Mechanisms of Diuretic Resistance in Heart Failure
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 75
- 试验地点
- 2
- 主要终点
- Change in fractional excretion of lithium(FELi) pre-diuretic to 1-hour post IV bumetanide infusion
研究概览
简要总结
This study will employ a randomized order, double-blind, repeated measures dose ranging design. This design was chosen in order to generate multiple within-subject serial loop diuretic dose response exposures. The overall study schema will include 75 heart failure (HF) patients.
详细描述
The protocol will begin with pre-study determination of diuretic response at the screening visit via administration of 10 mg IV bumetanide infused over 1 hour and measuring peak Fractional Excretion of Sodium (FENa), 1-hour post completion of infusion. Participants will begin a study diet provided by the metabolic kitchen five days prior to the first study visit with randomized treatment (Day 0). Participants in balance will present to the study site Day 0 and receive their first randomized dose of bumetanide (1.25mg, 2.5mg, 5mg, or 10mg) and undergo the bio-specimen collection protocol. They will return every 3 days, allowing 2 full days washout, to receive the other doses in random sequence.
Total sodium output in response to a loop diuretic differs based on Glomerular Filtration Rate (GFR). However, a diuretic responsive participant with normal or severely reduced GFR each will achieve a similar peak FENa of approximately 20% with high dose diuretic. In a cohort of 109 hospitalized diuretic resistance (DR) HF patients that received 12.5mg bumetanide, a peak FENa <5% occurred in 66% patients. The mean FENa in this group was 2.6 ± 1.3 %, thus FENa <5% is common and a clinically relevant threshold for DR, and thus was chosen as the threshold to define diuretic resistance for the proposed study.
Participants will be asked to follow the study diet as the design seeks to decrease the variability of diuretic response introduced by variations in dietary sodium intake. For the current study, a four-gram sodium (0.8 g/kg protein) diet will be utilized. Four grams was chosen since, in prior experience, this is the average pre-study sodium intake of outpatient HF study participants and thus will facilitate rapid transition into balance.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Sequential
- 主要目的
- Other
- 盲法
- Triple (Participant, Care Provider, Investigator)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Clinical diagnosis of HF
- •No plan for titration/change of heart failure medical or device therapies during the study period.
- •Absence of non-elective hospitalizations in the previous 3 months.
- •At optimal volume status by symptoms, exam, and dry weight
- •Age > 18 years
排除标准
- •GFR <20 ml/min/1.73m2 using the Chronic Kidney Disease- Epidemiology (CKD-EPI)equation or use of renal replacement therapies
- •Use of any non-loop type diuretic in the last 14 days with the exclusion of low dose aldosterone antagonist (e.g., spironolactone or eplerenone ≤50 mg). Examples of non-loop diuretics include but may not be limited to acetazolamide (oral or IV, not ophthalmic), metolazone, Hydrochlorothiazide (HCTZ), chlorthalidone, chlorothiazide, indapamide, triamterene, amiloride, finerenone, spironolactone dose > 50mg day, eplerenone > 50mg/day,
- •History of flash pulmonary edema requiring hospitalization and treatment with biphasic positive airway pressure or mechanical ventilation or a "brittle" volume sensitive HF phenotype such as an infiltrative or restrictive cardiomyopathy (i.e. amyloid cardiomyopathy, etc).
- •Hemoglobin < 8 g/dL
- •Pregnant or breastfeeding
- •Inability to give written informed consent or comply with study protocol or follow-up visits
- •Chronic Urinary retention limiting ability to perform timed urine collection procedures
研究组 & 干预措施
Bumetanide 10 mg
Randomized to doses 10 mg, 5 mg, 2.5 mg, 1.25 mg
干预措施: Bumetanide Injection (Drug)
Bumetanide 1.25 mg
1.25 mg Randomized to doses 10 mg, 5 mg, 2.5 mg, 1.25 mg
干预措施: Bumetanide Injection (Drug)
Bumetanide 5 mg
5 mg Randomized to doses 10 mg, 5 mg, 2.5 mg, 1.25 mg
干预措施: Bumetanide Injection (Drug)
Bumetanide 2.5 mg
2.5 mg Randomized to doses 10 mg, 5 mg, 2.5 mg, 1.25 mg
干预措施: Bumetanide Injection (Drug)
结局指标
主要结局
Change in fractional excretion of lithium(FELi) pre-diuretic to 1-hour post IV bumetanide infusion
时间窗: Baseline and 1 hour post bumetanide infusion.
The fractional excretion of lithium is used for interrogation of sodium handling in the proximal tubule and loop of Henle. Possible values range from 0 to 100%. Change = FELi 1 hour post bumetanide infusion - FELi pre-diuretic. Different doses of bumetanide will be given at days 0, 3, 6 and 9.
Tubular diuretic efficiency at baseline
时间窗: Baseline
The tubular diuretic efficiency is used to assess the response to loop diuretics based on the amount of sodium excreted but eliminates drug delivery as source of diuretic resistance. Possible values range from 0 to 100%. Greater numbers imply better diuretic efficiency. Tubular diuretic efficiency will be compared between diuretic resistant and diuretic responsive patients using the 6 hour urine collection after bumetanide infusion.
Ratio of A to F splice variant Messenger Ribonucleic Acid (mRNA )in urinary extracellular vesicles at baseline
时间窗: Baseline
The ratio of A to F splice variant mRNA in urinary extracellular vesicles refers to the splice variants in the NKCC2 channel. The F variant has low-chloride-affinity-high-capacity, and the A variant has high-chloride-affinity-high-capacity. Possible values are greater than zero. The ratio of A to F splice variant will be compared between diuretic resistant and diuretic responsive patients. The ratio will be compared using the baseline urine sample.
Change in distal sodium reabsorption pre-diuretic to 1-hour post IV bumetanide infusion
时间窗: Baseline and 1 hour post bumetanide infusion.
The distal sodium reabsorption is used to for interrogation of how much sodium is being reabsorbed in the distal tubule. Possible values range from 0 to 100%. Distal sodium reabsorption is calculated = Fractional excretion of lithium - fractional excretion of sodium. Change in distal sodium reabsorption = distal sodium reabsorption 1 hour post bumetanide infusion - distal sodium reabsorption pre-diuretic. Different doses of bumetanide will be given at days 0, 3, 6 and 9.
次要结局
未报告次要终点