The urinary sodium and diuresis-based treatment protocol in PUSH-AHF.
Schematic of the treatment protocol, showing that loop diuretics were administered twice daily (in black), at 12 h intervals. At the timepoints at which natriuresis and diuresis was assessed, in the case of an insufficient response as determined by predetermined cutoffs (box 1), treatment was intensified according to the treatment algorithm (box 2). First step was the administration of an additional dose of loop diuretics (double the previous dose to a maximum of 5 mg of bumetanide). If an additional, increased dose of loop diuretic was administered, the maintenance dose (the twice-daily administered loop diuretic dose) was further increased to a level that was double the previous dose, to a maximum of 5 mg bumetanide. If response continued to be insufficient despite two consecutive maximum doses of loop diuretic, combination diuretic therapy was started. First choice for combination diuretic therapy was the addition of hydrochlorothiazide; however, if a patient for instance already used combination diuretic therapy with hydrochlorothiazide before admission or response remained insufficient after addition of hydrochlorothiazide, acetazolamide or an SGLT2i was added. A cumulative total of 228 additional boluses of loop diuretics were administered in 123/150 patients in the natriuresis-guided group at all timepoints combined in the first 24 h. In 32/150 patients (21%) in the natriuresis-guided group a second diuretic was added (hydrochlorothiazide in 31 patients; acetazolamide in 3 patients). Two of these patients received triple nephron blockade with the addition of both hydrochlorothiazide and acetazolamide. In one patient in the natriuresis-guided group, a sodium glucose co-transporter 2 inhibitor (SGLT2i) was added according to protocol. No patients required ultrafiltration in the first 24 h of index hospitalization. In the first 24 h, the total administered loop diuretic dose in the natriuresis-guided arm was 12 [7–19] mg of bumetanide versus 6 [3–12] mg of bumetanide in the SOC arm (At 36 h, 43 patients received an additional bolus of loop diuretic, in 6 patients a second diuretic was added (hydrochlorothiazide in 5 patients, and acetazolamide in 1 patient) and in 1 patient a SGLT2i was added per protocol. Of note, only 4/50 patients were eligible for treatment intensification at 36 h for the first time. In the first 36 h, the total administered loop diuretic dose in the natriuresis-guided arm was 16 [10–24] mg of bumetanide versus 8 [5–14] mg of bumetanide in the SOC arm (The median spot urinary sodium values in the natriuresis-guided arm during the first 36 h is shown in Extended Data Fig. 