Plasma sRAGE is independently associated with increased mortality in ARDS: a meta-analysis of individual patient data

Purpose

The soluble receptor for advanced glycation end-products (sRAGE) is a marker of lung epithelial injury and alveolar fluid clearance (AFC), with promising values for assessing prognosis and lung injury severity in acute respiratory distress syndrome (ARDS). Because AFC is impaired in most patients with ARDS and is associated with higher mortality, we hypothesized that baseline plasma sRAGE would predict mortality, independently of two key mediators of ventilator-induced lung injury.

Methods

We conducted a meta-analysis of individual data from 746 patients enrolled in eight prospective randomized and observational studies in which plasma sRAGE was measured in ARDS articles published through March 2016. The primary outcome was 90-day mortality. Using multivariate and mediation analyses, we tested the association between baseline plasma sRAGE and mortality, independently of driving pressure and tidal volume.

Results

Higher baseline plasma sRAGE [odds ratio (OR) for each one-log increment, 1.18; 95% confidence interval (CI) 1.01–1.38; P?=?0.04], driving pressure (OR for each one-point increment, 1.04; 95% CI 1.02–1.07; P?=?0.002), and tidal volume (OR for each one-log increment, 1.98; 95% CI 1.07–3.64; P?=?0.03) were independently associated with higher 90-day mortality in multivariate analysis. Baseline plasma sRAGE mediated a small fraction of the effect of higher ΔP on mortality but not that of higher V_T.

Conclusions

Higher baseline plasma sRAGE was associated with higher 90-day mortality in patients with ARDS, independently of driving pressure and tidal volume, thus reinforcing the likely contribution of alveolar epithelial injury as an important prognostic factor in ARDS. Registration: PROSPERO (ID: CRD42018100241).

     

Opposite central cardiovascular effects of nifedipine and BAY k 8644 in anesthetized rats

The central cardiovascular effects of the calcium channel blocker nifedipine and the calcium channel activator BAY k 8644 were studied in anesthetized and ventilated normotensive Wistar-Kyoto (WKY) or spontaneously hypertensive rats (SHR). Both drugs were administered in a 1.5-microliter volume into the lateral ventricle of the brain (i.c.v.) or into the cisterna magna (i.c.). The injection of vehicle alone (i.c. or i.c.v.) did not significantly change mean arterial pressure (MAP) or heart rate. Nifedipine (5 and 50 micrograms/kg) and BAY k 8644 (5 and 50 micrograms/kg) induced opposite effects on MAP when centrally injected. Nifedipine decreased MAP and induced a bradycardia (i.c.v.) or no change in heart rate (i.c.), and BAY k 8644 increased MAP without any significant change in heart rate (i.c. or i.c.v.). These effects were more marked with the highest dose of either drug. These effects seemed to be of central origin, since they were suppressed by ganglionic blockade by hexamethonium (100 mg/kg i.v.), whereas after hexamethonium the hypotensive and the hypertensive responses to intravenously injected nifedipine and BAY k 8644, respectively, were preserved. Bilateral vagotomy suppressed the bradycardia induced by i.c.v. administered nifedipine. Previously i.c.v. administered nifedipine (5 micrograms/kg) antagonized the pressor response to BAY k 8644 (5 micrograms/kg i.c.v.). Changes in MAP and heart rate were significantly more marked in SHR than in WKY. These results indicate that a calcium channel inhibitor and a calcium channel activator can modulate in opposite fashion central mechanisms involved in blood pressure control.     

Long-term fluvastatin reduces the hazardous effect of renal impairment on four-year atherosclerotic outcomes (a LIPS substudy)

Mild renal impairment is an important risk factor for late cardiovascular complications. This substudy of the Lescol Intervention Prevention Study (LIPS) assessed the effect of fluvastatin on outcome of patients who had renal dysfunction and those who did not. Complete data for creatinine clearance calculation (Cockcroft-Gault formula) were available for 1,558 patients (92.9% of the LIPS population). Patients were randomized to fluvastatin or placebo after successful completion of a first percutaneous coronary intervention. Follow-up time was 3 to 4 years. The effect of baseline creatinine clearance on coronary atherosclerotic events (cardiac death, nonfatal myocardial infarction, and coronary reinterventions not related to restenosis) was evaluated. Baseline creatinine clearance (logarithmic transformation) was inversely associated with an incidence of adverse events among patients who received placebo (hazard ratio 0.99, 95% confidence interval 0.982 to 0.998, p = 0.01). However, no association was noted between creatinine clearance and the incidence of adverse events among patients who received fluvastatin (hazard ratio 1.0, 95% confidence interval 0.99 to 1.0, p = 0.63). No further deterioration in creatinine clearance was observed during follow-up, regardless of baseline renal function or allocated treatment. Occurrence of adverse events was not related to changes in renal function during follow-up. Fluvastatin therapy markedly decreased the risk of coronary atherosclerotic events after percutaneous intervention in patients who had lower values of creatinine clearance at baseline. The benefit of fluvastatin was unrelated to any effect on renal function.     

Complementary role of thallium-201 scintigraphy to predischarge exercise electrocardiography for patients stratification after a first myocardial infarction

The value of a predischarge exercise test combined with thallium-201 myocardial scintigraphy in detecting patients with severe multivessel disease (MVD) was studied in 58 consecutive patients discharged after a first acute myocardial infarction. Twelve electrocardiographic, clinical and scintigraphic variables were analysed. Angiography at one month revealed MVD (greater than 70% narrowing in vessels unrelated to infarction) in 26 patients (45%). ST segment depression of 1mm or greater, thallium defects in multiple vascular distributions (MVTL), and reversible thallium defects in a vascular distribution different from the infarct related vessel predicted patients at risk for MVD (predictive value respectively of 68%, 65% and 75%). The other variables were not significantly associated with the presence of MVD. Only ST segment depression and thallium defects in multiple vascular distributions emerged as independent predictors of MVD. Their combination yielded a 77% sensitivity and a 59% specificity for MVD. Combination of thallium imaging with the predischarge exercise ECG significantly improved the stratification provided by the exercise test alone (P less than 0.05). A positive thallium scan (MVTl defects) associated with a positive ECG (ST depression) carried a risk for MVD of 80% in the population studied. When both tests were negative, MVD was infrequent (risk 22%). Because improvement in the stratification of patients is not as clear as expected from studies performed at a later stage, it appears that exercise thallium scintigraphy at a submaximal level one or two weeks after infarction does not provide optimal information. Predischarge exercise thallium-201 scintigraphy, however, is superior to an exercise tolerance test alone in separating patients into those with high and low risk of MVD.     

Combined treatment of liver failure and hepatorenal syndrome with orthotopic liver transplantation.

Hepatorenal syndrome (HRS) is a severe complication of liver failure with high mortality. The pathogenesis of this reversible functional renal failure is not yet clearly understood. Diagnosis is based upon the association of clinical and biological criteria. A patient was admitted to our institution for severe liver failure secondary to an exacerbation of cirrhosis, where he developed a fulminant hepatorenal syndrome. Both, the renal and hepatic failure were successfully treated by orthotopic liver transplantation. Special attention was paid to the immunosuppressive treatment with Cyclosporine whose use, we believe, should be delayed until function has partially recovered.