Furosemide

Patients were eligible for enrollment if they had presented within the previous 24 hours with acute decompensated heart failure, diagnosed on the basis of the presence of at least one symptom (dyspnea, orthopnea, or edema) and one sign (rales, peripheral edema, ascites, or pulmonary vascular congestion on chest radiography) of heart failure. Additional eligibility criteria were a history of chronic heart failure and receipt of an oral loop diuretic for at least 1 month before hospitalization, at a dose between 80 mg and 240 mg daily in the case of furosemide and an equivalent dose in the case of a different loop diuretic (20 mg of torsemide or 1 mg of bumetanide was considered to be equivalent to 40 mg of furosemide). Thiazide diuretics were permitted if the patient had been taking them on a long-term basis. There was no prespecified inclusion criterion with respect to ejection fraction. Patients with systolic blood pressure of less than 90 mm Hg or a serum creatinine level that was greater than 3.0 mg per deciliter (265.2 μmol per liter) and patients requiring intravenous vasodilators or inotropic agents (other than digoxin) for heart failure were excluded.

The ESCAPE Trial was a National Heart, Lung and Blood Institute sponsored, randomized, multicenter trial of therapy guided by pulmonary artery catheter vs. clinical assessment in hospitalized patients with ADHF. Methods and results have been published previously.^{11 (link), 12} Briefly, 433 patients were enrolled at 26 sites from January 2000 to November 2003. Inclusion criteria included an ejection fraction of 30% or less, systolic blood pressure of 125 mmHg or less, hospitalization for HF within the preceding year, treatment during the preceding month with more than 160 mg of furosemide equivalents daily, and at least 1 sign and 1 symptom of congestion. Exclusion criteria included an admission creatinine level >3.5 mg/dL. Patients were randomized to therapy guided by clinical assessment alone vs. pulmonary artery catheter and clinical assessment. Treatment goals were resolution of the signs and symptoms of congestion and investigators were encouraged to “avoid progressive renal dysfunction or symptomatic systemic hypotension.” Patients in the ESCAPE population that did not have data available to calculate net urine output (n=19) and patients that did not have data available on peak loop diuretic dose (n=24) were not included in the current analysis. All-cause mortality was determined 180 days after randomization.
The relative diuretic efficiency in each patient was determined as the fluid output per mg of loop diuretic received (expressed as mL of net fluid output per 40 mg of furosemide equivalents). Forty milligrams of furosemide equivalents was chosen as a reference since this is a dose reported to produce near maximal rate of instantaneous natriuresis in a healthy volunteer naive to diuretics.¹³ For the Penn cohort, where detailed information on diuretic administration was available, diuretic efficiency was calculated using the cumulative in-hospital net fluid output divided by the cumulative in-hospital amount of intravenous (IV) loop diuretic received (Cumulative diuretic efficiency). For the ESCAPE cohort, only maximum loop diuretic dose received in a 24 hour period was available, thus diuretic efficiency was calculated using the average daily fluid output divided by the peak IV loop diuretic (Peak diuretic efficiency). Given the desire to compare effect sizes across variables and between cohorts, the median values for diuretic efficiency [Penn cohort median 480 (interquartile range 195–1024) mL net fluid output/40 mg furosemide equivalents; ESCAPE cohort median 148 (interquartile range 61–283) mL net fluid output/40 mg furosemide equivalents] was primarily employed. To allow direct comparison between the cohorts, the primary analyses were repeated using Peak diuretic efficiency in the Penn cohort calculated using the median from the ESCAPE cohort. Estimated glomerular filtration rate (eGFR) was calculated using the four variable Modified Diet and Renal Disease equation.^{14 (link)} Worsening renal function (WRF) was defined as a ≥ 20% decrease in eGFR at any time during the hospitalization, unless otherwise specified.^{15 (link)–20 (link)} Loop diuretic doses were converted to furosemide equivalents with 1 mg bumetanide = 20 mg torsemide = 80 mg furosemide for oral diuretics, and 1 mg bumetanide = 20 mg torsemide = 40 mg furosemide for intravenous diuretics.^{21 (link), 22 (link)} The study was approved or determined to qualify as exempt from Institutional Review Board review by the Hospital of the University of Pennsylvania and Yale University Institutional Review Boards.

The relaxivity index R2* was calculated in pigs (n=11 total) and a eventually confirmed in group of patients (n=9) using the new “compartmental” method and two other techniques. All subjects underwent BOLD-MRI under basal conditions and after administration of furosemide intravenously, and 1-4 days later underwent contrast-enhanced CT. In one of these analysis techniques contrast-enhanced CT images were utilized to define the ROI’s and subsequently select medullary and cortical ROIs to apply on MRI images. This “hybrid” method was used as the reference standard. In the conventional manual method the ROIs were selected manually from T2* MR images. To increase the spectrum of renal oxygenation and R2* values, some of the animals and humans included in this study had unilateral renal artery stenosis (RAS), which can lead to severe renal hypoxia (increased R2*).