The administration of intravenous loop diuretics to patients with heart failure (HF) and congestion results typically in a prompt diuretic effect. In most patients, the increased diuresis is accompanied by a decrease in LV ventricular filling pressures and improvement of symptoms by reducing pulmonary capillary wedge pressure and intra-alveolar edema [
25]. When used in combination with vasodilators, loop diuretics reduce ventricular remodeling and mitral regurgitation, resulting in increased cardiac output. In spite of these hemodynamic effects, no long-lasting benefits were demonstrated with this approach [
26]. In population studies, after adjustments for possible confounders, the highest diuretic quartile of loop diuretic dosing remained a significant predictor of mortality [
26]. An increased risk for in-hospital mortality and renal failure has been consistently associated with higher doses of intravenous loop diuretics compared with lower doses [
27,
28]. The Acute Decompensated Heart Failure Registry (ADHERE) analysis confirmed that patients receiving the lower doses had a lower risk of in-hospital mortality, intensive care unit stay, prolonged hospitalization, or adverse renal effects [
29]. A meta-analysis by Abdel-Qadir et al. including more than 4000 patients has demonstrated a clear relation among discharge diuretic dosage and recurrent events over a mean 3-year follow-up period and shown doubled mortality in the highest quartile compared with the lowest [
30]. In accordance with this study, the ESCAPE Trial showed that patients submitted to higher daily dosage (300 mg/day) had an unfavorable laboratory pattern in terms of elevated natriuretic peptide levels, increased creatinine and hyponatremia, and worsened clinical outcomes. In the same analysis, the authors observed an inverse linear relation between diuretic dosage and adverse outcome and suggested the lowest dosage feasible to resolve congestive symptoms [
7]. As mentioned above, these associations could all represent confounding by indication, meaning that the more severely ill require higher doses of diuretics, particularly when urine output does not respond, and hence could be at higher risk for adverse outcomes independent of the utilization of loop diuretics. As mentioned above, the DOSE trial, a prospective randomized double-blind controlled trial with a two-by-two factorial design that compared bolus versus continuous infusion and low-dose versus high-dose strategies in a large population, did not demonstrate any benefit (death or hospitalization) of one strategy with respect to the others: analysis regarding bolus versus continuous administration revealed a trend toward a higher rate of creatinine increase in the continuous arm, although this has not influenced outcome [
21]. Finally, a recent Cochrane analysis showed that bolus infusion was related to both increased urine output and fewer adverse effects compared with continuous infusions; unfortunately, no data were reported on long-term mortality and post-discharge events [
31]. Thus, it remains unclear whether high doses or continuous infusions of loop diuretics cause harm; but given all of the data to date, they are very unlikely to help patients. Taken together, these findings suggest that higher dosage administration of loop diuretics probably contributes to adverse events as well as serving as a proxy for more severe disease which itself confers a poor prognosis. This theory seems to be confirmed by a subanalysis of the DOSE trial showing that patients with higher furosemide dose experienced worse renal function, more advanced symptoms, and New York Heart Association class. Besides, the same authors demonstrated a close relation between higher diuretic dose and risk of rehospitalization [
32]. Further studies are warranted to determine whether high-dose diuretics are responsible for worsening renal function and whether coexisting renal dysfunction could be a marker of more severe HF.