Jeffrey M. Turner

Esophageal pressure has been measured in eight healthy men during breath holding (glottis open) at various fixed lung volumes with a rubber balloon (length: 10 cm; perimeter: 3.5 cm; wall thickness: ca. 0.06 mm) containing various volumes of air. The tip of the balloon was placed at a constant distance of 45 cm from the nares. Esophageal pressure was found to increase with balloon volume at all lung volumes but not uniformly, the effect of balloon volume being greatest at both extremes of the vital capacity. As a result, lung volume-pressure curves obtained from balloons containing volumes of gas such as are commonly used are distorted. One can avoid these distortions by repeating measurements at different balloon volumes and extrapolating esophageal pressure to zero balloon volume, or by making measurements at very small balloon volumes. A close approximation of the extrapolated pressures was obtained with the present balloon containing 0.2 ml air. The esophageal pressures at or near zero balloon volume probably reflect closely local absolute pleural pressures over the full vital capacity range in some subjects and above 20% of the vital capacity in most subjects. lung volume-pressure curves Submitted on August 13, 1963

Background: Sodium-glucose cotransporter-2 inhibitors improve heart failure–related outcomes. The mechanisms underlying these benefits are not well understood, but diuretic properties may contribute. Traditional diuretics such as furosemide induce substantial neurohormonal activation, contributing to the limited improvement in intravascular volume often seen with these agents. However, the proximal tubular site of action of the sodium-glucose cotransporter-2 inhibitors may help circumvent these limitations. Methods: Twenty patients with type 2 diabetes mellitus and chronic, stable heart failure completed a randomized, placebo-controlled crossover study of empagliflozin 10 mg daily versus placebo. Patients underwent an intensive 6-hour biospecimen collection and cardiorenal phenotyping at baseline and again after 14 days of study drug. After a 2-week washout, patients crossed over to the alternate therapy with the above protocol repeated. Results: Oral empagliflozin was rapidly absorbed as evidenced by a 27-fold increase in urinary glucose excretion by 3 hours ( P <0.0001). Fractional excretion of sodium increased significantly with empagliflozin monotherapy versus placebo (fractional excretion of sodium, 1.2±0.7% versus 0.7±0.4%; P =0.001), and there was a synergistic effect in combination with bumetanide (fractional excretion of sodium, 5.8±2.5% versus 3.9±1.9%; P =0.001). At 14 days, the natriuretic effect of empagliflozin persisted, resulting in a reduction in blood volume (−208 mL [interquartile range, −536 to 153 mL] versus −14 mL [interquartile range, −282 to 335 mL]; P =0.035) and plasma volume (−138 mL, interquartile range, −379 to 154±453 mL; P =0.04). This natriuresis was not, however, associated with evidence of neurohormonal activation because the change in norepinephrine was superior ( P =0.02) and all other neurohormones were similar ( P <0.34) during the empagliflozin versus placebo period. Furthermore, there was no evidence of potassium wasting ( P =0.20) or renal dysfunction ( P >0.11 for all biomarkers), whereas both serum magnesium ( P <0.001) and uric acid levels ( P =0.008) improved. Conclusions: Empagliflozin causes significant natriuresis, particularly when combined with loop diuretics, resulting in an improvement in blood volume. However, off-target electrolyte wasting, renal dysfunction, and neurohormonal activation were not observed. This favorable diuretic profile may offer significant advantage in the management of volume status in patients with heart failure and may represent a mechanism contributing to the superior long-term heart failure outcomes observed with these agents. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03027960.

BACKGROUND: Rather than the absolute dose of diuretic or urine output, the primary signal of interest when evaluating diuretic responsiveness is the efficiency with which the kidneys can produce urine after a given dose of diuretic. As a result, we hypothesized that a metric of diuretic efficiency (DE) would capture distinct prognostic information beyond that of raw fluid output or diuretic dose. METHODS AND RESULTS: We independently analyzed 2 cohorts: (1) consecutive admissions at the University of Pennsylvania (Penn) with a primary discharge diagnosis of heart failure (n=657) and (2) patients in the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) data set (n=390). DE was estimated as the net fluid output produced per 40 mg of furosemide equivalents, then dichotomized into high versus low DE based on the median value. There was only a moderate correlation between DE and both intravenous diuretic dose and net fluid output (r(2)≤0.26 for all comparisons), indicating that DE was describing unique information. With the exception of metrics of renal function and preadmission diuretic therapy, traditional baseline characteristics, including right heart catheterization variables, were not consistently associated with DE. Low DE was associated with worsened survival even after adjusting for in-hospital diuretic dose, fluid output, in addition to baseline characteristics (Penn: hazards ratio [HR], 1.36; 95% confidence interval [CI], 1.04-1.78; P=0.02; ESCAPE: HR, 2.86; 95% CI, 1.53-5.36; P=0.001). CONCLUSIONS: Although in need of validation in less-selected populations, low DE during decongestive therapy portends poorer long-term outcomes above and beyond traditional prognostic factors in patients hospitalized with decompensated heart failure.

Esophageal and mouth pressures were determined at various fixed lung volumes in seven normal subjects in various postures. Esophageal pressure was obtained from balloons placed at various levels of the esophagus. The balloons contained a volume of gas small enough to render its effect on the pressure recorded negligible. In approximately the upper third of the esophagus changes in mouth pressure, head posture, and external pressure on the trachea produced pressure variations which were unrelated to variations in pleural pressure and were probably the result of traction on, or compression of, the esophagus by the trachea. These artifacts were absent in the lower two-thirds of the esophagus. In the lower third of the esophagus, pressures were found to vary markedly from point to point and with body posture. In approximately the middle third of the esophagus pressures were relatively uniform from point to point, did not vary markedly with body posture, and probably more closely reflect local pleural pressures. It is concluded that in studies of respiratory mechanics esophageal pressure should be measured in the middle third of the esophagus. pleural pressure; lung volume-pressure curves; esophageal balloons Submitted on August 13, 1963