Exogenous Ketones for Acutely Decompensated HEart Failure

Study Overview
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Brief Summary
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This study will evaluate whether supplementation of exogenous ketones in patients with severe left ventricular dysfunction and acutely decompensated heart failure requiring inotropic therapy would improve the patient's hemodynamics and symptoms.

Detailed Description
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The study will include patients with acutely decompensated chronic heart failure requiring inotropic therapy for the syndrome of low cardiac output. While being on the inotropic therapy, the patients will be randomized to oral supplementation of exogenous ketones vs. placebo, which will be repeatedly administered over 9 hours. The patients will undergo continuous invasive hemodynamic monitoring by pulmonary artery catheter, repeated laboratory assessment, and repeated assessment of the severity of symptoms for 24 hours. Exogenous ketones will be administered orally using monoester 3-OHB concentrate without added salts (25g 3-OHB in 65ml H.V.M.N Ketone Ester, H.V.M.N, USA or equivalent). The drink will be administered over 10 mins every 3 hours, 3 times in a row (hour 0, 3, 6). All patients with K<3.7 mmol/l will receive a continuous infusion of 7.5% potassium until reach target K levels of 4.0-4.9 mmol /l. Glycemia will be controlled as needed by insulin and dextrose to maintain glucose concentration of 4 - 12 mmol/l All patients will receive standard treatment of acute heart failure, including intravenous diuretics and inotropic therapy. The recommended inotropic therapy will include milrinone 0.5 ug/kg/min, levosimendan 0.1 ug/kg/min up to 25mg without initial bolus, or dobutamine 0.5 ug/kg/min in patients without chronic therapy with beta-blockers. The severity of symptoms will be self-reported by the patient using 1-10 visual analog scale. Workflow: Hemodynamic assessment, assessment of ketones concentration: 1-3h before randomization, 0-9h hourly, 16-24h (next morning) Biochemical assessment (renal function, liver enzymes, BNP, hs-TnT) 0h, 9h, 16-24h Assessment of symptoms and Scv02: 0h, 1h, 3h, 9h, 16-24h Statistical methods: Each study arm will include 12 patients. The study size was estimated to have power of (1 - beta) of 0.8 and alpha of 5% for between-group comparison of changes in cardiac index and stroke volume index by ANOVA and for comparison of the changes in cardiac index and stroke volume index by paired t-tests.

Official Title
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Exogenous Ketones for Acutely Decompensated Heart Failure

Conditions
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Ketosis, Acute Heart Failure, Low Cardiac Output Syndrome, Hemodynamic Instability

Intervention / Treatment
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* Dietary Supplement: 25g Ketone monoester without added salts
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Chronic heart failure due ischemic or nonischemic cardiomyopathy Acute decompensation of heart failure with the need of inotropes Achievement of relative stabilization on inotropes (INTERMACS class >2) Left ventricular ejection fraction <= 35% Age >18 years Exclusion Criteria: Deteriorating cardiogenic shock with likely need of mechanical circulatory support in the subsequent 48 hours Chronic kidney disease grade 4 or 5 Diabetic ketoacidosis (3-OHB >2mmol/l at baseline) Hemodynamic severe arrhythmias Acute heart failure due to transient triggers (acute coronary syndrome, atrial fibrillation, infection etc..) Contraindications to invasive hemodynamic monitoring

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: randomisation 1:1 to active treatment (exogenous ketones) vs. placebo (drinking water of equivalent volume)
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Supplementation of exogenous ketones<br>Exogeneous ketones will be administered orally using monoester 3-OHB concentrate without added salts (25g 3-OHB in 65ml H.V.M.N Ketone Ester, H.V.M.N, USA or equivalent). The drink will be administered over 10 mins every 3 hours, 3 times in a row. | Dietary Supplement: 25g Ketone monoester without added salts<br>* oral supplementation of ketone monoester<br>* Other names: 25g 3-OHB in 65ml, H.V.M.N Ketone Ester, H.V.M.N, USA or equivalent;|
| Placebo Comparator: Control group<br>The patients will receive a placebo drink (drinking water) of equivalent volume (3x 65ml) | Other: Placebo<br>* The patients will receive a placebo drink (drinking water) of equivalent volume (3x 65ml)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum change of stroke volume index | Maximum change of stroke volume index (ml/m2) between baseline and hour 1 - 3 | Maximum value of stroke volume index measured between hour 1 - 3 of the study protocol at 15-minute intervals | 
| Maximum change of cardiac index | Maximum change of cardiac index (L/m2) between baseline and hour 1 - 3 | Maximum value of cardiac index measured between hour 1 - 3 of the study protocol at 15-minute intervals | 
| Change of mean stroke volume index | Difference between baseline stroke volume index and mean stroke volume index (ml/m2) during the study protocol | Mean value of stroke volume index measured every 15 minutes during 9 hours of the study protocol | 
| Change of mean cardiac index | Difference between baseline cardiac index (L/m2) and mean cardiac index during the study protocol | Mean value of cardiac index measured every 15 minutes during 9 hours of the study protocol | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in patient/symptoms | Change in patient-referred symptoms by visual-analog scale (1=unbearable dyspnea, 10=no symptoms) | Symptoms scored at hours 0, 1, 10, 24 and expressed as an area under the curve |