Effective diuresis is the primary goal of most acute decompensated heart failure hospitalizations, but diuretic resistance is common and our ability to detect it is limited. Further, there are therapeutically distinct groups of diuretic-resistant patients. These are not easily distinguished using currently available methods, leading to trial-and-error based treatment that promotes lengthy hospitalizations.

The aims of this study are:

1. To develop inexpensive and efficient tools to predict diuretic response
2. To understand the prevalence of therapeutically targetable mechanisms of diuretic resistance using endogenous lithium clearance
3. To develop methodology to differentiate diuretic resistance mechanisms using common/inexpensive laboratory tests
4. To provide proof of concept that mechanistically tailored diuretic therapy can improve natriuresis

This study is a minimal-risk observational open-label single center study with randomization between two standard of care interventions. Approximately 500 patients admitted to the hospital (Yale New Haven Health System) with a clinical diagnosis of heart failure will be enrolled in the overall study.

Patients will undergo sampling of their blood and collection of urine at a minimum of 4 timepoints (called "visits"), or a minimum of 5 in the interventional arm. Patients with a low urine sodium output (<100 mmol) on Visit 1 will be eligible for 1:1 randomization to either an increased dose of their Visit 1 loop diuretic or addition of IV chlorothiazide to their Visit 1 loop diuretic.

For all patients:

Inclusion criteria:

• Age ≥ 18 years
• Clinical diagnosis of ADHF with at least one objective sign of volume overload: rales, edema, elevated JVP, preadmission weight gain
• Current use of bolus IV loop diuretic therapy and projected need by the treating clinician for continued treatment with IV diuretics for at least 3 days with the goal of significant fluid removal (>1L net fluid loss/day)

Exclusion criteria:

• Inability to perform informed consent or comply with the serial urine collection procedures
• Significant bladder dysfunction or urinary incontinence
• Hematocrit less than 21% or active bleeding

For patients in the interventional arm:

Inclusion criteria:

• Cumulative 6-hour sodium output < 100 mmol following Visit 1 IV loop diuretic dose
• Visit 1 IV loop diuretic dose ≤ 160 mg of furosemide equivalents
• Serum sodium > 125 mmol/L
• At least 6 hours since last dose of diuretic

Exclusion criteria:

• Current use or projected future requirement by the treating physician for thiazide diuretics
• Use of high dose mineralocorticoid receptor antagonist therapy (>50mg of spironolactone or >100mg of eplerenone) or amiloride