Browsing by Author "Palmer, Scott M."

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    Development and Validation of Primary Graft Dysfunction Predictive Algorithm for Lung Transplant Candidates
    (Elsevier, 2024) Diamond, Joshua M.; Anderson, Michaela R.; Cantu, Edward; Clausen, Emily S.; Shashaty, Michael G. S.; Kalman, Laurel; Oyster, Michelle; Crespo, Maria M.; Bermudez, Christian A.; Benvenuto, Luke; Palmer, Scott M.; Snyder, Laurie D.; Hartwig, Matthew G.; Wille, Keith; Hage, Chadi; McDyer, John F.; Merlo, Christian A.; Shah, Pali D.; Orens, Jonathan B.; Dhillon, Ghundeep S.; Lama, Vibha N.; Patel, Mrunal G.; Singer, Jonathan P.; Hachem, Ramsey R.; Michelson, Andrew P.; Hsu, Jesse; Localio, A. Russell; Christie, Jason D.; Medicine, School of Medicine
    Background: Primary graft dysfunction (PGD) is the leading cause of early morbidity and mortality after lung transplantation. Accurate prediction of PGD risk could inform donor approaches and perioperative care planning. We sought to develop a clinically useful, generalizable PGD prediction model to aid in transplant decision-making. Methods: We derived a predictive model in a prospective cohort study of subjects from 2012 to 2018, followed by a single-center external validation. We used regularized (lasso) logistic regression to evaluate the predictive ability of clinically available PGD predictors and developed a user interface for clinical application. Using decision curve analysis, we quantified the net benefit of the model across a range of PGD risk thresholds and assessed model calibration and discrimination. Results: The PGD predictive model included distance from donor hospital to recipient transplant center, recipient age, predicted total lung capacity, lung allocation score (LAS), body mass index, pulmonary artery mean pressure, sex, and indication for transplant; donor age, sex, mechanism of death, and donor smoking status; and interaction terms for LAS and donor distance. The interface allows for real-time assessment of PGD risk for any donor/recipient combination. The model offers decision-making net benefit in the PGD risk range of 10% to 75% in the derivation centers and 2% to 10% in the validation cohort, a range incorporating the incidence in that cohort. Conclusion: We developed a clinically useful PGD predictive algorithm across a range of PGD risk thresholds to support transplant decision-making, posttransplant care, and enrich samples for PGD treatment trials.
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    Elevated Plasma Angiopoietin-2 Levels and Primary Graft Dysfunction after Lung Transplantation
    (Public Library of Science, 2012) Diamond, Joshua M.; Porteous, Mary K.; Cantu, Edward; Meyer, Nuala J.; Shah, Rupal J.; Lederer, David J.; Kawut, Steven M.; Lee, James; Bellamy, Scarlett L.; Palmer, Scott M.; Lama, Vibha N.; Bhorade, Sangeeta M.; Crespo, Maria; Demissie, Ejigayehu; Wille, Keith; Orens, Jonathan; Shah, Pali D.; Weinacker, Ann; Weill, David; Arcasoy, Selim; Wilkes, David S.; Ware, Lorraine B.; Christie, Jason D.; Lung Transplant Outcomes Group; Medicine, School of Medicine
    Introduction: 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. Methods: 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). Results: 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). Conclusions: 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.
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    Preoperative plasma club (clara) cell secretory protein levels are associated with primary graft dysfunction after lung transplantation
    (Wiley Blackwell (Blackwell Publishing), 2014-02) Shah, Rupal J.; Wickersham, Nancy; Lederer, David J.; Palmer, Scott M.; Cantu, Edward; Diamond, Joshua M.; Kawut, Steven M.; Lama, Vibha N.; Bhorade, Sangeeta; Crespo, Maria; Demissie, Ejigayehu; Sonett, Joshua; Wille, Keith; Orens, Jonathan; Weinacker, Ann; Shah, Pali; Arcasoy, Selim; Wilkes, David S.; Christie, Jason D.; Ware, Lorraine B.; Department of Medicine, IU School of Medicine
    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.
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    Quantitative Evidence for Revising the Definition of Primary Graft Dysfunction after Lung Transplant
    (American Thoracic Society, 2018-01-15) Cantu, Edward; Diamond, Joshua M.; Suzuki, Yoshikazu; Lasky, Jared; Schaufler, Christian; Lim, Brian; Shah, Rupal; Porteous, Mary; Lederer, David J.; Kawut, Steven M.; Palmer, Scott M.; Snyder, Laurie D.; Hartwig, Matthew G.; Lama, Vibha N.; Bhorade, Sangeeta; Bermudez, Christian; Crespo, Maria; McDyer, John; Wille, Keith; Orens, Jonathan; Shah, Pali D.; Weinacker, Ann; Weill, David; Wilkes, David; Roe, David; Hage, Chadi; Ware, Lorraine B.; Bellamy, Scarlett L.; Christie, Jason D.; Medicine, School of Medicine
    RATIONALE: Primary graft dysfunction (PGD) is a form of acute lung injury that occurs after lung transplantation. The definition of PGD was standardized in 2005. Since that time, clinical practice has evolved, and this definition is increasingly used as a primary endpoint for clinical trials; therefore, validation is warranted. OBJECTIVES: We sought to determine whether refinements to the 2005 consensus definition could further improve construct validity. METHODS: Data from the Lung Transplant Outcomes Group multicenter cohort were used to compare variations on the PGD definition, including alternate oxygenation thresholds, inclusion of additional severity groups, and effects of procedure type and mechanical ventilation. Convergent and divergent validity were compared for mortality prediction and concurrent lung injury biomarker discrimination. MEASUREMENTS AND MAIN RESULTS: A total of 1,179 subjects from 10 centers were enrolled from 2007 to 2012. Median length of follow-up was 4 years (interquartile range = 2.4-5.9). No mortality differences were noted between no PGD (grade 0) and mild PGD (grade 1). Significantly better mortality discrimination was evident for all definitions using later time points (48, 72, or 48-72 hours; P < 0.001). Biomarker divergent discrimination was superior when collapsing grades 0 and 1. Additional severity grades, use of mechanical ventilation, and transplant procedure type had minimal or no effect on mortality or biomarker discrimination. CONCLUSIONS: The PGD consensus definition can be simplified by combining lower PGD grades. Construct validity of grading was present regardless of transplant procedure type or use of mechanical ventilation. Additional severity categories had minimal impact on mortality or biomarker discrimination.
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    The relationship between plasma lipid peroxidation products and primary graft dysfunction after lung transplantation is modified by donor smoking and reperfusion hyperoxia
    (Elsevier, 2016-04) Diamond, Joshua M.; Porteous, Mary K.; Roberts, L. Jackson; Wickersham, Nancy; Rushefski, Melanie; Kawut, Steven M.; Shah, Rupal J.; Cantu, Edward; Lederer, David J.; Chatterjee, Shampa; Lama, Vibha N.; Bhorade, Sangeeta; Crespo, Maria; McDyer, John; Wille, Keith; Orens, Jonathan; Weinacker, Ann; Arcasoy, Selim; Shah, Pali D.; Wilkes, David S.; Hage, Chadi; Palmer, Scott M.; Snyder, Laurie; Calfee, Carolyn S.; Ware, Lorraine B.; Christie, Jason D.; Medicine, School of Medicine
    BACKGROUND: 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. METHODS: 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). RESULTS: 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. CONCLUSIONS: 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.
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    The Impact of Donor Smoking on Primary Graft Dysfunction and Mortality after Lung Transplantation
    (American Thoracic Society, 2024) Diamond, Joshua M.; Cantu, Edward; Calfee, Carolyn S.; Anderson, Michaela R.; Clausen, Emily S.; Shashaty, Michael G. S.; Courtwright, Andrew M.; Kalman, Laurel; Oyster, Michelle; Crespo, Maria M.; Bermudez, Christian A.; Benvenuto, Luke; Palmer, Scott M.; Snyder, Laurie D.; Hartwig, Matthew G.; Todd, Jamie L.; Wille, Keith; Hage, Chadi; McDyer, John F.; Merlo, Christian A.; Shah, Pali D.; Orens, Jonathan B.; Dhillon, Gundeep S.; Weinacker, Ann B.; Lama, Vibha N.; Patel, Mrunal G.; Singer, Jonathan P.; Hsu, Jesse; Localio, A. Russell; Christie, Jason D.; Medicine, School of Medicine
    Rationale: Primary graft dysfunction (PGD) is the leading cause of early morbidity and mortality after lung transplantation. Prior studies implicated proxy-defined donor smoking as a risk factor for PGD and mortality. Objectives: We aimed to more accurately assess the impact of donor smoke exposure on PGD and mortality using quantitative smoke exposure biomarkers. Methods: We performed a multicenter prospective cohort study of lung transplant recipients enrolled in the Lung Transplant Outcomes Group cohort between 2012 and 2018. PGD was defined as grade 3 at 48 or 72 hours after lung reperfusion. Donor smoking was defined using accepted thresholds of urinary biomarkers of nicotine exposure (cotinine) and tobacco-specific nitrosamine (4-[methylnitrosamino]-1-[3-pyridyl]-1-butanol [NNAL]) in addition to clinical history. The donor smoking–PGD association was assessed using logistic regression, and survival analysis was performed using inverse probability of exposure weighting according to smoking category. Measurements and Main Results: Active donor smoking prevalence varied by definition, with 34–43% based on urinary cotinine, 28% by urinary NNAL, and 37% by clinical documentation. The standardized risk of PGD associated with active donor smoking was higher across all definitions, with an absolute risk increase of 11.5% (95% confidence interval [CI], 3.8% to 19.2%) by urinary cotinine, 5.7% (95% CI, −3.4% to 14.9%) by urinary NNAL, and 6.5% (95% CI, −2.8% to 15.8%) defined clinically. Donor smoking was not associated with differential post–lung transplant survival using any definition. Conclusions: Donor smoking associates with a modest increase in PGD risk but not with increased recipient mortality. Use of lungs from smokers is likely safe and may increase lung donor availability.