Prolonged Diuretic Action of Intravenous Chlorothiazide in the LOT-MDR Mechanistic Randomized Controlled Trial: A Prespecified Analysis

Background: In the LOT-MDR trial, randomization to short acting IV chlorothiazide had a prolonged natriuretic action greatly exceeding the duration of action of the drug. This analysis explores the mechanisms behind this observation. Methods: Hospitalized AHF patients (N=100) with diuretic resistance, defined as 6-hour natriuresis <100 mmol after IV loop diuretic, were randomized to either 2.5X IV loop diuretic dose intensification or IV chlorothiazide added to the same loop dose. Results: In the 18-hour urine collection following the 6-hour collection (i.e., hours 7-24), total sodium excretion was 50 mmol greater (95% CI 24, 76, p<0.001) in the thiazide vs. intensified loop strategy, contributing nearly 50% to the total 107 mmol (95% CI 56, 157 mmol, P<0.001) larger 24-hour sodium excretion with adjuvant thiazide. Chlorothiazide’s prolonged natriuresis was not due to sustained tubular chlorothiazide delivery as 27% (IQR 20, 54) of the dose was excreted in the urine over the first 6 hours, and only 5% (IQR 4, 9) excreted in the subsequent 18 hours with no significant correlation between hour 7-24 chlorothiazide excretion and natriuresis (r=0.23 p=0.18). Participants with prolonged natriuresis had high pre-diuretic distal Na delivery (18.1±9.2% vs 8.4±3.9%, p<0.001), lower serum bicarbonate (26.5±4.8 vs 29.1±7.0 mmol/L, p=0.04), higher serum chloride (96.5±3.4 vs 94.5±4.3, p=0.013), and higher urine pH (6.1±0.9 vs 5.7±0.8, p=0.028), indicating enhanced distal sodium delivery compensation through a pathway such as pendrin. Conclusion: IV chlorothiazide’s prolonged natriuresis substantially contributed to diuretic response in the LOT-MDR trial. Prolonged natriuresis was restricted to patients with increased pre-diuretic distal nephron sodium reabsorption. This suggests a distal transport pathway was upregulated that could be “turned off” by chlorothiazide, such as pendrin. Funding: NIDDK Support