Aim This study aimed at evaluating the effects of sacubitril/valsartan on neprilysin (NEP), and the metabolism of natriuretic peptides in heart failure (HF) and providing additional mechanistic information on the mode of action of the drug. Methods and results We enrolled 73 chronic HF patients who were switched from angiotensin‐converting enzyme inhibitor or angiotensin receptor blocker to sacubitril/valsartan. In addition to clinical and echocardiographic assessment, plasma biomarkers were measured at baseline, day 30 and day 90 after initiation of treatment. Sacubitril/valsartan led to decrease in New York Heart Association class and improvement of echocardiographic parameters, as well as a dose‐dependent decrease in soluble NEP (sNEP) activity, while sNEP concentration remained unchanged. Neprilysin inhibition translated into an increase in its substrates such as atrial natriuretic peptide (ANP), substance P, and glucagon‐like peptide 1, the latter translating into a decrease in fructosamine. Cardiac troponin and soluble ST2 levels, biomarkers of HF severity unrelated to NEP metabolism also decreased. While there was a ∼4‐fold increase in ANP, we observed no change in plasma brain natriuretic peptide (BNP) and plasma BNP activity, and a mild decrease in N‐terminal proBNP (NT‐proBNP) concentrations. Finally, we found a progressive increase in the relationship between BNP and NT‐proBNP, which strongly correlated with an increase in T71 proBNP glycosylation (R2 = 0.94). Conclusion Sacubitril/valsartan rapidly and strongly reduced sNEP activity, leading to an increase in levels of NEP substrates. These data suggest a pleiotropic favourable impact of sacubitril/valsartan on the metabolism of HF patients with ANP rather than BNP as major effectors amongst natriuretic peptides.

The funder had no role in the design and conduct of the study, collection, management, analysis,

The physiology of venous and tissue CO 2 monitoring has a long and well-established physiological background, leading to the technological development of different tissue capnometric devices, such as transcutaneous capnometry monitoring (TCM). To outline briefly, measuring transcutaneous PCO 2 (tcPCO 2) depends on at least three main phenomena: (I) the production of CO 2 by tissues (VCO 2), (II) the removal of CO 2 from the tissues by perfusion (wash-out phenomenon), and (III) the reference value of CO 2 at tissue inlet represented by arterial CO 2 content (approximated by arterial PCO 2 , or artPCO 2). For this reason, there are, at present, roughly two clinical uses for tcPCO 2 measurement: a respiratory approach where tcPCO 2 is likely to estimate and non-invasively track artPCO 2 ; and a hemodynamic underestimate use where tcPCO 2 can reflect tissue perfusion, summarized by a so-called "tc-art PCO 2 gap". Recent research shows that these two uses are not incompatible and could be combined. The spectrum of indications and validation studies in ICUs is summarized in this review to give a survey of the potential applications of TCM in critically ill patients, focusing mainly on its potential (micro)circulatory monitoring contribution. We strongly believe that the greatest benefit of measuring tcPCO 2 is not to only to estimate artPCO 2 , but also to quantify the gap between these two values, which can then help clinicians continuously and noninvasively assess both respiratory and hemodynamic failures in critically ill patients.

Rational To evaluate the respective impact of standard oxygen, high-flow nasal cannula (HFNC) and noninvasive ventilation (NIV) on oxygenation failure rate and mortality in COVID-19 patients admitted to intensive care units (ICUs). Methods Multicenter, prospective cohort study (COVID-ICU) in 137 hospitals in France, Belgium, and Switzerland. Demographic, clinical, respiratory support, oxygenation failure, and survival data were collected. Oxygenation failure was defined as either intubation or death in the ICU without intubation. Variables independently associated with oxygenation failure and Day-90 mortality were assessed using multivariate logistic regression. Results From February 25 to May 4, 2020, 4754 patients were admitted in ICU. Of these, 1491 patients were not intubated on the day of ICU admission and received standard oxygen therapy (51%), HFNC (38%), or NIV (11%) (P < 0.001). Oxygenation failure occurred in 739 (50%) patients (678 intubation and 61 death). For standard oxygen, HFNC, and NIV, oxygenation failure rate was 49%, 48%, and 60% (P < 0.001). By multivariate analysis, HFNC (odds ratio [OR] 0.60, 95% confidence interval [CI] 0.36–0.99, P = 0.013) but not NIV (OR 1.57, 95% CI 0.78–3.21) was associated with a reduction in oxygenation failure). Overall 90-day mortality was 21%. By multivariable analysis, HFNC was not associated with a change in mortality (OR 0.90, 95% CI 0.61–1.33), while NIV was associated with increased mortality (OR 2.75, 95% CI 1.79–4.21, P < 0.001). Conclusion In patients with COVID-19, HFNC was associated with a reduction in oxygenation failure without improvement in 90-day mortality, whereas NIV was associated with a higher mortality in these patients. Randomized controlled trials are needed.