Cystic fibrosis (CF) is associated with chronic pulmonary inflammation and progressive lung dysfunction, possibly associated with the formation of neutrophil myeloperoxidase (MPO)-derived oxidants. Expectorated sputum specimens from adult CF patients were analyzed for MPO characteristic protein modifications and found to contain large amounts of active MPO as well as high levels of protein-associated 3-chlorotyrosine and 3,3'-dityrosine, products that result from MPO activity, compared with expectorated sputum from non-CF subjects. Sputum levels of nitrite (NO(2)(-)) and nitrate (NO(3)(-)), indicating local production of nitric oxide (NO. ), were not elevated but in fact were slightly reduced in CF. However, there was a slight increase in protein-associated 3-nitrotyrosine in CF sputum compared with controls, reflecting the formation of reactive nitrogen intermediates, possibly through MPO-catalyzed oxidation of NO(2)(-). CF sputum MPO was found to contribute to oxidant-mediated cytotoxicity toward cultured tracheobronchial epithelial cells; however, peroxidase-dependent protein oxidation occurred primarily within sputum proteins, suggesting scavenging of MPO-derived oxidants by CF mucus and perhaps formation of secondary cytotoxic products within CF sputum. Our findings demonstrate the formation of MPO-derived oxidizing and possibly nitrating species within the respiratory tract of subjects with CF, which collectively may contribute to bronchial injury and respiratory failure in CF.
Methods: We evaluated patients in annual intervals before and after bundle implementation in March 2013. We evaluated bundle compliance and compared outcome measures across groups with multivariable logistic regression. Because of their perceived risk for iatrogenic fluid overload, we also evaluated patients with a history of heart failure and/or chronic kidney disease.Measurements and Main Results: We identified 18,122 patients with sepsis and intermediate lactate values, including 36.1% treated after implementation. Full bundle compliance increased from 32.2% in 2011 to 44.9% after bundle implementation (P , 0.01). Hospital mortality was 8.8% in 2011, 9.3% in 2012, and 7.9% in 2013 (P = 0.02). Treatment after bundle implementation was associated with an adjusted hospital mortality odds ratio of 0.81 (95% confidence interval, 0.66-0.99; P = 0.04). Decreased hospital mortality was observed primarily in patients with a heart failure and/or kidney disease history (P , 0.01) compared with patients without this history (P . 0.40). This corresponded to notable changes in the volume of fluid resuscitation in patients with heart failure and/or kidney disease after implementation.Conclusions: Multicenter implementation of a treatment bundle for patients with sepsis and intermediate lactate values improved bundle compliance and was associated with decreased hospital mortality. These decreases were mediated by improved mortality and increased fluid administration among patients with a history of heart failure and/or chronic kidney disease.
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