Supine Exercise in Hepatopulmonary Syndrome Patients With Orthodeoxia

Design and Rationale for a Randomized Controlled Crossover Trial of Supine Versus Upright Exercise in Patients With Hepatopulmonary Syndrome and Orthodeoxia

Hepatopulmonary syndrome (HPS) is a rare condition that presents in about a quarter of patients with liver cirrhosis. In addition, a small subset of these HPS patients also have orthodeoxia, defined as a drop in oxygen levels when they are sitting up (upright), as opposed to lying flat (supine). At present, there is little known about this condition. Patients diagnosed with HPS and orthodeoxia experience reduced ability to exercise, especially when upright. While standard cardiopulmonary exercise is routinely performed in the sitting position, there are machines that enable candidates to exercise in the supine position. This is especially relevant in patients with severe HPS, with clinically significant orthodeoxia, where conventional upright exercise is difficult. Currently there is a gap in the literature regarding the efficacy of supine exercise compared to upright exercise in these patients. Due to their improvement in dyspnea when lying supine, it is predicted that these patients will be able to exercise for a greater length of time and have increased exercise capacity, which can be projected to improve outcomes pre- and post-transplant.

Overall, HPS patients tend to experience hypoxemia and exercise limitation. Exercise limitation impacts quality of life, incidence and severity of comorbid conditions, and in those who are liver transplant candidates, low exercise tolerance deleteriously impacts transplant outcomes. Accordingly, a strategy that enables patients to exercise more often and/or for longer periods would offer direct benefits to patients with HPS, and if employed as part of an exercise program, could also improve exercise capacity, and thus, liver transplant outcomes.

The purpose of this study is to investigate the effect of supine, compared to upright position on exercise in patients with HPS and orthodeoxia. We hypothesize that these patients will be able to exercise for longer in the supine compared to the upright position, given improved oxygen levels when supine.

Study Overview

• Status: Recruiting
• Conditions: Hepatopulmonary Syndrome
• Intervention / Treatment: Diagnostic test: Upright Exercise; Diagnostic test: Supine Exercise

Detailed Description

This is a 1 year randomized crossover controlled trial study of the effect of supine exercise position (intervention arm) compared to the upright exercise position (control arm) within 4 weeks. This is a single-center study conducted at St. Michael's Hospital, Toronto, Ontario.

The exercise will be performed at a constant work rate, individualized for each participant. Peak work rate will be calculated using results from the most recent room air 6-minute walk test (6MWT), within the past 6 months. The equation used to estimate peak work rate is: Peak Work Rate = 0.168 x 6MWD (m) - 4.085 (ref Kozu Respirology 2010). The individualized constant work rate will be set at 70-80% of this estimated peak work rate.

The main stopping criterion will be the point at which, after standardized encouragement, the subject is unable to continue because of symptoms (i.e. patient does not wish to continue or cannot maintain a minimum peddling frequency of 40 rpm for ≥ 10 seconds). This is defined as the "tolerable limit" (tLIM). Additional safety-related stopping criteria will include: the appearance of life-threatening arrhythmias, a drop in systolic blood pressure by ≥ 10 mm Hg from baseline, or a desaturation below a set point for ≥ 30 s. The set saturation point will be chosen individually for each patient, as the lower of: 80% or the lowest saturation seen on room air 6MWT.

Exercise tests in each position, for each subject, will be standardized with respect to the proper seat adjustment relative to leg length and pedaling cadence (50-60 rpm). Inspiratory capacity will be measured before and after the exercise maneuver.

The cycle ergometer resistance will be set to the pre-determined constant work rate, as described above. There will be continuous monitoring of saturation, ECG, gas exchange, blood pressure, and subjective dyspnea/leg fatigue (Borg scale), with standardized verbal encouragement throughout. Participants will be asked to bring running shoes and comfortable exercise clothes, ensure that they have eaten before the test, to take all usual medications, and to avoid major exercise for 24 hours before the test.

• Study Type: Interventional
• Enrollment (Anticipated): 10
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Samir Gupta, MD, MSc; Phone Number: 2252 (416) 864-6060; Email: guptas@smh.ca

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5B 1W8
      • Recruiting
      • St. Michael's Hospital
      • Contact: Samir Gupta, MD, MSc; Phone Number: 2252 (416) 864-6060; Email: guptas@smh.ca
      • Principal Investigator: Samir Gupta, MD, MSc

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Diagnosis of moderate HPS (defined by liver disease, hypoxemia [PaO2 < 80 mmHg and AaDo2 (alveolar-arterial PO2 difference) ≥ 15 mmHg or ≥ 20 mmHg if age > 64 years] and IPVD (intrapulmonary vasodilatations) as shown by contrast echocardiography])
2. Presence of orthodeoxia (PaO2 decrease by >4 mmHg when patient moves from supine to upright position).

Exclusion Criteria:

1. Pulmonary hypertension (echocardiographic estimated right ventricular systolic pressure >/=50 mmHg and/or right heart catheterization mean pulmonary artery pressure >25 mmHg with pulmonary capillary wedge pressure </= 15 mmHg);
2. Significant obstructive ventilatory impairment (FEV1/FVC ratio < 0.65) (FEV=forced expiratory volume in 1 second; FVC=forced vital capacity)
3. Known significant coronary artery disease;
4. Significant neurologic, orthopedic or rheumatological disorders preventing the use of a cycle ergometer;
5. Other absolute contraindications to submaximal tests (uncontrolled cardiac arrhythmia with hemodynamic compromise, symptomatic severe aortic stenosis, decompensated heart failure and acute cardiopulmonary illness);
6. Moderate or severe ascites.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Control - Upright Exercise; Participants will perform upright exercise on a cycle ergometer. The opposite test will be completed within 4 weeks.	Diagnostic test: Upright Exercise; Exercise is generally performed in the upright position.
Experimental: Intervention - Supine Exercise; Participants will perform supine exercise on a cycle ergometer. The opposite test will be completed within 4 weeks.	Diagnostic test: Supine Exercise; Since HPS patients with orthodeoxia experience an improvement in their symptoms and oxygen levels when supine, the intervention will involve them performing exercise in the supine position.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Stopping time (tLIM)	The main stopping criterion will be the point at which, after standardized encouragement, the subject is unable to continue because of symptoms [defined as the "tolerable limit" (tLIM)]. Additional safety-related stopping criteria will include: the appearance of complex ventricular arrhythmias, intraventricular and/or atrioventricular conduction disorders, bradyarrhythmias, or a desaturation below a set point for ≥ 10 s. The set saturation point will be chosen individually for each patient, as the lower of: 80%, or the nadir desaturation seen on room air six-minute walk test (6MWT).	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Isotime Oxygen Uptake (VO2)	Comparing oxygen uptake in the supine and upright position.	12 months
Dyspnea	Patient's subjective measure of shortness of breath using Borg scale. This scale ranges from 0 to 10, with 0 being no shortness of breath to 10 being maximal shortness of breath.	12 months
Leg Fatigue	Patient's subjective measure of leg fatigue using Borg scale. This scale ranges from 0 to 10, with 0 being no leg fatigue at all to 10 being maximal leg fatigue.	12 months
Work Rate	Constant work rate / resistance at which the cycle ergometer was set.	12 months
Arterial Oxygen Saturation	The saturation of oxygen in the arteries.	12 months
Change in Inspiratory Capacity	Measuring volume of air that can be maximally inspired after normal tidal breaths and comparing between supine and upright.	12 months
Reason for Stopping Exercise	Reason due to which tLIM was reached and exercise was stopped.	12 months
Minute Ventilation (VE)	The quantity of air expired out of the lungs per minute.	12 months
Heart Rate	The number of heart beats per minute, also known as pulse.	12 months
VCO2	Carbon dioxide output per unit of time.	12 months
VCO2 over VO2	The volume of carbon dioxide produced to the volume of oxygen consumed in respiration over a period of time, also known as respiratory quotient (RQ).	12 months
HR over VO2	The change of heart rate to the volume of oxygen consumed in respiration over a period of time.	12 months
VE over time	The change of VE during the entire duration of the exercise.	12 months
VO2/ HR over time	The change of oxygen pulse during the entire duration of the exercise.	12 months
Heart rate over time	The change of heart rate during the entire duration of the exercise.	12 months
Cardiac output	The volume of the blood pumped by the heart through the circulatory system in a minute.	12 months
Change in inspiratory capacity	The difference of the maximum volume of air that can be inspired following a normal, quiet expiration	12 months
VE max	Maximum minute ventilation	12 months
End tidal CO2 over time	The point at the end of exhalation when the CO2 reaches its highest concentration.	12 months

Collaborators and Investigators

• Sponsor: Unity Health Toronto
• Investigators: Principal Investigator: Samir Gupta, MD, MSc, Clinician-Scientist

Publications and helpful links

General Publications

• Parikh H, Lui E, Faughnan ME, Al-Hesayen A, Segovia S, Gupta S. Supine vs upright exercise in patients with hepatopulmonary syndrome and orthodeoxia: study protocol for a randomized controlled crossover trial. Trials. 2021 Oct 9;22(1):683. doi: 10.1186/s13063-021-05633-7.

Helpful Links

• Peak work rate estimated from 6-minute walk distance.

Study record dates

Study Major Dates

• Study Start (Actual): July 24, 2019
• Primary Completion (Anticipated): December 1, 2023
• Study Completion (Anticipated): August 31, 2024

Study Registration Dates

• First Submitted: June 27, 2019
• First Submitted That Met QC Criteria: June 27, 2019
• First Posted (Actual): July 1, 2019

Study Record Updates

• Last Update Posted (Actual): May 10, 2023
• Last Update Submitted That Met QC Criteria: May 9, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Keywords: Supine Exercise; Orthodeoxia
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Respiratory Tract Diseases; Lung Diseases; Disease; Liver Diseases; Syndrome; Hepatopulmonary Syndrome
• Other Study ID Numbers: 19-127

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No