Sodium Depletion Versus Plasma Dilution

The presence of clinical signs reflecting hypovolemia and/or intensive diuretic regiments may suggest sodium depletion. If in doubt, one might consider a fluid challenge with 1 L of isotonic saline over 24 h, measuring the effect on serum sodium levels. However, this should be avoided in case of clear fluid overload and/or severe hyponatremia (serum sodium <125 mmol/L). Indeed, signs of volume overload indicate a component of dilutional hyponatremia, in which case an improvement is unlikely and the risk of further deteriorating congestion substantial. Alternatively, one could measure urine osmolality, which should be adequately suppressed (<100 mOsm/L) in patients with sodium depletion, but not in patients with dilution hyponatremia. If urine osmolality is >150 mOsm/L, isotonic solutions should certainly be avoided as administration would result in further worsening of hyponatremia. Finally, very low urinary sodium and/or chloride concentrations (≤50 mmol/L) are a relatively strong argument for electrolyte depletion in AHF [45].

Treatment of Dilution Hyponatremia

Hypernatremia

Hypernatremia is rather infrequent during decongestive treatment in AHF. Its incidence has been less systematically studied when compared to hyponatremia, but is probably <5% [63]. Similar to hyponatremia, hypernatremia in AHF is associated with higher in-hospital mortality, prolonged hospitalization and increased healthcare costs [63, 64]. Its most common cause is likely over-diuresis with excessive free water loss in patients unable to drink because of illness or frailty. Such cases are easily managed by decreasing the dose of diuretics and offering more free water, either through oral or intravenous administration. It is important to acknowledge that loop diuretics induce the production of hypotonic urine [65]. Therefore, they generally remove more water that sodium. Frequent use of these agents in combination with iso- or hypertonic fluids (most often in mechanically ventilated patients in the intensive care unit) might occasionally cause the situation of hypervolemic hypernatremia. In HFrEF patients, aldosterone breakthrough further exacerbates this problem [66, 67]. Thiazide-type diuretics, MRA and amiloride, used alone or in combination, are the preferred agents to add in such cases because they increase the urinary sodium concentration directly, thereby limiting free water excretion [38].

Potassium Derangements

Hypokalemia and hyperkalemia are common electrolyte abnormalities in chronic heart failure, both associated with worse survival [68]. Due to the ubiquitous use of potassium-losing loop and thiazide-type diuretics, potassium losses are exacerbated during decongestive treatment for AHF, often necessitating the need for oral and/or intravenous repletion therapy. It is important to acknowledge that concomitant magnesium losses may cause refractory hypokalemia and predispose to cardiac arrhythmias, so clinicians should have a low threshold to provide magnesium supplements in AHF patients who develop hypokalaemia [69]. Moreover, both hypokalemia and hypomagnesemia may contribute to hyponatremia by shifting sodium into the intracellular compartment [38]. In contrast, hyperkalemia in AHF occurs almost exclusively in patients with advanced chronic kidney disease and low GFR. The treatment of hyperkalemia is similar, irrespectively the presence of AHF. However, its most important implication is a contraindication for the use of MRA and/or (uptitration of) renin-angiotensin system inhibitors. Whether this is an absolute or relative contraindication depends on the severity of hyp0erkalemia and the reversibility of kidney dysfunction. Interestingly, new agents like zirconium cyclosilicate and patiromer that impair potassium absorption in the gut offer the prospect of preventing the problem of hyp0erkalemia and still allow these important evidence-based treatments in heart failure [70, 71].

Treatment Pearls for the Case Vignette

The patient from the case vignette demonstrates clear signs of persistent volume overload (i.e., the combination of edema and orthopnea) despite adequately dosed bolus therapy with loop diuretics. Notwithstanding the presence of WRF, this should be a strong incentive to pursue further decongestion with diuretic therapy as outcomes are abysmal when volume overload persists. Reasons for the poor loop diuretic response should be considered. Hypotension is a major contributor to WRF as well as diuretic resistance and should be avoided. If necessary, neurohumoral blocker therapy with lisinopril and/or bisoprolol could temporarily be decreased or even withheld. If renal perfusion is severely compromised due to low cardiac output, this should be addressed with sodium nitroprusside, inotropes, or even mechanical assist devices, depending on the arterial blood pressure and severity of cardiogenic shock. I would have a low threshold for paracentesis when meaningful ascites is present in a patient like the one described by the case vignette, as elevated intra-abdominal pressure is another potentially reversible cause of WRF.

With the estimated GFR down to 36 mL/min/1.73 m², my recommendation would be to increase the dose of subsequent furosemide bolus therapy to 120 mg. In addition, more frequent administrations at 6 h intervals are indicated to avoid post-diuretic sodium retention. Alternatively, loop diuretic therapy could be administered through continuous infusion, but this strategy is associated with more pronounced neurohumoral activation that could potentially aggravate hyponatremia [72]. Besides, I would consider compression stockings to recruit peripheral oedema more easily and albumin administration if serum levels are below 3.0 g/dL, which may impair furosemide delivery at its site of action in the nepron [13].

My final recommendation would be to add an intravenous bolus of acetazolamide 500 mg OD to the current diuretic regimen. Sequential nephron blockade with thiazide-type diuretics or high-dose MRA would be an alternative to break diuretic resistance, yet expected to exacerbate hyponatremia as free water excretion by the kidneys is impaired with these agents [38]. In contrast, acetazolamide increases free water excretion, making it an attractive agent when dilution hyponatremia is present in AHF. As urinary potassium and magnesium losses are exacerbated by combination diuretic therapy and may contribute to hyponatremia by shifting sodium to the intracellular compartment, I would provide intravenous and/or oral repletion therapy. If worsening hyponatremia would occur despite this treatment approach, administration of hypertonic saline or vasopressin antagonists would be among my considerations. Importantly, after successful decongestion, optimizing therapies for chronic heart failure as described above is important to prevent recurrence or worsening of hyponatremia.