Route of Administration

When patients develop congestion despite chronic oral loop diuretic therapy, it is standard procedure to shift to intravenous administration. This eliminates the effect of gut malabsorption due to gut edema and congestion. Therapy may be started administering intravenously the same dose that the patient was receiving orally, low dose regimen in the Diuretic Optimization Strategies Evaluation (DOSE) trial [46]. Alternatively, 1.5 times or higher doses may be administered intravenously, high dose regimen in DOSE trial. No difference in outcomes between the two dosing regimens was shown in the DOSE trial. The high dose regimen was associated with a tendency to a greater symptoms’ relief, a larger body weight decrease and fluid loss and a greater likelihood to develop worsening renal function [46].

Intravenous loop diuretic treatment is generally done in a hospital setting. However, the practice of short-term intravenous administration of furosemide in specialized outpatient units is cost-effective and more and more often used [47, 48]. Short-stay unit treatment for <24 hours is compared with standard hospitalization in an ongoing randomized trial (NCT03302910).

A novel subcutaneous furosemide formulation was recently developed. First studies in healthy volunteers and a first phase II trial on CHF patients with refractory congestion showed a remarkable increase in furosemide bioavailability compared with oral formulation, and similar safety, length of action and efficacy as intravenous furosemide in HF patients [49].

Combining Different Diuretics: Sequential Nephron Blockade

When the previous strategies fail to achieve adequate diuresis, nephron remodeling with hyperfunction and hypertrophy of the nephron distally to the ascending branch of the loop of Henle is the most likely mechanism [36, 37, 39]. Thiazide-like diuretics and metolazone promote sodium excretion in the distal tubule and thus counteract the distal tubular hypertrophy that impairs loop diuretic response. A stepped pharmacologic approach with the combination of these drugs on top of loop diuretic treatment is now indicated for the treatment of diuretic resistance [7, 36, 50]. Caution is, however, needed above all when administered on a long-term basis and with frequent, e.g. daily, administrations for the increased risk of hypokaliemia, hyponatremia, worsening renal function and even mortality [51]. Although based on retrospective analysis of existing database, these data made the Authors suggest that a strategy of increasing loop diuretics doses may be preferred to the early combination of thiazide-like diuretics in patients with decompensated HF resistant to standard doses of loop diuretics [51].

Mineralocorticoid receptor antagonists (MRA), administered at relatively high doses, e.g. spironolactone 100 mg, can promote natriuresis and prevent potassium loss associated with loop diuretic therapy, acting on the distal convoluted tubule. Properly powered studies have, however, failed to show a beneficial effect on outcomes of their administration to patients with acute HF [8, 52].

Vasopressin receptor antagonists exert inhibition of aquaporin 2, the receptor responsible for free water reabsorption in the collecting duct. They may be particularly effective in hyponatremic patients [53]. Results of randomized trials have, however, been failed to show beneficial effects on outcomes despite larger body weight reduction and fluid loss with these agents versus placebo [54, 55].

Acetazolamide inhibits carbonic anhydrase in the proximal tubule thus favoring sodium bicarbonate excretion at this level. The increased delivery of sodium to the loop of Henle provides the substrate for loop diuretic action without compromising renal ability to excrete diluted urine [56]. Moreover, it downregulates pendrin expression in the distal tubule, one mechanism of nephron remodeling and diuretic resistance [8, 36]. Small studies suggested the efficacy of acetazolamide added to furosemide in patients with diuretic resistance. The ongoing randomized Acetazolamide in Decompensated Heart Failure With Volume OveRload (ADVOR) trial is testing the hypothesis that the addition of acetazolamide to standard therapy may improve decongestion and outcomes in patients with acute HF [8, 57].

Sodium-glucose cotransporter 2 (SGLT2) is located in the early proximal tubule and is the major mechanism of renal glucose reabsorption. In addition it also cause reabsorption of about 5% of the filtered sodium. SGLT2 inhibitors can therefore cause glycosuria, osmotic diuresis and natriuresis. Empaglifozin, dapaglifozin and canaglifozin have reduced HF hospitalizations in large randomized controlled trials where they were administered to diabetic patients at high risk of cardiovascular events. Ongoing studies are evaluating their role in patients with established HF with or without diabetes [58, 59].

Sodium Restriction

Conflicting results exist about the optimal amount of sodium to be included in the HF patients’ diet [60]. Sodium restriction showed some benefit in stable HF patients (NYHA class II-III) in the Study of Dietary Intervention Under 100 mmol in Heart Failure (SODIUM-HF) [61]. Because of lack of evidence, current ESC hf guidelines recommend to avoid excessive sodium intake (>6 g of salt/die, equal to 100 mmol of sodium, no class recommendation), while strict sodium restriction is not recommended, to date [12].

Other Therapies

Patients with advanced HF who do not respond to increased loop diuretic doses and/or to combination therapy with thiazide-like diuretics may need intravenous inotropic treatment in order to improve renal perfusion and reduce systemic venous congestion. This is still considered palliative therapy as no benefit on patients’ outcomes have been shown [12, 13]. However, an improvement in diuretic response may be observed I individual cases. Similarly, low dose dopamine infusion or nesiritide infusion, also proposed to selectively improve renal function have failed to show benefit in properly designed randomized trials [62] but may be of help in individual cases. At a late stage, patients may need ultrafiltration or continuous venous-venous hemofiltration, peritoneal dialysis or hemodialysis as renal replacement therapies. Ultrafiltration has been tested also at an earlier stage as alternative to high dose loop diuretic therapy but no indication to this treatment can be done based on current data. The Peripheral Ultrafiltration for the RElief From Congestion in Heart Failure (PURE-HF) trial (NCT03161158) is evaluating whether tailored, peripheral veno–venous ultrafiltration added to low-dose diuretics can decrease cardiovascular mortality and HF hospitalization at 90 days after randomization compared to usual care in patients with acute HF and fluid overload [8].

Treatment Pearls for the Case Vignette

The patient in the case vignette showed signs and symptoms of fluid overload, despite the ongoing diuretic therapy. The attending resident should therefore interview the patient about her symptoms, measure her vital signs (blood pressure, heart rate and O₂ saturation) and perform a careful physical examination looking for signs of congestion and precipitating factors of the acute decompensation (e.g. new onset/recurrence of atrial fibrillation, infection, coronary artery disease, poor blood pressure control, non-compliance to prescribed medications) [12, 13]. Blood sample collection for blood cell count, creatinine, electrolytes and natriuretic peptides measurement, and spot urine analysis may provide further useful information to establish the best treatment plan. Echocardiography and possibly lung ultrasound should also be performed [32]. It may detect treatable causes of decompensation, e.g. acute mitral regurgitation, pulmonary embolism, pericardial effusion. Second, it allows categorization of the patients into the low, mid-range and preserved ejection fraction categories with only those with a low ejection fraction having evidence based therapies. Third, echocardiography allows the detection of LV diastolic dysfunction as well as signs of increased intraventricular pressure, pulmonary artery pressure, inferior vena cava dilation and collpsability… Lung ultrasound allows the detection of lung comets.

Given the additional information provided on the patient from the case vignette, i.e. stage IV CKD and a recent hospitalization for HF, it might be prudent to hospitalize this patient to start intravenous diuretic treatment and monitor laboratory exams, such as serum creatinine and electrolytes, and possibly reassess the patient for echocardiographic signs of congestion.

On the other hand, if patient’s symptoms are not severely limiting the patient with no signs of hypoperfusion and no treatable precipitating factor, an attempt to manage the patient in the outpatient setting can be made and oral diuretic dose can be doubled. Alternatively, intravenous loop diuretics may be administered in the outpatients clinic and the patient should be reassessed in the following days. With close follow-up visits.