Ketones for Pulmonary Hypertension - Effects on Hemodynamics

Study Overview
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Brief Summary
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In the present study, patients with idiopathic pulmonary hypertension (IPAH) and chronic thromboembolic pulmonary hypertenion will be investigated in a randomized cross-over design with ketone infusions and placebo. Invasive and non-invasive hemodynamics will be evaluated

Detailed Description
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Pulmonary hypertension (PH) is a debilitating disease that affects both the pulmonary vasculature and the heart. It is associated with increased mortality and hospitalization and impairs daily life for the affected patients. Despite substantial advances in treatment within the past decade the prognosis remains poor with an 1-year mortality of more than 10%.1 The pathophysiology of PH is multifactorial and can be caused by left sided cardiac disease, pulmonary pathophysiological changes in the pulmonary vessels, respiratory diseases and pulmonary embolism.The treatment is targeted at the underlying cause. Hence, left sided heart disease is treated with anticongestive medications4 and respiratory disease by pulmonary medications. However, pulmonary vascular diseases such as chronic thromboembolic pulmonary hypertension (CTEPH) and idiopathic pulmonary arterial hypertension (IPAH) are treated with pulmonary endarterectomy and vasodilators targeting the pulmonary vasculature, respectively. However, not all patients have an optimal pulmonary hemodynamic response on treatment. If patients are left with persistent pulmonary hypertension the disease may progress further and cause right heart failure which worsens the prognosis. Data from a recent study conducted at the investigator's institution demonstrated 40% increase in cardiac output during infusion of the ketone body 3-hydroxybutyrate (3-OHB). Intriguingly, this was associated with an increase in RV function and a decrease in the pulmonary vascular resistance of approximately 20%. In the present study, 10 patients with IPAH and 10 patients with CETPH will be subjected to placebo and 3-OHB infusion in a randomized cross-over design. Each of the infusions will be given for 2.5 hours and cross-over will be carried out on the same day. Echocardiography and right sided heart catheterization will be applied and blood will be sampled.

Official Title
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Ketone Administration in Patients With Pulmonary Hypertension - Effects on Hemodynamics

Conditions
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Pulmonary Hypertension, Ketonemia

Intervention / Treatment
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* Dietary Supplement: Hyperketonemia - use of ketone (3-OHB) infusion
* Dietary Supplement: Placebo - use of saline infusion


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Persistent pulmonary hypertension (defined as PVR > 3 WU, pulmonary capillary wedge pressure (PCWP) < 15 mmHG, mean pulmonary arterial pressure (mPAP) ≥25 mmHg) on the most resent right heart catheterization. Preserved left ventricular ejection fraction (<50%) on most recent echocardiography Able to give informed consent Exclusion Criteria: Other Significant pulmonary, mitral or aortic valve disease Other disease or treatment making subject unsuitable for study participation

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: Crossover Assignment
Interventional Model Description: Randomized cross-over I.e. Ketone infusion is compared to saline infusion in a randomised cross-ove design. (Ketones are considered dietary supplement as glucose or lipids)
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 3-OHB vs Saline<br>3-OHB will be infused for 2.5 hours in IPAH (n=5) and CETPH (n=5) patients- 6 in each group is recruited for taking drop-out into account | Dietary Supplement: Hyperketonemia - use of ketone (3-OHB) infusion<br>* The effect of intravenous ketone supplement<br>Dietary Supplement: Placebo - use of saline infusion<br>* Saline is infused as an comparator<br>|
| Experimental: Saline vs 3-OHB<br>Saline will be infused for 2.5 hours in IPAH (n=5) and CETPH (n=5) patients- 6 in each group is recruited for taking drop-out into account | Dietary Supplement: Hyperketonemia - use of ketone (3-OHB) infusion<br>* The effect of intravenous ketone supplement<br>Dietary Supplement: Placebo - use of saline infusion<br>* Saline is infused as an comparator<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cardiac output (L/min | Measured by Swan-Ganz monitoring | changes during the infusion for 2.5 hours compared to 2.5 hours of Saline infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| mixed venous saturation (%) | Hemodynamics - Swan Ganz monitoring | changes during the infusion for 2.5 hours compared to 2.5 hours of Saline infusion | 
| systemic blood pressure (mmHg) | Hemodynamics - non-invasive blood pressure measurement | changes during the infusion for 2.5 hours compared to 2.5 hours of Saline infusion | 
| pulmonary capillary pressure (mmHg) | Hemodynamics - Swan Ganz monitoring | changes during the infusion for 2.5 hours compared to 2.5 hours of Saline infusion | 
| Pulmonary pressure (mmHg) | Hemodynamics - Swan Ganz monitoring | changes during the infusion for 2.5 hours compared to 2.5 hours of Saline infusion | 
| TAPSE (mm) | Echocardiography | changes during the infusion for 2.5 hours compared to 2.5 hours of Saline infusion | 
| RV strain (%) | Echocardiography | changes during the infusion for 2.5 hours compared to 2.5 hours of Saline infusion | 
| LV strain (%) | Echocardiography | changes during the infusion for 2.5 hours compared to 2.5 hours of Saline infusion | 
| systolic tricuspid plane velocity (cm/sec) | Echocardiography | changes during the infusion for 2.5 hours compared to 2.5 hours of Saline infusion | 
| Left ventricular ejection fraction (%) | Echocardiography | changes during the infusion for 2.5 hours compared to 2.5 hours of Saline infusion | 
| Changes in Prostaglandines (pmol/L) | Blood samples | changes during the infusion for 2.5 hours compared to 2.5 hours of Saline infusion | 
| pH | Blood samples | changes during the infusion for 2.5 hours compared to 2.5 hours of Saline infusion | 
| sodium (mM) | Blood samples | changes during the infusion for 2.5 hours compared to 2.5 hours of Saline infusion | 
| potassium (mM) | Blood samples | changes during the infusion for 2.5 hours compared to 2.5 hours of Saline infusion | 
| lactate (mM) | Blood samples | changes during the infusion for 2.5 hours compared to 2.5 hours of Saline infusion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Right sided heart catheterization, Echocardiography, Hemodynamics