Shaver discusses the study by M.C. McKelvey and colleagues on the role of cathepsin S in triggering neutrophilic inflammation during ARDS. The authors use BAL samples from patients with ARDS to show ...clinical relevance of elevated cathepsin S. Patients with ARDS have elevated cathepsin S levels and activity and lower levels of its inhibitor cystatin SN in bronchoalveolar lavage. Patients with both pulmonary and nonpulmonary ARDS have significant changes in cathepsin S and cystatin SN, suggesting that this pathway could be of broad importance across the ARDS population. These observations are coupled with a series of elegant mechanistic studies in mouse models of acute lung injury to show that cathepsin S augments lung inflammation in vivo. The authors demonstrate that interruption of cathepsin S pathways attenuates neutrophilic inflammation and acute lung injury in mice.
Thousands of patients with end-stage kidney, liver, heart, and lung disease die each year while awaiting availability of a suitable organ for transplantation.1 There are several potential approaches ...to increase the availability of organs for transplantation, including improved organ preservation, development of techniques to facilitate donation after circulatory death, and increased public awareness of the utility of organ donation. Control samples showed that these findings were not present after kidney ischaemia-reperfusion or after transplantation of pig kidneys into other pigs.5 Using state-of-the-art spatial techniques, the authors show that the transcriptional immune activation was enriched in the glomeruli rather than in tubulointerstitial areas of interest. ...Loupy and colleagues’ study did not assess the recipients’ systemic immune responses other than quantifying immune cell and antibody deposition.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Increased endothelial permeability is central to the pathogenesis of sepsis and leads to organ dysfunction and death but the endogenous mechanisms that drive increased endothelial permeability are ...not completely understood. We previously reported that cell-free hemoglobin (CFH), elevated in 80% of patients with sepsis, increases lung microvascular permeability in an ex vivo human lung model and cultured endothelial cells. In this study, we augmented a murine model of polymicrobial sepsis with elevated circulating CFH to test the hypothesis that CFH increases microvascular endothelial permeability by inducing endothelial apoptosis. Mice were treated with an intraperitoneal injection of cecal slurry with or without a single intravenous injection of CFH. Severity of illness, mortality, systemic and lung inflammation, endothelial injury and dysfunction and lung apoptosis were measured at selected time points. We found that CFH added to CS increased sepsis mortality, plasma inflammatory cytokines as well as lung apoptosis, edema and inflammation without affecting large vessel reactivity or vascular injury marker concentrations. These results suggest that CFH is an endogenous mediator of increased endothelial permeability and apoptosis in sepsis and may be a promising therapeutic target.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background Direct (pulmonary) and indirect (extrapulmonary) ARDS are distinct syndromes with important pathophysiologic differences. The goal of this study was to determine whether clinical ...characteristics and predictors of mortality differ between direct or indirect ARDS. Methods This retrospective observational cohort study included 417 patients with ARDS. Each patient was classified as having direct (pneumonia or aspiration, n = 250) or indirect (nonpulmonary sepsis or pancreatitis, n = 167) ARDS. Results Patients with direct ARDS had higher lung injury scores (3.0 vs 2.8; P < .001), lower Simplified Acute Physiology Score II scores (51 vs 62; P < .001), lower Acute Physiology and Chronic Health Evaluation II scores (27 vs 30; P < .001), and fewer nonpulmonary organ failures (1 vs 2; P < .001) compared with patients with indirect ARDS. Hospital mortality was similar (28% vs 31%). In patients with direct ARDS, age (OR, 1.29 per 10 years; P = .01; test for interaction, P = .03), lung injury scores (OR, 2.29 per point; P = .001; test for interaction, P = .058), and number of nonpulmonary organ failures (OR, 1.67; P = .01) were independent risk factors for increased hospital mortality. Preexisting diabetes mellitus was an independent risk factor for reduced hospital mortality (OR, 0.47; P = .04; test for interaction, P = .02). In indirect ARDS, only the number of organ failures was an independent predictor of mortality (OR, 2.08; P < .001). Conclusions Despite lower severity of illness and fewer organ failures, patients with direct ARDS had mortality rates similar to patients with indirect ARDS. Factors previously associated with mortality during ARDS were only associated with mortality in direct ARDS. These findings suggest that direct and indirect ARDS have distinct features that may differentially affect risk prediction and clinical outcomes.
Calabrese and Shaver discuss a study by Keller and colleagues whether the quantification of dd-cfDNA could predict patients at the highest risk for the development of s chronic lung allograft ...dysfunction (CLAD) after acute cellular rejection (ACR). ACR is a reversible T cell's mediated perivascular injury to the lung allograft that is diagnosed by transbronchial biopsy and graded based on the degree of mononuclear cell infiltration. ACR is a risk factor for BOS; however, BOS does not develop in all patients with ACR. They identified that ACR conferred a nearly threefold increased risk for CLAD independent of ACR grade. Notably, this risk was greater for the development of RAS than for BOS. These findings validate ACR as an important clinical syndrome and patient-centered outcome.
The acute respiratory distress syndrome (ARDS) is a heterogeneous group of illnesses affecting the pulmonary parenchyma with acute onset bilateral inflammatory pulmonary infiltrates with associated ...hypoxemia. ARDS occurs after 2 major types of pulmonary injury: direct lung injury affecting the lung epithelium or indirect lung injury disrupting the vascular endothelium. Greater understanding of the differences between direct and indirect lung injury may refine the classification of patients with ARDS and lead to development of new therapeutics targeted at specific subpopulations of patients with ARDS.
Traditional measures of ARDS severity such as Pao2/Fio2 may not reliably predict clinical outcomes. The oxygenation index (OI Fio2 × mean airway pressure × 100)/Pao2) may more accurately reflect ARDS ...severity but requires arterial blood gas measurement. We hypothesized that the oxygenation saturation index (OSI Fio2 × mean airway pressure × 100)/oxygen saturation by pulse oximetry (Spo2)) is a reliable noninvasive surrogate for the OI that is associated with hospital mortality and ventilator-free days (VFDs) in patients with ARDS.
Critically ill patients enrolled in a prospective cohort study were eligible if they developed ARDS (Berlin criteria) during the first 4 ICU days and had mean airway pressure, Spo2/Fio2, and Pao2/Fio2 values recorded on the first day of ARDS (N = 329). The highest mean airway pressure and lowest Spo2/Fio2 and Pao2/Fio2 values were used to calculate OI and OSI. The association between OI or OSI and hospital mortality or VFD was analyzed by using logistic regression and linear regression, respectively. The area under the receiver-operating characteristic curve (AUC) for mortality was compared among OI, OSI, Spo2/Fio2, Pao2/Fio2, and Acute Physiology and Chronic Health Evaluation II scores.
OI and OSI were strongly correlated (rho = 0.862; P < .001). OSI was independently associated with hospital mortality (OR per 5-point increase in OSI, 1.228 95% CI, 1.056-1.429; P = .008). OI and OSI were each associated with a reduction in VFD (OI, P = .023; OSI, P = .005). The AUC for mortality prediction was greatest for Acute Physiology and Chronic Health Evaluation II scores (AUC, 0.695; P < .005) and OSI (AUC, 0.602; P = .007). The AUC for OSI was substantially better in patients aged < 40 years (AUC, 0.779; P < .001).
In patients with ARDS, the OSI was correlated with the OI. The OSI on the day of ARDS diagnosis was significantly associated with increased mortality and fewer VFDs. The findings suggest that OSI is a reliable surrogate for OI that can noninvasively provide prognostic information and assessment of ARDS severity.
There is no accurate, non-invasive measurement to estimate the degree of pulmonary oedema in acute respiratory distress syndrome (ARDS). We developed the Radiographic Assessment of Lung Oedema (RALE) ...score to evaluate the extent and density of alveolar opacities on chest radiographs. After first comparing the RALE score to gravimetric assessment of pulmonary oedema in organ donors, we then evaluated the RALE score in patients with ARDS for its relationship to oxygenation and clinical outcomes.
We compared radiographs with excised lung weights from 72 organ donors (derivation cohort) and radiographs with clinical data from 174 patients with ARDS in the ARDSNet Fluid and Catheter Treatment Trial (validation cohort). To calculate RALE, each radiographic quadrant was scored for extent of consolidation (0-4) and density of opacification (1-3). The product of the consolidation and density scores for each of the four quadrants was summed (maximum score=48).
Agreement between two independent reviewers for RALE score was excellent (intraclass correlation coefficient=0.93, 95% CI 0.91 to 0.95). In donors, pre-procurement RALE score correlated with height-adjusted total lung weight (ρ=0.59, p<0.001). In patients with ARDS, higher RALE scores were independently associated with lower PaO
/fractional inspired oxygen and worse survival. Conservative fluid management significantly decreased RALE score over 3 days compared with liberal fluid management.
The RALE score can be used to assess both the extent of pulmonary oedema and the severity of ARDS, by utilising information that is already obtained routinely, safely and inexpensively in every patient with ARDS. This novel non-invasive measure should be useful for assessing ARDS severity and monitoring response to therapy.
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