CAP Profiles

Bio

Bio

Ann Weinacker is the Senior Vice Chair of Medicine for Clinical Operations, and is Associate Chief Medical Officer, Patient Care Services. She is also the Interim Chief Quality Officer at SHC. She served as Chief of Staff from 2011-2014 after serving as Vice Chief of Staff from 2010-2011. Dr. Weinacker has extensive experience in SHC clinical and administrative leadership, in addition to serving since 1999 as a full-time faculty member in the Stanford University School of Medicine. She is currently Professor of Medicine, Division of Pulmonary and Critical Care Medicine and is Associate Director of the Intensive Care Unit. A strong advocate for patient centricity, Dr. Weinacker was appointed in November 2009 to be one of four leaders designated to actively design, guide and implement strategies to improve the patient experience at Stanford, and she copntinues to serve in that capacity. Her research focus is predicting lung transplant outcomes.

Dr. Weinacker began her career as a nurse and nurse anesthetist before completing her M.D. at the University of South Alabama College of Medicine, Mobile, in 1986. Her advanced training includes a pulmonary and critical care fellowship and a cardiovascular postdoctoral research fellowship, completed at the University of California, San Francisco in 1994. She is the winner of numerous national honors, editorial posts. Locally, she received the SHC Board of Hospital Director’s coveted Denise O’Leary Award for Clinical Excellence in 2008.

Clinical Focus

  • Critical Care Medicine
  • Pulmonary Disease

Academic Appointments

Administrative Appointments

  • Interim Chief Quality Officer, Stanford Health Care (2017 - Present)
  • Senior Vice Chair of Medicine for Clinical Affairs, Stanford University (2017 - Present)
  • Associate Chief Medical Officer, Patient Care Services, Stanford Health Care (2016 - Present)
  • Fellowship Director, Critical Care Medicine, Department of Medicine, Stanford University (2014 - 2017)
  • Immediate Past Chief of Staff, Stanford Health Care (2014 - 2017)
  • Vice Chair, Quality -- Implementation, Department of Medicine, Stanford University (2014 - 2017)
  • Chief of Staff, Stanford Hospital and Clinics (2011 - 2014)
  • Vice Chief of Staff, Stanford Hospital and Clinics (2010 - 2011)
  • Quality Improvement & Patient Safety Committee, Stanford University Medical Center (2007 - Present)
  • Chair, Emergency Medical Response Team Committee, Stanford University Medical Center (2007 - 2011)
  • Dean's Task Force for Clinical Excellence, Stanford University School of Medicine (2007 - 2008)
  • Vice Chair, Clinical Affairs, Department of Medicine, Stanford University (2007 - 2008)
  • Chair, Rapid Response Team Committee, Stanford University Medical Center (2005 - 2007)
  • Interim Director, Heart-Lung and Lung Transplant Program, Stanford University School of Medicine (2005 - 2006)
  • Continuing Quality Improvement in the ICU Committee, Stanford University School of Medicine (2003 - Present)
  • Fellowship Director, Pulmonary & Critical Care Medicine, Department of Medicine, Stanford University (2001 - 2002)
  • Credentials Committee, American College of Chest Physicians (2000 - 2004)
  • Associate Director, Intensive Care Unit, Stanford University Medical Center (1999 - Present)

Honors & Awards

  • Award for Service to Medical School, University of South Alabama College of Medicine (1986)
  • Best Intern Award, University of South Alabama (1987)
  • Victor Benator Award for Best Teaching Resident, University of South Alabama (1989)
  • Leadership Development in Pulmonary & Critical Care Medicine, American College of Chest Physicians (1999)
  • Chief Residents' Teaching Award, Stanford School of Medicine (2003)
  • Excellence in Teaching, Stanford University School of Medicine (2004)
  • Honor Medical Society, Alpha Omega Alpha (2006)
  • Denise O'Leary Award for Clinical Excellence, Stanford Hospital and Clinics Board of Directors (2008)

Boards, Advisory Committees, Professional Organizations

  • Member, Society of Critical Care Medicine (2000 - Present)
  • Member, American Thoracic Society (1990 - Present)
  • Fellow, American College of Chest Physicians (1990 - Present)

Professional Education

  • Residency:University of South Alabama Medical Center (1990) AL
  • Internship:University of South Alabama Medical Center (1987) AL
  • Board Certification: Critical Care Medicine, American Board of Internal Medicine (1993)
  • Board Certification: Pulmonary Disease, American Board of Internal Medicine (1992)
  • Fellowship:UCSF Medical Center (1994) CA
  • Board Certification: Internal Medicine, American Board of Internal Medicine (1989)
  • Medical Education:University of South Alabama Medical Center (1986) AL
  • M.D., University of South Alabama, Medicine (1986)
  • R.N. Anesthetist, University of South Alabama, Anesthesia (1980)

Contact

    • Tel: (650) 723-6381
    Fax: (650) 725-5489
  • Chest Clinic 300 Pasteur Dr A283 MC 5351 Stanford, CA 94305
    • Tel: (650) 725-7061
    Fax: (650) 725-5489

Links

Research & Scholarship

Current Research and Scholarly Interests

Dr. Weinacker's research interests center around ICU outcomes. Her specific interests include primary graft dysfunction in lung transplant recipients.

Teaching

2017-18 Courses

Graduate and Fellowship Programs

  • Critical Care Medicine (Fellowship Program)
  • Pulmonary & Critical Care Medicine (Fellowship Program)

Publications

All Publications

  • A Multidisciplinary Initiative to Increase Inpatient Discharges Before Noon JOURNAL OF NURSING ADMINISTRATION Kane, M., Weinacker, A., Arthofer, R., Seay-Morrison, T., Elfman, W., Ramirez, M., Ahuja, N., Pickham, D., Hereford, J., Welton, M. 2016; 46 (12): 630-635

    Abstract

    The aim of this study is to evaluate the effect of 2 hospital-wide interventions on achieving a discharge-before-noon rate of 40%.A multidisciplinary team led by administrative and physician leadership developed a plan to diminish capacity constraints by minimizing late afternoon hospital discharges using 2 patient flow management techniques.The study was a preintervention/postintervention retrospective analysis observing all inpatients discharged across 19 inpatient units in a 484-bed, academic teaching hospital measuring calendar month discharge-before-noon percentage, patient satisfaction, and readmission rates. Patient satisfaction and readmission rates were used as baseline metrics.The discharge-before-noon percentage increased from 14% in the 11-month preintervention period to an average of 24% over the 11-month postintervention period, whereas patient satisfaction scores and readmission rates remained stable.Implementation of the 2 interventions successfully increased the percentage of discharges before noon yet did not achieve the goal of 40%. Patient satisfaction and readmission rates were not negatively impacted by the program.

    View details for DOI 10.1097/NNA.0000000000000418

    View details for Web of Science ID 000388955800005

    View details for PubMedID 27851703

  • The relationship between plasma lipid peroxidation products and primary graft dysfunction after lung transplantation is modified by donor smoking and reperfusion hyperoxia. journal of heart and lung transplantation Diamond, J. M., Porteous, M. K., Jackson Roberts, L., Wickersham, N., Rushefski, M., Kawut, S. M., Shah, R. J., Cantu, E., Lederer, D. J., Chatterjee, S., Lama, V. N., Bhorade, S., Crespo, M., McDyer, J., Wille, K., Orens, J., Weinacker, A., Arcasoy, S., Shah, P. D., Wilkes, D. S., Hage, C., Palmer, S. M., Snyder, L., Calfee, C. S., Ware, L. B., Christie, J. D. 2016; 35 (4): 500-507

    Abstract

    Donor smoking history and higher fraction of inspired oxygen (Fio2) at reperfusion are associated with primary graft dysfunction (PGD) after lung transplantation. We hypothesized that oxidative injury biomarkers would be elevated in PGD, with higher levels associated with donor exposure to cigarette smoke and recipient hyperoxia at reperfusion.We performed a nested case-control study of 72 lung transplant recipients from the Lung Transplant Outcomes Group cohort. Using mass spectroscopy, F2-isoprostanes and isofurans were measured in plasma collected after transplantation. Cases were defined in 2 ways: grade 3 PGD present at day 2 or day 3 after reperfusion (severe PGD) or any grade 3 PGD (any PGD).There were 31 severe PGD cases with 41 controls and 35 any PGD cases with 37 controls. Plasma F2-isoprostane levels were higher in severe PGD cases compared with controls (28.6 pg/ml vs 19.8 pg/ml, p = 0.03). Plasma F2-isoprostane levels were higher in severe PGD cases compared with controls (29.6 pg/ml vs 19.0 pg/ml, p = 0.03) among patients reperfused with Fio2 >40%. Among recipients of lungs from donors with smoke exposure, plasma F2-isoprostane (38.2 pg/ml vs 22.5 pg/ml, p = 0.046) and isofuran (66.9 pg/ml vs 34.6 pg/ml, p = 0.046) levels were higher in severe PGD compared with control subjects.Plasma levels of lipid peroxidation products are higher in patients with severe PGD, in recipients of lungs from donors with smoke exposure, and in recipients exposed to higher Fio2 at reperfusion. Oxidative injury is an important mechanism of PGD and may be magnified by donor exposure to cigarette smoke and hyperoxia at reperfusion.

    View details for DOI 10.1016/j.healun.2015.12.012

    View details for PubMedID 26856667

  • Protein Quantitative Trait Loci Analysis Identifies Genetic Variation in the Innate Immune Regulator TOLLIP in Post-Lung Transplant Primary Graft Dysfunction Risk. American journal of transplantation Cantu, E., Suzuki, Y., Diamond, J. M., Ellis, J., Tiwari, J., Beduhn, B., NELLEN, J. R., Shah, R., Meyer, N. J., Lederer, D. J., Kawut, S. M., Palmer, S. M., Snyder, L. D., Hartwig, M. G., Lama, V. N., Bhorade, S., Crespo, M., DeMissie, E., Wille, K., Orens, J., Shah, P. D., Weinacker, A., Weill, D., Wilkes, D., Roe, D., Ware, L. B., Wang, F., Feng, R., Christie, J. D. 2016; 16 (3): 833-840

    Abstract

    The authors previously identified plasma plasminogen activator inhibitor-1 (PAI-1) level as a quantitative lung injury biomarker in primary graft dysfunction (PGD). They hypothesized that plasma levels of PAI-1 used as a quantitative trait could facilitate discovery of genetic loci important in PGD pathogenesis. A two-stage cohort study was performed. In stage 1, they tested associations of loci with PAI-1 plasma level using linear modeling. Genotyping was performed using the Illumina CVD Bead Chip v2. Loci meeting a p < 5 × 10(-4) cutoff were carried forward and tested in stage 2 for association with PGD. Two hundred ninety-seven enrollees were evaluated in stage 1. Six loci, associated with PAI-1, were carried forward to stage 2 and evaluated in 728 patients. rs3168046 (Toll interacting protein [TOLLIP]) was significantly associated with PGD (p = 0.006). The increased risk of PGD for carrying at least one copy of this variant was 11.7% (95% confidence interval 4.9-18.5%). The false-positive rate for individuals with this genotype who did not have PGD was 6.1%. Variants in the TOLLIP gene are associated with higher circulating PAI-1 plasma levels and validate for association with clinical PGD. A protein quantitative trait analysis for PGD risk prioritizes genetic variations in TOLLIP and supports a role for Toll-like receptors in PGD pathogenesis.

    View details for DOI 10.1111/ajt.13525

    View details for PubMedID 26663441

  • Objective Estimates Improve Risk Stratification for Primary Graft Dysfunction after Lung Transplantation AMERICAN JOURNAL OF TRANSPLANTATION Shah, R. J., Diamond, J. M., Cantu, E., Flesch, J., Lee, J. C., Lederer, D. J., Lama, V. N., Orens, J., Weinacker, A., Wilkes, D. S., Roe, D., Bhorade, S., Wille, K. M., Ware, L. B., Palmer, S. M., Crespo, M., DeMissie, E., SONNET, J., Shah, A., Kawut, S. M., Bellamy, S. L., Localio, A. R., Christie, J. D. 2015; 15 (8): 2188-2196

    Abstract

    Primary graft dysfunction (PGD) is a major cause of early mortality after lung transplant. We aimed to define objective estimates of PGD risk based on readily available clinical variables, using a prospective study of 11 centers in the Lung Transplant Outcomes Group (LTOG). Derivation included 1255 subjects from 2002 to 2010; with separate validation in 382 subjects accrued from 2011 to 2012. We used logistic regression to identify predictors of grade 3 PGD at 48/72 h, and decision curve methods to assess impact on clinical decisions. 211/1255 subjects in the derivation and 56/382 subjects in the validation developed PGD. We developed three prediction models, where low-risk recipients had a normal BMI (18.5-25 kg/m(2) ), chronic obstructive pulmonary disease/cystic fibrosis, and absent or mild pulmonary hypertension (mPAP<40 mmHg). All others were considered higher-risk. Low-risk recipients had a predicted PGD risk of 4-7%, and high-risk a predicted PGD risk of 15-18%. Adding a donor-smoking lung to a higher-risk recipient significantly increased PGD risk, although risk did not change in low-risk recipients. Validation demonstrated that probability estimates were generally accurate and that models worked best at baseline PGD incidences between 5% and 25%. We conclude that valid estimates of PGD risk can be produced using readily available clinical variables.

    View details for DOI 10.1111/ajt.13262

    View details for Web of Science ID 000358505600022

  • Genetic Variation in the Prostaglandin E-2 Pathway Is Associated with Primary Graft Dysfunction AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE Diamond, J. M., Akimova, T., Kazi, A., Shah, R. J., Cantu, E., Feng, R., Levine, M. H., Kawut, S. M., Meyer, N. J., Lee, J. C., Hancock, W. W., Aplenc, R., Ware, L. B., Palmer, S. M., Bhorade, S., Lama, V. N., Weinacker, A., Orens, J., Wille, K., Crespo, M., Lederer, D. J., Arcasoy, S., Demissie, E., Christie, J. D. 2014; 189 (5): 567-575

    Abstract

    Biologic pathways with significant genetic conservation across human populations have been implicated in the pathogenesis of primary graft dysfunction (PGD). The evaluation of the role of recipient genetic variation in PGD has thus far been limited to single, candidate gene analyses.We sought to identify genetic variants in lung transplant recipients that are responsible for increased risk of PGD using a two-phase large-scale genotyping approach.Phase 1 was a large-scale candidate gene association study of the multicenter, prospective Lung Transplant Outcomes Group cohort. Phase 2 included functional evaluation of selected variants and a bioinformatics screening of variants identified in phase 1.After genetic data quality control, 680 lung transplant recipients were included in the analysis. In phase 1, a total of 17 variants were significantly associated with PGD, four of which were in the prostaglandin E2 family of genes. Among these were a coding variant in the gene encoding prostaglandin E2 synthase (PTGES2; P = 9.3 × 10(-5)) resulting in an arginine to histidine substitution at amino acid position 298, and three variants in a block containing the 5' promoter and first intron of the PTGER4 gene (encoding prostaglandin E2 receptor subtype 4; all P < 5 × 10(-5)). Functional evaluation in regulatory T cells identified that rs4434423A in the PTGER4 gene was associated with differential suppressive function of regulatory T cells.Further research aimed at replication and additional functional insight into the role played by genetic variation in prostaglandin E2 synthetic and signaling pathways in PGD is warranted.

    View details for DOI 10.1164/rccm.201307-1283OC

    View details for Web of Science ID 000332512500011

    View details for PubMedID 24467603

  • Preoperative Plasma Club (Clara) Cell Secretory Protein Levels Are Associated With Primary Graft Dysfunction After Lung Transplantation AMERICAN JOURNAL OF TRANSPLANTATION Shah, R. J., Wickersham, N., Lederer, D. J., Palmer, S. M., Cantu, E., Diamond, J. M., Kawut, S. M., Lama, V. N., Bhorade, S., Crespo, M., DeMissie, E., Sonett, J., Wille, K., Orens, J., Weinacker, A., Shah, P., Arcasoy, S., Wilkes, D. S., Christie, J. D., Ware, L. B. 2014; 14 (2): 446-452

    Abstract

    Inherent recipient factors, including pretransplant diagnosis, obesity and elevated pulmonary pressures, are established primary graft dysfunction (PGD) risks. We evaluated the relationship between preoperative lung injury biomarkers and PGD to gain further mechanistic insight in recipients. We performed a prospective cohort study of recipients in the Lung Transplant Outcomes Group enrolled between 2002 and 2010. Our primary outcome was Grade 3 PGD on Day 2 or 3. We measured preoperative plasma levels of five biomarkers (CC-16, sRAGE, ICAM-1, IL-8 and Protein C) that were previously associated with PGD when measured at the postoperative time point. We used multivariable logistic regression to adjust for potential confounders. Of 714 subjects, 130 (18%) developed PGD. Median CC-16 levels were elevated in subjects with PGD (10.1 vs. 6.0, p<0.001). CC-16 was associated with PGD in nonidiopathic pulmonary fibrosis (non-IPF) subjects (OR for highest quartile of CC-16: 2.87, 95% CI: 1.37, 6.00, p=0.005) but not in subjects with IPF (OR 1.38, 95% CI: 0.43, 4.45, p=0.59). After adjustment, preoperative CC-16 levels remained associated with PGD (OR: 3.03, 95% CI: 1.26, 7.30, p=0.013) in non-IPF subjects. Our study suggests the importance of preexisting airway epithelial injury in PGD. Markers of airway epithelial injury may be helpful in pretransplant risk stratification in specific recipients.

    View details for DOI 10.1111/ajt.12541

    View details for Web of Science ID 000330265500023

    View details for PubMedID 24400993

  • Latent class analysis identifies distinct phenotypes of primary graft dysfunction after lung transplantation. Chest Shah, R. J., Diamond, J. M., Cantu, E., Lee, J. C., Lederer, D. J., Lama, V. N., Orens, J., Weinacker, A., Wilkes, D. S., Bhorade, S., Wille, K. M., Ware, L. B., Palmer, S. M., Crespo, M., Localio, A. R., Demissie, E., Kawut, S. M., Bellamy, S. L., Christie, J. D. 2013; 144 (2): 616-622

    Abstract

    ABSTRACT BACKGROUND: There is significant heterogeneity within the primary graft dysfunction (PGD) syndrome. We aimed to identify distinct grade 3 PGD phenotypes based on severity of lung dysfunction and patterns of resolution. METHODS: Subjects from the Lung Transplant Outcomes Group (LTOG) cohort study with grade 3 PGD within 72 hours after transplantation were included. Latent Class Analysis (LCA) was used to statistically identify classes based on changes in PGD ISHLT grade over time. Construct validity of the classes was assessed by testing for divergence of recipient, donor, and operative characteristics between classes. Predictive validity was assessed using time to death. RESULTS: 361 of 1255 subjects had grade 3 PGD within the first 72 hours after transplantation. LCA identified 3 distinct phenotypes: 1) severe persistent dysfunction (class 1); 2) complete resolution of dysfunction within 72 hours (class 2); and 3) attenuation, without complete resolution within 72 hours (class 3). Increased use of cardiopulmonary bypass, greater red blood cell transfusion and higher mean pulmonary artery pressure were associated with persistent PGD (class 1). Subjects in class 1 also had the greatest risk of death (HR 2.39, 95% CI: 1.57, 3.63, p<0.001). CONCLUSIONS: There are distinct phenotypes of resolution of dysfunction within the severe PGD syndrome. Subjects with early resolution may represent a different mechanism of lung pathology, such as resolving pulmonary edema, whereas classes with persistent PGD may represent a more severe phenotype. Future studies aimed at PGD mechanism or treatment may focus on phenotypes based on resolution of graft dysfunction.

    View details for DOI 10.1378/chest.12-1480

    View details for PubMedID 23429890

  • Clinical Risk Factors for Primary Graft Dysfunction after Lung Transplantation AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE Diamond, J. M., Lee, J. C., Kawut, S. M., Shah, R. J., Localio, A. R., Bellamy, S. L., Lederer, D. J., Cantu, E., Kohl, B. A., Lama, V. N., Bhorade, S. M., Crespo, M., Demissie, E., Sonett, J., Wille, K., Orens, J., Shah, A. S., Weinacker, A., Arcasoy, S., Shah, P. D., Wilkes, D. S., Ware, L. B., Palmer, S. M., Christie, J. D. 2013; 187 (5): 527-534

    Abstract

    Rationale: Primary graft dysfunction (PGD) is the main cause of early morbidity and mortality after lung transplantation. Previous studies have yielded conflicting results for PGD risk factors. Objectives: We sought to identify donor, recipient, and perioperative risk factors for PGD. Methods: We performed a 10-center prospective cohort study enrolled between March 2002 and December 2010 (the Lung Transplant Outcomes Group). The primary outcome was International Society for Heart and Lung Transplantation grade 3 PGD at 48 or 72 hours post-transplant. The association of potential risk factors with PGD was analyzed using multivariable conditional logistic regression. Measurements and Main Results: A total of 1,255 patients from 10 centers were enrolled; 211 subjects (16.8%) developed grade 3 PGD. In multivariable models, independent risk factors for PGD were any history of donor smoking (odds ratio [OR], 1.8; 95% confidence interval [CI], 1.2-2.6; P = 0.002); FiO2 during allograft reperfusion (OR, 1.1 per 10% increase in FiO2; 95% CI, 1.0-1.2; P = 0.01); single lung transplant (OR, 2; 95% CI, 1.2-3.3; P = 0.008); use of cardiopulmonary bypass (OR, 3.4; 95% CI, 2.2-5.3; P < 0.001); overweight (OR, 1.8; 95% CI, 1.2-2.7; P = 0.01) and obese (OR, 2.3; 95% CI, 1.3-3.9; P = 0.004) recipient body mass index; preoperative sarcoidosis (OR, 2.5; 95% CI, 1.1-5.6; P = 0.03) or pulmonary arterial hypertension (OR, 3.5; 95% CI, 1.6-7.7; P = 0.002); and mean pulmonary artery pressure (OR, 1.3 per 10 mm Hg increase; 95% CI, 1.1-1.5; P < 0.001). PGD was significantly associated with 90-day (relative risk, 4.8; absolute risk increase, 18%; P < 0.001) and 1-year (relative risk, 3; absolute risk increase, 23%; P < 0.001) mortality. Conclusions: We identified grade 3 PGD risk factors, several of which are potentially modifiable and should be prioritized for future research aimed at preventative strategies. Clinical trial registered with www.clinicaltrials.gov (NCT 00552357).

    View details for DOI 10.1164/rccm.201210-1865OC

    View details for Web of Science ID 000315977200012

    View details for PubMedID 23306540

  • Still a man's world, but why? Critical care (London, England) 2013; 17 (1): 113

    Abstract

    ABSTRACT: Women are generally under-represented in many academic medical settings. Through a brief commentary on this issue, the present article discusses possible explanations for this under-representation as well as potential solutions. Issues examined include women in leadership positions, attrition out of academic medicine, salary imbalance between men and women, potential bias among both genders, and the need for cultural change. We believe this is an extremely important issue of which we all need to be aware and hope that articles such as this will aid in starting a crucial conversation about gender issues in academic medicine.

    View details for DOI 10.1186/cc11915

    View details for PubMedID 23360580

  • Elevated Plasma Angiopoietin-2 Levels and Primary Graft Dysfunction after Lung Transplantation PLOS ONE Diamond, J. M., Porteous, M. K., Cantu, E., Meyer, N. J., Shah, R. J., Lederer, D. J., Kawut, S. M., Lee, J., Bellamy, S. L., Palmer, S. M., Lama, V. N., Bhorade, S. M., Crespo, M., Demissie, E., Wille, K., Orens, J., Shah, P. D., Weinacker, A., Weill, D., Arcasoy, S., Wilkes, D. S., Ware, L. B., Christie, J. D. 2012; 7 (12)

    Abstract

    Primary graft dysfunction (PGD) is a significant contributor to early morbidity and mortality after lung transplantation. Increased vascular permeability in the allograft has been identified as a possible mechanism leading to PGD. Angiopoietin-2 serves as a partial antagonist to the Tie-2 receptor and induces increased endothelial permeability. We hypothesized that elevated Ang2 levels would be associated with development of PGD.We performed a case-control study, nested within the multi-center Lung Transplant Outcomes Group cohort. Plasma angiopoietin-2 levels were measured pre-transplant and 6 and 24 hours post-reperfusion. The primary outcome was development of grade 3 PGD in the first 72 hours. The association of angiopoietin-2 plasma levels and PGD was evaluated using generalized estimating equations (GEE).There were 40 PGD subjects and 79 non-PGD subjects included for analysis. Twenty-four PGD subjects (40%) and 47 non-PGD subjects (59%) received a transplant for the diagnosis of idiopathic pulmonary fibrosis (IPF). Among all subjects, GEE modeling identified a significant change in angiopoietin-2 level over time in cases compared to controls (p = 0.03). The association between change in angiopoietin-2 level over the perioperative time period was most significant in patients with a pre-operative diagnosis of IPF (p = 0.02); there was no statistically significant correlation between angiopoietin-2 plasma levels and the development of PGD in the subset of patients transplanted for chronic obstructive pulmonary disease (COPD) (p = 0.9).Angiopoietin-2 levels were significantly associated with the development of PGD after lung transplantation. Further studies examining the regulation of endothelial cell permeability in the pathogenesis of PGD are indicated.

    View details for DOI 10.1371/journal.pone.0051932

    View details for Web of Science ID 000312694300063

    View details for PubMedID 23284823

  • Variation in PTX3 Is Associated with Primary Graft Dysfunction after Lung Transplantation AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE Diamond, J. M., Meyer, N. J., Feng, R., Rushefski, M., Lederer, D. J., Kawut, S. M., Lee, J. C., Cantu, E., Shah, R. J., Lama, V. N., Bhorade, S., Crespo, M., Demissie, E., Sonett, J., Wille, K., Orens, J., Weinacker, A., Weill, D., Arcasoy, S., Shah, P. D., Belperio, J. A., Wilkes, D., Ware, L. B., Palmer, S. M., Christie, J. D. 2012; 186 (6): 546-552

    Abstract

    Elevated long pentraxin-3 (PTX3) levels are associated with the development of primary graft dysfunction (PGD) after lung transplantation. Abnormalities in innate immunity, mediated by PTX3 release, may play a role in PGD pathogenesis.Our goal was to test whether variants in the gene encoding PTX3 are risk factors for PGD.We performed a candidate gene association study in recipients from the multicenter, prospective Lung Transplant Outcomes Group cohort enrolled between July 2002 and July 2009. The primary outcome was International Society for Heart and Lung Transplantation grade 3 PGD within 72 hours of transplantation. Targeted genotyping of 10 haplotype-tagging PTX3 single-nucleotide polymorphisms (SNPs) was performed in lung transplant recipients. The association between PGD and each SNP was evaluated by logistic regression, adjusting for pretransplantation lung disease, cardiopulmonary bypass use, and population stratification. The association between SNPs and plasma PTX3 levels was tested across genotypes in a subset of recipients with idiopathic pulmonary fibrosis.Six hundred fifty-four lung transplant recipients were included. The incidence of PGD was 29%. Two linked 5' region variants, rs2120243 and rs2305619, were associated with PGD (odds ratio, 1.5; 95% confidence interval, 1.1 to 1.9; P = 0.006 and odds ratio, 1.4; 95% confidence interval, 1.1 to 1.9; P = 0.007, respectively). The minor allele of rs2305619 was significantly associated with higher plasma PTX3 levels measured pretransplantation (P = 0.014) and at 24 hours (P = 0.047) after transplantation in patients with idiopathic pulmonary fibrosis.Genetic variants of PTX3 are associated with PGD after lung transplantation, and are associated with increased PTX3 plasma levels.

    View details for DOI 10.1164/rccm.201204-0692OC

    View details for Web of Science ID 000308849800015

    View details for PubMedID 22822025

  • A panel of lung injury biomarkers enhances the definition of primary graft dysfunction (PGD) after lung transplantation JOURNAL OF HEART AND LUNG TRANSPLANTATION Shah, R. J., Bellamy, S. L., Localio, A. R., Wickersham, N., Diamond, J. M., Weinacker, A., Lama, V. N., Bhorade, S., Belperio, J. A., Crespo, M., Demissie, E., Kawut, S. M., Wille, K. M., Lederer, D. J., Lee, J. C., Palmer, S. M., Orens, J., Reynolds, J., Shah, A., Wilkes, D. S., Ware, L. B., Christie, J. D. 2012; 31 (9): 942-949

    Abstract

    We aimed to identify combinations of biomarkers to enhance the definition of primary graft dysfunction (PGD) for translational research.Biomarkers reflecting lung epithelial injury (soluble receptor for advance glycation end products [sRAGE] and surfactant protein-D [SP-D]), coagulation cascade (plasminogen activator inhibitor-1 [PAI-1] and protein C), and cell adhesion (intracellular adhesion molecule-1 [ICAM-1]) were measured in the plasma of 315 individuals derived from the Lung Transplant Outcomes Group cohort at 6 and 24 hours after transplantation. We assessed biomarker utility in 2 ways: first, we tested the discrimination of grade 3 PGD within 72 hours; second, we tested the predictive utility of plasma biomarkers for 90-day mortality.PGD developed in 86 of 315 individuals (27%). Twenty-patients (8%) died within 90 days of transplantation, of which 16 (70%) had PGD. Biomarkers measured at 24 hours had greater discrimination than at 6 hours. Individually, sRAGE (area under the curve [AUC], 0.71) and PAI-1 (AUC, 0.73) had the best discrimination of PGD. The combinations of sRAGE with PAI-1 (AUC, 0.75), PAI-1 with ICAM-1 (AUC, 0.75), and PAI-1 with SP-D (AUC, 0.76) had the best discrimination. Combinations of greater than 2 biomarkers did not significantly enhance discrimination of PGD. ICAM-1 with PAI-1 (AUC, 0.72) and ICAM-1 with sRAGE (AUC, 0.72) had the best prediction for 90-day mortality. The addition of ICAM-1, PAI-1, or sRAGE to the concurrent clinical PGD grade significantly improved the prediction of 90-day mortality (p < 0.001 each).Measurement of the combination of a marker of impaired fibrinolysis with an epithelial injury or cell adhesion marker had the best discrimination for PGD and prediction for early death and may provide an alternative outcome useful in future research.

    View details for DOI 10.1016/j.healun.2012.05.001

    View details for Web of Science ID 000308120200003

    View details for PubMedID 22694851

  • High prevalence of corrected QT interval prolongation in acutely ill patients is associated with mortality: Results of the QT in Practice (QTIP) Study CRITICAL CARE MEDICINE Pickham, D., Helfenbein, E., Shinn, J. A., Chan, G., Funk, M., Weinacker, A., Liu, J., Drew, B. J. 2012; 40 (2): 394-399

    Abstract

    To test the potential value of more frequent QT interval measurement in hospitalized patients.We performed a prospective, observational study.All adult intensive care unit and progressive care unit beds of a university medical center.All patients admitted to one of six critical care units over a 2-month period were included in analyses.All critical care beds (n = 154) were upgraded to a continuous QT monitoring system (Philips Healthcare).QT data were extracted from the bedside monitors for offline analysis. A corrected QT interval >500 msecs was considered prolonged. Episodes of QT prolongation were manually over-read. Electrocardiogram data (67,648 hrs, mean 65 hrs/patient) were obtained. QT prolongation was present in 24%. There were 16 cardiac arrests, with one resulting from Torsade de Pointes (6%). Predictors of QT prolongation were female sex, QT-prolonging drugs, hypokalemia, hypocalcemia, hyperglycemia, high creatinine, history of stroke, and hypothyroidism. Patients with QT prolongation had longer hospitalization (276 hrs vs. 132 hrs, p < .0005) and had three times the odds for all-cause in-hospital mortality compared to patients without QT prolongation (odds ratio 2.99 95% confidence interval 1.1-8.1).We find QT prolongation to be common (24%), with Torsade de Pointes representing 6% of in-hospital cardiac arrests. Predictors of QT prolongation in the acutely ill population are similar to those previously identified in ambulatory populations. Acutely ill patients with QT prolongation have longer lengths of hospitalization and nearly three times the odds for mortality then those without QT prolongation.

    View details for DOI 10.1097/CCM.0b013e318232db4a

    View details for Web of Science ID 000299313500004

    View details for PubMedID 22001585

  • Obesity and Primary Graft Dysfunction after Lung Transplantation The Lung Transplant Outcomes Group Obesity Study AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE Lederer, D. J., Kawut, S. M., Wickersham, N., Winterbottom, C., Bhorade, S., Palmer, S. M., Lee, J., Diamond, J. M., Wille, K. M., Weinacker, A., Lama, V. N., Crespo, M., Orens, J. B., Sonett, J. R., Arcasoy, S. M., Ware, L. B., Christie, J. D. 2011; 184 (9): 1055-1061

    Abstract

    Obesity has been linked to acute lung injury and is a risk factor for early mortality after lung transplantation.To examine the associations of obesity and plasma adipokines with the risk of primary graft dysfunction after lung transplantation.We performed a prospective cohort study of 512 adult lung transplant recipients with chronic obstructive pulmonary disease or interstitial lung disease enrolled in the Lung Transplant Outcomes Group Study. In a nested case-control study, we measured plasma leptin, adiponectin, and resistin before lung transplantation and 6 and 24 hours after lung transplantation in 40 cases of primary graft dysfunction and 80 control subjects. Generalized linear mixed models and logistic regression were used to estimate risk ratios and odds ratios.Grade 3 primary graft dysfunction developed within 72 hours of transplantation in 29% participants. Obesity was associated with a twofold increased risk of primary graft dysfunction (adjusted risk ratio 2.1; 95% confidence interval, 1.7-2.6). The risk of primary graft dysfunction increased by 40% (confidence interval, 30–50%) for each 5 kg/m(2) increase in body mass index after accounting for center, diagnosis, cardiopulmonary bypass, and transplant procedure. Higher plasma leptin levels were associated with a greater risk of primary graft dysfunction (sex-adjusted P = 0.02). The associations of both obesity and leptin with primary graft dysfunction tended to be stronger among those who did not undergo cardiopulmonary bypass.Obesity is an independent risk factor for primary graft dysfunction after lung transplantation.

    View details for DOI 10.1164/rccm.201104-0728OC

    View details for Web of Science ID 000296613900015

    View details for PubMedID 21799077

  • Elevated Plasma Long Pentraxin-3 Levels and Primary Graft Dysfunction After Lung Transplantation for Idiopathic Pulmonary Fibrosis AMERICAN JOURNAL OF TRANSPLANTATION Diamond, J. M., Lederer, D. J., Kawut, S. M., Lee, J., Ahya, V. N., Bellamy, S., Palmer, S. M., Lama, V. N., Bhorade, S., Crespo, M., DeMissie, E., Sonett, J., Wille, K., Orens, J., Shah, P. D., Weinacker, A., Weill, D., Kohl, B. A., Deutschman, C. C., Arcasoy, S., Shah, A. S., Belperio, J. A., Wilkes, D., Reynolds, J. M., Ware, L. B., Christie, J. D. 2011; 11 (11): 2517-2522

    Abstract

    Primary graft dysfunction (PGD) after lung transplantation may result from ischemia reperfusion injury (IRI). The innate immune response to IRI may be mediated by Toll-like receptor and IL-1-induced long pentraxin-3 (PTX3) release. We hypothesized that elevated PTX3 levels were associated with PGD. We performed a nested case control study of lung transplant recipients with idiopathic pulmonary fibrosis (IPF) or chronic obstructive pulmonary disease (COPD) from the Lung Transplant Outcomes Group cohort. PTX3 levels were measured pretransplant, and 6 and 24 h postreperfusion. Cases were subjects with grade 3 PGD within 72 h of transplantation and controls were those without grade 3 PGD. Generalized estimating equations and multivariable logistic regression were used for analysis. We selected 40 PGD cases and 79 non-PGD controls. Plasma PTX3 level was associated with PGD in IPF but not COPD recipients (p for interaction < 0.03). Among patients with IPF, PTX3 levels at 6 and 24 h were associated with PGD (OR = 1.6, p = 0.02 at 6 h; OR = 1.4, p = 0.008 at 24 h). Elevated PTX3 levels were associated with the development of PGD after lung transplantation in IPF patients. Future studies evaluating the role of innate immune activation in IPF and PGD are warranted.

    View details for DOI 10.1111/j.1600-6143.2011.03702.x

    View details for Web of Science ID 000296335800029

    View details for PubMedID 21883907

  • Effect of Single vs Bilateral Lung Transplantation on Plasma Surfactant Protein D Levels in Idiopathic Pulmonary Fibrosis CHEST Sims, M. W., Beers, M. F., Ahya, V. N., Kawut, S. M., Sims, K. D., Lederer, D. J., Palmer, S. M., Wille, K., Lama, V. N., Shah, P. D., Orens, J. B., Bhorade, S., Crespo, M., Weinacker, A., Demissie, E., Bellamy, S., Christie, J. D., Ware, L. B. 2011; 140 (2): 489-496

    Abstract

    Serum levels of surfactant protein D (SP-D) have been suggested as reflecting epithelial damage in acute lung injury, COPD, and idiopathic pulmonary fibrosis (IPF). However, little is known about SP-D levels in the setting of lung transplantation.We examined plasma SP-D levels in 104 subjects from a prospective, multicenter cohort study of lung allograft recipients. Plasma SP-D was measured by enzyme-linked immunosorbent assay prior to transplant and daily for 3 days after transplant.Subjects undergoing transplant for IPF had higher baseline SP-D levels (median, 325 ng/mL) compared with subjects with cystic fibrosis, COPD, and pulmonary hypertension (median, 100, 80, and 82 ng/mL, respectively; P = .0001). Among subjects with IPF undergoing bilateral transplant, SP-D levels declined rapidly postoperatively. In contrast, SP-D levels in subjects undergoing single lung transplant for IPF remained significantly higher than those of bilateral allograft recipients. Among subjects undergoing single lung transplant for IPF, the development of primary graft dysfunction (PGD) was associated with a subsequent rise in SP-D levels, whereas SP-D levels in IPF subjects undergoing bilateral transplant declined, even in the presence of grade 3 PGD. Importantly, single lung allograft recipients without PGD had higher postoperative SP-D levels than bilateral allograft recipients with PGD.Subjects undergoing lung transplant for IPF have significantly higher baseline plasma SP-D levels compared with those with other diagnoses. Plasma SP-D is likely a biomarker of the air-blood barrier integrity in the native IPF lung, but may be less useful as a biomarker of PGD after transplant.

    View details for DOI 10.1378/chest.10-2065

    View details for Web of Science ID 000293994100036

    View details for PubMedID 21349925

  • Elevated Pulmonary Artery Pressure Is a Risk Factor for Primary Graft Dysfunction Following Lung Transplantation for Idiopathic Pulmonary Fibrosis CHEST Fang, A., Studer, S., Kawut, S. M., Ahya, V. N., Lee, J., Wille, K., Lama, V., Ware, L., Orens, J., Weinacker, A., Palmer, S. M., Crespo, M., Lederer, D. J., Deutschman, C. S., Kohl, B. A., Bellamy, S., Demissie, E., Christie, J. D. 2011; 139 (4): 782-787

    Abstract

    Idiopathic pulmonary fibrosis (IPF) is often associated with elevations in pulmonary artery pressures. Although primary pulmonary arterial hypertension (PAH) has been associated with primary graft dysfunction (PGD), the role of secondary PAH in mediating PGD risk in patients with IPF is incompletely understood. The purpose of this study was to evaluate the relationship between mean pulmonary artery pressure (mPAP) and PGD among patients with IPF.We performed a multicenter prospective cohort study of 126 lung transplant procedures performed for IPF between March 2002 and August 2007. The primary outcome was grade 3 PGD at 72 h after lung transplant. The mPAP was measured as the initial reading following insertion of the right-sided heart catheter during lung transplant. Multivariable logistic regression was used to adjust for confounding variables.The mPAP for patients with PGD was 38.5 ± 16.3 mm Hg vs 29.6 ± 11.5 mm Hg for patients without PGD (mean difference, 8.9 mm Hg [95% CI, 3.6-14.2]; P = .001). The increase in odds of PGD associated with each 10-mm Hg increase in mPAP was 1.64 (95% CI, 1.18-2.26; P = .003). In multivariable models, this relationship was independent of confounding by other clinical variables, although the use of cardiopulmonary bypass partially attenuated the relationship.Higher mPAP in patients with IPF is associated with the development of PGD.

    View details for DOI 10.1378/chest.09-2806

    View details for Web of Science ID 000289538500010

    View details for PubMedID 20864607

  • Elevated Plasma Clara Cell Secretory Protein Concentration Is Associated with High-Grade Primary Graft Dysfunction AMERICAN JOURNAL OF TRANSPLANTATION Diamond, J. M., Kawut, S. M., Lederer, D. J., Ahya, V. N., Kohl, B., Sonett, J., Palmer, S. M., Crespo, M., Wille, K., Lama, V. N., Shah, P. D., Orens, J., Bhorade, S., Weinacker, A., DeMissie, E., Bellamy, S., Christie, J. D., Ware, L. B. 2011; 11 (3): 561-567

    Abstract

    Primary graft dysfunction (PGD) is the leading cause of early posttransplant morbidity and mortality after lung transplantation. Clara cell secretory protein (CC16) is produced by the nonciliated lung epithelium and may serve as a plasma marker of epithelial cell injury. We hypothesized that elevated levels of CC16 would be associated with increased odds of PGD. We performed a prospective cohort study of 104 lung transplant recipients. Median plasma CC16 levels were determined at three time points: pretransplant and 6 and 24 h posttransplant. The primary outcome was the development of grade 3 PGD within the first 72 h after transplantation. Multivariable logistic regression was performed to evaluate for confounding by donor and recipient demographics and surgical characteristics. Twenty-nine patients (28%) developed grade 3 PGD within the first 72 h. The median CC16 level 6 h after transplant was significantly higher in patients with PGD [13.8 ng/mL (IQR 7.9, 30.4 ng/mL)] than in patients without PGD [8.2 ng/mL (IQR 4.5, 19.1 ng/mL)], p = 0.02. Elevated CC16 levels were associated with increased odds of PGD after lung transplantation. Damage to airway epithelium or altered alveolar permeability as a result of lung ischemia and reperfusion may explain this association.

    View details for DOI 10.1111/j.1600-6143.2010.03431.x

    View details for Web of Science ID 000287578400025

    View details for PubMedID 21299834

  • The "Slow Code" Should Be a "No Code" AMERICAN JOURNAL OF BIOETHICS Weinacker, A. 2011; 11 (11): 27-29

    View details for DOI 10.1080/15265161.2011.608244

    View details for Web of Science ID 000297290100011

    View details for PubMedID 22047122

  • Construct validity of the definition of primary graft dysfunction after lung transplantation JOURNAL OF HEART AND LUNG TRANSPLANTATION Christie, J. D., Bellamy, S., Ware, L. B., Lederer, D., Hadjiliadis, D., Lee, J., Robinson, N., Localio, A. R., Wille, K., Lama, V., Palmer, S., Orens, J., Weinacker, A., Crespo, M., Demissie, E., Kimmel, S. E., Kawut, S. M. 2010; 29 (11): 1231-1239

    Abstract

    This study tested the discriminant validity of International Society for Heart and Lung Transplantation (ISHLT) primary graft dysfunction (PGD) grades with lung injury biomarker profiles and survival.The study samples consisted of a multicenter prospective cohort study for the biomarker analysis and a cohort study of 450 patients for the mortality analyses. PGD was defined according to ISHLT consensus at 24, 48, and 72 hours after transplantation. We compared the changes in plasma markers of acute lung injury between PGD grades using longitudinal data models. To test predictive validity, we compared differences in the 30-day mortality and long-term survival according to PGD grade.PGD Grade 3 demonstrated greater differences between plasma intercellular adhesion molecule 1 (ICAM-1), protein C, and plasminogen activator inhibitor type 1 (PAI-1) levels than did PGD Grades 0 to 2 at 24, 48, and 72 hours after lung transplantation (p < 0.05 for each). Grade 3 had the highest 30-day (test for trend p < 0.001) and overall mortality (log rank p < 0.001), with PGD Grades 1 and 2 demonstrating intermediate risks of mortality. The ability to discriminate both 30-day and overall mortality improved as the time of grading moved away from the time of transplantation (test for trend p < 0.001).The ISHLT grading system has good discriminant validity, based on plasma markers of lung injury and mortality. Grade 3 PGD was associated with the most severely altered plasma biomarker profile and the worst outcomes, regardless of the time point of grading. PGD grade at 48 and 72 hours discriminated mortality better than PGD grade at 24 hours.

    View details for DOI 10.1016/j.healun.2010.05.013

    View details for Web of Science ID 000284030700005

    View details for PubMedID 20655249

  • Plasma Levels of Receptor for Advanced Glycation End Products, Blood Transfusion, and Risk of Primary Graft Dysfunction AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE Christie, J. D., Shah, C. V., Kawut, S. M., Mangalmurti, N., Lederer, D. J., Sonett, J. R., Ahya, V. N., Palmer, S. M., Wille, K., Lama, V., Shah, P. D., Shah, A., Weinacker, A., Deutschman, C. S., Kohl, B. A., Demissie, E., Bellamy, S., Ware, L. B. 2009; 180 (10): 1010-1015

    Abstract

    The receptor for advanced glycation end products (RAGE) is an important marker of lung epithelial injury and may be associated with impaired alveolar fluid clearance. We hypothesized that patients with primary graft dysfunction (PGD) after lung transplantation would have higher RAGE levels in plasma than patients without PGD.To test the association of soluble RAGE (sRAGE) levels with PGD in a prospective, multicenter cohort study.We measured plasma levels of sRAGE at 6 and 24 hours after allograft reperfusion in 317 lung transplant recipients at seven centers. The primary outcome was grade 3 PGD (Pa(O(2))/Fi(O(2)) < 200 with alveolar infiltrates) within the first 72 hours after transplantation.Patients who developed PGD had higher levels of sRAGE than patients without PGD at both 6 hours (median 9.3 ng/ml vs. 7.5 ng/ml, respectively; P = 0.028) and at 24 hours post-transplantation (median 4.3 ng/ml vs. 1.9 ng/ml, respectively; P < 0.001). Multivariable logistic regression analyses indicated that the relationship between levels of sRAGE and PGD was attenuated by elevated right heart pressures and by the use of cardiopulmonary bypass. Median sRAGE levels were higher in subjects with cardiopulmonary bypass at both 6 hours (P = 0.003) and 24 hours (P < 0.001). sRAGE levels at 6 hours were significantly associated with intraoperative red cell transfusion (Spearman's rho = 0.39, P = 0.002 in those with PGD), and in multivariable linear regression analyses this association was independent of confounding variables (P = 0.02).Elevated plasma levels of sRAGE are associated with PGD after lung transplantation. Furthermore, plasma sRAGE levels are associated with blood product transfusion and use of cardiopulmonary bypass.

    View details for DOI 10.1164/rccm.200901-0118OC

    View details for Web of Science ID 000271797600017

    View details for PubMedID 19661249

  • Soluble P-Selectin and the Risk of Primary Graft Dysfunction After Lung Transplantation CHEST Kawut, S. M., Okun, J., Shimbo, D., Lederer, D. J., De Andrade, J., Lama, V., Shah, A., Milstone, A., Ware, L. B., Weinacker, A., Demissie, E., Christie, J. D. 2009; 136 (1): 237-244

    Abstract

    Platelet activation with subsequent neutrophilic adherence to the vasculature initiates ischemia-reperfusion injury. We hypothesized that higher plasma P-selectin levels reflecting platelet activation would therefore be associated with primary graft dysfunction (PGD) after lung transplantation.In a prospective, multicenter cohort study of 376 patients who had undergone lung transplantation between 2002 and 2007, we measured soluble P-selectin levels before lung transplantation and at 6 and 24 h after lung reperfusion in 20 patients with grade III PGD (Pao(2)/fraction of inspired oxygen, < 200 mm Hg [with alveolar infiltrates seen on chest radiographs]) at 72 h after transplantation and 61 control subjects without PGD.Higher postoperative soluble P-selectin levels were associated with an increased risk of PGD at 72 h after transplantation (odds ratio [OR] per 1 natural log increase in soluble P-selectin at 6 h after lung allograft reperfusion, 3.5; 95% confidence interval [CI], 1.01 to 11.8; p = 0.048) and at 24 h after lung allograft reperfusion (OR, 4.8; 95% CI, 1.4 to 16.1; p = 0.01). Higher preoperative mean pulmonary artery pressure and the use of cardiopulmonary bypass were also associated with an increased risk of PGD.Higher postoperative soluble P-selectin levels were associated with an increased risk of PGD at 72 h following lung transplantation.

    View details for DOI 10.1378/chest.08-2697

    View details for Web of Science ID 000267779000034

    View details for PubMedID 19255296

  • Plasma Cytokines and Chemokines in Primary Graft Dysfunction Post-Lung Transplantation AMERICAN JOURNAL OF TRANSPLANTATION Hoffman, S. A., Wang, L., Shah, C. V., Ahya, V. N., Pochettino, A., Olthoff, K., Shaked, A., Wille, K., Lama, V. N., Milstone, A., Ware, L. B., Orens, J., Weinacker, A., DeMissie, E., Bellamy, S., Kawut, S. M., Hancock, W. W., Christie, J. D. 2009; 9 (2): 389-396

    Abstract

    Primary graft dysfunction (PGD) after lung transplantation causes significant morbidity and mortality. We aimed to determine the role of cytokines and chemokines in PGD. This is a multicenter case-control study of PGD in humans. A Luminex analysis was performed to determine plasma levels of 25 chemokines and cytokines before and at 6, 24, 48 and 72 h following allograft reperfusion in 25 cases (grade 3 PGD) and 25 controls (grade 0 PGD). Biomarker profiles were evaluated using a multivariable logistic regression and generalized estimating equations. PGD cases had higher levels of monocyte chemotactic protein-1 (MCP-1)/chemokine CC motif ligand 2 (CCL2) and interferon (IFN)-inducible protein (IP-10)/chemokine CXC motif ligand 10 (CXCL10) (both p < 0.05), suggesting recruitment of monocytes and effector T cells in PGD. In addition, PGD cases had lower levels of interleukin (IL-13) (p = 0.05) and higher levels of IL-2R (p = 0.05). Proinflammatory cytokines, including tumor necrosis factor (TNF)-alpha, and IFN-gamma decreased to very low levels after transplant in both PGD cases and controls, exhibiting no differences between the two groups. These findings were independent of clinical variables including diagnosis in multivariable analyses, but may be affected by cardiopulmonary bypass. Profound injury in clinical PGD is distinguished by the upregulation of selected chemokine pathways, which may useful for the prediction or early detection of PGD if confirmed in future studies.

    View details for DOI 10.1111/j.1600-6143.2008.02497.x

    View details for Web of Science ID 000262781400020

    View details for PubMedID 19120076

  • Randomized clinical trial of activated protein C for the treatment of acute lung injury AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE Liu, K. D., Levitt, J., Zhuo, H., Kallet, R. H., Brady, S., Steingrub, J., Tidswell, M., Siegel, M. D., Soto, G., Peterson, M. W., Chesnutt, M. S., Phillips, C., Weinacker, A., Thompson, B. T., Eisner, M. D., Matthay, M. A. 2008; 178 (6): 618-623

    Abstract

    Microvascular injury, inflammation, and coagulation play critical roles in the pathogenesis of acute lung injury (ALI). Plasma protein C levels are decreased in patients with acute lung injury and are associated with higher mortality and fewer ventilator-free days.To test the efficacy of activated protein C (APC) as a therapy for patients with ALI.Eligible subjects were critically ill patients who met the American/European consensus criteria for ALI. Patients with severe sepsis and an APACHE II score of 25 or more were excluded. Participants were randomized to receive APC (24 microg/kg/h for 96 h) or placebo in a double-blind fashion within 72 hours of the onset of ALI. The primary endpoint was ventilator-free days.APC increased plasma protein C levels (P = 0.002) and decreased pulmonary dead space fraction (P = 0.02). However, there was no statistically significant difference between patients receiving placebo (n = 38) or APC (n = 37) in the number of ventilator-free days (median [25-75% interquartile range]: 19 [0-24] vs. 19 [14-22], respectively; P = 0.78) or in 60-day mortality (5/38 vs. 5/37 patients, respectively; P = 1.0). There were no differences in the number of bleeding events between the two groups.APC did not improve outcomes from ALI. The results of this trial do not support a large clinical trial of APC for ALI in the absence of severe sepsis and high disease severity.

    View details for DOI 10.1164/rccm.200803-419OC

    View details for Web of Science ID 000259158600011

    View details for PubMedID 18565951

    View details for PubMedCentralID PMC2542435

  • Plasma intercellular adhesion molecule-1 and von willebrand factor in primary graft dysfunction after lung transplantation AMERICAN JOURNAL OF TRANSPLANTATION Covarrubias, M., Ware, L. B., Kawut, S. M., de Andrade, J., Milstone, A., Weinacker, A., Orens, J., Lama, V., Wille, K., Bellamy, S., Shah, C., DeMissie, E., Christie, J. D. 2007; 7 (11): 2573-2578

    Abstract

    Primary graft dysfunction (PGD), a form of acute lung injury occurring within 72 h following lung transplantation, is characterized by pulmonary edema and diffuse alveolar damage. We hypothesized that higher concentrations of intercellular adhesion molecule-1 (ICAM-1) and von Willebrand factor (vWF) would be associated with the occurrence of PGD. A total of 128 lung transplant recipients among 7 lung transplant centers were enrolled in a multicenter, prospective, cohort study. Blood specimens were collected preoperatively and at 6, 24, 48 and 72 h following lung transplantation. The primary outcome was Grade 3 PGD at 72 h after transplant. Logistic regression and generalized estimating equations (GEE) were used to analyze plasma ICAM-1 and vWF. At each postoperative timepoint, mean plasma ICAM-1 concentrations were higher for patients with PGD versus no PGD. The GEE contrast estimate for the association of plasma ICAM-1 with PGD was 107.5 ng/mL (95% CI 38.7, 176.3), p = 0.002. In the multivariate analyses, this finding was independent of all clinical variables except pulmonary artery pressures prior to transplant. There was no association between plasma vWF levels and PGD. We conclude that higher levels of plasma ICAM-1 are associated with PGD following lung transplantation.

    View details for DOI 10.1111/j.1600-6143.2007.01981.x

    View details for Web of Science ID 000250077600019

    View details for PubMedID 17908278

  • Management strategies for patients with pulmonary hypertension in the intensive care unit CRITICAL CARE MEDICINE Zamanian, R. T., Haddad, F., Doyle, R. L., Weinacker, A. B. 2007; 35 (9): 2037-2050

    Abstract

    Pulmonary hypertension may be encountered in the intensive care unit in patients with critical illnesses such as acute respiratory distress syndrome, left ventricular dysfunction, and pulmonary embolism, as well as after cardiothoracic surgery. Pulmonary hypertension also may be encountered in patients with preexisting pulmonary vascular, lung, liver, or cardiac diseases. The intensive care unit management of patients can prove extremely challenging, particularly when they become hemodynamically unstable. The objective of this review is to discuss the pathogenesis and physiology of pulmonary hypertension and the utility of various diagnostic tools, and to provide recommendations regarding the use of vasopressors and pulmonary vasodilators in intensive care.We undertook a comprehensive review of the literature regarding the management of pulmonary hypertension in the setting of critical illness. We performed a MEDLINE search of articles published from January 1970 to March 2007. Medical subject headings and keywords searched and cross-referenced with each other were: pulmonary hypertension, vasopressor agents, therapeutics, critical illness, intensive care, right ventricular failure, mitral stenosis, prostacyclin, nitric oxide, sildenafil, dopamine, dobutamine, phenylephrine, isoproterenol, and vasopressin. Both human and animal studies related to pulmonary hypertension were reviewed.Pulmonary hypertension presents a particular challenge in critically ill patients, because typical therapies such as volume resuscitation and mechanical ventilation may worsen hemodynamics in patients with pulmonary hypertension and right ventricular failure. Patients with decompensated pulmonary hypertension, including those with pulmonary hypertension associated with cardiothoracic surgery, require therapy for right ventricular failure. Very few human studies have addressed the use of vasopressors and pulmonary vasodilators in these patients, but the use of dobutamine, milrinone, inhaled nitric oxide, and intravenous prostacyclin have the greatest support in the literature. Treatment of pulmonary hypertension resulting from critical illness or chronic lung diseases should address the primary cause of hemodynamic deterioration, and pulmonary vasodilators usually are not necessary.

    View details for DOI 10.1097/01.CCM.0000280433.74246.9E

    View details for Web of Science ID 000249038700005

    View details for PubMedID 17855818

  • Association of protein C and type 1 plasminogen activator inhibitor with primary graft dysfunction AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE Christie, J. D., Robinson, N., Ware, L. B., Plotnick, M., De Andrade, J., Lama, V., Milstone, A., Orens, J., Weinacker, A., Demissie, E., Bellamy, S., Kawut, S. M. 2007; 175 (1): 69-74

    Abstract

    Acute lung injury is characterized by hypercoagulability and impaired fibrinolysis. We hypothesized that lower protein C and higher type 1 plasminogen activator inhibitor (PAI-1) levels in plasma would be associated with primary graft dysfunction (PGD) after lung transplantation. Design: Prospective, multicenter cohort study.We measured plasma levels of protein C and PAI-1 before lung transplantation and 6, 24, 48, and 72 h after allograft reperfusion in 128 lung transplant recipients at six centers. The primary outcome was grade 3 PGD (Pa(O(2))/Fi(O(2)) < 200 with alveolar infiltrates) 72 h after transplantation. Biomarker profiles were evaluated using logistic regression and generalized estimating equations.Patients who developed PGD had lower protein C levels 24 h posttransplantation than did patients without PGD (mean +/- SD [relative to control]: 64 +/- 27 vs. 92 +/- 41%, respectively; p = 0.002). Patients with PGD also had PAI-1 levels that were almost double those of patients without PGD at 24 h (213 +/- 144 vs. 117 +/- 89 ng/ml, respectively; p < 0.001). Throughout the 72-h postoperative period, protein C levels were significantly lower (p = 0.007) and PAI-1 levels were higher (p = 0.026) in subjects with PGD than in others. These differences persisted despite adjustment for potential confounders in multivariate analyses. Higher recipient pulmonary artery pressures, measured immediately pretransplantation, were associated with higher PAI-1 levels and increased risk of PGD.Lower postoperative protein C and higher PAI-1 plasma levels are associated with PGD after lung transplantation. Impaired fibrinolysis and enhanced coagulation may be important in PGD pathogenesis.

    View details for DOI 10.1164/rccm.200606-827OC

    View details for Web of Science ID 000243289800014

    View details for PubMedID 17023732

  • Smoking in movies CHEST Glantz, S. A., Polansky, J. 2006; 129 (2): 495-495

    View details for Web of Science ID 000235646100047

    View details for PubMedID 16478874

  • High dose cyclophosphamide efficacy in a patient with refractory anti-MuSK positive myasthenia gravis Muscle & Nerve Lin P, Martin B, Weinacker A, So Y 2006; 33: 433-435
  • Smoking in contemporary American cinema CHEST Omidvari, K., Lessnau, K., Kim, J., Mercante, D., Weinacker, A., Mason, C. 2005; 128 (2): 746-754

    Abstract

    The true prevalence of smoking among characters portrayed in the movies is unknown. This study examines this prevalence objectively.The top 10 movies on the weekly box office charts were reviewed. Whether or not the top five characters in these movies smoked, was documented. It was determined prior to the start of the study that 300 male characters and 300 female characters were needed to detect any significant difference. A total of 447 movies, composed of 193 movies rated restricted (R) [children < 17 years of age must be accompanied by an adult], 131 movies rated PG13 for parental guidance suggested for children < 13 years of age (PG) and 123 movies rated PG for parental guidance suggested, were examined until the sample size was reached.Smoking prevalence is the same in contemporary American movies and in the general US population (23.3% vs 24.8%, respectively). However, there was more smoking in these movies among men than among women (25.5% vs 20.5%, respectively; p < 0.006), among antagonists than among protagonists (35.7% vs 20.6%, respectively; p < 0.001), lower vs middle vs upper socioeconomic class (SEC) [48.2%, 22.9%, and 10.5%, respectively; p < 0.001], among independent vs studio movies (46.2% vs 18.2%, respectively; p < 0.001); and among R-rated vs PG13-rated vs PG-rated movies (37.3%, 16.2%, and 8.1%, respectively; p < 0.001). In R-rated movies, and in both subcategories of R-rated studio movies and R-rated independent movies, smoking prevalence is higher than in the US population (37.3%, 30.5%, and 50.6% vs 24.8%, respectively; p < 0.001 for all). Additionally, compared to the US population, men, women and lower SEC members smoke more in R-rated movies, R-rated studio movies, and R-rated independent movies. In R-rated movies, antagonists smoke more than protagonists (43.9% vs 35.8%, respectively; p < 0.001), and whites smoke more than nonwhites (38.3% vs 26.4%, respectively; p < 0.001). In R-rated studio movies, antagonists smoke more than protagonists (42.6% vs 26.6%, respectively; p < 0.001), and men smoke more than women (32.0% vs 27.9%, respectively; p = 0.03). In R-rated independent movies, whites smoke more than nonwhites (51.8% vs 40.5%, respectively; p < 0.001). Smoking prevalence is higher in R-rated independent movies than in R-rated studio movies (50.6% vs 30.5%, respectively; p < 0.001). Smoking prevalence is also higher in R-rated independent movies than in R-rated studio movies in subcategories of men (32.0% vs 49.8%, respectively; p < 0.001), women (21.8 vs 51.8%, respectively; p < 0.001), protagonists (26.6% vs 51.6%, respectively; p < 0.001), whites (31.5% vs 51.8%, respectively; p < 0.001), nonwhites (24.7% vs 40.5%, respectively; p < 0.001), and all three SECs.In contemporary American cinema, the smoking prevalence is higher for men, antagonistic characters, lower SEC, independent movies, and R-rated movies. Smoking prevalence is higher than in the general US population in R-rated movies, and in both its subcategories of R-rated studio movies and R-rated independent movies. There is more smoking in R-rated independent movies than in R-rated studio movies. Smoking in contemporary American cinema is associated with male sex, lower SEC, and antagonistic (ie, bad) characters.

    View details for Web of Science ID 000231198900040

    View details for PubMedID 16100163

  • The value of preoperative pulmonary rehabilitation. Thoracic surgery clinics Takaoka, S. T., Weinacker, A. B. 2005; 15 (2): 203-211

    Abstract

    Although data are limited for preoperative pulmonary rehabilitation, benefit can be inferred largely from studies done on COPD and pulmonary rehabilitation because of the similarity of patient populations. Although underlying lung function is unchanged, patients who undergo preoperative pulmonary rehabilitation seem to experience an enhanced quality of life and increased functional capacity. Likewise, multidisciplinary rehabilitation programs can result in better patient compliance with medications and smoking cessation and decreased use of various health care resources. Although pulmonary rehabilitation works to benefit patients anticipating surgery, it also represents a valuable treatment alternative to patients who are poor surgical candidates. Pulmonary rehabilitation seems to be a cost-effective, benign intervention with no adverse effects and should remain an essential component of patient management before lung transplantation, LVRS, lung resection, and potentially any other elective thoracic surgical procedure.

    View details for PubMedID 15999518

  • Lung transplantation: A decade of experience J Heart Lung Transplant Moffatt SD, Demers P, Robbins RC, Doyle R, Weinacker A, Henig N, Theodore J, Reitz BA, Whyte RI 2005; 24: 145-151
  • Intensive care unit support of hematopoietic stem cell transplant recipients: A case for cautious optimism CRITICAL CARE MEDICINE Weinacker, A. 2003; 31 (6): 1873-1875

    View details for DOI 10.1097/01.CCM.0000065685.13578.EE

    View details for Web of Science ID 000183588700047

    View details for PubMedID 12794440

  • Variability in antibiotic prescribing patterns and outcomes in patients with clinically suspected ventilator-associated pneumonia CHEST Fowler, R. A., Flavin, K. E., Barr, J., Weinacker, A. B., Parsonnet, J., Gould, M. K. 2003; 123 (3): 835-844

    Abstract

    To describe the variation in clinical practice strategies for the treatment of suspected ventilator-associated pneumonia (VAP) in a population of critically ill patients, and to determine whether initial empiric treatment with certain antibiotics, monotherapy vs combination antibiotic therapy, or appropriate vs inappropriate antibiotic therapy is associated with survival, length of hospital stay, or days free of antibiotics.Prospective, observational cohort study.Medical-surgical ICUs of two university-affiliated tertiary medical centers.Between May 1, 1998, and August 1, 2000, we screened 7,030 ICU patients and identified 156 patients with clinically suspected VAP. Patients were followed up until death or discharge from the hospital.The mean age was 62 years, mean APACHE (acute physiology and chronic health evaluation) II score was 14, and mortality was 34%. Combination antibiotic therapy was used in 53% of patients. Piperacillin-tazobactam, fluoroquinolones, vancomycin, cephalosporins, and aminoglycosides were the most commonly employed antibiotics. Initial empiric antibiotics were deemed appropriate in 92% of patients. The predominant organisms isolated from respiratory secretions included Pseudomonas aeruginosa and Staphylococcus aureus. Patients had lower in-hospital mortality rates if their initial treatment regimen included an antipseudomonal penicillin plus beta-lactamase inhibitor (hazard ratio [HR], 0.41; 95% confidence interval [CI], 0.21 to 0.80; p = 0.009). There was also a strong trend toward reduced mortality rates in patients treated with aminoglycosides (HR, 0.43; 95% CI, 0.16 to 1.11; p = 0.08). Specific antibiotic therapy was not associated with length of hospital stay or days free of antibiotics. Outcomes were similar for patients treated with monotherapy vs combination therapy, and for patients who received initial appropriate vs inappropriate therapy.Patients with clinically suspected VAP who receive initial empiric therapy with antipseudomonal penicillins plus beta-lactamase inhibitors, and possibly aminoglycosides, have lower in-hospital mortality rates when compared with those who are not treated with these antibiotics. These agents should be considered for the initial empiric therapy of VAP.

    View details for Web of Science ID 000181536500035

    View details for PubMedID 12628886

  • Blood cultures in the critical care unit - Improving utilization and yield CHEST Shafazand, S., Weinacker, A. B. 2002; 122 (5): 1727-1736

    Abstract

    Sepsis is a common cause of morbidity and death in critically ill patients, and blood culture samples are often drawn in an effort to identify a responsible pathogen. Blood culture results are usually negative, however, and even when positive are sometimes difficult to interpret. Distinguishing between true bacteremia and a false-positive blood culture result is important, but complicated by a variety of factors in the ICU. False-positive culture results are costly because they often prompt more diagnostic testing and more antibiotic prescriptions, and increase hospital length of stay. A number of factors influence the yield of blood cultures in critically ill patients, including the use of antibiotics, the volume of blood drawn, the frequency with which culture samples are drawn, and the site from which the culture samples are taken. Skin preparation techniques, handling of the cultures in the microbiology laboratory, and the type of blood culture system employed also influence blood culture yield. Attempts to identify predictors of true bacteremia in critically ill patients have been disappointing. In this review, we discuss factors that influence blood culture yield in critically ill patients, suggest ways to improve yield, and discuss true bacteremia vs false-positive blood culture results. We also discuss the costs and consequences of false-positive blood culture results, and list noninfectious causes of fever in the ICU.

    View details for Web of Science ID 000179376600040

    View details for PubMedID 12426278

  • Ethical issues in the long term management of progressive degenerative neuromuscular diseases SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE Vaszar, L. T., Weinacker, A. B., Henig, N. R., Raffin, T. A. 2002; 23 (3): 307-314

    Abstract

    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

  • Nodular invasive tracheobronchitis due to Aspergillus in a patient with systemic lupus erythematosus LUPUS Angelotti, T., Krishna, G., Scott, J., Berry, G., Weinacker, A. 2002; 11 (5): 325-328

    Abstract

    Nodular or pseudomembranous tracheobronchitis due to infection by Aspergillus species is an uncommon presentation of invasive aspergillosis. Most cases have been described in severely immunocompromised hosts. We describe the case of a 23-year-old woman, with recently diagnosed systemic lupus erythematosus, who developed worsening respiratory function. Bronchoscopy revealed rapid development and progression of multiple nodular plaques in her trachea and bronchi. Endobronchial biopsy demonstrated invasive fungal infection with tissue necrosis and the presence of hyphal elements consistent with aspergillosis. To the best of our knowledge, this is only the second report of fulminant invasive tracheobronchitis due to Aspergillus in a patient with an autoimmune disease.

    View details for DOI 10.1191/0961203302lu206cr

    View details for Web of Science ID 000176537200011

    View details for PubMedID 12090570

  • A cystic upper lobe lesion in a healthy nonsmoking man - Angiosarcoma of the left upper lobe, presumed metastatic CHEST Leonard, C. T., Weinacker, A., Berry, G., Whyte, R. I. 2001; 120 (5): 1725-1727

    View details for Web of Science ID 000172274300051

    View details for PubMedID 11713159

  • Diagnostic yield of screening colonoscopies in lung transplant candidates 96th International Conference of the American-Thoracic-Society Singer, L. G., Weinacker, A. B., Levin, L., Doyle, R. L., Theodore, J. LIPPINCOTT WILLIAMS & WILKINS. 2001: 530–32

    Abstract

    Colonoscopy has been used to screen lung transplant candidates for colorectal diseases that would preclude transplantation. The diagnostic yield of this procedure is unknown.This is a retrospective cohort study of patients 50 years of age and over who underwent lung transplant evaluations from 1996 to 1999. We assessed the prevalence and location of colonoscopic abnormalities, the predictive value of risk factors for colonic neoplasms, and the impact of colonoscopic findings on management.Thirty-one patients were evaluated. Twenty-four patients had at least one abnormal endoscopic finding. Six patients (19%) had adenomatous polyps; no carcinomas were detected. The 13 patients with risk factors were more likely to have adenomas (relative risk=2.8, P=0.2). The negative predictive value of risk factors for adenomas was 89%. One patient's management was altered and none were denied transplant listing because of the colonoscopic findings.Screening colonoscopy did not substantively alter the management of lung transplant candidates. More selective screening strategies may be warranted.

    View details for Web of Science ID 000170587000030

    View details for PubMedID 11502989

  • Acute respiratory distress syndrome: Physiology and new management strategies ANNUAL REVIEW OF MEDICINE Weinacker, A. B., Vaszar, L. T. 2001; 52: 221-237

    Abstract

    The acute respiratory distress syndrome (ARDS) has been recognized for more than three decades as a cause of respiratory failure in patients with a variety of illnesses. Clinically, it is characterized by pulmonary edema, refractory hypoxemia, diffuse pulmonary infiltrates, and altered lung compliance. Pathologically, it is distinguished by infiltration of the lungs with inflammatory cells, interstitial and alveolar edema, hyaline membrane formation, and ultimately fibrosis. Although we have learned much about the pathophysiology of this inflammatory syndrome since its earliest descriptions, ARDS continues to claim the lives of 40%-70% of its victims. Many treatment strategies have been used to prevent or treat ARDS, but thus far the most encouraging strategy to prevent lung injury and improve survival is mechanical ventilation with low tidal volumes and high levels of positive end-expiratory pressure.

    View details for Web of Science ID 000167302900013

    View details for PubMedID 11160776

  • A brave new world: Remote intensive care unit care for the 21st century CRITICAL CARE MEDICINE Shafazand, S., Shigemitsu, H., Weinacker, A. B. 2000; 28 (12): 3945-3946

    View details for Web of Science ID 000166186200033

    View details for PubMedID 11153646

  • Withdrawing life support from the critically ill CHEST McGee, D. C., Weinacker, A. B., Raffin, T. A. 2000; 118 (5): 1238-1239

    View details for Web of Science ID 000165286600005

    View details for PubMedID 11083669

  • The patient's response to medical futility ARCHIVES OF INTERNAL MEDICINE McGee, D. C., Weinacker, A. B., Raffin, T. A. 2000; 160 (11): 1565-1566

    View details for Web of Science ID 000087426700001

    View details for PubMedID 10847247

  • Inhalational anthrax - Epidemiology, diagnosis, and management CHEST Shafazand, S., Doyle, R., Ruoss, S., Weinacker, A., Raffin, T. A. 1999; 116 (5): 1369-1376

    Abstract

    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

  • Quality of life and lung volume reduction surgery. American journal of critical care Faul, J. L., Doyle, R. L., Weinacker, A. B., Raffin, T. A. 1999; 8 (6): 359-360

    View details for PubMedID 10553176

  • beta-adrenergic-blocking agents in bronchospastic diseases: A therapeutic dilemma PHARMACOTHERAPY Tafreshi, M. J., Weinacker, A. B. 1999; 19 (8): 974-978

    Abstract

    Cardioselective beta-blockers should be administered starting with a low dosage under direct medical observation. Bronchodilators should be readily available or may be coadministered. Because of several advantages, agents such as metoprolol, atenolol, and, in some cases, esmolol should be the first agents considered. In contrast to noncardioselective agents, if bronchospasm occurs, the effect of cardioselective agents is believed to be easier to reverse. Clinicians should avoid noncardioselective beta-blockers in asthmatics, even in small doses, such as those administered as eye drops. For asthmatic patients who are intolerant to noncardioselective beta-blockers, switching to a cardioselective beta-blocker might be a safe alternative. The significance of beta2-blockade usually varies with the patient's ventilatory condition, with more serious consequences being anticipated in patients with more severe asthma.

    View details for Web of Science ID 000081873300007

    View details for PubMedID 10453968

  • Systematic reviews and evidence-based critical care medicine: A step in the right direction AMERICAN JOURNAL OF MEDICINE Gould, M. K., Leonard, C. T., Weinacker, A. B., Raffin, T. A. 1998; 105 (6): 551-553

    View details for Web of Science ID 000077731900017

    View details for PubMedID 9870845

  • The treatment of malignant mesothelioma with a gene modified cancer cell line: A phase I study HUMAN GENE THERAPY Schwarzenberger, P., Harrison, L., Weinacker, A., Marrogi, A., Byrne, P., Ramesh, R., Theodossiou, C., Gaumer, R., Summer, W., Freeman, S. M., Kolls, J. K. 1998; 9 (17): 2641-2649

    Abstract

    Malignant mesothelioma is a tumor of the pleura for which there is no satisfactory treatment. It is almost universally fatal, regardless of the stage of the tumor at the time of diagnosis. Current treatment modalities include surgery, chemotherapy, and radiation therapy, although in some series none of these modalities is superior to no treatment at all. Because of the dismal prognosis for patients with malignant mesothelioma, a new mode of treatment is desperately needed. A promising area of research into the treatment of various malignancies is gene therapy. Recent studies have demonstrated the utility of exposing tumor cells to cells transduced to express the Herpes simplex virus gene for thymidine kinase (HSV-tk). By virtue of their expression of HSV-tk, the transduced cells are rendered susceptible to the antiviral drug, ganciclovir (GCV). and nearby tumor cells are killed by a phenomenon termed the bystander effect. In this protocol we propose a Phase I trial to study the safety and determine the maximal tolerated dose of an HSV-tk-transduced ovarian cancer cell line (PA1-STK cells) infused into the pleural cavities of patients with malignant pleural mesothelioma, followed by systemic administration of ganciclovir. The hope is that administration of ganciclovir will result in killing of the HSV-tk transduced ovarian cancer cells as well as the nearby malignant mesothelioma cells. This is a standard dose-escalation protocol.

    View details for Web of Science ID 000077221800019

    View details for PubMedID 9853530

  • Antitumor activity with the HSV-tk-gene-modified cell line PA-1-STK in malignant mesothelioma AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY Schwarzenberger, P., Lei, D. H., Freeman, S. M., Ye, P., Weinacker, A., Theodossiou, C., Summer, W., Kolls, J. K. 1998; 19 (2): 333-337

    Abstract

    Malignant mesothelioma (MM) is a thoracic malignancy that is increasing in incidence. Since it is uniformly fatal and kills by local spread, investigators have proposed that MM is a good target for novel treatment approaches, such as gene therapy. We hypothesized that delivery of the HSV-tk gene, using gene-modified tumor cells (PA-1-STK cells), would result in an antitumor effect after treatment with ganciclovir. In in vitro mixing experiments, we found that PA-1-STK cells killed both mouse and human mesothelioma cells in a dose-dependent manner. Moreover, we found that PA-1-STK cells also prolonged survival of mice with MM when the percentage of total tumor cells was high (70%), but observed no survival benefit when the percentage of PA-1-STK cells was low (30%). These data support the rationale for a cell-based gene therapy approach to MM.

    View details for Web of Science ID 000075414100018

    View details for PubMedID 9698607

  • Gene therapy for malignant mesothelioma: a novel approach for an incurable cancer with increased incidence in Louisiana. journal of the Louisiana State Medical Society Schwarzenberger, P., Harrison, L., Weinacker, A., Gaumer, R., Theodossiou, C., Summer, W., Ye, P., Marrogi, A. J., Ramesh, R., Freeman, S., Kolls, J. 1998; 150 (4): 168-174

    Abstract

    Malignant mesothelioma (MM) is a tumor of the pleura for which there is no satisfactory treatment. It is an almost universally fatal disease, regardless of the stage of the tumor at the time of diagnosis. Current treatment modalities include surgery, chemotherapy, and radiation therapy, although in some series none of these modalities is superior to no treatment at all. Because of the dismal prognosis for patients with MM, new modes of treatment are desperately needed. A promising area of research into the treatment of various malignancies is gene therapy. Recent studies have demonstrated the utility of exposing tumor cells to cells transduced to express the Herpes simplex virus gene for thymidine kinase (HSV-TK). By virtue of their expression of HSV-TK, the transduced cells are rendered susceptible to the antiviral drug, ganciclovir (GCV). Nearby untransduced tumor cells are killed by a so-called bystander effect. We are describing a Phase I clinical gene therapy trial for MM, which we are presently conducting at the Louisiana State University Medical Center of New Orleans. The purpose is to study the safety and to determine the maximal tolerated dose of an HSV-TK-transduced ovarian cancer cell line (PA1-STK cells) that is infused into the pleural cavities of patients. This infusion is followed by systemic administration of GCV. The hope is that administration of GCV will result in killing of both the transduced ovarian cancer cells as well as the nearby malignant cells.

    View details for PubMedID 9610071

  • DISTRIBUTION OF INTEGRINS ALPHA-V-BETA-6 AND ALPHA-9-BETA-1 AND THEIR KNOWN LIGANDS, FIBRONECTIN AND TENASCIN, IN HUMAN AIRWAYS AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY Weinacker, A., Ferrando, R., Elliott, M., Hogg, J., Balmes, J., Sheppard, D. 1995; 12 (5): 547-556

    Abstract

    We have previously identified two integrins, alpha 9 beta 1 and alpha v beta 6, from guinea pig airway epithelium. The extracellular matrix protein tenascin is a ligand for both of these receptors, and fibronectin is also a ligand for alpha v beta 6. In the present study, we used immunohistochemistry to examine the expression and spatial distribution of the alpha 9 subunit, alpha v beta 6, tenascin, and fibronectin in the proximal airways of 10 normal nonsmoking subjects and eight patients undergoing lung resection for cancer. We also performed the same analyses on sections of peripheral lung obtained from an additional seven subjects undergoing lung resection. alpha 9 was highly expressed throughout the airway epithelium (but not on alveolar epithelium) irrespective of clinical status. In contrast, alpha v beta 6 was expressed on proximal airway epithelial cells in four of eight smokers undergoing lung resection, but in none of the normal subjects and none of the distal airways examined. On bronchial epithelial cells cultured from resected airways, alpha v beta 6 was highly expressed on cells grown from patients who did not appear to express the receptor in vivo, as well as from subjects who did, suggesting that some component of the in vitro environment can induce expression. Although both tenascin and fibronectin were present below the proximal airway epithelium of both normal nonsmoking subjects and smokers, the spatial patterns of integrin and ligand expression were not congruent, because the integrins were present diffusely on the cell surface and on some cells that were not in contact with the basement membrane, whereas the ligands were present principally in the subepithelial layer. These findings are compatible with the existence of as-yet unidentified ligands for each of these integrins--for example, ligands involved in homotypic cell-cell interactions within the epithelium.

    View details for Web of Science ID A1995QY91300012

    View details for PubMedID 7537970

  • ROLE OF THE INTEGRIN ALPHA-V-BETA-6 IN CELL ATTACHMENT TO FIBRONECTIN - HETEROLOGOUS EXPRESSION OF INTACT AND SECRETED FORMS OF THE RECEPTOR JOURNAL OF BIOLOGICAL CHEMISTRY Weinacker, A., Chen, A., Agrez, M., CONE, R. I., Nishimura, S., Wayner, E., Pytela, R., Sheppard, D. 1994; 269 (9): 6940-6948

    Abstract

    The integrin alpha v beta 6 has been shown to be a fibronectin-binding protein. To determine whether the cytoplasmic and transmembrane domains of alpha v beta 6 are necessary for binding to fibronectin, a truncated, secreted form of the integrin lacking these domains was engineered and expressed in Chinese hamster ovary cells. Fibronectin affinity chromatography demonstrated that the secreted integrin, like its full-length counterpart, was capable of binding fibronectin. Monoclonal antibodies were made to secreted alpha v beta 6 and to beta 6-transfected NIH 3T3 cells. In experiments designed to determine whether alpha v beta 6 can mediate cell attachment to fibronectin, full-length human beta 6 was expressed in Chinese hamster ovary cells and in the human colon carcinoma cell line SW480. beta 6-expressing cells were identified by alpha v beta 6-specific antibodies, and the beta 6-transfectants were used in cell-adhesion assays. In Chinese hamster ovary cells, human beta 6 associated with hamster alpha v but was incapable of mediating cell attachment to fibronectin. However, expression of beta 6 in these cells had the dominant negative effect of decreasing alpha v beta 5-dependent adhesion to vitronectin. In SW480 cells, beta 6 expression conferred the ability to bind to fibronectin even in the presence of inhibitory antibodies against beta 1 integrins. In such cells, fibronectin binding ability could be blocked by an antibody to alpha v integrins. These results constitute the first direct evidence that alpha v beta 6 mediates cell attachment to fibronectin.

    View details for Web of Science ID A1994MZ50300104

    View details for PubMedID 8120056

  • IDIOPATHIC GIANT BULLOUS EMPHYSEMA (VANISHING LUNG SYNDROME) - IMAGING FINDINGS IN 9 PATIENTS AMERICAN JOURNAL OF ROENTGENOLOGY Stern, E. J., Webb, W. R., Weinacker, A., Muller, N. L. 1994; 162 (2): 279-282

    Abstract

    We reviewed the imaging findings in nine patients with idiopathic giant bullous emphysema. This progressive condition is characterized by large bullae, usually seen in association with several forms of emphysema, and usually occurs in young men, most of whom are smokers.Nine patients with chest radiographic evidence of a bulla or bullae occupying at least one third of a hemithorax, who had also been examined with high-resolution CT, were included in this retrospective study. We examined the size, distribution, and locations of bullae. On high-resolution CT scans, bullae were categorized as predominantly subpleural or intraparenchymal.In eight of the nine cases, the chest radiographs showed variable asymmetry in the distribution of bullae. Bullous disease involved predominantly the upper lobes. High-resolution CT showed bullae from 1 to 20 cm in diameter, but most were 2-8 cm in diameter. Paraseptal emphysema and subpleural bullae were the predominant findings in all nine patients. Seven patients had separate centrilobular emphysema of various degrees and intraparenchymal bullae. None of the intraparenchymal bullae were larger than 2-3 cm. Additionally, two non-small-cell lung cancers were seen in our series.The dominant and consistent feature seen on high-resolution CT scans in both smokers and nonsmokers is extensive paraseptal emphysema merging into giant bullae. Associated centrilobular emphysema, seen in cigarette smokers, is the important variable finding for determining the extent of underlying parenchymal disease, which may help in the preoperative assessment of giant bullous lung disease.

    View details for Web of Science ID A1994MU88000004

    View details for PubMedID 8310909

  • EFFECTS OF BETA-SUBUNIT CYTOPLASMIC DOMAIN DELETIONS ON THE RECRUITMENT OF THE INTEGRIN ALPHA-NU-BETA-6 TO FOCAL CONTACTS CELL ADHESION AND COMMUNICATION CONE, R. I., Weinacker, A., Chen, A., Sheppard, D. 1994; 2 (2): 101-113

    Abstract

    The integrin alpha v beta 6 is expressed primarily in epithelial cells and mediates attachment to the extracellular matrix protein fibronectin. We recently observed that alpha v beta 6 localizes to focal contacts when cells that express the receptor are plated on fibronectin. To determine which regions of the beta 6 cytoplasmic domain are required for recruitment to focal contacts, the wild type human beta 6 cytoplasmic domain are required for recruitment to focal contacts, the wild type human beta 6 subunit and mutants containing selective deletions within the beta 6 cytoplasmic domain were stably expressed in Chinese Hamster Ovary cells. The beta 6 cytoplasmic domain is composed of a 41 amino acid region that is highly conserved among integrin beta subunits, and a unique 11 amino acid carboxy terminal extension. The 11 amino acid extension was not required for localization to focal contacts; in fact, its removal appeared to increase receptor localization. However, removal of any of the 3 conserved regions previously identified as important for the localization of beta 1 integrins to focal contacts (Reszka, et al., 1992, J. Cell Biol. 117:1321-30) eliminated recruitment of beta 6 to focal contacts. These data suggest that, as with the integrin beta 1 subunit, multiple regions within the first 41 amino acids of the beta 6 cytoplasmic domain are necessary for recruitment of alpha v beta 6 to focal contacts. However, the unique 11 amino acid carboxy terminus of beta 6 is not required for this recruitment, and may actually play a negative regulatory role.

    View details for Web of Science ID A1994NV06500002

    View details for PubMedID 8081887

  • UPPER AND MIDDLE LOBE BRONCHOALVEOLAR LAVAGE TO DIAGNOSE PNEUMOCYSTIS-CARINII PNEUMONIA AMERICAN REVIEW OF RESPIRATORY DISEASE Yung, R. C., Weinacker, A. B., Steiger, D. J., Miller, T. R., Stern, E. J., SALMON, C. J., Chernoff, D. N., LUISTRO, M. G., Kuntz, S., Golden, J. A. 1993; 148 (6): 1563-1566

    Abstract

    Pneumocystis carinii pneumonia (PCP) remains the most common lethal opportunistic pulmonary infection in patients infected with the human immunodeficiency virus (HIV). Although the use of prophylactic inhaled pentamidine has effectively reduced the frequency of primary and recurrent episodes of PCP, the aerosolization of pentamidine may have altered the localization of active PCP, resulting in more upper lobe disease. The distribution of disease may have also affected the diagnostic accuracy of standard bronchoalveolar lavage of the middle lobe, with a reduction in sensitivity from about 90 to 65%. In retrospective surveys of patients from our institution, Steiger and Fahy found that pooled multiple-lobe radiographic site-directed bronchoalveolar lavage resulted in diagnostic sensitivities of 91 and 100%, respectively. We performed a follow-up prospective study of 38 consecutive patients on aerosolized pentamidine in whom we lavaged both the middle lobe and an upper lobe. We found that bilobar lavage including routine lavage of an upper lobe increases the diagnostic sensitivity of bronchoalveolar lavage alone to 95% compared with 65% if lavage is performed only in the middle lobe (p < 0.05). Radiographic studies demonstrate a concordant increase in exclusive or predominant upper lobe disease in patients on aerosolized pentamidine, but our results indicate that PCP is recovered more frequently from the upper lobe regardless of the radiographic appearance. We conclude that all patients on prophylactic inhaled pentamidine should undergo bilobar lavage with the inclusion of an upper lobe in the initial evaluation of possible PCP. The diagnostic sensitivity of 95% makes bilobar bronchoalveolar lavage an acceptable sole initial diagnostic modality without the need for initial transbronchial lung biopsy.

    View details for Web of Science ID A1993NG37900022

    View details for PubMedID 8256901