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2.
Intensive Care Med ; 2020 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-32206845

RESUMO

PURPOSE: Previous studies assessing impact of acute respiratory distress syndrome (ARDS) on mortality have shown conflicting results. We sought to assess the independent association of ARDS with in-hospital mortality among intensive care unit (ICU) patients with sepsis. METHODS: We studied two prospective sepsis cohorts drawn from the Early Assessment of Renal and Lung Injury (EARLI; n = 474) and Validating Acute Lung Injury markers for Diagnosis (VALID; n = 337) cohorts. ARDS was defined by Berlin criteria. We used logistic regression to compare in-hospital mortality in patients with and without ARDS, controlling for baseline severity of illness. We also estimated attributable mortality, adjusted for illness severity by stratification. RESULTS: ARDS occurred in 195 EARLI patients (41%) and 99 VALID patients (29%). ARDS was independently associated with risk of hospital death in multivariate analysis, even after controlling for severity of illness, as measured by APACHE II (odds ratio [OR] 1.65 (95% confidence interval [CI] 1.02, 2.67), p = 0.04 in EARLI; OR 2.12 (CI 1.16, 3.92), p = 0.02 in VALID). Patients with severe ARDS (P/F < 100) primarily drove this relationship. The attributable mortality of ARDS was 27% (CI 14%, 37%) in EARLI and 37% (CI 10%, 51%) in VALID. ARDS was independently associated with ICU mortality, hospital length of stay (LOS), ICU LOS, and ventilator-free days. CONCLUSIONS: Development of ARDS among ICU patients with sepsis confers increased risk of ICU and in-hospital mortality in addition to other important outcomes. Clinical trials targeting patients with severe ARDS will be best poised to detect measurable differences in these outcomes.

3.
Br J Pharmacol ; 2020 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-32133621

RESUMO

BACKGROUND AND PURPOSE: Lung oedema in association with suppressed fibrinolysis is a hallmark of lung injury. We aimed to test whether plasmin cleaves epithelial sodium channels (ENaC) to resolve lung oedema fluid. EXPERIMENTAL APPROACHES: Human lungs and airway acid-instilled mice were used for analysing fluid resolution. In silico prediction, mutagenesis, Xenopus oocytes, immunoblotting, voltage clamp, mass spectrometry, protein docking, and alveolar fluid clearance were combined for identifying plasmin specific cleavage sites and benefits. KEY RESULTS: Plasmin led to a marked increment in lung fluid resolution in both human lungs ex vivo and injured mice. Plasmin specifically activated αßγENaC channels in oocytes in a time-dependent manner. Deletion of four consensus proteolysis tracts (αΔ432-444, γΔ131-138, γΔ178-193, and γΔ410-422) eliminated plasmin-induced activation significantly. Further, immunoblotting assays identified 7 cleavage sites (K126, R135, K136, R153, K168, R178, K179) for plasmin to trim both furin-cleaved C-terminal fragments and full-length human γENaC proteins. In addition to confirming the 7 cleavage sites, 9 new sites (R122, R137, R138, K150, K170, R172, R180, K181, K189) in synthesized peptides were found to be cleaved by plasmin with mass spectrometry. These cleavage sites were located in the finger and the thumb, particularly the GRIP domain of human ENaC 3D model composed of two proteolytic centres for plasmin. Novel uncleaved sites beyond the GRIP domain in both α and γ subunits were identified to interrupt the plasmin cleavage-induced conformational change in ENaC channel complexes. Additionally, plasmin could regulate ENaC activity via the G protein signal. CONCLUSION AND IMPLICATIONS: We demonstrate that plasmin could cleave ENaC to benefit the blood-gas exchange by resolving oedema fluid as a potent fibrinolytic therapy for oedematous pulmonary diseases.

4.
Artigo em Inglês | MEDLINE | ID: mdl-32150460

RESUMO

Preventing, treating, and promoting recovery from critical illness due to pulmonary disease are foundational goals of the critical care community and the National Heart, Lung, and Blood Institute. Decades of clinical research in acute respiratory distress syndrome, acute respiratory failure, pneumonia, and sepsis have yielded improvements in supportive care, which have translated into improved patient outcomes. Novel therapeutics have largely failed to translate from promising pre-clinical findings into improved patient outcomes in late-phase clinical trials. Recent advances in personalized medicine, "big data", causal inference using observational data, novel clinical trial designs, pre-clinical disease modeling, and understanding recovery from acute illness promise to transform the methods of pulmonary and critical care clinical research. To assess the current state, research priorities, and future directions for adult pulmonary and critical care research, the NHLBI assembled a multidisciplinary working group of investigators. This working group identified recommendations for future research, including: (1) focusing on understanding the clinical, physiological, and biological underpinnings of heterogeneity in syndromes, diseases, and treatment-response with the goal of developing targeted, personalized interventions; (2) optimizing pre-clinical models by incorporating comorbidities, co-interventions, and organ support; (3) developing and applying novel clinical trial designs; and (4) advancing mechanistic understanding of injury and recovery in order to develop and test interventions targeted at achieving long-term improvements in the lives of patients and families. Specific areas of research are highlighted as especially promising for making advances in pneumonia, acute hypoxemic respiratory failure, and acute respiratory distress syndrome.

6.
Physiol Rev ; 100(3): 1065-1075, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32216698

RESUMO

Patients with hypertension, diabetes, coronary heart disease, cerebrovascular illness, chronic obstructive pulmonary disease, and kidney dysfunction have worse clinical outcomes when infected with SARS-CoV-2, for unknown reasons. The purpose of this review is to summarize the evidence for the existence of elevated plasmin(ogen) in COVID-19 patients with these comorbid conditions. Plasmin, and other proteases, may cleave a newly inserted furin site in the S protein of SARS-CoV-2, extracellularly, which increases its infectivity and virulence. Hyperfibrinolysis associated with plasmin leads to elevated D-dimer in severe patients. The plasmin(ogen) system may prove a promising therapeutic target for combating COVID-19.

7.
Artigo em Inglês | MEDLINE | ID: mdl-32109144

RESUMO

Recent research on extracellular vesicles (EVs) has provided new insights into pathogenesis and potential therapeutic options for acute respiratory distress syndrome (ARDS). EVs are membrane-bound anuclear structures which carry important inter-cellular communication mechanisms, allowing targeted transfer of diverse biologic cargo including protein, mRNA and microRNA among several different cell types. In this review, we discuss the important role EVs play in both inducing and attenuating inflammatory lung injury in ARDS as well as in sepsis, the most important clinical cause of ARDS. We discuss the translational challenges which need to be overcome before EVs can also be utilized as prognostic biomarkers in patients with ARDS and sepsis. We also consider how EVs may provide a platform for novel therapeutics in ARDS.

8.
Intensive Care Med ; 2020 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-32072303

RESUMO

BACKGROUND: Conducting research in critically-ill patient populations is challenging, and most randomized trials of critically-ill patients have not achieved pre-specified statistical thresholds to conclude that the intervention being investigated was beneficial. METHODS: In 2019, a diverse group of patient representatives, regulators from the USA and European Union, federal grant managers, industry representatives, clinical trialists, epidemiologists, and clinicians convened the First Critical Care Clinical Trialists (3CT) Workshop to discuss challenges and opportunities in conducting and assessing critical care trials. Herein, we present the advantages and disadvantages of available methodologies for clinical trial design, conduct, and analysis, and a series of recommendations to potentially improve future trials in critical care. CONCLUSION: The 3CT Workshop participants identified opportunities to improve critical care trials using strategies to optimize sample size calculations, account for patient and disease heterogeneity, increase the efficiency of trial conduct, maximize the use of trial data, and to refine and standardize the collection of patient-centered and patient-informed outcome measures beyond mortality.

10.
Lancet Respir Med ; 8(3): 247-257, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31948926

RESUMO

BACKGROUND: Using latent class analysis (LCA) in five randomised controlled trial (RCT) cohorts, two distinct phenotypes of acute respiratory distress syndrome (ARDS) have been identified: hypoinflammatory and hyperinflammatory. The phenotypes are associated with differential outcomes and treatment response. The objective of this study was to develop parsimonious models for phenotype identification that could be accurate and feasible to use in the clinical setting. METHODS: In this retrospective study, three RCT cohorts from the National Lung, Heart, and Blood Institute ARDS Network (ARMA, ALVEOLI, and FACTT) were used as the derivation dataset (n=2022), from which the machine learning and logistic regression classifer models were derived, and a fourth (SAILS; n=715) from the same network was used as the validation test set. LCA-derived phenotypes in all of these cohorts served as the reference standard. Machine-learning algorithms (random forest, bootstrapped aggregating, and least absolute shrinkage and selection operator) were used to select a maximum of six important classifier variables, which were then used to develop nested logistic regression models. Only cases with complete biomarker data in the derivation dataset were used for variable selection. The best logistic regression models based on parsimony and predictive accuracy were then evaluated in the validation test set. Finally, the models' prognostic validity was tested in two external ARDS clinical trial datasets (START and HARP-2) by assessing mortality at days 28, 60, and 90 and ventilator-free days to day 28. FINDINGS: The six most important classifier variables were interleukin (IL)-8, IL-6, protein C, soluble tumour necrosis factor receptor 1, bicarbonate, and vasopressor use. From the nested models, three-variable (IL-8, bicarbonate, and protein C) and four-variable (3-variable plus vasopressor use) models were adjudicated to be the best performing. In the validation test set, both models showed good accuracy (AUC 0·94 [95% CI 0·92-0·95] for the three-variable model and 0·95 [95% CI 0·93-0·96] for the four-variable model) against LCA classifications. As with LCA-derived phenotypes, the hyperinflammatory phenotype as identified by the classifier model was associated with higher mortality at day 90 (87 [39%] of 223 patients vs 112 [23%] of 492 patients; p<0·0001) and fewer ventilator-free days (median 14 days [IQR 0-22] vs 22 days [0-25]; p<0·0001). In the external validation datasets, three-variable models developed in the derivation dataset identified two phenotypes with distinct clinical features and outcomes consistent with previous findings, including differential survival with simvastatin versus placebo in HARP-2 (p=0·023 for survival at 28 days). INTERPRETATION: ARDS phenotypes can be accurately identified with parsimonious classifier models using three or four variables. Pending the development of real-time testing for key biomarkers and prospective validation, these models could facilitate identification of ARDS phenotypes to enable their application in clinical trials and practice. FUNDING: National Institutes of Health.

11.
Am J Respir Crit Care Med ; 201(7): 840-847, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-31968182

RESUMO

Rationale: Gender gaps exist in academic leadership positions in critical care. Peer-reviewed publications are crucial to career advancement, and yet little is known regarding gender differences in authorship of critical care research.Objectives: To evaluate gender differences in authorship of critical care literature.Methods: We used a validated database of author gender to analyze authorship of critical care articles indexed in PubMed between 2008 and 2018 in 40 frequently cited journals. High-impact journals were defined as those in the top 5% of all journals. We used mixed-effects logistic regression to evaluate the association of senior author gender with first and middle author gender, as well as association of first author gender with journal impact factor.Measurements and Main Results: Among 18,483 studies, 30.8% had female first authors, and 19.5% had female senior authors. Female authorship rose slightly over the last decade (average annual increases of 0.44% [P < 0.01] and 0.51% [P < 0.01] for female first and senior authors, respectively). When the senior author was female, the odds of female coauthorship rose substantially (first author adjusted odds ratio [aOR], 1.93; 95% confidence interval [CI], 1.71-2.17; middle author aOR, 1.48; 95% CI, 1.29-1.69). Female first authors had higher odds than men of publishing in lower-impact journals (aOR, 1.30; 95% CI, 1.16-1.45).Conclusions: Women comprise less than one-third of first authors and one-fourth of senior authors of critical care research, with minimal increase over the past decade. When the senior author was female, the odds of female coauthorship rose substantially. However, female first authors tend to publish in lower-impact journals. These findings may help explain the underrepresentation of women in critical care academic leadership positions and identify targets for improvement.

12.
Crit Care Med ; 48(2): 200-209, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31939788

RESUMO

OBJECTIVES: Early identification of sepsis is critical to improving patient outcomes. Impact of the new sepsis definition (Sepsis-3) on timing of recognition in the emergency department has not been evaluated. Our study objective was to compare time to meeting systemic inflammatory response syndrome (Sepsis-2) criteria, Sequential Organ Failure Assessment (Sepsis-3) criteria, and quick Sequential Organ Failure Assessment criteria using electronic health record data. DESIGN: Retrospective, observational study. SETTING: The emergency department at the University of California, San Francisco. PATIENTS: Emergency department encounters between June 2012 and December 2016 for patients greater than or equal to 18 years old with blood cultures ordered, IV antibiotic receipt, and identification with sepsis via systemic inflammatory response syndrome or Sequential Organ Failure Assessment within 72 hours of emergency department presentation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We analyzed timestamped electronic health record data from 16,612 encounters identified as sepsis by greater than or equal to 2 systemic inflammatory response syndrome criteria or a Sequential Organ Failure Assessment score greater than or equal to 2. The primary outcome was time from emergency department presentation to meeting greater than or equal to 2 systemic inflammatory response syndrome criteria, Sequential Organ Failure Assessment greater than or equal to 2, and/or greater than or equal to 2 quick Sequential Organ Failure Assessment criteria. There were 9,087 patients (54.7%) that met systemic inflammatory response syndrome-first a median of 26 minutes post-emergency department presentation (interquartile range, 0-109 min), with 83.1% meeting Sequential Organ Failure Assessment criteria a median of 118 minutes later (interquartile range, 44-401 min). There were 7,037 patients (42.3%) that met Sequential Organ Failure Assessment-first, a median of 113 minutes post-emergency department presentation (interquartile range, 60-251 min). Quick Sequential Organ Failure Assessment was met in 46.4% of patients a median of 351 minutes post-emergency department presentation (interquartile range, 67-1,165 min). Adjusted odds of in-hospital mortality were 39% greater in patients who met systemic inflammatory response syndrome-first compared with those who met Sequential Organ Failure Assessment-first (odds ratio, 1.39; 95% CI, 1.20-1.61). CONCLUSIONS: Systemic inflammatory response syndrome and Sequential Organ Failure Assessment initially identified distinct populations. Using systemic inflammatory response syndrome resulted in earlier electronic health record sepsis identification in greater than 50% of patients. Using Sequential Organ Failure Assessment alone may delay identification. Using systemic inflammatory response syndrome alone may lead to missed sepsis presenting as acute organ dysfunction. Thus, a combination of inflammatory (systemic inflammatory response syndrome) and organ dysfunction (Sequential Organ Failure Assessment) criteria may enhance timely electronic health record-based sepsis identification.

13.
Eur Respir J ; 55(1)2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31619475

RESUMO

Shorter peripheral blood leukocyte (PBL) telomere length (TL) has been associated with poor outcomes in various chronic lung diseases. Whether PBL-TL is associated with survival from critical illness was tested in this study.We analysed data from a prospective observational cohort study of 937 critically ill patients at Vanderbilt University Medical Center (VUMC). PBL-TL was measured using quantitative PCR of DNA isolated from PBLs. Findings were validated in an independent cohort of 394 critically ill patients with sepsis admitted to the University of California San Francisco (UCSF).In the VUMC cohort, shorter PBL-TL was associated with worse 90-day survival (adjusted hazard ratio (aHR) 1.3, 95% CI 1.1-1.6 per 1 kb TL decrease; p=0.004); in subgroup analyses, shorter PBL-TL was associated with worse 90-day survival for patients with sepsis (aHR 1.5, 95% CI 1.2-2.0 per 1 kb TL decrease; p=0.001), but not trauma. Although not associated with development of acute respiratory distress syndrome (ARDS), among ARDS subjects, shorter PBL-TL was associated with more severe ARDS (OR 1.7, 95% CI 1.2-2.5 per 1 kb TL decrease; p=0.006). The associations of PBL-TL with survival (adjusted HR 1.6, 95% CI 1.2-2.1 per 1 kb TL decrease; p=0.003) and risk for developing severe ARDS (OR 2.5, 95% CI 1.1-6.3 per 1 kb TL decrease; p=0.044) were validated in the UCSF cohort.Short PBL-TL is strongly associated with worse survival and more severe ARDS in critically ill patients, especially patients with sepsis. These findings suggest that telomere dysfunction may contribute to outcomes from critical illness.

14.
Am J Respir Crit Care Med ; 201(1): 47-56, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31487195

RESUMO

Rationale: Acute respiratory distress syndrome (ARDS) lacks known causal biomarkers. Plasma concentrations of sRAGE (soluble receptor for advanced glycation end products) strongly associate with ARDS risk. However, whether plasma sRAGE contributes causally to ARDS remains unknown.Objectives: Evaluate plasma sRAGE as a causal intermediate in ARDS by Mendelian randomization (MR), a statistical method to infer causality using observational data.Methods: We measured early plasma sRAGE in two critically ill populations with sepsis. The cohorts were whole-genome genotyped and phenotyped for ARDS. To select validated genetic instruments for MR, we regressed plasma sRAGE on genome-wide genotypes in both cohorts. The causal effect of plasma sRAGE on ARDS was inferred using the top variants with significant associations in both populations (P < 0.01, R2 > 0.02). We applied the inverse variance-weighted method to obtain consistent estimates of the causal effect of plasma sRAGE on ARDS risk.Measurements and Main Results: There were 393 European and 266 African ancestry patients in the first cohort and 843 European ancestry patients in the second cohort. Plasma sRAGE was strongly associated with ARDS risk in both populations (odds ratio, 1.86; 95% confidence interval [1.54-2.25]; 2.56 [2.14-3.06] per log increase). Using genetic instruments common to both populations, plasma sRAGE had a consistent causal effect on ARDS risk with a ß estimate of 0.50 (95% confidence interval [0.09-0.91] per log increase).Conclusions: Plasma sRAGE is genetically regulated during sepsis, and MR analysis indicates that increased plasma sRAGE leads to increased ARDS risk, suggesting plasma sRAGE acts as a causal intermediate in sepsis-related ARDS.

15.
Crit Care Med ; 48(1): e78, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31833991
16.
Crit Care Med ; 2019 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-31794436

RESUMO

OBJECTIVES: Early identification of sepsis is critical to improving patient outcomes. Impact of the new sepsis definition (Sepsis-3) on timing of recognition in the emergency department has not been evaluated. Our study objective was to compare time to meeting systemic inflammatory response syndrome (Sepsis-2) criteria, Sequential Organ Failure Assessment (Sepsis-3) criteria, and quick Sequential Organ Failure Assessment criteria using electronic health record data. DESIGN: Retrospective, observational study. SETTING: The emergency department at the University of California, San Francisco. PATIENTS: Emergency department encounters between June 2012 and December 2016 for patients greater than or equal to 18 years old with blood cultures ordered, IV antibiotic receipt, and identification with sepsis via systemic inflammatory response syndrome or Sequential Organ Failure Assessment within 72 hours of emergency department presentation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We analyzed timestamped electronic health record data from 16,612 encounters identified as sepsis by greater than or equal to 2 systemic inflammatory response syndrome criteria or a Sequential Organ Failure Assessment score greater than or equal to 2. The primary outcome was time from emergency department presentation to meeting greater than or equal to 2 systemic inflammatory response syndrome criteria, Sequential Organ Failure Assessment greater than or equal to 2, and/or greater than or equal to 2 quick Sequential Organ Failure Assessment criteria. There were 9,087 patients (54.7%) that met systemic inflammatory response syndrome-first a median of 26 minutes post-emergency department presentation (interquartile range, 0-109 min), with 83.1% meeting Sequential Organ Failure Assessment criteria a median of 118 minutes later (interquartile range, 44-401 min). There were 7,037 patients (42.3%) that met Sequential Organ Failure Assessment-first, a median of 113 minutes post-emergency department presentation (interquartile range, 60-251 min). Quick Sequential Organ Failure Assessment was met in 46.4% of patients a median of 351 minutes post-emergency department presentation (interquartile range, 67-1,165 min). Adjusted odds of in-hospital mortality were 39% greater in patients who met systemic inflammatory response syndrome-first compared with those who met Sequential Organ Failure Assessment-first (odds ratio, 1.39; 95% CI, 1.20-1.61). CONCLUSIONS: Systemic inflammatory response syndrome and Sequential Organ Failure Assessment initially identified distinct populations. Using systemic inflammatory response syndrome resulted in earlier electronic health record sepsis identification in greater than 50% of patients. Using Sequential Organ Failure Assessment alone may delay identification. Using systemic inflammatory response syndrome alone may lead to missed sepsis presenting as acute organ dysfunction. Thus, a combination of inflammatory (systemic inflammatory response syndrome) and organ dysfunction (Sequential Organ Failure Assessment) criteria may enhance timely electronic health record-based sepsis identification.

17.
Crit Care ; 23(1): 400, 2019 12 09.
Artigo em Inglês | MEDLINE | ID: mdl-31818332

RESUMO

BACKGROUND: Enrichment strategies improve therapeutic targeting and trial efficiency, but enrichment factors for sepsis trials are lacking. We determined whether concentrations of soluble tumor necrosis factor receptor-1 (sTNFR1), interleukin-8 (IL8), and angiopoietin-2 (Ang2) could identify sepsis patients at higher mortality risk and serve as prognostic enrichment factors. METHODS: In a multicenter prospective cohort study of 400 critically ill septic patients, we derived and validated thresholds for each marker and expressed prognostic enrichment using risk differences (RD) of 30-day mortality as predictive values. We then used decision curve analysis to simulate the prognostic enrichment of each marker and compare different prognostic enrichment strategies. MEASUREMENTS AND MAIN RESULTS: An admission sTNFR1 concentration > 8861 pg/ml identified patients with increased mortality in both the derivation (RD 21.6%) and validation (RD 17.8%) populations. Among immunocompetent patients, an IL8 concentration > 94 pg/ml identified patients with increased mortality in both the derivation (RD 17.7%) and validation (RD 27.0%) populations. An Ang2 level > 9761 pg/ml identified patients at 21.3% and 12.3% increased risk of mortality in the derivation and validation populations, respectively. Using sTNFR1 or IL8 to select high-risk patients improved clinical trial power and efficiency compared to selecting patients with septic shock. Ang2 did not outperform septic shock as an enrichment factor. CONCLUSIONS: Thresholds for sTNFR1 and IL8 consistently identified sepsis patients with higher mortality risk and may have utility for prognostic enrichment in sepsis trials.

18.
PLoS One ; 14(11): e0225601, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31770424

RESUMO

BACKGROUND: In acute kidney injury (AKI), medication dosing based on Cockcroft-Gault creatinine clearance (CrCl) or Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) estimated glomerular filtration rates (eGFR) are not valid when serum creatinine (SCr) is not in steady state. The aim of this study was to determine the impact of a kinetic estimating equation that incorporates fluctuations in SCrs on drug dosing in critically ill patients. METHODS: We used data from participants enrolled in the NIH Acute Respiratory Distress Syndrome Network Fluid and Catheters Treatment Trial to simulate drug dosing category changes with the application of the kinetic estimating equation developed by Chen. We evaluated whether kinetic estimation of renal function would change medication dosing categories (≥60, 30-59, 15-29, and <15mL/min) compared with the use of CrCl or CKD-EPI eGFR. RESULTS: The use of kinetic CrCl and CKD-EPI eGFR resulted in a large enough change in estimated renal function to require medication dosing recategorization in 19.3% [95 CI 16.8%-21.9%] and 23.4% [95% CI 20.7%-26.1%] of participants, respectively. As expected, recategorization occurred more frequently in those with AKI. When we examined individual days for those with AKI, dosing discordance was observed in 8.5% of total days using the CG CrCl and 10.2% of total days using the CKD-EPI equation compared with the kinetic counterparts. CONCLUSION: In a critically ill population, use of kinetic estimates of renal function impacted medication dosing in a substantial proportion of AKI participants. Use of kinetic estimates in clinical practice should lower the incidence of medication toxicity as well as avoid subtherapeutic dosing during renal recovery.

19.
Theranostics ; 9(26): 8155-8170, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31754387

RESUMO

Lung epithelial sodium channel (ENaC) encoded by Scnn1 genes is essential for maintaining transepithelial salt and fluid homeostasis in the airway and the lung. Compared to α, ß, and γ subunits, the role of respiratory δ-ENaC has not been studied in vivo due to the lack of animal models. Methods: We characterized full-length human δ802-ENaC expressed in both Xenopus oocytes and humanized transgenic mice. AT2 proliferation and differentiation in 3D organoids were analysed with FACS and a confocal microscope. Both two-electrode voltage clamp and Ussing chamber systems were applied to digitize δ802-ENaC channel activity. Immunoblotting was utilized to analyse δ802-ENaC protein. Transcripts of individual ENaC subunits in human lung tissues were quantitated with qPCR. Results: The results indicate that δ802-ENaC functions as an amiloride-inhibitable Na+ channel. Inhibitory peptide α-13 distinguishes δ802- from α-type ENaC channels. Modified proteolysis of γ-ENaC by plasmin and aprotinin did not alter the inhibition of amiloride and α-13 peptide. Expression of δ802-ENaC at the apical membrane of respiratory epithelium was detected with biophysical features similar to those of heterologously expressed channels in oocytes. δ802-ENaC regulated alveologenesis through facilitating the proliferation of alveolar type 2 epithelial cells. Conclusion: The humanized mouse line conditionally expressing human δ802-ENaC is a novel model for studying the expression and function of this protein in vivo .

20.
Am J Physiol Lung Cell Mol Physiol ; 317(5): L717-L736, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31509438

RESUMO

Pneumonia is responsible for more deaths in the United States than any other infectious disease. Severe pneumonia is a common cause of acute respiratory failure and acute respiratory distress syndrome (ARDS). Despite the introduction of effective antibiotics and intensive supportive care in the 20th century, death rates from community-acquired pneumonia among patients in the intensive care unit remain as high as 35%. Beyond antimicrobial treatment, no targeted molecular therapies have yet proven effective, highlighting the need for additional research. Despite some limitations, small animal models of pneumonia and the mechanistic insights they produce are likely to continue to play an important role in generating new therapeutic targets. Here we describe the development of an innovative mouse model of pneumococcal pneumonia developed for enhanced clinical relevance. We first reviewed the literature of small animal models of bacterial pneumonia that incorporated antibiotics. We then did a series of experiments in mice in which we systematically varied the pneumococcal inoculum and the timing of antibiotics while measuring systemic and lung-specific end points, producing a range of models that mirrors the spectrum of pneumococcal lung disease in patients, from mild self-resolving infection to severe pneumonia refractory to antibiotics. A delay in antibiotic treatment resulted in ongoing inflammation and renal and hepatic dysfunction despite effective bacterial killing. The addition of fluid resuscitation to the model improved renal function but worsened the severity of lung injury based on direct measurements of pulmonary edema and lung compliance, analogous to patients with pneumonia and sepsis who develop ARDS following fluid administration.

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