several studies have shown that hostility, as measured by the Minnesota Multiphasic Personality Inventory-derived Cook-Medley Hostility Scale (Ho), is positively associated with several cardiovascular risk factors, possibly accounting for the relationship between Ho scores and cardiovascular mortality. This study was undertaken to examine associations between hostility and cardiovascular risk factors representing the metabolic syndrome in 1,081 older men who participated in the Normative Aging Study. METHODS: Subjects included men who completed the Minnesota Multiphasic Personality Inventory in 1986 and who participated in a subsequent laboratory examination within 1 to 4 years. Total and subscale Ho scores were computed, and associations with anthropometric data, cigarette smoking, dietary information, serum lipids, blood pressure, and fasting glucose and insulin levels were examined. RESULTS: The total Ho score was positively associated with waist/hip ratio, body mass index, total caloric intake, fasting insulin level, and serum triglycerides. The Ho score was inversely related to education and high-density lipoprotein cholesterol concentration. Path analysis also suggested that the effects of hostility on insulin, triglycerides, and high-density lipoprotein cholesterol were mediated by its effects on body mass index and waist/hip ratio, which, in turn, exerted their effects on lipids and blood pressure through insulin. CONCLUSIONS: The results are consistent with those of prior research and also suggest that, in older men, hostility may be associated with a pattern of obesity, central adiposity, and insulin resistance, which can exert effects on blood pressure and serum lipids. Furthermore, effects of hostility on the metabolic syndrome appear to be mediated by body mass index and waist/hip ratio.
Subject(s)
Aging/physiology , Hostility , Hyperglycemia/diagnosis , Adult , Aged , Aged, 80 and over , Anthropometry , Body Mass Index , Cholesterol, LDL/blood , Coronary Disease/diagnosis , Humans , Hyperglycemia/blood , Insulin/blood , MMPI , Male , Middle Aged , Prospective Studies , Triglycerides/bloodABSTRACT
There is widespread agreement that chronic pain develops from, and is maintained by, a combination of neurobiological, psychological, and social factors. Nevertheless, few comprehensive models have been proposed that present specific testable predictions about how these factors interact. We propose a vulnerability-diathesis-stress model of the pathogenesis of chronic pain. This model is based on diathesis-stress models of psychopathology and on the results of recent research on psychosocial aspects of chronic pain. The goals of research on chronic pain are to understand its pathogenesis, improve its treatment, and prevent its development. To achieve these goals, prospective studies of the development and maintenance of chronic pain are needed. The vulnerability-diathesis-stress model can serve as a basis for designing and analyzing studies of the interaction among biological, psychological, and social risk factors for chronic pain.
Subject(s)
Depressive Disorder, Major/etiology , Pain/psychology , Psychological Theory , Chronic Disease , Disease Susceptibility , Humans , Life Change Events , Personality Disorders/psychology , Risk Factors , Stress, Psychological/psychologyABSTRACT
The authors describe the use of risk-adjusted hospitalization rates to measure community mental health treatment outcomes. The risk adjustment involves comparing rates of hospitalization subsequent to treatment with rates of hospitalization prior to treatment. The research uses a probabilistic methodology that reliably estimates caseload overlap by comparing the distribution of the dates of birth observed in data sets to the distribution of dates of birth in the general population. Findings indicate that risk-adjusted hospitalization rates are substantially different than unadjusted rates. Half of the community programs in one state consistently achieved positive outcomes in four consecutive years; other programs had mixed results or no change.
Subject(s)
Community Mental Health Services/standards , Hospitalization/statistics & numerical data , Outcome Assessment, Health Care/methods , Program Evaluation/methods , Adult , Community Mental Health Services/statistics & numerical data , Confidence Intervals , Female , Humans , Male , Middle Aged , Probability , Risk Adjustment , VermontABSTRACT
We investigated whether inhibiting an endothelial adhesion molecule [intracellular adhesion molecule 1 (ICAM-1)] would alter outcome and lung injury in a similar fashion to inhibition of a leukocyte adhesion molecule (integrin CD11b) in a rat model of gram-negative pneumonia. Inhibition of ICAM-1 with monoclonal antibody (MAb) 1A29 (1 mg/kg sc or 0.2 or 2 mg/kg iv, q 12 h x 3) or of CD11b with MAb 1B6 (1 mg/kg sc, q 12 h x 3) were compared against similarly administered placebo proteins in rats challenged with intrabronchial Escherichia coli. After challenge, all animals were treated with antibiotics. ICAM-1 MAb (6 mg/kg, iv, total dose) increased mortality vs. control (P = 0.03). CD11b MAb (3 mg/kg, sc, total dose) did not significantly (P = 0.16) increase mortality rates, but this was not in a range of probability to exclude a harmful effect. All other doses of MAb had no significant effect on survival rates. ICAM-1 and CD11b MAbs had significantly different effects on the time course of lung injury, circulating white cells and lymphocytes, and lung lavage white cells and neutrophils (P = 0.04-0.003). CD11b MAb decreased, whereas ICAM-1 MAb increased these measures compared with control from 6 to 12 h after E. coli. However, from 144 to 168 h after E. coli both MAbs increased these measures compared with control rats but to a greater level with CD11b MAb. Thus both ICAM-1 and CD11b appear to be necessary for survival during E. coli pneumonia. Although these adhesion molecules may participate differently in early lung injury, with CD11b increasing and ICAM-1 decreasing inflammation and injury, both are important for the resolution of later injury. During gram-negative pneumonia the protective roles of ICAM-1 and CD11b may make their therapeutic inhibition difficult.
Subject(s)
Escherichia coli Infections/immunology , Intercellular Adhesion Molecule-1/metabolism , Macrophage-1 Antigen/metabolism , Pneumonia, Bacterial/immunology , Animals , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal/adverse effects , Escherichia coli Infections/etiology , Escherichia coli Infections/therapy , Inflammation/immunology , Inflammation/prevention & control , Lung/immunology , Lung Injury , Male , Pneumonia, Bacterial/etiology , Pneumonia, Bacterial/therapy , Prognosis , Rats , Rats, Sprague-DawleyABSTRACT
We investigated if bacteria type alters outcome with prophylactic granulocyte colony stimulating factor (G-CSF) therapy during pneumonia. Rats received G-CSF or placebo daily for 6 d and after the third dose were intrabronchially inoculated with either Escherichia coli or Staphylococcus aureus. Without G-CSF, E. coli and S. aureus produced similar (p = NS) mortality rates (36 versus 38%) and serial changes in mean circulating neutrophil counts (CNC), but differing mean (+/- SE) tumor necrosis factor (TNF) levels (E. coli, 259 +/- 104 versus S. aureus, 51 +/- 17 pg/ml, p = 0.01). G-CSF prior to bacteria increased mean CNC more than six times compared with placebo (p = 0.001). However, with G-CSF in the first 6 h after E. coli, there was a greater than 20-fold decrease in mean (+/- SE) CNC (x 10(3)/ mm3) to below placebo (0.5 +/- 0.1 versus 0.8 +/- 0.1), whereas with G-CSF after S. aureus, there was only a fivefold decrease in mean CNC and CNC were greater than placebo (1.8 +/- 0.2 versus 0.8 +/- 0.1) (E. coli versus S. aureus decrease in CNC with G-CSF, p = 0.001). With E. coli, G-CSF worsened oxygenation and increased bacteremia and mortality, whereas with S. aureus, G-CSF improved oxygenation and decreased bacteremia and mortality (G-CSF therapy, E. coli versus S. aureus, p = 0.03, 0.05, and 0.001, respectively). Thus, during S. aureus pneumonia with low TNF levels, G-CSF increased CNC and bacterial clearance, resulting in less pulmonary injury and decreased death. During E. coli pneumonia with high TNF levels, G-CSF paradoxically decreased CNC, resulting in impaired bacterial clearance and worsened pulmonary injury and death. Bacterial species and the associated inflammatory mediator response can alter outcome with prophylactic G-CSF therapy during pneumonia.
Subject(s)
Escherichia coli Infections/therapy , Granulocyte Colony-Stimulating Factor/therapeutic use , Pneumonia/microbiology , Staphylococcal Infections/therapy , Animals , Arteries , Leukocyte Count/drug effects , Male , Neutrophils/pathology , Oxygen/blood , Oxygen/metabolism , Pneumonia/mortality , Pneumonia/physiopathology , Pulmonary Alveoli/metabolism , Rats , Rats, Sprague-Dawley , Tumor Necrosis Factor-alpha/analysisABSTRACT
The tumorigenicity of adenovirus (Ad) 12-transformed mouse cells was evaluated by analyzing the relationship of tumor cell dose to tumor incidence and tumor latency. The tumor producing dose 50% endpoint values used to define these relationships remained stable during 52 weeks of serial passage in tissue culture and were not determined by low frequency events within the cell population. The data from these analyses suggest that the phenotype of Ad12-transformed mouse cells is influenced by two set of traits--those traits that determine the threshold number of cells required for tumor formation and those that extend the cell dose-dependent tumor latency period. Both traits are established independently of cell immortalization, and both can be influenced by the immunological status of tumor-challenged animals. These observations were verified by using mouse cells transformed by Ad5 and SV40. The biological and molecular processes that contribute to these traits remain to be determined. The approach developed by this analysis provides a reliable, quantitative means of evaluating endogenous traits that determine transformed cell tumorigenicity. This method can also be used to test the effects of tumor cell manipulations or changes in host response that could alter expression or detection of these neoplastic cell traits.
Subject(s)
Adenoviridae/physiology , Cell Transformation, Neoplastic , Cell Transformation, Viral/physiology , Neoplasms, Experimental/virology , Simian virus 40/physiology , Animals , Cell Line, Transformed , Cell Transplantation , Cricetinae , Evaluation Studies as Topic , Mice , Mice, Inbred BALB C , PhenotypeABSTRACT
Ibuprofen has been shown in vitro to modulate production of nitric oxide (NO), a mediator of sepsis-induced hypotension. We sought to determine whether ibuprofen alters NO production and, thereby, vascular tone, in normal and endotoxin-challenged volunteers. Techniques for detecting NO were validated in 17 subjects infused with sodium nitroprusside, a NO donor. Then, endotoxin (4 ng/kg) or saline (vehicle alone) was administered in a single-blinded, crossover design to 12 other subjects randomized to receive either ibuprofen (2400 mg p.o.) or a placebo. Endotoxin decreased mean arterial pressure (MAP; P =.002) and increased alveolar NO flow rates (P =.04) and urinary excretion of nitrite and nitrate (P =.07). In both endotoxemic and normal subjects, ibuprofen blunted the small fall in MAP associated with bed rest (P =.005) and decreased alveolar NO flow rates (P =.03) and urinary excretion of nitrite and nitrate (P =.02). However, ibuprofen had no effect on the decrease in MAP caused by endotoxin, although it blocked NO production to the point of disrupting the normal relationship between increases in exhaled NO flow rate and decreases in MAP (P =.002). These are the first in vivo data to demonstrate that ibuprofen down-regulates NO in humans. Ibuprofen impaired the NO response to bed rest, producing a small rise in blood pressure. Although ibuprofen also interfered with the ability of endotoxin to induce NO production, it had no effect on the fall in blood pressure, suggesting that the hemodynamic response to endotoxin is not completely dependent on NO under these conditions.
Subject(s)
Ibuprofen/pharmacology , Nitric Oxide/biosynthesis , Nitroprusside/pharmacology , Pulmonary Alveoli/physiology , Adult , Blood Pressure/drug effects , Carbon Dioxide/analysis , Cross-Over Studies , Cyclic GMP/blood , Cyclic GMP/urine , Endotoxins/toxicity , Female , Heart Rate/drug effects , Humans , Infusions, Intravenous , Male , Nitrates/blood , Nitrates/urine , Nitroprusside/administration & dosage , Pulmonary Alveoli/drug effects , Reproducibility of Results , Single-Blind MethodABSTRACT
We investigated effects of pentoxifylline during septic shock. Two-year-old (10-12 kg), purpose-bred beagles were infected i.p. with Escherichia coli 0111:B4 (1.2-1.5 x 10(9) colony-forming units per kilogram b.wt.) in a fibrin clot and then immediately treated with one of five doses of pentoxifylline (0.5-20 mg. kg-1. h-1 i.v.) as a 36-h continuous infusion or placebo. All animals received antibiotics and fluid resuscitation. Pentoxifylline levels increased in a dose-dependent manner during (p =.001) and were undetectable 12 h after stopping the infusion. During infusion of pentoxifylline at all doses, there were increases (p =.003), and once the infusion was stopped, there were decreases (p =.049) in endotoxin levels compared with controls. After clot implantation, at all pentoxifylline doses there was a significant increase in tumor necrosis factor levels, compared with controls (p =.025). The relative risk of death was significantly increased with pentoxifylline therapy in a dose-dependent fashion (20 >/= 10 >/= 5.0 >/= 1.0 >/= 0.5 mg. kg-1, p =.008). One hypothesis consistent with these data is that high pentoxifylline levels slowed endotoxin clearance, resulting in high levels of endotoxemia and increased proinflammatory mediator release and death. Pentoxifylline, used as a long-term continuous infusion as is commonly done clinically, can be harmful during Gram-negative septic shock.