Emeritus Faculty, Acad Council, Medicine
Co-Founder and Director Emeritus, Stanford Center for Biomedical Ethics (1989 - Present)
Chief, Pulmonary and Critical Care Medicine, Stanford Department of Medicine (1991 - 2004)
Director and Founder, Stanford University-Asia Medical Fund, Stanford University fellowships from Pacific Rim (1982 - Present)
Board Member, NewLink Genetics, NewLink Genetics, Inc. (2000 - Present)
Advisor, Broncus Technologies, Inc. (1996 - Present)
Consultant, Nektar, Inc. (1999 - Present)
Co-Founder, Hutchison Program in Translational Medicine at Stanford University($5,000,000) (1998 - 2003)
Co-Founder and Co-Director, Stanford Program in Genomics, Ethics and Society (1995 - Present)
Course Founder and Director - Intensive Life Support Systems: Present Practice and Moral Issues, Stanford University Undergraduate Curriculum (1984 - 1988)
Course Founder and Director - Ethical Values in Health Care: Lessons from the Nazi Period, Stanford University Undergraduate Curriculum (1994 - 1996)
Honors & Awards
Henry J. Kaiser Foundation Award for Excellence in Clinical Teaching, Stanford University Medical School (1980)
Arthur L. Bloomfield Award for Excellence in the Teaching of Clinical Medicine, Stanford University Medical School (1981)
Henry J. Kaiser Foundation Award for Excellence in Clinical Teaching, Stanford University Medical School (1984)
Henry J. Kaiser Award for Excellence in Clinical Teaching, Stanford University Medical School (1988)
Henry J. Kaiser Foundation Award for Excellence in Preclinical Teaching, Stanford University Medical School (1997)
Fellow, Stanford Medical School, Pulmonary and Critical Care (1978)
Resident, Peter Bent Brigham Hospital, Internal Medicine (1975)
MD, Stanford School of Medicine, Medicine (1973)
AB, Stanford University, Biological Sciences (1968)
Community and International Work
Stanford University-Asia Medical Fund, Stanford University
Training Pacific Rim Fellows
Pacific Rim universities
Opportunities for Student Involvement
Current Research and Scholarly Interests
Acute lung tissue injury is often mediated by neutrophils. Our laboratory studied the basic biology of neutrophils and mechanisms of neutrophil-mediated pulmonary injury. Investigative approaches included the molecular biology of neutrophil activation, neutrophil ion channel regulation, mechanisms of signal transduction with an emphasis on protein phosphorylation, control of neutrophil activation and the use of animal models to investigate the use of agents and intermediaries which might attenuate neutrophil-mediated acute lung injury. Besides these areas of basic investigation, clinical studies in biomedical ethics were also pursued. For example: End-of-life decision making, differences in informed consent and decision making between patients and physicians in Japan and America, the efficacy of ethics committees in the United States, the new role of biomedical ethics in managed care; social, ethical and legal issues in genomics and genetic testing, and neuroethics.
Advertising, patient decision making, and self-referral for computed tomographic and magnetic resonance imaging
ARCHIVES OF INTERNAL MEDICINE
2004; 164 (22): 2415-2419
Self-referred imaging is one of the latest health care services to be marketed directly to consumers. Most aspects of these services are unregulated, and little is known about the messages in advertising used to attract potential consumers. We conducted a detailed analysis of print advertisements and informational brochures for self-referred imaging with respect to themes, content, accuracy, and emotional valence.Forty print advertisements from US newspapers around the country and 20 informational brochures were analyzed by 2 independent raters according to 7 major themes: health care technology; emotion, empowerment, and assurance; incentives; limited supporting evidence; popular appeal; statistics; and images. The Fisher exact test was used to identify significant differences in information content.Both the advertisements and the brochures emphasized health care and technology information and provided assurances of good health and incentives to self-refer. These materials also encouraged consumers to seek further information from company resources; virtually none referred to noncomplying sources of information or to the risks of having a scan. Images of people commonly portrayed European Americans. We found statistical differences between newspaper advertisements and mailed brochures for references to "prevalence of disease" (P<.001), "death" (P<.003), and "radiation" (P<.001). Statements lacking clear scientific evidence were identified in 38% of the advertisements (n = 15) and 25% of the brochures (n = 5).Direct-to-consumer marketing of self-referred imaging services, in both print advertisements and informational brochures, fails to provide prospective consumers with comprehensive balanced information vital to informed autonomous decision making. Professional guidelines and oversight for advertising and promotion of these services are needed.
View details for Web of Science ID 000225701900003
View details for PubMedID 15596630
Discovery and disclosure of incidental findings in neuroimaging research
33rd Annual Meeting of the Society-for-Neuroscience
JOHN WILEY & SONS INC. 2004: 743–47
To examine different protocols for handling incidental findings on brain research MRIs, and provide a platform for establishing formal discussions of related ethical and policy issues.Corresponding authors identified from a database of peer-reviewed publications in 1991-2002 involving functional MRI (fMRI), alone or in combination with other imaging modalities, were invited to participate in this web-based survey. The survey asked questions regarding knowledge and handling of incidental findings, as well as characteristics of the scanning environment, training required, IRB protocol requirements, and neuroradiologist involvement.Seventy-four investigators who conduct MRI studies in the United States and abroad responded. Eighty-two percent (54/66) reported discovering incidental findings in their studies, such as arteriovenous malformations, brain tumors, and developmental abnormalities. Substantial variability was found in the procedures for handling and communicating findings to subjects, neuroradiologist involvement, personnel permitted to operate equipment, and training.Guidelines for minimum and optimum standards for detecting and communicating incidental findings on brain MRI research are needed.
View details for DOI 10.1002/jmri.20180
View details for Web of Science ID 000224762700001
View details for PubMedID 15503329
View details for PubMedCentralID PMC1506385
Chylothorax after heart/lung transplantation
JOURNAL OF HEART AND LUNG TRANSPLANTATION
2004; 23 (5): 627-631
Chylothorax is a potentially serious complication of lung and heart-lung transplantation. This article describes the clinical course of chylothorax in 3 heart-lung allograft recipients. We discuss management options, including dietary modifications, octreotide infusion, thoracic duct ligation and embolization, and surgical pleurodesis. In addition, we describe the novel use of aminocaproic acid to reduce lymph flow. We propose a multidisciplinary approach for the management of chylothorax that includes both medical and surgical options.
View details for Web of Science ID 000221393700018
View details for PubMedID 15135382
Ethical consideration of incidental findings on adult brain MRI in research
2004; 62 (6): 888-890
To characterize the frequency and severity of incidental findings in brain MRIs of young and older adult research volunteers, and to provide an evaluation of the ethical challenges posed by the detection of such findings.The authors reviewed 151 research MRI scans obtained retrospectively from subjects recruited to studies as healthy volunteers. Incidental findings were classified into four categories: no referral, routine, urgent, or immediate referral. p Values for significance were computed from chi(2) tests of contingency.Of 151 studies, the authors found an overall occurrence of incidental findings having required referral of 6.6%. By age, there were more findings in the older cohort (aged >60 years) than in the younger cohort (p < 0.05) and in more men than women in the older cohort (p < 0.001). Three of four (75%) findings in the younger cohort were classified in the urgent referral category; 100% of the findings in the older cohort were classified as routine (p < 0.05).The significant presence but different characteristics of incidental findings in young and older subjects presumed to be neurologically healthy suggest that standards of practice are needed to guide investigators in managing and communicating their discovery.
View details for Web of Science ID 000220365300010
View details for PubMedID 15037687
View details for PubMedCentralID PMC1506751
Thoracic lymphatic disorders.
Lymphatic research and biology
2004; 2 (3): 131-137
Thoracic complications of lymphatic disorders can culminate in respiratory failure and death and should be considered in any patient with a lymphatic disease and clinical or radiographic evidence of chest disease. Congenital lymphatic disorders are being increasingly recognized in the adult population. The spectrum of thoracic manifestations of lymphatic disorders ranges from incidental radiographic findings to diffuse lymphatic disease with respiratory failure. This article serves to review some recent advances that allow improved diagnosis and management of thoracic lymphatic disorders. Herein, we describe their anatomical and physiologic effects, the time course of their progression, and the therapies that are currently available. The management of malignant (cancerous) lymphatic disorders of the thorax is beyond the scope of this paper.
View details for PubMedID 15609812
Self-referred whole-body CT imaging: Current implications for health care consumers
2003; 228 (2): 346-351
To conduct an empirical analysis of self-referred whole-body computed tomography (CT) and develop a profile of the geographic and demographic distribution of centers, types of services and modalities, costs, and procedures for reporting results.An analysis was conducted of Web sites for imaging centers accepting self-referred patients identified by two widely used Internet search engines with large indexes. These Web sites were analyzed for geographic location, type of screening center, services, costs, and procedures for managing imaging results. Demographic data were extrapolated for analysis on the basis of center location. Descriptive statistics, such as frequencies, means, SDs, ranges, and CIs, were generated to describe the characteristics of the samples. Data were compared with national norms by using a distribution-free method for calculating a 95% CI (P <.05) for the median.Eighty-eight centers identified with the search methods were widely distributed across the United States, with a concentration on both coasts. Demographic analysis further situated them in areas of the country characterized by a population that consisted largely of European Americans (P <.05) and individuals of higher education (P <.05) and socioeconomic status (P <.05). Forty-seven centers offered whole-body screening; heart and lung examinations were most frequently offered. Procedures for reporting results were highly variable.The geographic distribution of the centers suggests target populations of educated health-conscious consumers who can assume high out-of-pocket costs. Guidelines developed from within the profession and further research are needed to ensure that benefits of these services outweigh risks to individuals and the health care system.
View details for DOI 10.1148/radiol.2282021083
View details for Web of Science ID 000184381100010
View details for PubMedID 12893896
Privacy issues in personalized medicine
2003; 4 (2): 107-112
Pharmacogenomics is the emerging study of why individuals respond differently to drugs. It aims to replace the current 'one size fits all' therapeutic approach with 'personalized medicine' that will use pharmacogenomic tests to predict drug response. In a simple conceptualization, these tests challenge privacy as a result of two factors: how comprehensive is the test and how is the access to samples or digital information controlled. Point-of-care tests are likely to be limited in scope, fit seamlessly into medical records and do not raise qualitatively new ethical and privacy challenges. In order to define practically relevant pharmacogenomic predictive patterns however, large-scale clinical trials and research on human specimens will be required, resulting in large databases of genomic information. The genomic scans' magnitude, stability, implications to kin and ease of dissemination together represent a qualitatively different challenge compared to traditional, self-limited and often temporally transient medical information.
View details for Web of Science ID 000181475000001
View details for PubMedID 12605543
Ethical and practical considerations in managing incidental findings in functional magnetic resonance imaging
BRAIN AND COGNITION
2002; 50 (3): 358-365
Functional magnetic resonance imaging has emerged as a powerful tool for mapping the neurologic underpinnings of sensory, motor and cognitive function. Much of this evolution carries assumptions about the subject population under study and, in particular, the neurologic status of subjects entered into studies either as healthy controls or as belonging to a specific disease group. Recent reports of incidental MRI abnormalities in normal volunteers for fMRI studies have brought to attention a variety of practical challenges and ethical dilemmas for researchers, many of whom are not physicians and most of whom have no formal radiological training. We propose a minimum standard for consenting subjects in fMRI protocols, and consider strategies over the longer term that call for expert physician participation, archiving of incidental findings including false positives, and the adoption of guidelines for handling variation in neural activations or performance that appear outside expected norms.
View details for Web of Science ID 000180058100003
View details for PubMedID 12480483
Neuroethics: An emerging new discipline in the study of brain and cognition
BRAIN AND COGNITION
2002; 50 (3): 341-344
The vision for the special issue in Brain and Cognition is rooted in the need to bring to the foreground the state of scientific knowledge in research and clinical neuroimaging ethics. To this end, the issue highlights a broad range of relatively unexplored ethical challenges in functional neuroimaging with MR, alone or in combination with other neuroimaging modalities, from imaging the central nervous system of the fetus in utero through neural activation patterns associated with cognition and behavior in childhood and in adulthood. Theoretical, practical, and ethical considerations at the heart of imaging healthy research subjects and cognitively compromised patients are explored.
View details for Web of Science ID 000180058100001
View details for PubMedID 12480481
Lymphoid interstitial pneumonia - A narrative review
2002; 122 (6): 2150-2164
Lymphoid interstitial pneumonia (LIP) is regarded as both a disease and a nonneoplastic, inflammatory pulmonary reaction to various external stimuli or systemic diseases. It is an uncommon condition with incidence and prevalence rates that are largely unknown. Liebow and Carrington originally classified LIP as an idiopathic interstitial pneumonia in 1969. Although LIP had since been removed from that category, the most recent consensus classification sponsored by the American Thoracic Society and the European Respiratory Society recognizes that some cases remain idiopathic in origin, and its clinical, radiographic, and pathologic features warrant the return of LIP to its original classification among the idiopathic interstitial pneumonias. LIP also belongs within a spectrum of pulmonary lymphoproliferative disorders that range in severity from benign, small, airway-centered cellular aggregates to malignant lymphomas. It is characterized by diffuse hyperplasia of bronchus-associated lymphoid tissue. The dominant microscopic feature of LIP is a diffuse, polyclonal lymphoid cell infiltrate surrounding airways and expanding the lung interstitium. Classically, LIP occurs in association with autoimmune diseases, most often Sjögren syndrome. This has led to consideration of an autoimmune etiology for LIP, but its pathogenesis remains poorly understood. Persons who are seropositive for HIV, and children in particular, are at increased risk of acquiring LIP. Some studies suggest causal roles for both HIV and Epstein-Barr virus. The incidence of LIP is approximately twofold greater in women than men. The average age at diagnosis is between 52 years and 56 years. Symptoms of progressive cough and dyspnea predominate. There is great variability in the clinical course of LIP, from resolution without treatment to progressive respiratory failure and death. Although LIP is often regarded as a steroid-responsive condition, and oral corticosteroids continue to be the mainstay of therapy, response is unpredictable. Approximately 33 to 50% of patients die within 5 years of diagnosis, and approximately 5% of cases of LIP transform to lymphoma.
View details for Web of Science ID 000179985600047
View details for PubMedID 12475860
Ethical issues in the long term management of progressive degenerative neuromuscular diseases
SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE
2002; 23 (3): 307-314
Degenerative neuromuscular diseases are characterized by a gradual decline of motor function leading to respiratory collapse, while the patients retain consciousness and cognition. The ethical challenges of caring for such patients result from the need to implement various combinations of initiating, withholding, and withdrawing life-sustaining interventions. In caring for this population of patients physicians should adhere to the ethical principles of autonomy, beneficence, nonmaleficence, and justice. A central goal of care is to avoid a decisional impasse by anticipating end-of-life issues in discussion with patients and families. The evolution of these diseases is usually slow enough to allow ample patient education, and thus physicians should foster early and frank discussions and encourage the patient to set up advance directives, designate a durable power of attorney for health care, and plan end-of-life care. Competent patients have the right to accept or refuse life-sustaining therapies, and such requests should be honored. In delivering palliative care, adequate sedation and analgesia must be provided when needed. If a decision to withhold or withdraw life support is made, patient comfort and dignity are the ultimate objectives.
View details for Web of Science ID 000176888400014
View details for PubMedID 16088623
The burden of out-of-pocket payments for health care in Tbilisi, Republic of Georgia
JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION
2002; 287 (8): 1043-1049
In the 1990s, the Republic of Georgia instituted health care reforms to convert the centralized, state-operated health care system inherited from the Soviet Union to a decentralized, market-driven system of health care delivery. Under the new system, 87% of health care expenditures are financed through out-of-pocket payments at the point of service.To describe the effects of health care reforms on access to care and health care financing among ill residents of Tbilisi, Georgia.A probability-proportionate-to-size cluster survey conducted in 1999 of 248 households containing 306 household members who had been ill in the past 6 months in Tbilisi, Georgia.Reported health care utilization, out-of-pocket expenditures, and financing practices.Of sick household members, 51% used official health care services at hospitals and clinics; 49% did not use official services and sought advice from relatives or friends, used traditional medicines, or did nothing. Those with serious illness were more likely to seek care through official services (82%) than those with nonserious illness (27%). Ninety-three percent of respondents said costs were the major deterrent to obtaining health care. Ten percent of ill household members reported that they were unable to obtain health care because of high costs; 16% reported being unable to afford all the medications necessary to treat their illness. Sixty-one percent of ill household members used savings to pay for health care expenditures and 19% of those able to obtain care had to use strategies such as borrowing money or selling personal items to pay for health care. Total out-of-pocket health care expenditures (53%) were paid for by borrowing money or selling personal items. A significant portion of households with ill members (87%) reported an interest in purchasing health care insurance.Economic disruption and health care reforms have led to access problems and out-of-pocket financing strategies that include reliance on personal savings, selling personal items, and borrowing money. Future reforms should consider an appropriate system for health care insurance risk pooling for the population of Tbilisi, Georgia.
View details for Web of Science ID 000174052100036
View details for PubMedID 11866656
Pharmacogenomics and the challenge to privacy.
2002; 2 (3): 144-147
View details for PubMedID 12082584
PG490-88, a derivative of triptolide, blocks bleomycin-induced lung fibrosis
AMERICAN JOURNAL OF PATHOLOGY
2001; 158 (3): 997-1004
In this study we evaluate the antifibrotic properties of PG-490-88, a water-soluble derivative of triptolide. Triptolide is an oxygenated diterpene that is derived from a traditional Chinese herb that has potent immunosuppressive and antitumor activity. We used the intratracheal bleomycin mouse model and found that PG490-88 inhibits fibrosis in the bleomycin group when given the same day or 5 days after bleomycin. PG490-88 also markedly reduced the number of myofibroblasts in the bleomycin treatment group. An enzyme-linked immunosorbent assay of transforming growth factor (TGF)-beta in the bronchoalveolar lavage fluid showed a significant decrease in TGF-beta in the PG490-88-treated groups compared to the bleomycin-treated group. Additionally, triptolide blocked bleomycin-induced increase in TGF-beta mRNA in cultured normal human lung fibroblasts. The efficacy of PG490-88 when administered late after bleomycin installation suggests a potential role in the treatment of idiopathic pulmonary fibrosis.
View details for Web of Science ID 000167411100023
View details for PubMedID 11238047
View details for PubMedCentralID PMC1850337
The impact of practice setting on physician perceptions of the quality of practice and patient care in the managed care era
ARCHIVES OF INTERNAL MEDICINE
2001; 161 (2): 202-211
Managed care is practiced in both traditional institutional health maintenance organization (HMO) settings and in a variety of complex and decentralized office-based arrangements. This study examines how practice setting affects physician perceptions of the quality of professional practice and patient care in a managed care environment.A survey was conducted in 1998 of 1081 physicians in San Mateo County, California, who practice in either a traditional staff group model HMO (SGM-HMO) (n = 113) or office-based independent practice (OBIP) (n = 250). Respondents were surveyed about current and past practice characteristics, income changes, current satisfaction with professional and patient care matters, utility of treatment guidelines and formularies, and general perceptions of managed care. Responses were compared between practice settings using bivariate comparisons and logistic regression analyses.Physicians in the SGM-HMO and those in OBIP reported similar hours worked per week, time spent with patients during office visits, and total patient encounters per week. Declining income was more frequent in OBIP (61% vs 47%) and relatively more substantial (27% with income declines >25% vs 4% in SGM-HMO). Adjusting for income changes, practice setting, years in practice, and sex, SGM-HMO physicians were significantly more satisfied with a variety of professional and quality of care issues (P<.001), viewed more favorably the utility of treatment guidelines and drug formularies (P<.001), and held more positive general perceptions of managed care (P<.001) than OBIP physicians.In a managed care environment, SGM-HMO physicians are significantly more satisfied with the quality of practice and patient care than physicians in OBIP. This study suggests that the myriad managed care contracts, formularies, and guidelines received by physicians in OBIPs may lead to more negative perceptions of the quality of professional practice and patient care.
View details for Web of Science ID 000166480500008
View details for PubMedID 11176733
Biomedical ethics and the withdrawal of advanced life support
ANNUAL REVIEW OF MEDICINE
2001; 52: 79-92
It is common for health care providers to deal with the complex and difficult issue of withdrawing advanced life support. The patient is always the key source of authority in these decisions. The most important ingredient in end-of-life decision making is effective communication. It is important to try to ascertain what the patient thought about quality-of-life values before surrogate decisions can be made on the patient's behalf. The concepts of beneficence, nonmaleficence, autonomy, and justice are the foundation of ethical decision making. Numerous legal precedents have laid the groundwork for end-of-life decision making. Most state courts have supported withholding and withdrawing life support from patients who will not regain a reasonable quality of life. The recent Patient Self-Determination Act encourages patients to fill out advance directives that state their desires. When continued intensive care is futile, advanced life support should be withdrawn. However, a narrow definition of futility in this situation is the key, since the concept of futility could lead to inappropriate decisions. It is best to consider a situation futile when the patient is terminally ill, the condition is irreversible, and death is imminent. During the withdrawal of advanced life support, terminal or rapid weaning is preferable to extubation. Combinations of opiates, benzodiazepines, and other agents help provide comfort to patients who are suffering.
View details for Web of Science ID 000167302900006
View details for PubMedID 11160769
Ethical decision making and patient autonomy - A comparison of physicians and patients in Japan and the United States
2000; 118 (4): 1172-1182
Patient-centered decision making, which in the United States is typically considered to be appropriate, may not be universally endorsed, thereby harboring the potential to complicate the care of patients from other cultural backgrounds in potentially unrecognized ways. This study compares the attitudes toward ethical decision making and autonomy issues among academic and community physicians and patients of medical center outpatient clinics in Japan and the United States.A questionnaire requesting judgments about seven clinical vignettes was distributed (in English or Japanese) to sample groups of Japanese physicians (n = 400) and patients (n = 65) as well as US physicians (n = 120) and patients (n = 60) that were selected randomly from academic institutions and community settings in Japan (Tokyo and the surrounding area) and the United States (the Stanford/Palo Alto, CA, area). Responses were obtained from 273 Japanese physicians (68%), 58 Japanese patients (89%), 98 US physicians (82%), and 55 US patients (92%). Physician and patient sample groups were compared on individual items, and composite scores were derived from subsets of items relevant to patient autonomy, family authority, and physician authority.A majority of both US physicians and patients, but only a minority of Japanese physicians and patients, agreed that a patient should be informed of an incurable cancer diagnosis before their family is informed and that a terminally ill patient wishing to die immediately should not be ventilated, even if both the doctor and the patient's family want the patient ventilated (Japanese physicians and patients vs US physicians and patients, p < 0.001). A majority of respondents in both Japanese sample groups, but only a minority in both US sample groups, agreed that a patient's family should be informed of an incurable cancer diagnosis before the patient is informed and that the family of an HIV-positive patient should be informed of this disease status despite the patient's opposition to such disclosure (Japanese physicians and patients vs US physicians and patients, p < 0.001). Physicians in both Japan and the United States were less likely than patients in their respective countries to agree with physician assistance in the suicide of a terminally ill patient (Japanese physicians and patients vs US physicians and patients, p < 0.05). Across various clinical scenarios, all four respondent groups accorded greatest authority to the patient, less to the family, and still less to the physician when the views of these persons conflicted. Japanese physicians and patients, however, relied more on family and physician authority and placed less emphasis on patient autonomy than the US physicians and patients sampled. Younger respondents placed less emphasis on family and physician authority.Family and physician opinions are accorded a larger role in clinical decision making by the Japanese physicians and patients sampled than by those in the United States, although both cultures place a greater emphasis on patient preferences than on the preferences of the family or physician. Our results are consistent with the view that cultural context shapes the relationship of the patient, the physician, and the patient's family in medical decision making. The results emphasize the need for clinicians to be aware of these issues that may affect patient and family responses in different clinical situations, potentially affecting patient satisfaction and compliance with therapy.
View details for Web of Science ID 000090008300046
View details for PubMedID 11035693
- Thoracic lymphangiomas, lymphangiectasis, lymphangiomatosis, and lymphatic dysplasia syndrome AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE 2000; 161 (3): 1037-1046
Inhalational anthrax - Epidemiology, diagnosis, and management
1999; 116 (5): 1369-1376
Anthrax, a disease of great historical interest, is once again making headlines as an agent of biological warfare. Bacillus anthracis, a rod-shaped, spore-forming bacterium, primarily infects herbivores. Humans can acquire anthrax by agricultural or industrial exposure to infected animals or animal products. More recently, the potential for intentional release of anthrax spores in the environment has caused much concern. The common clinical manifestations of anthrax are cutaneous disease, pulmonary disease from inhalation of anthrax spores, and GI disease. The course of inhalational anthrax is dramatic, from the insidious onset of nonspecific influenza-like symptoms to severe dyspnea, hypotension, and hemorrhage within days of exposure. A rapid decline, culminating in septic shock, respiratory distress, and death within 24 h is not uncommon. The high mortality seen in inhalational anthrax is in part due to delays in diagnosis. Classic findings on the chest radiograph include widening of the mediastinum as well as pleural effusions. Pneumonia is less common; key pathologic manifestations include severe hemorrhagic mediastinitis, diffuse hemorrhagic lymphadenitis, and edema. Diagnosis requires a high index of suspicion. Treatment involves supportive care in an intensive care facility and high doses of penicillin. Resistance to third-generation cephalosporins has been noted. Vaccines are currently available and have been shown to be effective against aerosolized exposure in animal studies.
View details for Web of Science ID 000083723900041
View details for PubMedID 10559102
Selective downregulation of neutrophils by a phosphatidic acid generation inhibitor in a porcine sepsis model
JOURNAL OF SURGICAL RESEARCH
1999; 81 (2): 147-155
Effects of lisofylline (1-(5-R-hydroxyhexyl)-3,7-dimethylxanthine), a functional inhibitor of phosphatidic acid (PA) generation derived from de novo synthesis, on neutrophil function were examined in a porcine sepsis model. Hanford minipigs (18-25 kg) were randomly separated into six groups of six animals each: (1) saline control group; (2) sepsis control group, infused with Pseudomonas aeruginosa (1 x 10(6) colony-forming units/kg/min) for 2 h; (3) lisofylline control group, given a 25 mg/kg bolus of lisofylline 30 min prior to time zero, followed by a continuous infusion of 10 mg/kg/h throughout the study; (4) lisofylline pretreatment sepsis group, given lisofylline 30 min prior to sepsis, (5) lisofylline 1-h post-treatment sepsis group, and (6) lisofylline 2-h post-treatment sepsis group. All animals were studied for 6 h. Neutrophils were isolated at -0.5, 2, and 6 h. In the pretreatment and 1-h post-treatment groups, sepsis-induced neutrophil attachment to fibronectin was significantly attenuated. Sepsis-enhanced phagocytic activity was significantly reduced in the lisofylline pretreatment sepsis group, but not in the post-treatment groups. No treatment affected phorbol 12-myristate 13-acetate-induced chemiluminescence and basal filamentous actin content, which increased in sepsis, and cap formation, which declined in sepsis. Sepsis caused neutropenia, pretreatment produced neutrophilia, and 1-h post-treatment caused the neutropenia to recover to control levels. Interestingly, toward the end of the 6-h period, the neutrophil count was higher in the lisofylline control group than in the saline control groups. Thus, the inhibition of PA generation from de novo synthesis during sepsis not only can selectively downregulate some neutrophil functions but can also reverse neutropenia.
View details for Web of Science ID 000078582700005
View details for PubMedID 9927533
Genetic testing and Alzheimer disease: Recommendations of the Stanford Program in Genomics, Ethics, and Society
49th Annual Meeting of the American-Society-of-Human-Genetics
MARY ANN LIEBERT INC. 1999: 3–12
Several genes associated with Alzheimer disease (AD) have been localized and cloned; two genetic tests are already commercially available, and new tests are being developed. Genetic testing for AD--either for disease prediction or for diagnosis--raises critical ethical concerns. The multidisciplinary Alzheimer Disease Working Group of the Stanford Program in Genomics, Ethics, and Society (PGES) presents comprehensive recommendations on genetic testing for AD. The Group concludes that under current conditions, genetic testing for AD prediction or diagnosis is only rarely appropriate. Criteria for judging the readiness of a test for introduction into routine clinical practice typically rely heavily on evaluation of technical efficacy. PGES recommends a broader and more comprehensive approach, considering: 1) the unique social and historical meanings of AD; 2) the availability of procedures to promote good surrogate decision making for incompetent patients and to safeguard confidentiality; 3) access to sophisticated genetic counselors able to communicate complex risk information and effectively convey the social costs and psychological burdens of testing, such as unintentional disclosure of predictive genetic information to family members; 4) protection from inappropriate advertising and marketing of genetic tests; and 5) recognition of the need for public education about the meaning and usefulness of predictive and diagnostic tests for AD. In this special issue of Genetic Testing, the PGES recommendations are published along with comprehensive background papers authored by Working Group members.
View details for Web of Science ID 000087218200002
View details for PubMedID 10464572
The dying thoracic patient.
Chest surgery clinics of North America
1998; 8 (3): 723-739
Health care providers should understand that the practice of good medicine includes not only diagnosing and curing diseases, but also effectively communicating with patients and families and helping terminally ill patients die a peaceful and dignified death. Patients in America come from varied backgrounds, and it is important for physicians to consider cultural and religious issues. Physicians should combine their clinical judgment with objective outcome data to provide optimal care for patients. Informed consent should be obtained from patients after offering a detailed plan of care that would include appropriate interventions and the consequences of no intervention. The physician should then assist the patient in making a decision that would provide the best possible future for that individual. The four fundamental principles of biomedical ethics, namely beneficence, nonmaleficence, autonomy, and justice, should be considered when analyzing an ethical problem. Voluntary active euthanasia, which means performing a deliberate act (e.g., administering a lethal injection) to end a patient's life, should not be performed by a physician. Withholding and withdrawing basic and advanced life support constitutes passive euthanasia. Good communication with patients early in the clinical course whenever possible results in an ethically correct decision. A nonconfrontational, sympathetic, and compassionate approach to family members and legal surrogates facing the immediate death of their loved ones leads to the best possible outcome. It is the duty of the physician to assure the patient and the family that he or she will not abandon the patient. Effective communication is the key to solving almost all ethical dilemmas when caring for the dying thoracic patient.
View details for PubMedID 9742345
- Genetic testing and Alzheimer disease: Has the time come? NATURE MEDICINE 1998; 4 (7): 757-759
- Genetic testing for BRCA1 and BRCA2: Recommendations of the Stanford Program in Genomics, Ethics, and Society JOURNAL OF WOMENS HEALTH 1998; 7 (5): 531-545
Effects of the lazaroid, tirilazad mesylate, on sepsis-induced acute lung injury in minipigs
CRITICAL CARE MEDICINE
1998; 26 (3): 538-547
To assess the effects of the lazaroid, tirilazad mesylate, a potent lipid peroxidation inhibitor, in an animal model of Pseudomonas sepsis.Comparison of four experimental groups: a) saline control; b) Pseudomonas sepsis control; c) tirilazad mesylate control; and d) sepsis with tirilazad mesylate pre treatment.University animal laboratory.Hanford minipigs (20 to 25 kg), anesthetized with pentobarbital and mechanically ventilated on an FIO2 of 0.4.Sepsis was induced by infusing Pseudomonas aeruginosa at 1 x 10(6) colony-forming units/kg/min over 120 mins. The tirilazad mesylate-treated group received a 5-mg/kg bolus 30 mins before, and a 3-mg/kg bolus 3 hrs after, the onset of sepsis. Hemodynamics, PaO2, and neutrophil counts were measured for 6 hrs. Thiobarbituric acid reactive material (TBARM) in tissue (lung, liver, and intestine), lung wet/dry weight ratio, lung myeloperoxidase activity, plasma tumor necrosis factor (TNF)-alpha concentrations, protein content, and percent neutrophils in bronchoalveolar lavage fluid were evaluated at the time the animals were killed (6 hrs).Sepsis induced significant systemic hypotension, pulmonary hypertension, hypoxemia, and neutropenia. Sepsis also significantly increased TBARM content, lung wet/dry weight ratio, myeloperoxidase activity, plasma TNF-alpha concentrations, and bronchoalveolar lavage neutrophil percentage. Treatment with tirilazad mesylate significantly attenuated hypoxemia and decreased TBARM content, lung wet/dry weight ratio, myeloperoxidase activity, bronchoalveolar lavage protein, and bronchoalveolar lavage neutrophil percentage, but did not affect sepsis-induced hemodynamics, including systemic hypotension and pulmonary hypertension, plasma TNF-alpha concentrations, or neutropenia.Pretreatment with the tirilazad mesylate did not change P. aeruginosa sepsis-induced hemodynamic consequences. However, tirilazad mesylate attenuated sepsis-induced acute lung injury.
View details for Web of Science ID 000072384100026
View details for PubMedID 9504584
- Lymphangioleiomyomatosis: New insights AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE 1997; 155 (4): 1183-1186
The effects of post-treatment with lisofylline, a phosphatidic acid generation inhibitor, on sepsis-induced acute lung injury in pigs
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
1997; 155 (3): 928-936
The effects of lisofylline [(R)-1-(5-hydroxyhexyl)-3,7-dimethylxanthine] (LSF), an inhibitor of de novo phosphatidic acid (PA) generation, on sepsis-induced acute lung injury was studied using Hanford minipigs weighing 18 to 25 kg. Sepsis was induced by an intravenous infusion of Pseudomonas aeruginosa (1 x 10(6)/colony-forming units/kg/min over 2 h). Saline was used as the control vehicle. Six groups were studied: saline control group (SALINE: n = 5); sepsis control group (SEPSIS: n = 5); LSF control group (LSF: n = 5), which received a 25-mg/kgbolus of LSF 30 min before time zero followed by continuous infusion of 10 mg/kg/h throughout the study; LSF-treated septic groups, which were treated with LSF 30 min prior to sepsis (Pre: n = 5), 1 h postonset (Post-1 h: n = 8) or h postonset (Post-2 h: n = 8) of the bacterial infusion. Hemodynamics PaO2, neutrophil counts, and plasma porcine tumor necrosis factor-alpha concentrations were monitored for 6 h. After the minipigs were killed, lung tissue was sampled to measured wet-to-dry weight ratio (W/D), tissue albumin index (TAI), thiobarbituric acid-reactive material content (TBARM), and myeloperoxidase (MPO) activity. Compared with the SALINE group, the SEPSIS group showed significant systemic hypotension, pulmonary hypertension, arterial hypoxemia, neutropenia, and increase in TNF-alpha, MPO activity, W/D, TBARM, and TAI. LSF treatment attenuated sepsis-induced pulmonary hypertension, neutropenia, and hypoxemia, and increased MPO activity and lung injury measurements in the Pre and Post-1 h groups, but its efficacy was blunted in the Post-2 h group. Plasma TNF-alpha was decreased only in the Pre group. Thus, inhibition of intracellular PA generation through de novo pathways attenuates sepsis-induced acute lung injury.
View details for Web of Science ID A1997WN85700024
View details for PubMedID 9117028
Pulmonary capillaritis and alveolar hemorrhage - Update on diagnosis and management
1996; 110 (5): 1305-1316
Pulmonary vascular inflammatory disorders may involve all components of the pulmonary vasculature, including capillaries. The principal histopathologic features of pulmonary capillaritis include capillary wall necrosis with infiltration by neutrophils, interstitial erythrocytes, and/or hemosiderin, and interalveolar septal capillary occlusion by fibrin thrombi. Immune complex deposition is variably present. Patients often present clinically with diffuse alveolar hemorrhage, which is characterized by dyspnea and hemoptysis; diffuse, bilateral, alveolar infiltrates on chest radiograph; and anemia. Pulmonary capillaritis has been reported with variable frequency and severity as a manifestation of Wegener's granulomatosis, microscopic polyarteritis, systemic lupus erythematosus, Goodpasture's syndrome, idiopathic pulmonary renal syndrome, Behçet's syndrome, Henoch-Schönlein purpura, IgA nephropathy, antiphospholipid syndrome, progressive systemic sclerosis, and diphenylhydantoin use. In addition to history, physical examination, and routine laboratory studies, certain ancillary laboratory tests, such as antineutrophil cytoplasmic antibodies, antinuclear antibodies, and antiglomerular basement membrane antibodies, may help diagnose an underlying disease. Diagnosis of pulmonary capillaritis can be made by fiberoptic bronchoscopy with transbronchial biopsy, but thoracoscopic biopsy is often employed. Since many disorders can result in pulmonary capillaritis with diffuse alveolar hemorrhage, it is crucial for clinicians and pathologists to work together when attempting to identify an underlying disease. Therapy depends on the disorder that gave rise to the pulmonary capillaritis and usually includes corticosteroids and cyclophosphamide or azathioprine. Since most diseases that result in pulmonary capillaritis are treated with immunosuppression, infection must be excluded aggressively.
View details for Web of Science ID A1996VR83500037
View details for PubMedID 8915239
How to withdraw mechanical ventilation: more studies are needed.
American journal of critical care
1996; 5 (5): 323-325
View details for PubMedID 8870854
Whose death is it, anyway?
ANNALS OF INTERNAL MEDICINE
1996; 125 (2): 137-141
As medicine has increasingly gained the power to prolong life in the face of devastating illness, patients have increasingly become concerned about maintaining some control over how and when death arrives. Competent patients have the legal right to refuse treatment, but critically ill patients are frequently unable to participate in decision making. Advance directives were designed to help patients establish the level of care they would receive if they were to be rendered incompetent; yet, as the case discussed in this essay shows, even a valid advance directive does not guarantee that unwanted medical interventions will not be forced on us. The problem of physicians ignoring their patients' wishes goes beyond issues of communication and reflects an ongoing ambivalence about power and control in the physician-patient relationship. Unfortunately, many physicians find it easier to define success in terms of life and death than to try to determine what sort of existence is meaningful to an individual patient.
View details for Web of Science ID A1996UV92100012
View details for PubMedID 8678368
1996; 110 (1): 219-229
Necrotizing fasciitis is an uncommon soft-tissue infection, usually caused by toxin-producing, virulent bacteria, which is characterized by widespread fascial necrosis with relative sparing of skin and underlying muscle. It is accompanied by local pain, fever, and systemic toxicity and is often fatal unless promptly recognized and aggressively treated. The disease occurs more frequently in diabetics, alcoholics, immunosuppressed patients, i.v. drug users, and patients with peripheral vascular disease, although it also occurs in young, previously healthy individuals. Although it can occur in any region of the body, the abdominal wall, perineum, and extremities are the most common sites of infection. Introduction of the pathogen into the subcutaneous space occurs via disruption of the overlying skin or by hematogenous spread from a distant site of infection. Polymicrobial necrotizing fasciitis is usually caused by enteric pathogens, whereas monomicrobial necrotizing fasciitis is usually due to skin flora. Tissue damage and systemic toxicity are believed to result from the release of endogenous cytokines and bacterial toxins. Due to the paucity of skin findings early in the disease, diagnosis is often extremely difficult and relies on a high index of suspicion. Definitive diagnosis is made at surgery by demonstration of a lack of resistance of normally adherent fascia to blunt dissection. Treatment modalities include surgery, antibiotics, supportive care, and hyperbaric oxygen. Early and adequate surgical debridement and fasciotomy have been associated with improved survival. Initial antibiotic therapy should include broad aerobic and anaerobic coverage. If available, hyperbaric oxygen therapy should be considered, although to our knowledge, there are no prospective, randomized clinical trials to support this. Mortality rates are as high as 76%. Delays in diagnosis and/or treatment correlate with poor outcome, with the cause of death being overwhelming sepsis syndrome and/or multiple organ system failure.
View details for Web of Science ID A1996UY85400040
View details for PubMedID 8681631
Upper airway obstruction caused by low-grade tracheal papillary adenocarcinoma: An unusual flow-volume loop pattern
JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY
1996; 111 (6): 1286-1288
View details for PubMedID 8642833
The effects of recombinant human thrombomodulin on endotoxin-induced multiple-system organ failure in rats
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
1996; 153 (6): 1831-1837
Activation of the coagulation system is postulated to play an important role in the pathogenesis of endotoxin-induced tissue injury. Thrombomodulin (TM) is an endothelial cell membrane glycoprotein receptor for thrombin. Once bound to TM, thrombin loses its procoagulant activity, which results in decreased clotting. In addition, the binding of thrombin to TM activates the endogenous anticoagulant pathway through protein C. We studied the effect of recombinant human TM (rh-TM) on endotoxin-induced multiple-system organ failure (MSOF) in Sprague-Dawley rats weighing 400 to 450 g: 2 mg/kg of rh-TM was injected (T1/2 = 4.5 h) 30 min prior to intravenous injection of 20 mg/kg of Escherichia coli endotoxin. The study presented here consisted of three separate experiments. Experiment 1: 24-h survival study. Experiment 2: multiple-system organ microthrombi study in which 125I-human fibrinogen was injected 30 min prior to an endotoxin or saline injection and tissue microthrombi formation was assessed by measuring the percentage of organ radioactivity (lung, heart, liver, and kidney) against total injected radioactivity (microthrombi index, MI) 2.25 h after an endotoxin or saline injection. Experiment 3: endotoxin-induced MSOF study in which 125I-rat albumin was injected 5 h after an endotoxin or saline injection, and endotoxin-induced organ injury was evaluated by measuring tissue wet-to-dry ratios (W/D) and tissue-to-plasma 125I-rat albumin concentration ratios (T/P) 8 h after the endotoxin or saline injection. Blood contamination in samples from Experiments 2 and 3 was corrected by using 131I-rat albumin measurements. Pretreatment with rh-TM improved the survival from 12 h through 23 h as compared with that of the endotoxin control group (p < 0.05). However, at 24 h, after essentially all injected rh-TM had been eliminated, there was no difference in survival. Significant reductions in MI, W/D, and T/P in the organs sampled were observed in the rh-TM pretreated groups (p < 0.05). In conclusion, rh-TM improved short-term but not overall survival and decreased MSOF in endotoxemic rats.
View details for Web of Science ID A1996UR22300014
View details for PubMedID 8665042
- Withdrawing life support: Extubation and prolonged terminal weans are inappropriate CRITICAL CARE MEDICINE 1996; 24 (2): 352-353
- End-of-life discussions with patients: timing and truth-telling Chest 1996: 11-12
- RAPID WITHDRAWAL OF SUPPORT CHEST 1995; 108 (5): 1407-1408
1995; 108 (5): 1420-1424
Melioidosis is the name given to all diseases caused by the bacterium Pseudomonas pseudomallei. Melioidosis is a tropical disease and prevails in parts of Southeast Asia, northern Australia, and Central and South America. However, in recent years, cases of melioidosis have been reported in the United States and other areas. The organism can infect any organ system, although the lung is the most common organ affected. Pulmonary melioidosis presents either as an acute fulminant pneumonia or as an indolent cavitary disease. In northeastern Thailand, the incidence of P pseudomallei infection is extremely high with significant mortality. One of the key problems with treating melioidosis is its recalcitrance to therapy and high relapse rate. In addition, this Gram-negative rod is resistant to aminoglycosides. In nonendemic regions, patients with melioidosis more typically present with reactivation disease occurring months to years after initial exposure to the organism. The pulmonary disease is mainly in the apices and resembles tuberculosis. With the increasing mobility of people throughout the world and the influx of immigrants from endemic to nonendemic areas, it is important that clinicians be aware of this disease. This article will review the epidemiology, clinical presentations, diagnosis, and treatment of pulmonary melioidosis.
View details for Web of Science ID A1995TD70800046
View details for PubMedID 7587451
ACTIVATION OF NADPH-OXIDASE AND ITS ASSOCIATED WHOLE-CELL H+ CURRENT IN HUMAN NEUTROPHILS BY RECOMBINANT HUMAN TUMOR-NECROSIS-FACTOR-ALPHA AND FORMYL-METHIONYL-LEUCYL-PHENYLALANINE
JOURNAL OF BIOLOGICAL CHEMISTRY
1995; 270 (22): 13124-13132
Proton accumulation and efflux associated specifically with NADPH oxidation in neutrophils remains to be elucidated. Using confocal fluorescence and patch-clamp recordings from single human neutrophils, in the presence of protein kinase C inhibitors, we studied the transient cytosolic acidification and whole-cell H+ current induced by N-formyl-methionyl-leucyl-phenylalanine (fMLP) and recombinant human tumor necrosis factor alpha (rhTNF alpha). Intracellular pH changes were monitored utilizing the ratiometric imaging of the dual emission fluoroprobe, carboxyseminaphthorhodafluor-1, AM acetate. Bath application of 1000 units/ml rhTNF alpha or 0.1 microM fMLP changed the fluorescence of fluoroprobe-loaded cells, indicating generation of cytosolic H+ ions. In the absence of Ca2+ in the pipette solution, exposure of cells to rhTNF alpha or fMLP for 10 s activated voltage-dependent H+ currents. From tail current analysis, the threshold voltage for H+ current activation was approximately -50 mV. These fMLP- or rhTNF alpha-activated voltage-dependent H+ currents were augmented further in the presence of 0.1 mM of NADPH in the pipette solution, and they were inhibited by bath application of 50 microM of apocynin, an NADPH oxidase inhibitor. These results indicate that rhTNF alpha- or fMLP-induced NADPH oxidase in human neutrophils gives rise to the activation of voltage-dependent H+ currents.
View details for Web of Science ID A1995RB43900030
View details for PubMedID 7539423
TNF-ALPHA INDUCES TYROSINE PHOSPHORYLATION OF MITOGEN-ACTIVATED PROTEIN-KINASE IN ADHERENT HUMAN NEUTROPHILS
JOURNAL OF IMMUNOLOGY
1995; 154 (9): 4785-4792
Recombinant human TNF-alpha induces increased tyrosine phosphorylation of several proteins in human neutrophils (PMN) adhered to serum-coated plastic. When PMN are kept in suspension, TNF does not induce significant tyrosine phosphorylation. In adherent PMN, a 42-kDa protein (p42) displayed the most striking increase in tyrosine phosphorylation after TNF stimulation. Cell lysates of TNF-stimulated PMN were separated by two-dimensional gel electrophoresis and were immunoblotted with either anti-phosphotyrosine (alpha-PY) mAb or anti-mitogen-activated protein kinase (alpha-MAPK) mAb. Both Abs detected p42, and the spots were superimposable. Cell lysates were immunoprecipitated with agarose-conjugated alpha-PY mAb, electrophoresed, and then immunoblotted with alpha-MAPK Ab; alternatively, cell lysates were immunoprecipitated with agarose-conjugated alpha-MAPK Ab, electrophoresed, and then immunoblotted with alpha-PY mAb. In both cases, p42 was detected. These results demonstrate that p42 is a member of the MAPK family. TNF induces a time-and dose-dependent increase in tyrosine phosphorylation of p42 and MAPK activity. The degree of p42 tyrosine phosphorylation parallels the level of MAPK activity. MAPK activity was determined by measuring 32P phosphorylation of a synthetic peptide containing the recognition site on myelin basic protein for MAPK. PMN pretreatment with genistein, a tyrosine kinase inhibitor, inhibited the TNF-induced increase in tyrosine phosphorylation and MAPK activity. These results indicate that TNF signaling involves activation of MAPK.
View details for PubMedID 7722327
EFFECT OF BLOOD AND ALBUMIN ON PULMONARY-HYPERTENSION AND EDEMA IN PERFUSED RABBIT LUNGS
JOURNAL OF APPLIED PHYSIOLOGY
1995; 78 (2): 499-504
Perfusate composition may alter pulmonary hemodynamics and edema formation in perfused lungs. Perfusion for 3 h with Krebs-Henseleit solution with 3% bovine serum albumin did not produce pulmonary hypertension, pulmonary edema (assessed by lung wet-to-dry wt ratio), or increased macromolecular permeability (assessed by 125I-albumin uptake). Addition of blood to hematocrit levels of 10 or 20% resulted in pulmonary hypertension during the final hour of perfusion but not pulmonary edema or increased macromolecular permeability. Pulmonary hypertension during blood perfusion was primarily due to increased precapillary resistance. Perfusion with buffer solution without albumin produced edema and increased macromolecular permeability but not pulmonary hypertension. In lungs perfused with blood (20% hematocrit), thromboxane B2 levels increased in parallel with the pulmonary hypertension, and inhibition of cyclooxygenase or thromboxane synthase with indomethacin or dazmegrel prevented pulmonary hypertension. Perfusion with leukopenic blood (from prior nitrogen mustard administration or from filtration) also prevented pulmonary hypertension. We conclude that blood perfusion produces pulmonary hypertension via thromboxane A2 generation, which depends on leukocyte activation, and that perfusion with buffer solutions without albumin produces edema and increased permeability without pulmonary hypertension.
View details for Web of Science ID A1995QG47700018
View details for PubMedID 7759418
- Withdrawing life support: How is the decision made? JAMA 1995: 738-739.
Investigating the causes of fever in critically ill patients. Are you overlooking noninfectious causes?
The Journal of critical illness
1995; 10 (1): 51-?
Fever is common in the ICU because of patients' underlying chronic and critical illnesses, their tendency to receive multiple medications, and their frequent need for invasive procedures. Precise data on the etiology of fever in the ICU are lacking. However, common noninfectious causes include postoperative fever, drug fever, intramuscular injections, hemorrhage, and pulmonary atelectasis. Urinary tract infection appears to be the most common infectious cause, followed by pneumonia and sepsis. Many noninfectious conditions are potentially life-threatening; nevertheless, it is crucial to first exclude an infectious cause, since an untreated infection may cause rapid deterioration.
View details for PubMedID 10150399
Techniques for evaluating fever in the ICU. A stepwise approach for detecting infectious and noninfectious causes.
The Journal of critical illness
1995; 10 (1): 67-71
The initial work-up of a critically ill patient with fever begins with a hunt for an infectious cause. A positive urine culture, or the presence of dysuria or suprapubic tenderness, suggests urinary tract infection. Diagnosing pneumonia in ventilated patients is particularly difficult; CT may be helpful when chest films are hard to interpret. Blood cultures can rule out septicemia. Other common causes of fever in the ICU include abdominal abscesses and catheter-related infections; atelectasis has not been shown to cause fever. If the initial work-up fails to establish a cause of postoperative fever, and the fever resolves within 4 days, no further work-up is required.
View details for PubMedID 10150400
Pharmacological management of acute and chronic bronchial asthma.
Advances in pharmacology (San Diego, Calif.)
1995; 32: 169-204
View details for PubMedID 7748795
EFFECT OF THE NADPH OXIDASE INHIBITOR APOCYNIN ON SEPTIC LUNG INJURY IN GUINEA-PIGS
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
1994; 150 (5): 1449-1452
Reactive oxygen species (ROS) produced by NADPH oxidase activation in neutrophils play a major role in mediating sepsis-induced acute lung injury. To provide insight into whether the NADPH oxidase inhibitor apocynin might attenuate oxidant-induced lung injury, we examined the effect of apocynin on (1) sepsis-induced lung injury in guinea pigs, (2) ROS generation by LPS-stimulated neutrophils measured by chemiluminescence (CL), and (3) LPS-stimulated neutrophil-mediated human umbilical vein endothelial cell (HUVEC) injury assessed by 51Cr release. Sepsis-induced lung injury in guinea pigs was assessed by comparing 125I-labeled albumin concentrations in lung tissue and bronchoalveolar lavage (BAL) fluid relative to plasma (L/P and BAL/P), lung wet-to-dry weight ratios, and the number of neutrophils in BAL fluid. The lung wet-to-dry weight ratio, L/P, and the number of neutrophils in BAL fluid decreased after pretreatment and post-treatment with apocynin. BAL/P decreased upon pretreatment but not upon post-treatment with apocynin. Apocynin at concentrations from 10 to 100 micrograms/ml significantly reduced LPS-stimulated neutrophil CL and neutrophil-mediated HUVEC 51Cr release. We conclude that the NADPH oxidase inhibitor apocynin attenuates (1) sepsis-induced lung injury in guinea pigs, (2) neutrophil ROS generation measured by CL, and (3) neutrophil-mediated HUVEC injury assessed by 51Cr release.
View details for Web of Science ID A1994PR66400037
View details for PubMedID 7952574
TGF-BETA(1) CAUSES INCREASED ENDOTHELIAL ICAM-1 EXPRESSION AND LUNG INJURY
JOURNAL OF APPLIED PHYSIOLOGY
1994; 77 (3): 1281-1287
Neutrophil adherence to vascular endothelium is partially mediated by adhesion molecules, including intracellular adhesion molecule 1 (ICAM-1), on endothelial cells. We examined the effect of transforming growth factor-beta 1 (TGF-beta 1) on the expression of ICAM-1 in human umbilical vein endothelial cells (HUVEC). TGF-beta 1 (1 ng/ml) increased ICAM-1 and ICAM-1 mRNA expression in HUVEC, as assessed by flow cytometry and Northern blot analysis, respectively. In addition, we investigated whether exogenous recombinant TGF-beta 1 can cause neutrophil-mediated lung injury in guinea pigs. The plasma half-life of 125I-labeled TGF-beta 1 in guinea pigs was 4.6 +/- 0.1 min, and the 125I activity was 2.8 +/- 0.2% 8 h after injection. The ratio of 125I-labeled albumin concentration in lung tissue and bronchoalveolar lavage (BAL) fluid to that in plasma, lung wet-to-dry weight ratio, numbers of neutrophils in BAL fluid, and numbers of neutrophils per alveolus in fixed lung sections increased in guinea pigs that received a high dose of TGF-beta 1 (25 micrograms i.v. followed by 2 micrograms/h for 8 h) compared with the control group. These results suggest that TGF-beta 1 causes neutrophil-mediated lung injury, possibly through upregulation of ICAM-1 on endothelial cells, and might be important in the pathogenesis of lung injury.
View details for Web of Science ID A1994PG91600032
View details for PubMedID 7836132
THE PROTEIN-KINASE-C INHIBITOR, H-7, INDUCES ACUTE LUNG INJURY IN GUINEA-PIGS
CRITICAL CARE MEDICINE
1994; 22 (7): 1167-1173
To determine if the protein kinase C inhibitor, H-7, alone can cause acute lung injury. In cell studies, H-7 inhibited phorbol myristate acetate-induced neutrophil oxygen radical release. Additionally, one animal study demonstrated that H-7 inhibited phorbol myristate acetate-induced lung injury. There have been no studies on the effect of H-7 alone on lung function or on neutrophil release of oxygen radicals.Prospective, randomized, laboratory study along with in vitro studies using flow cytometry and lucigenin-dependent chemiluminescence.Experimental laboratory.Specific, pathogen-free guinea pigs and isolated human peripheral neutrophils.Guinea pigs were randomized into three experimental groups: saline control, H-7 low dose (2 mg/kg bolus + 0.2 mg/kg/hr), and H-7 high dose (6 mg/kg bolus + 0.5 mg/kg/hr). Human neutrophils were randomized into control and experimental groups. The effects of H-7 on pulmonary permeability in guinea pigs were examined over an 8-hr period.We measured the wet/dry weight ratio as an index of pulmonary edema and we measured the concentration ratios of 125I-labeled albumin in lung tissue and in bronchoalveolar lavage fluid and compared the ratios with those values in plasma as indices of pulmonary permeability. We also studied the in vitro effect of H-7 on human neutrophil oxygen radical production, using flow cytometry and lucigenin-dependent chemiluminescence. By flow cytometry, we measured oxygen radical production using the 2',7'-dichlorofluorescin and hydroethidine assays. The 2',7'-dichlorofluorescin assay mainly measures hydrogen peroxide, while the hydroethidine assay measures either superoxide anion alone or in combination with other oxygen intermediaries like hydrogen peroxide. Neutrophils (5 x 10(5)) were obtained by Ficoll-Hypaque gradient centrifugation and were incubated with H-7 (5, 25, 100 microM). In the H-7 high-dose group, wet/dry weight ratio, and 125I-labeled albumin ratios in lung/plasma, and bronchoalveolar lavage/plasma were significantly increased (p < .05 for each ratio). Pulmonary endothelial gap and subendothelial bleb formation were demonstrated in the high-dose group by electron microscopy. One hundred micromols of H-7 caused a small, significant decrease (23.3%, p < .05) in neutrophil oxygen radical production assessed by 2',7'-dichlorofluorescin. H-7 had no other effects on neutrophil oxygen radical production. H-7 did not stimulate neutrophil chemiluminescence; it decreased chemiluminescence.a) Protein kinase C inhibition with high-dose H-7 increased wet/dry weight and albumin in lung/plasma and bronchoalveolar lavage/plasma ratios in guinea pigs; b) the H-7 high-dose group demonstrated damaged pulmonary endothelium by electron microscopy; and c) since neutrophil oxygen radical production was not increased by H-7 as assessed by flow cytometry and chemiluminescence, it appears that H-7-induced acute lung injury and endothelial damage are not mediated by increased neutrophil oxygen radical production.
View details for Web of Science ID A1994PA69600024
View details for PubMedID 8026208
- MAGNETIC-RESONANCE-IMAGING MARKETING AND INVESTMENT - TENSIONS BETWEEN THE FORCES OF BUSINESS AND THE PRACTICE OF MEDICINE CHEST 1994; 105 (3): 920-928
ETHICAL DILEMMAS IN THE CRITICALLY ILL ELDERLY
CLINICS IN GERIATRIC MEDICINE
1994; 10 (1): 91-101
Elderly people in the United States often receive treatment through an enormous array of medical technology when they become critically ill. Some, or all, such interventions may be unwanted, and patients have the right to be informed about what prospects lie ahead. CPR, with survival rates of 2% to 20%, rarely has the effect for which it was intended, as studies over the last two decades have repeatedly demonstrated. Although it is not clear that elderly people are at higher risk for poor outcomes of CPR, it is clear most of them do not possess sufficient knowledge about either CPR or its usual outcome to make an informed choice. Ideally, an individual should choose his or her own resuscitation status, but evidence exists indicating surrogates more often than not make this decision. This is unfortunate, because both surrogates and physicians are poor judges of patients' resuscitation preferences. Advance directives, especially when coupled with effective physician-patient communication, will aid elderly persons in making decisions about life support. We encourage all physicians who care for the elderly to avert many of tomorrow's ethical dilemmas by communicating with their healthy patients today.
View details for Web of Science ID A1994PK09100007
View details for PubMedID 8168029
ACTIVATION OF A VOLTAGE-DEPENDENT CHLORIDE CURRENT IN HUMAN NEUTROPHILS BY PHORBOL 12-MYRISTATE 13-ACETATE AND FORMYL-METHIONYL-LEUCYL-PHENYLALANINE - THE ROLE OF PROTEIN-KINASE-C
JOURNAL OF BIOLOGICAL CHEMISTRY
1994; 269 (4): 2389-2398
Calcium-activated, voltage-independent Cl- currents have been demonstrated in human neutrophils (Krause, K.-H., and Welsh, M.J. (1990) J. Clin. Invest. 85, 491-498). The activation is mediated by calcium/calmodulin-dependent protein kinase and not by protein kinase C (PKC) (Schumann, M., Gardner, A.P., and Raffin, T.A. (1993) J. Biol. Chem. 268, 2134-2140). It is not known whether there are Ca(2+)-independent, voltage-dependent Cl- currents in these cells. Using K(+)-free solutions and patch-clamp recordings from human neutrophils, we separated the whole cell Cl- current. Base-line Cl- currents of unstimulated cells were small and displayed time and voltage independence; some showed voltage dependence. With a Ca(2+)-free pipette solution, bath-administered 1 microM phorbol 12-myristate 13-acetate (PMA) or 0.1 microM N-formyl-methionyl-leucyl-phenylalanine (fMLP) for 10 s induced augmented Cl- currents with voltage- and time-dependent outwardly rectifying properties. The threshold voltage of tail Cl- current activation was -69 mV. With a pipette solution containing 0.1 mM Ca2+, bath-administered 0.1 microM fMLP, 1 microM PMA, or 1 microM Ca2+ ionophore A23187 for 30 s induced augmented Cl- currents with voltage-independent properties. With intracellular application of 5 microM PKC inhibitor PKC(19-36), voltage-dependent Cl- currents were no longer activated by PMA or fMLP. Similar application of 5 microM PKC noninhibitory analog [Glu27]PKC(19-36) did not block PMA (or fMLP)-induced Cl- currents. These results indicate that, in addition to Ca(2+)-activated Cl- currents, human neutrophils have voltage-dependent Cl- currents which are regulated by PKC.
View details for Web of Science ID A1994MV43200011
View details for PubMedID 8300564
- ROLE OF THE COAGULATION SYSTEM IN ARDS CHEST 1994; 105 (1): 268-277
ETHICS OF FETAL TISSUE-TRANSPLANTATION
WESTERN JOURNAL OF MEDICINE
1993; 159 (3): 400-407
Now that the Clinton Administration has overturned the ban on federal funding for fetal tissue transplantation, old ethical issues renew their relevance and new ethical issues arise. Is fetal tissue transplantation necessary and beneficial? Are fetal rights violated by the use of fetal tissue in research? Is there a moral danger that the potential of fetal tissue donation will encourage elective abortions? Should pregnant women be allowed to designate specific fetal transplant recipients? What criteria should be used to select fetal tissue transplants? Whose consent should be required for the use of fetal tissue for transplantation? We review the current state of clinical research with fetal tissue transplantation, the legal history of fetal tissue research, the major arguments against the use of fetal tissue for transplantation, and the new postmoratorium ethical dilemmas. We include recommendations for guidelines to govern the medical treatment of fetal tissue in transplantation.
View details for Web of Science ID A1993MA37000022
View details for PubMedID 8236984
ATTENUATION OF ACUTE LUNG INJURY AND OXYGEN RADICAL PRODUCTION BY THE 21-AMINOSTEROID, U-78518F
JOURNAL OF APPLIED PHYSIOLOGY
1993; 74 (5): 2155-2160
Oxygen radicals play an important role in the mechanism of acute lung injury. The 21-aminosteroid lazaroid, U-78518F, is a potent antioxidant. We examined the effect of intravenous U-78518F on acute lung injury in septic guinea pigs over 8 h. The experimental groups (n = 6) were 1) saline control, 2) Escherichia coli (2 x 10(9)/kg i.v.), 3) pretreatment (U-78518F 5 mg/kg bolus + 1 mg.kg-1 x h-1, 15 min before E. coli injection), and 4) posttreatment (U-78518F 30 min after E. coli injection). We measured wet-to-dry weight ratio (W/D) as an index of pulmonary edema and concentration ratios of 125I-labeled albumin in lung tissue and bronchoalveolar lavage fluid compared with plasma (L/P and BAL/P, respectively) as indexes of lung protein fluxes. In septic guinea pigs, pretreatment with U-78518F attenuated W/D, L/P, and BAL/P and posttreatment attenuated W/D and BAL/P (P < 0.05 for each). Furthermore, we studied the effect of U-78518F on human neutrophil oxygen radical production (ORP) by using flow cytometry to assess intracellular ORP and lucigenin-dependent chemiluminescence to assess extracellular ORP. Neutrophils (5 x 10(5) were stimulated with 0.5 micrograms/ml of phorbol myristate acetate. With flow cytometry, we measured intracellular ORP, cross-sectional cell area, and degranulation in neutrophils. U-78518F (minimum concn 1.0 microM) decreased intracellular ORP (n = 4; P < 0.05) when the dihydrorhodamine 123 assay was used. U-78518F (minimum concn 1.0 microM) inhibited phorbol myristate acetate-induced neutrophil chemiluminescence (n = 4; P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
View details for Web of Science ID A1993LD69900016
View details for PubMedID 8335543
The ethics of withholding and withdrawing critical care.
Cambridge quarterly of healthcare ethics
1993; 2 (2): 175-184
View details for PubMedID 8293207
RECOMBINANT HUMAN TUMOR-NECROSIS-FACTOR-ALPHA INDUCES CALCIUM OSCILLATION AND CALCIUM-ACTIVATED CHLORIDE CURRENT IN HUMAN NEUTROPHILS - THE ROLE OF CALCIUM CALMODULIN-DEPENDENT PROTEIN-KINASE
JOURNAL OF BIOLOGICAL CHEMISTRY
1993; 268 (3): 2134-2140
The role of calcium in the action of tumor necrosis factor (TNF) on human neutrophils is not clear. With fluorescent cytometry, using the visible wavelength calcium probe, fluo-3, and patch clamping, we investigated whether TNF induces cytosolic free Ca2+ changes and Ca(2+)-activated Cl- current, respectively. Bath application of 1000 units/ml recombinant human TNF alpha (rhTNF alpha) induced a rise in cytosolic free Ca2+ in 75% of fluo-3-loaded cells, 25% of which displayed irregular patterns of oscillation. Addition of rhTNF alpha activated Cl- current in 80% of tested cells; the activated current was blocked by 10 microM 5-nitro-2-3-phenylpropylamino)benzoic acid, a Cl- channel blocker. The current was similarly activated by 1 microM ionomycin, a Ca2+ ionophore. To study the mechanism by which rhTNF alpha induced Ca(2+)-activated Cl- current, we examined the involvement of calcium/calmodulin-dependent protein kinase (CaM kinase). With intracellular application of the Ca2+ chelator 1,2-bis (2-aminophenoxy)ethane-N,N,N',N'-tetraacetate (5 mM), the calmodulin antagonist (2 microM), CaM kinase II-(290-309), or the inhibitory peptide (10 microM), CaM kinase II-(273-302), the current was no longer activated by rhTNF alpha. The intracellular application of the control peptide (10 microM), CaM kinase II-(284-302), or the protein kinase C (PKC) inhibitory, PKC-(19-36), or control, [Glu27]PKC-(19-36), peptide (5 microM) did not block the rhTNF alpha-induced Cl- current. These results show that Ca2+ changes are associated with the effects of rhTNF alpha and that CaM kinase plays a role in the mechanism underlying rhTNF alpha-induced activation of Ca(2+)-activated Cl- current in human neutrophils.
View details for Web of Science ID A1993KH62000095
View details for PubMedID 8380590
- THE ORGAN-DONATION-COMMITTEE - AN ETHICALLY RESPONSIBLE APPROACH TO INCREASING THE ORGAN DONATION RATE CHEST 1992; 102 (5): 1572-1577
CARE OF THE DYING - AN ETHICAL AND HISTORICAL-PERSPECTIVE
CRITICAL CARE MEDICINE
1992; 20 (10): 1473-1482
To provide a historical perspective, from ancient Greece to the middle of the 20th century, on ethical issues and principles commonly associated with medical care for the dying in Western civilization.Writings of noted philosophers, historians, ethicists, and physicians, as well as published legal and ethical guidelines. INFORMATION EXTRACTION: The sources used highlight the origins of various ethical principles associated with care of the dying. They also identify the opinions of prominent individuals throughout the history of medical ethics.Devotion to medical beneficence, concern for the quality of life, and respect for the sanctity of life are all expressed in the earliest medical and philosophical writings of ancient Greece. With regard to care of the dying, these considerations led to a wide acceptance of avoiding or terminating treatment in hopeless cases. They also led to active debate regarding medicine's role in hastening the dying process. The rise of Christianity during the Middle Ages markedly suppressed such debate by strongly reinforcing the principle of sanctity of life. Later, the optimism of the enlightenment added the hope of prolonging life. Finally, modern advances in medical science have made that hope a reality of complex ethical dimensions.Ethical debates regarding appropriate care for the dying are as old as medicine itself. Although beneficent concerns have characterized the medical community in almost every period of history, tensions have repeatedly arisen as diverse religious and philosophical ideologies have produced varying standards to define such beneficence. In the Christian world, the sanctity of life was often extolled as the paramount standard. For the ancient Greeks and Romans, and again in many post-Renaissance philosophies, quality of life considerations assumed equal or greater importance. Modern life-prolonging technologies heighten the debate by allowing these two standards to dramatically conflict, particularly in the critical care setting.
View details for Web of Science ID A1992JT93700018
View details for PubMedID 1395671
ATRIOPEPTIN-INDUCED INCREASES IN ENDOTHELIAL-CELL PERMEABILITY ARE ASSOCIATED WITH ELEVATED CGMP LEVELS
AMERICAN JOURNAL OF PHYSIOLOGY
1992; 263 (3): L363-L369
To investigate the mechanism of nonrenal capillary hyperfiltration, we studied the effect of atriopeptin (AP) III and AP I on permeability and intracellular cyclic nucleotide levels in cultured bovine pulmonary artery endothelial cell monolayers. Permeability to albumin was assessed by the albumin transfer rate across endothelial cell monolayers, following a 4-h incubation with atriopeptins. AP III (0.01, 0.1, and 1 microM) caused a concentration-dependent increase in the albumin transfer rate. AP III induced a threefold increase in intracellular guanosine 3',5'-cyclic monophosphate (cGMP) levels during the incubation period. A phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine (IBMX), enhanced the AP III-induced increase in permeability and cGMP accumulation by 16-fold at maximum. 8-Bromoguanosine 3',5'-cyclic monophosphate, a hydrolysis-resistant cGMP analogue, caused a slight but significant increase in permeability. In contrast, AP I, a weak agonist of the cGMP-coupled ANP receptor, did not elicit an increase in permeability at concentrations of 0.1 and 1 microM. Although AP I (1 microM) caused a significant increase in cGMP by 33 and 60% in the absence and presence of IBMX, the increase was markedly less compared with AP III. AP III did not cause a change in intracellular cAMP levels during the incubation period. These observations suggest that in our system AP III increases the permeability of endothelial cell monolayers in association with an elevated cGMP level. Thus an increase in permeability might be involved in the mechanism of ANP-induced capillary hyperfiltration.
View details for Web of Science ID A1992JP90100079
View details for PubMedID 1329530
- THE MANAGEMENT OF CHYLOTHORAX CHEST 1992; 102 (2): 586-591
CA-2+-DEPENDENT AND CA-2+-INDEPENDENT MECHANISMS MODULATE WHOLE-CELL CATIONIC CURRENTS IN HUMAN NEUTROPHILS
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
1992; 185 (2): 531-538
We used whole-cell, voltage-clamp methodology to study the activation and inhibition of cationic currents in neutrophil. Cationic channels involved were impermeable to N-methyl-D-glucamine and to choline, but permeable to Na+, K+, Cs+, tris(hydroxymethyl)amino-ethane, and tetraethylammonium. N-formyl-L-methionyl-L-leucyl-L-phenylalanine, the Ca(2+)-ionophore A23187, and phorbol myristate acetate activated the cationic current. Activated currents showed voltage dependence and outward rectification. The Ca(2+)-chelator 1,2 bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetate markedly inhibited A23187-induced currents, but only partially decreased phorbol ester- or chemoattractant-induced currents. Dibutyryl cAMP diminished only the chemoattractant-induced currents. The adenosine analogs 5'N-ethylcarboxamidoadenosine and N6-cyclohexyladenosine blocked the currents induced by all agents. Thus, we conclude that activation and inhibition of cationic channels in human neutrophils involve both Ca(2+)-dependent and Ca(2+)-independent mechanisms.
View details for Web of Science ID A1992HZ25200007
View details for PubMedID 1376989
- EFFICACY OF COMPUTERS IN TEACHING ARTERIAL BLOOD-GAS ANALYSIS ACADEMIC MEDICINE 1992; 67 (6): 365-366
EFFECT OF NADPH OXIDASE INHIBITION ON ENDOTHELIAL-CELL ELAM-1 MESSENGER-RNA EXPRESSION
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
1992; 184 (3): 1339-1343
Neutrophil adherence to endothelium is partially mediated by the expression of endothelial leukocyte adhesion molecule-1 (ELAM-1) on endothelial cells activated by agents such as lipopolysaccharide (LPS) and phorbol myristate acetate (PMA). To elucidate molecular mechanisms involved in the induction of ELAM-1 on endothelial cells, we investigated the effect of the NADPH oxidase inhibitor, apocynin (4-hydroxy-3-methoxyacetophenone), on ELAM-1 mRNA expression in human umbilical vein endothelial cells (HUVEC) by Northern blot analysis. Apocynin downregulated both LPS- and PMA-induced ELAM-1 mRNA expression in a dose-dependent manner. Our results suggest NADPH oxidase might play a key role in ELAM-1 mRNA expression in HUVEC.
View details for Web of Science ID A1992HV38800029
View details for PubMedID 1375459
POLYETHYLENE GLYCOL-CONJUGATED SUPEROXIDE-DISMUTASE ATTENUATES SEPTIC LUNG INJURY IN GUINEA-PIGS
AMERICAN REVIEW OF RESPIRATORY DISEASE
1992; 145 (2): 388-393
Reactive oxygen species (ROS), including superoxide anions, play an important role in mediating acute lung injury. We examined whether polyethylene glycol-conjugated superoxide dismutase (PEG-SOD) attenuates lung injury in Escherichia coli-treated guinea pigs. Twenty-four guinea pigs were divided into four groups: (1) control group; (2) septic group, in which live E. coli (2 x 10(9)/kg) were injected intravenously; (3) pretreatment group, in which PEG-SOD (2,000 IU/kg) was injected intravenously 15 min before E. coli; and (4) posttreatment group, in which PEG-SOD (2,000 IU/kg) was injected intravenously 30 min after E. coli. Lung injury was assessed by the concentration ratio of 125I-labeled albumin in lung tissue and bronchoalveolar lavage (BAL) fluid relative to plasma (L/P and BAL/P), lung wet-to-dry weight ratio, and the number of neutrophils in BAL fluid. Plasma half-life of PEG-SOD in normal guinea pigs was 13.5 h. L/P, lung wet-to-dry weight ratio, and the number of neutrophils in BAL fluid decreased in both pretreatment and posttreatment groups compared with the septic group. BAL/P decreased in the pretreatment group but not in the posttreatment group compared with the septic group. After the animal model studies, we investigated the effect of PEG-SOD on the human neutrophil extracellular generation of ROS stimulated by phorbol myristate acetate (PMA) in lucigenin-dependent chemiluminescence (CL). PEG-SOD at concentrations greater than or equal to 0.1 U/ml inhibited PMA-induced CL in a dose-dependent manner. We also examined the effect of PEG-SOD on the neutrophil intracellular generation of ROS using flow cytometry to assess intracellular hydroethidine oxidation.(ABSTRACT TRUNCATED AT 250 WORDS)
View details for Web of Science ID A1992HC99800025
View details for PubMedID 1736747
- DEFINING PATIENT COMPETENCE FOR MEDICAL DECISION-MAKING CHEST 1991; 100 (5): 1404-1409
TUMOR-NECROSIS-FACTOR INDUCED PROTEIN-PHOSPHORYLATION IN HUMAN NEUTROPHILS
AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY
1991; 5 (3): 284-291
Protein phosphorylation is central to multiple regulatory processes in cells. Tumor necrosis factor (TNF), a cytokine synthesized by macrophages, effects polymorphonuclear leukocyte (neutrophil) chemotaxis, induces superoxide anion generation, and mediates neutrophil adhesion to endothelial cells. Although protein phosphorylation is almost certainly involved in many TNF-mediated neutrophil functions, little is known about TNF's impact on neutrophil protein phosphorylation. Therefore, we studied human recombinant TNF-alpha-induced protein phosphorylation in human neutrophils. Neutrophils were preincubated with 32PO(4)2- and treated with a variety of stimulatory agents. One- and two-dimensional polyacrylamide gel electrophoresis was used to analyze phosphorylated proteins. Phosphoaminoacids were identified by two-dimensional thin layer chromatography electrophoresis. The findings were as follows: (1) TNF induces the phosphorylation of two 16-kD proteins (pI = 5.9 and 6.1) by 5- to 6-fold, and a 57-kD protein (pI = 5.8) by 3- to 4-fold compared with untreated neutrophils; (2) these proteins are phosphorylated as early as 15 min after stimulation with TNF, and phosphorylation is induced by concentrations of TNF as low as 1 ng/ml (10 U/ml); (3) TNF induces the phosphorylation of proteins at either serine or threonine residues and not at tyrosine; (4) TNF-stimulated neutrophils show a unique pattern of protein phosphorylation when compared to neutrophils treated with formylmethionylleucylphenylalanine; (5) lipopolysaccharide does not induce protein phosphorylation in neutrophils; (6) a 16-kD protein is phosphorylated in response to TNF in neutrophils but not in mononuclear cells; and (7) protein kinase inhibitors appear to have no effect on TNF-induced protein phosphorylation. Thus, the mechanism of action of TNF on neutrophils may involve protein phosphorylation.
View details for Web of Science ID A1991GF25500012
View details for PubMedID 1910814
PENTOXIFYLLINE DOES NOT ATTENUATE ACUTE LUNG INJURY IN THE ABSENCE OF GRANULOCYTES
JOURNAL OF APPLIED PHYSIOLOGY
1991; 71 (1): 342-351
Pentoxifylline (PTX), a methylxanthine, can suppress polymorphonuclear leukocyte (PMN) activation and attenuate sepsis-induced acute lung injury. We investigated whether PTX prevents non-PMN-dependent lung injury. First we studied four groups of granulocyte-depleted guinea pigs (control, PTX, Escherichia coli, and E. coli + PTX). Lung injury was assessed by wet-to-dry lung weight (W/D) ratio and lung tissue-to-plasma 125I-albumin ratio (albumin index, AI). The E. coli group showed a significant increase in the lung W/D ratio and AI compared with the control and PTX groups. However, PTX did not prevent the E. coli-induced increase in the lung W/D ratio and AI. Next we investigated the effects of PTX on endothelial cell monolayer permeability and adenosine 3',5'-cyclic monophosphate (cAMP) levels. Whereas E. coli lipopolysaccharide (LPS) alone increased the endothelial permeability, PMNs added to the endothelial monolayers and exposed to LPS enhanced the increase. PTX attenuated the permeability increase mediated by LPS-exposed PMNs. PTX did not prevent the LPS-induced increase in permeability when PMNs were not present, although PTX increased endothelial cell cAMP levels. These data demonstrate that 1) PTX does not prevent lung injury in granulocyte-depleted guinea pigs; 2) PTX does not prevent LPS-induced increases in endothelial cell permeability, despite increased cAMP levels; and 3) PTX attenuates PMN-dependent increases in endothelial cell permeability.
View details for Web of Science ID A1991FV26200050
View details for PubMedID 1655691
- SALMONELLA LUNG ABSCESS COMPLICATING WEGENERS GRANULOMATOSIS RESPIRATORY MEDICINE 1991; 85 (4): 339-341
WITHHOLDING AND WITHDRAWING LIFE-SUPPORT
1991; 26 (3): 133-?
What does the physician do when health cannot be restored or suffering relieved? When the fundamental principles of biomedical ethics are used as guidelines for life support decisions, patients, their families, and the medical staff all benefit. These principles--beneficence, nonmaleficence, autonomy, and justice--are discussed in the context of legal precedents and clinical application.
View details for Web of Science ID A1991FB99400014
View details for PubMedID 1900849
PNEUMOCYSTIS-CARINII PNEUMONIA COMPLICATING LOW-DOSE METHOTREXATE TREATMENT FOR RHEUMATOID-ARTHRITIS
1991; 46 (3): 205-207
Low dose methotrexate has been used effectively for various rheumatic and non-rheumatic diseases. Three cases of Pneumocystis carinii pneumonia occurring during treatment of rheumatoid arthritis with low dose methotrexate are presented. Several mechanisms might contribute to impaired immunity and the rare development of opportunist lung infection with methotrexate. A high degree of suspicion may result in earlier diagnosis and treatment.
View details for Web of Science ID A1991FE31500014
View details for PubMedID 2028435
View details for PubMedCentralID PMC463037
ATTENUATION OF LPS-INDUCED NEUTROPHIL THROMBOXANE-B2 RELEASE AND CHEMILUMINESCENCE
JOURNAL OF CELLULAR PHYSIOLOGY
1991; 146 (2): 264-269
Polymorphonuclear leukocytes (PMN) may play a key role in acute lung injury and ARDS. The mechanisms of PMN-mediated lung injury include the release of inflammatory mediators, such as oxygen free radicals which cause direct tissue injury, and arachidonic acid metabolites which cause pulmonary vasoconstriction and increased vascular permeability. The goals of this in vitro study were 1) to assess the effects of PMN-activating agents (lipopolysaccharide, LPS; phorbol myristate acetate, PMA; tumor necrosis factor, TNF) on PMN thromboxane B2 (TXB2) release and oxygen free radical production and 2) to determine the effects of agents purported to suppress PMN activity (pentoxifylline, PTX; adenosine; dibutyryl cyclic AMP, DBcAMP; and terbutaline, TBN) on activator-induced PMN TXB2 release and oxygen free radical production. PMN TXB2 release was determined by radioimmunoassay and oxygen free radical production was monitored by chemiluminescence. Our results show that 1) LPS and PMA significantly increase PMN TXB2 release, whereas tumor necrosis factor (TNF) has no effect; 2) LPS and PMA significantly increase PMN chemiluminescence; 3) DBcAMP and TBN significantly reduce LPS-induced PMN TXB2 release whereas PTX and adenosine do not; 4) TBN significantly reduces PMA-induced PMN TXB2 release whereas other agents do not; 5) All agents (PTX, adenosine, DBcAMP, and TBN) significantly reduce LPS-induced PMN chemiluminescence but none attenuate PMA-induced PMN chemiluminescence. We conclude that: LPS and PMA activate PMN manifested by TXB2 release and chemiluminescence. Additionally, all the PMN suppressing agents do attenuate some PMN functions. Of interest, PTX, adenosine, DBcAMP, and TBN have different effects depending upon functional assay and activating agent. It will be important to investigate the mechanisms by which PMN suppressing agents alter signal transduction resulting in differential effects on PMN function.
View details for Web of Science ID A1991FA39500010
View details for PubMedID 1847934
EARLY POSTTREATMENT WITH PENTOXIFYLLINE OR DIBUTYRYL CAMP ATTENUATES ESCHERICHIA-COLI-INDUCED ACUTE LUNG INJURY IN GUINEA-PIGS
AMERICAN REVIEW OF RESPIRATORY DISEASE
1991; 143 (2): 289-293
We examined effects of early post-treatment with the methylxanthine pentoxifylline (PTXF), or the cell-permeable adenosine 3', 5'-cyclic monophosphate (cAMP) analog dibutyryl cAMP (db-cAMP) on Escherichia-coli-induced acute lung injury in guinea pigs. Acute lung injury was assessed by measurements of lung water (lung wet/dry weight ratio; W/D ratio), the concentration ratio of 125I-albumin in bronchoalveolar lavage (BAL) fluid and lung tissue compared with plasma (albumin index; BAL-AI or tissue-AI), and total differential leukocyte count in BAL fluid. Mean arterial pressure (Pa) and peripheral WBC counts were monitored continuously over the 8-h experiment. Septicemia was induced by a bolus injection of 2 x 10(9)/kg live E. coli. Thirty minutes later the animals received a bolus injection followed by continuous infusion of PTXF (20 mg/kg + 20 mg/kg/h; n = 8) or db-cAMP (2 mg/kg + 2 mg/kg/h; n = 8) or saline (septic control; n = 8). Nonseptic control groups were also studied. The lung W/D ratio, BAL-AI, lung tissue-AI, and BAL leukocyte count increased significantly in the septic control group. The PTXF-septic and db-cAMP-septic groups showed no significant increase in lung W/D ratio, BAL-AI, and lung tissue-AI. However, there was no difference in BAL total and differential leukocyte count as compared with the septic control group. PTXF and db-cAMP had no effect on E. coli-induced changes in peripheral WBC count and Pa. Comparison in vitro experiments demonstrated that PTXF and db-cAMP inhibited the endotoxin-induced (E. coli) chemiluminescent response of isolated guinea-pig polymorphonuclear leukocytes (PMN).(ABSTRACT TRUNCATED AT 250 WORDS)
View details for Web of Science ID A1991EX24500017
View details for PubMedID 1846727
ISOPROTERENOL PREVENTS OXIDANT-INDUCED INJURY IN ISOLATED RABBIT LUNGS
1991; 43 (2): 78-83
Increased vascular permeability in the adult respiratory distress syndrome is due in part to toxic oxygen metabolites. In the present study, we produced lung injury in the isolated rabbit lung with hydrogen peroxide (H2O2) and examined its prevention with isoproterenol. Pulmonary arterial pressure (Ppa) and the fluid filtration coefficient (Kf) were measured as indices of lung injury. Rabbits were divided into two groups, and 7 mmol/l H2O2 was administered in both groups. In one group, isoproterenol (2 micrograms/ml) was administered 10 min before H2O2 injury. Ppa increased transiently after H2O2 administration in the control group but was unchanged in the isoproterenol group. Kf was significantly increased by H2O2 administration in the control group but not in the isoproterenol group. We conclude that H2O2 increases pulmonary vascular permeability and that isoproterenol may protect against H2O2-induced pulmonary injury.
View details for Web of Science ID A1991GP44100004
View details for PubMedID 1775513
ATTENUATION OF TUMOR NECROSIS FACTOR-INDUCED ENDOTHELIAL-CELL CYTOTOXICITY AND NEUTROPHIL CHEMILUMINESCENCE
AMERICAN REVIEW OF RESPIRATORY DISEASE
1990; 142 (5): 1073-1078
Our laboratory has previously shown that the administration of tumor necrosis factor (TNF), a cytokine produced by activated mononuclear cells, to guinea pigs produces a syndrome similar to gram-negative sepsis or ARDS. Pentoxifylline (PTX), a methylxanthine, protects against TNF-induced and sepsis-induced acute lung injury in vivo. We now report on in vitro cellular studies of PMN-mediated cellular injury and its attenuation. We studied TNF-induced bovine pulmonary artery endothelial cell (EC) cytotoxicity both with and without PMN. A 51Cr release assay was used to measure EC damage. Further, we investigated PMN function in response to TNF by measuring chemiluminescence. Agents that attenuate EC damage and PMN activation were evaluated in the above assays. Results revealed that TNF causes EC injury (p less than 0.05) and PMN increase TNF-induced EC injury. Furthermore, PTX, aminophylline (AMPH), caffeine, and forskolin attenuate TNF-induced EC cytotoxicity only in the presence of PMN (p less than 0.05). Of interest, dibutyryl cAMP (DBcAMP) protects EC from TNF-induced injury both with and without PMN. Agents that may increase cAMP levels in PMN (PTX, DBcAMP, forskolin, isobutyl methylxanthine, and terbutaline) significantly attenuate TNF-induced PMN chemiluminescence (p less than 0.05). We conclude that TNF causes EC damage and PMN increase this damage. Furthermore, PTX, AMPH, caffeine, and forskolin can attenuate TNF-induced EC injury in the presence of PMN, whereas DBcAMP attenuates TNF-induced EC injury with and without PMN. In addition, agents that may increase intracellular cAMP levels in PMN can attenuate TNF-induced PMN chemiluminescence. Thus, these agents likely attenuate TNF-induced PMN-mediated EC injury through their inhibitory effects on PMN.
View details for Web of Science ID A1990EG08800017
View details for PubMedID 2173454
- LYMPHANGIOLEIOMYOMATOSIS - CLINICAL COURSE IN 32 PATIENTS NEW ENGLAND JOURNAL OF MEDICINE 1990; 323 (18): 1254-1260
SEQUENTIAL ASSESSMENT OF PULMONARY EPITHELIAL DIETHYLENE TRIAMINE PENTA-ACETATE CLEARANCE AND INTRAPULMONARY TRANSFERRIN ACCUMULATION DURING ESCHERICHIA-COLI PERITONITIS
AMERICAN REVIEW OF RESPIRATORY DISEASE
1990; 141 (3): 631-639
The individual roles of pulmonary capillary endothelial and alveolar epithelial permeability in the pathogenesis of the adult respiratory distress syndrome (ARDS) are unclear. We developed a method for the sequential assessment of pulmonary macromolecule accumulation and small solute clearance in vivo using a gamma camera. We measured the exponential clearance coefficient of 111In-labeled diethylene triamine penta-acetate (111In-DTPA) to assess airway clearance of small solutes. We also calculated the exponential equilibration coefficient of 111In-labeled transferrin (111In-TF) to assess intrapulmonary accumulation of transferrin. We determined these parameters in guinea pigs with Escherichia coli peritonitis and compared them with a saline-treated control group, oleic-acid-treated groups, and a group treated with low molecular weight dextran Ringer solution. The pulmonary DTPA clearance and the intrapulmonary transferrin accumulation were significantly increased in the peritonitis group (29.4 +/- 8.2 x 10(-3) min-1, p less than 0.02, and 15.1 +/- 3.1 x 10(-3) min-1, p less than 0.02) when compared with the control group (3.1 +/- 0.8 x 10(-3) min-1 and 4.5 +/- 0.5 x 10(-3) min-1). These changes developed within 5.5 h of the initial insult. Neither increased extravascular lung water nor elevated pulmonary artery and left atrial pressures were detected in the peritonitis group. The low molecular weight dextran Ringer group did not show a significant increase in the pulmonary DTPA clearance and the intrapulmonary transferrin accumulation.(ABSTRACT TRUNCATED AT 250 WORDS)
View details for Web of Science ID A1990CT66700020
View details for PubMedID 2178527
KINETICS OF LEUKOCYTE SEQUESTRATION IN THE LUNGS OF ACUTELY SEPTIC PRIMATES - A STUDY USING IN-111 LABELED AUTOLOGOUS LEUKOCYTES
JOURNAL OF SURGICAL RESEARCH
1990; 48 (3): 196-203
To further clarify the role of leukocytes in the pathogenesis of ARDS, we studied the localization and kinetics of leukocyte migration using 111In-labeled autologous white cell scans (111In wbc scans) in four primates made acutely septic with infusions of Escherichia coli. Whole body images were obtained with a gamma camera and were acquired on computer every 15 min beginning immediately after the E. coli infusion. Simultaneous measurements of C5a and peripheral blood leukocyte count were also obtained. Within 5 min of initiating sepsis, three major events occurred: complement activation as measured by the production of C5a, a profound fall in peripheral leukocyte count, and a significant increase in the sequestration of leukocytes in the lungs. The pulmonary sequestration reached a peak at 15 min with a mean of 152% of baseline activity. This sequestration consisted of a population that was predominantly neutrophils. Damage to the pulmonary capillary endothelium was demonstrated by an increase in extravascular lung water. The results support a role for neutrophils and complement as mediators in the pathogenesis of ARDS.
View details for Web of Science ID A1990CV60600003
View details for PubMedID 2314092
MANAGEMENT OF CARBON-MONOXIDE POISONING
1990; 97 (1): 165-169
Carbon monoxide poisoning is a major cause of illness and death in the United States. Most cases result from exposure to the internal combustion engine and to stoves burning fossil fuels. Most cases of accidental exposure are preventable if proper precautions are taken; however, when cases arise, their presenting signs and symptoms are nonspecific and often lead to a misdiagnosis resembling a flu-like viral illness. As a result, the incidence of acute CO poisoning is underestimated. The effects of CO poisoning are due to tissue hypoxia, with the CNS and the heart being the most susceptible target organs due to their high oxygen needs. Prolonged hypoxia due to high CO levels may lead to cardiac arrhythmias or arrest (or both) and a variety of neurologic sequelae. Treatment is directed toward the relief of tissue hypoxia and the removal of CO from the body. Severity of poisoning can be divided into three levels based on CO levels in the blood. Administration of normobaric 100 percent oxygen is the therapy of choice for most cases, while hyperbaric oxygen therapy is reserved for severe poisonings.
View details for Web of Science ID A1990CG29200034
View details for PubMedID 2403894
PREVENTION OF INTERLEUKIN-2-INDUCED ACUTE LUNG INJURY IN GUINEA-PIGS BY PENTOXIFYLLINE
JOURNAL OF APPLIED PHYSIOLOGY
1989; 67 (6): 2432-2437
We administered recombinant human interleukin 2 (IL-2) to guinea pigs to investigate whether IL-2 would cause acute lung injury. In addition, we examined the effects of pentoxifylline (PTXF) on IL-2-induced acute lung injury. Three groups of animals were studied over a period of 8 h. The saline control group was injected intravenously with 2 ml of pyrogen-free saline; the IL-2 group was injected intravenously with 4 X 10(6) U/kg recombinant IL-2; and the IL-2-PTXF group was injected with a 20-mg/kg bolus of PTXF followed by a continuous infusion (6 mg.kg-1.h-1) started 60 min before injection of 4 X 10(6) U/kg IL-2. Lung water (wet-to-dry lung weight ratio), the concentration ratios of 125I-albumin in bronchoalveolar lavage (BAL) fluid and lung tissue compared with plasma (125I-albumin BAL-to-plasma, 125I-albumin lung-to-plasma), and cell counts in BAL fluid were examined. An intravenous injection of IL-2 caused an increased lung water (P less than 0.01), an increased 125I-albumin lung-to-plasma ratio (P less than 0.05), and a significant increase in the absolute number of neutrophils, lymphocytes, and macrophages in BAL fluid compared with the saline control. In contrast, the PTXF-pretreated group did not demonstrate IL-2-induced acute lung injury (lung water, 125I-albumin lung-to-plasma) or increased accumulation of neutrophils, lymphocytes, and macrophages in the BAL. These data suggest a possible role for PTXF in attenuating the side effects of IL-2.
View details for Web of Science ID A1989CG43300033
View details for PubMedID 2606851
EFFECTS OF TUMOR NECROSIS FACTOR ON PMN CHEMOTAXIS, CHEMI-LUMINESCENCE, AND ELASTASE ACTIVITY
JOURNAL OF LABORATORY AND CLINICAL MEDICINE
1989; 114 (6): 674-681
Tumor necrosis factor (TNF) has been proposed as an important mediator of the inflammatory response in acute lung injury. To better understand polymorphonuclear leukocyte (PMN) activation during acute lung injury, we evaluated the effects of TNF on several in vitro PMN functions, including chemotaxis, chemiluminescence, and elastase activity. In the chemotaxis assay using a modified Boyden chamber, TNF alone or with N-formyl-methionyl-leucyl-phenylalanine (FMLP, 10(-8) mol/L) did not alter PMN migration. TNF suspended with 1% zymosan-activated serum (ZAS) increased PMN migration at low concentrations and decreased migration at high concentrations (control 99 +/- 4.8 microns, n = 9; TNF 0.1 ng/ml 135 +/- 9.4 microns, n = 5, p less than 0.01; TNF 1000 ng/ml 62 +/- 7.5 microns, n = 5, p less than 0.01). In the chemiluminescence assay, TNF (1000 ng/ml) induced a 3-fold increase in the PMN chemiluminescent response. However, TNF incubated with PMN did not cause an increase in supernatant elastase activity. These data reveal TNF induced the production of PMN reactive oxygen species as evidenced by an increased chemiluminescent response. Whereas TNF increased chemotaxis at low concentrations in the presence of 1% ZAS, high concentrations of TNF similar to levels detected in septic shock caused a decrease in chemotaxis that might contribute to retaining PMN in sites of inflammation. It is thus suggested that TNF may contribute to inflammation by stimulating the production of PMN-reactive oxygen species and modulating-PMN chemotaxis.
View details for Web of Science ID A1989CE13100008
View details for PubMedID 2592855
EFFECTS OF ANTI-C5A ANTIBODIES ON HUMAN POLYMORPHONUCLEAR LEUKOCYTE FUNCTION - CHEMOTAXIS, CHEMI-LUMINESCENCE, AND LYSOSOMAL-ENZYME RELEASE
JOURNAL OF BIOLOGICAL RESPONSE MODIFIERS
1989; 8 (6): 614-624
Previous investigation has demonstrated that in vivo complement activation can produce acute lung injury. Complement component C5a has been implicated as a key factor in this damage. In addition, C5a is thought to play a central role in mediating polymorphonuclear leukocyte (PMN) function. Studies suggest that administering antibodies to C5a might play a role in attenuating lung injury in animal models of sepsis. To evaluate further the effects of anti-C5a antibodies, we compared the effects of anti-human C5a des-Arg monoclonal (MAb) and polyclonal (PAb) antibodies on PMN functions including chemotaxis, chemiluminescence, and lysosomal release. PMN chemotaxis was assayed in Boyden chambers using 0.5% zymosan-activated serum (ZAS) as a source of C5a and 0.5% normal human serum (NHS) as a control. PMN chemiluminescence was measured by scintillation counting using ZAS as a stimulant and NHS as control. In addition, the lysosomal marker enzyme beta-D-glucuronidase was spectrophotometrically determined to assess lysosomal release. The PMN chemotactic response to ZAS was completely abolished with MAb and PAb anti-C5a antibodies (p less than 0.01). Control antibodies had no effect on ZAS-stimulated chemotaxis. The anti-C5a MAb markedly inhibited PMN chemotaxis at concentrations ranging from 20 to 0.2 microgram/ml, and was approximately 30 times more potent than the PAb. ZAS-stimulated PMN chemiluminescence was markedly decreased in response to monoclonal antibodies to C5a. In contrast, the control antibody did not inhibit ZAS-stimulated PMN chemiluminescence. Anti-C5a antibodies also significantly attenuated the release of the lysosomal enzyme beta-D-glucuronidase from ZAS-stimulated PMN. Anti-C5a antibody treatment did not cause a significant lytic effect when incubated with PMN, as demonstrated by the absence of the cytoplasmic marker lactate dehydrogenase in the supernatant. These studies suggest that in states of complement activation, MAbs and PAbs may decrease PMN functions including chemotaxis, chemiluminescence, and lysosomal enzyme release.
View details for Web of Science ID A1989CA56900005
View details for PubMedID 2600603
Diagnosis and management of the adult respiratory distress syndrome.
1989; 15 (12): 21-27
View details for PubMedID 2691188
THE EFFECTS OF AMINOPHYLLINE AND PENTOXIFYLLINE ON MULTIPLE ORGAN DAMAGE AFTER ESCHERICHIA-COLI SEPSIS
AMERICAN REVIEW OF RESPIRATORY DISEASE
1989; 140 (4): 974-980
We studied the effects of the methylxanthines, aminophylline (AMPH) and pentoxifylline (PTXF), on multiple organ damage following Escherichia coli sepsis in guinea pigs. To assess multiple organ damage, 125I-labeled albumin accumulation was measured in bronchoalveolar lavage (BAL) fluid, lung, kidneys, liver, heart, adrenal glands, and spleen and expressed as a ratio of BAL fluid or tissue to 125I-labeled albumin plasma (albumin index: Al). Wet-to-dry lung weight (W/D) ratios were also measured. The methylxanthines were administered by a bolus injection followed by a continuous infusion. The seven experimental groups included: saline-control, AMPH-control, PTXF-control, E. coli septic-control, E. coli septic-AMPH high dose, E coli septic-AMPH low dose, and E. coli septic-PTXF. The AI of the BAL fluid and all examined organs significantly increased in the septic-control group compared to those in the saline-, AMPH-, and PTXF-control groups, In all septic-methylxanthine groups, the AI of the BAL fluid and all organs, except for the spleen, were significantly lower than those of the septic-control group. Compared to the saline-, AMPH-, and PTXF-control groups, the septic-control group revealed a significant increase in lung W/D ratios, whereas the septic-AMPH high and low dose groups and the septic-PTXF group did not. Of importance, the septic-PTXF group did not cause a significant decrease in mean arterial pressure (MAP) as compared to the control groups, whereas the septic-AMPH groups did cause a significant decrease in MAP compared to the septic-control group. Therefore, the data from this experiment demonstrate that both AMPH and PTXF attenuate the multiple organ albumin leak seen in septic guinea pigs. However, PTXF exerted this protective effect with no discernible effect on the MAP whereas the MAP of AMPH-treated guinea pigs was significantly decreased.
View details for Web of Science ID A1989AW37000021
View details for PubMedID 2529804
THE STATUS OF TRANSPLANTATION OF THE HUMAN-LUNG
SURGERY GYNECOLOGY & OBSTETRICS
1989; 169 (2): 179-185
Transplantation for end-stage pulmonary disease is now established as an effective therapy for selected patients. Initially, combined heart and lung transplantation was the only therapeutic option for these patients. Recent developments that include improved immunosuppression, preservation of grafts and technical advances and markedly decreasing bronchial anastomotic complications have made unilateral pulmonary transplantation a clinical reality.
View details for Web of Science ID A1989AJ07100022
View details for PubMedID 2667179
Intensive care unit survival of patients with systemic illness.
American review of respiratory disease
1989; 140 (2): S28-35
Many patients with systemic illness are admitted to intensive care units (ICUs) and placed on life support. This occurs in patient populations even when the projected mortality rate might be as high as 80 to 90%. Patients with systemic illness often are life-support-dependent in ICUs as chronically critically ill patients for many weeks. In order to make decisions concerning withholding or withdrawing life support, more information is needed concerning the survival of ICU patients with systemic illness. Historically, it has been well recognized that critically ill patients who have major organ-system failure have high mortality rates. Studies began to be published in the middle to late 1970s. However, the patient populations studied in different ICUs could not be compared because the evaluation and classification criteria were different. A well-tested and effective classification system that will assist in determining the ICU survival of patients with systemic illness has been developed in the last several years. This system depends upon an acute physiology assessment and chronic health evaluation and is known as the APACHE II system. This generalizable classification system has helped in showing that patients with systemic illness and multisystem organ failure have very high mortality rates. For example, mortality for patients with three or more organ-system failures persisting after 3 days is 98%. Numerous studies have identified that chronologic age is associated with increased mortality rates. However, a better assessment would be biologic age, which would take into account both chronologic age and health status. ICU survival of patients with cancer, hematologic neoplasms, renal failure, liver failure, AIDS, and burns is reviewed.(ABSTRACT TRUNCATED AT 250 WORDS)
View details for PubMedID 2669587
PENTOXIFYLLINE PREVENTS TUMOR NECROSIS FACTOR-INDUCED LUNG INJURY
AMERICAN REVIEW OF RESPIRATORY DISEASE
1989; 139 (6): 1361-1368
Human tumor necrosis factor-alpha (TNF) is a monokine produced by mononuclear cells after many stimuli, including bacterial endotoxin. Full exploration of its antineoplastic effects has been limited by side effects. We have previously shown that the administration of TNF to guinea pigs is associated with a syndrome similar to gram-negative septic shock, which includes capillary permeability lung injury. In this study, we measured the effects of pentoxifylline (PTX) on parameters of TNF-induced lung injury including: lung wet-to-dry weight ratio, the ratio of lung-to-plasma 125I-labeled albumin (albumin index), bronchoalveolar lavage (BAL) and peripheral leukocyte counts, and serial measurements of mean arterial pressure (MAP). Four groups of animals were studied: a TNF group received 3.75 x 10(6) U/kg TNF; a PTX group received a 20-mg/kg bolus of PTX followed by an infusion of 6 mg/kg/h; the PTX-TNF group received both; and the final group was a saline control. ANOVA analysis revealed significant elevations of lung wet-to-dry ratio only in the TNF group (5.9 [5.6 to 6.3], p less than 0.001), expressed as the mean followed by 95% confidence intervals). Lung albumin index was elevated only in the TNF group (0.24 [0.19 to 0.29], p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)
View details for Web of Science ID A1989AB08400011
View details for PubMedID 2524981
MULTIPLE ORGAN DAMAGE CAUSED BY TUMOR NECROSIS FACTOR AND PREVENTED BY PRIOR NEUTROPHIL DEPLETION
1989; 95 (5): 1114-1120
The effect of TNF on nonpulmonary multiple organ damage (MOD) was studied. Since polymorphonuclear leukocytes (PMN) are thought to play an important role in septic or TNF-induced MOD, we investigated both neutrophil sufficient (PMN+) and neutropenic (PMN-) guinea pigs. Sepsis was induced by Escherichia coli administration (2 x 10(9)/kg) or recombinant human TNF (1.4 x 10(6) U/kg) was infused into PMN+ and PMN- guinea pigs. During necropsy, the PMN+/TNF and PMN+/E coli animals exhibited marked damage in the adrenal glands, kidneys and liver as evidenced by hemorrhage, congestion, and PMN sequestration on histopathologic examination. There was also increased tissue albumin accumulation in the adrenal glands, kidneys, spleen, heart, and liver as demonstrated by 125I-labeled albumin determinations. In contrast, the PMN-/TNF group did not reveal histopathologic damage in any organ system and there was no abnormal organ accumulation of 125I-albumin. However, in PMN-/E coli animals, marked histopathologic damage in the adrenal glands and liver was evident. Furthermore, there were marked accumulations of 125I-albumin in the adrenals, heart, kidneys, liver, and spleen. Moreover, the PMN-/E coli guinea pigs had a much greater accumulation (p less than 0.01) of 125I-albumin in the kidneys than any other group including the PMN+/E coli group. Thus, nonpulmonary MOD in guinea pigs is caused by TNF administration and can be prevented by PMN depletion. However, while E coli administration also caused marked nonpulmonary MOD in neutrophil sufficient guinea pigs, equivalent or greater damage was produced in neutropenic animals. This suggests that while TNF-induced MOD may be primarily mediated by PMN, E coli-induced MOD seems to be mediated by more than PMN.
View details for Web of Science ID A1989U490600037
View details for PubMedID 2523293
- THE ETHICAL USE OF HUMAN-FETAL TISSUE IN MEDICINE NEW ENGLAND JOURNAL OF MEDICINE 1989; 320 (16): 1093-1096
COMPLEMENT LEVELS IN SEPTIC PRIMATES TREATED WITH ANTI-C5A ANTIBODIES
JOURNAL OF SURGICAL RESEARCH
1989; 46 (3): 195-199
During gram-negative sepsis it is known that endotoxin activates complement by the alternate pathway. The complement anaphylatoxin C5a, a result of this activation, is thought to play a key role in attracting and activating neutrophils in the lungs, leading to the adult respiratory distress syndrome. Complement levels were measured in primates made septic by Escherichia coli infusions. Anti-human C5a antibodies were administered to study their effect on neutrophil-mediated lung injury. Control (I), septic (II) and septic + anti-C5a antibody (III) groups (n = 4) were studied. The antibody-treated group (III) demonstrated a significant attenuation of septic shock and pulmonary edema as has been previously reported. All complement profiles were corrected for varying hemoglobin concentrations. C3, C4, and C5 levels were measured by radial immunodiffusion and were depleted in both septic groups. Once the levels were depleted from the plasma, they did not recover. The depletion of C4 indicates that classical pathway activation also occurred. C3a, C4a, and C5a levels were measured by radioimmunoassay. Significantly increased peak levels were reached in the septic groups 15 min after initiation of the E. coli infusion. There were no significant differences in early peak C3a and C4a levels between groups II and III. However, the mean peak C5a level in group III (anti-C5a antibodies) was 42% lower than that in group II, and after this early peak, C5a levels were not elevated above control levels in group III. The antibody to human C5a was thus shown to be cross-reactive with primate C5a and was specific since C3a and C4a levels were not decreased in group III.(ABSTRACT TRUNCATED AT 250 WORDS)
View details for Web of Science ID A1989T752100002
View details for PubMedID 2493531
LIFE-SUSTAINING TREATMENT FOR PATIENTS WITH AIDS
1989; 95 (3): 647-652
Physicians increasingly are being called upon to make difficult decisions about intensive care for patients with the acquired immunodeficiency syndrome (AIDS). AIDS patients who require intensive care have a poor prognosis; the in-hospital mortality rate of those receiving mechanical ventilation for P carinii pneumonia is 86-100 percent in most studies. However, in the past year, two studies documenting improved outcome have been published. Physicians should understand these outcome data and use well-established ethical principles to allow informed competent patients with AIDS to express their preferences regarding intensive care. Patients should be encouraged to provide advanced directives regarding life-sustaining treatments or to designate surrogate decision-makers to be consulted should they lose mental competence. The health care system should provide alternatives to the ICU for compassionate terminal care. However, arbitrary policies denying intensive care to AIDS patients for whom it is medically indicated and desired are not warranted.
View details for Web of Science ID A1989T563000038
View details for PubMedID 2646078
ATTENUATION OF ACUTE LUNG INJURY IN SEPTIC GUINEA-PIGS BY A NEW XANTHINE DERIVATIVE (HWA-138)
1989; 5 (6): 407-415
The protective effect of xanthines against E. coli-induced and cytokine-induced lung injury in guinea-pigs has been demonstrated recently. In the present study, the possible protective effects were examined of an analogue of pentoxifylline, HWA-138, a xanthine derivative, on lung injury in septic guinea-pigs. Three groups of animals were studied over a period of 8 hours: Group I animals--saline control injected intravenously with 3 ml 2% lysine/normal saline followed by a continuous lysine/saline infusion (1 ml/kg/hr); Group II--septic control injected intravenously with 2 x 10(9)/kg Escherichia coli followed by a continuous lysine/saline infusion (1 ml/kg/hr); and Group III--E. coli septicaemia plus HWA-138 continuous infusion (HWA-138 dissolved in lysine/saline) began with a bolus (10 mg/kg) followed by a HWA-138 continuous infusion (3 mg/kg/hr) started 60 minutes before injection of E. coli. Arterial blood pressure and white blood cell counts were monitored serially for 8 hours. Lung water (wet-to-dry ratio) and the concentration ratio of 125I-labelled albumin in bronchoalveolar lavage (BAL) fluid and lung tissue compared to plasma (125I-albumin BAL/plasma, 125I-albumin lung/plasma) were examined. Results demonstrated that an intravenous injection of E. coli caused an increased W/D ratio (p less than 0.01) and an increased 125I-albumin lung/plasma ratio (p less than 0.01). In contrast, the HWA-138-treated group did not demonstrate significantly increased W/D lung ratios (p less than 0.01) and 125I-albumin lung/plasma ratios (p less than 0.05). The data suggest a possible role for HWA-138 in attenuating sepsis-induced lung injury.
View details for Web of Science ID A1989AP82700007
View details for PubMedID 2687896
GRANULOCYTE DEPLETION PREVENTS TUMOR NECROSIS FACTOR-MEDIATED ACUTE LUNG INJURY IN GUINEA-PIGS
AMERICAN REVIEW OF RESPIRATORY DISEASE
1988; 138 (5): 1300-1307
To examine the role of polymorphonuclear neutrophils (PMN) and other granulocytes in the pathogenesis of acute lung injury caused by tumor necrosis factor alpha (TNF), we compared the permeability edema and pulmonary histopathology in normal (granulocyte sufficient) guinea pigs and in granulocytopenic guinea pigs treated with TNF. Circulating granulocytes were depleted with cyclophosphamide. Two groups of normal animals were treated with either saline (PMN+/Control) or 1.4 x 10(6) U/kg recombinant human TNF (PMN+/TNF). Three granulocytopenic groups were treated with either saline (PMN-/Control), TNF (PMN-/TNF), or intravenous infusion of 2 x 10(9) E. coli strain J96 (PMN-/Sepsis). We measured the amount of 125I-labeled albumin in bronchoalveolar lavage (BAL) fluid and whole lung tissue and the wet/dry lung weight ratio to assess pulmonary transvascular protein flux and edema. We also quantified PMN in BAL fluid and fixed lung tissue. There were no statistically significant differences in any of these parameters between the PMN+/Control, PMN-/Control, or PMN-/TNF groups, except that the PMN+/Control predictably had more PMN/alveolus than the PMN- groups. However, both the PMN+/TNF and the PMN-/Sepsis groups had increased amounts of 125I-labeled albumin in BAL fluid and lung tissue (p less than 0.01) and increased wet/dry lung weight ratios (p less than 0.05), compared to all other groups. Histopathologically, capillary congestion and moderate inflammation were seen in the PMN+/TNF group, and acute inflammation and gross alveolar hemorrhage were seen in the PMN-/Sepsis group.(ABSTRACT TRUNCATED AT 250 WORDS)
View details for Web of Science ID A1988Q844800032
View details for PubMedID 3059892
ATTENUATION OF ACUTE LUNG INJURY IN SEPTIC GUINEA-PIGS BY PENTOXIFYLLINE
AMERICAN REVIEW OF RESPIRATORY DISEASE
1988; 138 (2): 376-382
Pentoxifylline (PTXF), a drug demonstrated to improve intermittent claudication, is a methylxanthine that increases intracellular cyclic AMP (cAMP) and, unlike theophylline, has few side effects. Because increased cAMP levels have been associated with a decrease in lung injury, we examined the effects of PTXF on acute lung injury in a septic guinea pig model. Five groups of guinea pigs were studied over a period of 8 h. (Group I: saline control injected intravenously with 2 ml of saline; Group II: septic control injected intravenously with 2 x 10(9) Escherichia coli; Group III: E. coli septicemia plus PTXF bolus 20 mg/kg injected 5 min before E. coli injection; Group IV: E. coli septicemia plus PTXF continuous infusion, begun with bolus [20 mg/kg] followed by continuous infusion [20 mg/kg/h] started 60 min before injection of E. coli; Group V: PTXF continuous infusion [20 mg/kg/h] control). Arterial blood gases, arterial blood pressure, and blood WBC counts were monitored serially for 8 h. Lung water (wet-to-dry ratio), the concentration ratio of 125I-labeled albumin in bronchoalveolar lavage (BAL) fluid to that in plasma (albumin index; AI), total cell count in BAL fluid, thiobarbituric-acid-reactive material (TBARM), and the lysosomal enzyme beta-glucuronidase (beta-G) were examined. Lung tissue was studied histologically to assess neutrophil accumulation. Our results showed that E. coli septicemia caused significant peripheral neutropenia and histopathologic evidence of neutrophil alveolitis associated with an increased ratio of TBARM and beta-G in BAL fluid as compared with those in plasma (TBARM BAL ratio and beta-G BAL ratio).(ABSTRACT TRUNCATED AT 250 WORDS)
View details for Web of Science ID A1988P626400024
View details for PubMedID 3057964
TUMOR NECROSIS FACTOR CAUSES INCREASED PULMONARY PERMEABILITY AND EDEMA - COMPARISON TO SEPTIC ACUTE LUNG INJURY
AMERICAN REVIEW OF RESPIRATORY DISEASE
1988; 137 (6): 1364-1370
Tumor necrosis factor alpha (TNF), a monokine produced by mononuclear cells in response to bacterial endotoxin (LPS), creates a syndrome similar to septic shock in animal models. To study whether TNF could induce acute lung injury similar to that seen in gram-negative sepsis, we injected recombinant human TNF (rHuTNF alpha) into guinea pigs and monitored arterial blood gases, leukocyte counts, and left atrial (Pla), pulmonary artery (Ppa), and mean arterial pressures (MAP) serially for 8 h. Pulmonary histopathology was assessed microscopically, and cell counts and 125I-labeled albumin (125I-albumin) in bronchoalveolar lavage (BAL) fluid and lung wet/dry weight ratios were determined. Five groups of animals were studied; the 2 TNF groups received high (1.4 X 10(6) U/kg) or low (1.0 X 10(6) U/kg) doses of rHuTNF alpha, the sepsis group received 2 X 10(9) Escherichia coli/kg intravenously, and the control group received saline. An LPS control group receiving 40 ng/kg E. coli LPS was also included because the rHuTNF alpha contained a small amount of LPS as a contaminant. Pulmonary permeability was assessed by studying the Pla and the BAL fluid/plasma 125I-albumin ratio (permeability index). The permeability index was significantly increased in the high-dose TNF (0.0408 +/- 0.0041, p less than 0.05) and sepsis groups (0.0466 +/- 0.0068, p less than 0.01) relative to controls (0.0215 +/- 0.0028). The wet/dry lung weight ratios were also significantly increased in the high-dose TNF (6.07 +/- 0.29, p less than 0.05) and sepsis groups (6.22 +/- 0.30, p less than 0.05) relative to the control group (5.18 +/- 0.20).(ABSTRACT TRUNCATED AT 250 WORDS)
View details for Web of Science ID A1988N997000021
View details for PubMedID 3059859
PULMONARY-EDEMA AFTER ESCHERICHIA-COLI PERITONITIS CORRELATES WITH THIOBARBITURIC-ACID-REACTIVE MATERIALS IN BRONCHOALVEOLAR LAVAGE FLUID
AMERICAN REVIEW OF RESPIRATORY DISEASE
1988; 137 (4): 783-789
We developed a new model of acute lung injury caused by live Escherichia coli peritonitis in guinea pigs. Arterial blood gas determinations, arterial blood pressure, and white blood cell counts were monitored serially for 12 h after the injection of either 2 x 10(9) E. coli J96 or saline. Lung water, albumin concentration in bronchoalveolar lavage fluid (BALF) and in lung tissue, WBC counts in BALF, and thiobarbituric-acid-reactive materials (TBARM) in plasma, lung tissue, and BALF were examined. Increased TBARM might be associated with pulmonary injury and are produced either by the generation of lipoperoxides secondary to oxygen-free radicals or as metabolic byproducts of prostanoid metabolism. Lung tissue sections were studied by light microscopy. E. coli peritonitis, as compared with control animals, caused significant peripheral neutropenia, histopathologic evidence of lung inflammation, acidosis, and hypotension. The wet-to-dry lung ratio was increased in the peritonitis group when compared with that in the control group (p less than 0.01). Pulmonary edema in the peritonitis group was associated with significantly increased albumin concentrations in BALF and lung tissue. We report the new finding of increased TBARM concentrations in BALF after E. coli peritonitis (p less than 0.01 and p less than 0.05, respectively). In contrast, plasma TBARM concentrations were unchanged. The levels of TBARM in the BALF correlated significantly with both lung water (p less than 0.01) and lung tissue albumin concentration (p less than 0.01). The measurement of elevated TBARM in BALF may allow acute lung injury to be detected. We conclude that this model may be useful for further studies of acute lung injury caused by E. coli peritonitis.
View details for Web of Science ID A1988M720500006
View details for PubMedID 3281528
- INITIATING AND WITHDRAWING LIFE SUPPORT - PRINCIPLES AND PRACTICE IN ADULT MEDICINE NEW ENGLAND JOURNAL OF MEDICINE 1988; 318 (1): 25-30
- ARDS - MECHANISMS AND MANAGEMENT HOSPITAL PRACTICE 1987; 22 (11): 65-?
- IMPORTANCE OF VENOUS RETURN, VENOUS RESISTANCE, AND MEAN CIRCULATORY PRESSURE IN THE PHYSIOLOGY AND MANAGEMENT OF SHOCK CHEST 1987; 92 (5): 906-912
NASAL CONTINUOUS POSITIVE AIRWAY PRESSURE IN ATELECTASIS
1987; 92 (4): 621-624
Nasal continuous positive airway pressure (CPAP) has been widely and safely used in the treatment of sleep disorders but has not been previously utilized for therapy of pulmonary atelectasis in adults. We observed three patients with significant atelectasis which was refractory to conventional chest physiotherapy. Bronchoscopy was not a viable therapeutic option in any patient. Therapy with continuous nasal CPAP was initiated at 10 to 15 cm H2O. The patients tolerated the therapy well and had prompt resolution of atelectasis. Nasal CPAP may be an effective modality for therapy of pulmonary atelectasis in spontaneously breathing patients, particularly when conventional therapies are not tolerated or are ineffectual.
View details for Web of Science ID A1987K327500012
View details for PubMedID 3308344