NIRS and Exercise Intensity in Patients With FLIA

Study Overview
=================
Brief Summary
-----------------
The research objectives of this project are to increase the understanding of pathophysiology and performance limitations related to sport-related flow limitation in the iliac artery (FLIA) using non-invasive measurement of muscle oxygenation at the working muscles of the leg and mechanical power output recorded during cycling exercise. Skeletal muscle oxygenation measured with Near-Infrared Spectroscopy (NIRS) is growing more accessible for use by coaches, teams, and individual athletes for use in performance testing. Describing how muscle oxygenation profiles in endurance athletes diagnosed with FLIA differ in comparison with healthy athletes may allow the use of this non-invasive, accessible measurement device for the screening of athletes at risk of developing FLIA. The relevance of this work is that FLIA imposes risk of irreversible injury to the main artery of the leg in endurance athletes, limiting their ability to participate in exercise, with further consequences for health, fitness, and quality of life. Currently, the early course of this progressive condition is poorly understood, as early detection is difficult and hence appropriate treatment is often delayed. If impairment becomes severe, often more invasive (and risky) treatment is necessary. Earlier detection and monitoring of FLIA may allow for improved patient management and outcomes. The design of this experiment will compare a patient group of trained cyclists diagnosed with FLIA, to healthy control subjects including cyclists of a similar fitness level without signs of FLIA. Both groups will perform an incremental ramp cycling test and an intermittent multi-stage cycling exercise test. Incremental ramp cycling testing is used as part of clinical diagnosis of FLIA, as well as performance (eg. VO2max) testing of healthy athletes. Multi-stage exercise protocols are also often used for performance testing of endurance athletes and allows for observation of (path)physiological responses during submaximal work stages. Outcome measures of muscle oxygenation kinetics with NIRS and cycling power will be analysed and compared between patients and healthy subjects.

Detailed Description
-----------------
A professional cyclist covers approximately 25,000 km a year and flexes the hip 8,000,000 times in a year, while leg blood flow is in the range of 10-15 litres per minute. This poses a substantial hemodynamic load on the iliac artery. As a result, a proportion of endurance athletes develop a limitation in leg circulation due to arterial narrowing in this iliac artery. An early 'Lancet' study of the department of Sports Medicine of Máxima Medical Centre (MMC) found that 20% of professional cyclists were suffering from such a sport-related Flow Limitation in the Iliac Artery (FLIA) necessitating treatment. The incidence in recreational cyclists is unknown, but with 849,000 recreational cyclists in the Netherlands cycling over 3,000 km a year with an impressive 1,000,000 hip flexions, many of them travel similar distances as a professional cyclist, incurring similar risks for developing FLIA. If untreated, FLIA may have a pronounced impact on quality of life. Professional athletes may have to end their careers prematurely. In a substantial subset of cyclists, abnormalities may even lead to complete occlusion and/or thrombosis, with severe symptoms in daily life. Clinical experience suggests that early detection and treatment leads to better outcomes. If diagnosed at a late stage, conservative management including changes in training behaviours and body position, or least-invasive surgical repair options will no longer suffice. The only options remaining would be to cease participation in the provocative activities altogether, or to undergo extensive and risky reconstructive vascular surgery. Understanding the early pathogenesis in order to improve detection is thus of paramount importance. Unfortunately, early detection is often missed due to the non-specific presentation of symptoms and the high level of specialisation required for clinical evaluation. There is a wide range of differential diagnoses that could contribute to the non-specific symptoms observed in the early stages of FLIA, including common musculoskeletal and tendinous injuries, mechanical or neurogenic pain referred from the low back or SI joint, hip acetabular labral tear, chronic exertional compartment syndrome, or fibromuscular dysplasia.8 Currently available diagnostic evaluations can have low sensitivity for an athletic population. There is no single gold-standard evaluation for diagnosing FLIA. The current consensus suggests that the best single functional test is a provocative maximal exercise test on a cycle ergometer, followed by measuring blood pressure at the ankle and brachial arteries (ankle-brachial blood pressure index; ABI) in a competitive posture. In the rare case that the problem is unilateral, the sensitivity is 73%. If the problem is bilateral, the sensitivity is only 43%. Imaging techniques, including echo-Doppler examination, magnetic resonance angiogram (MRA), and computed tomography (CT) scan are more sensitive, but they are more expensive, less accessible, and not part of primary care evaluation, instead being typically reserved for investigation of more severe or complex presentations, and to guide surgical repair. Near-infrared Spectroscopy (NIRS) is an innovative technique that measures relative oxygenation in the muscle, as the balance of oxygenated and deoxygenated haemoglobin and myoglobin. Impaired arterial leg circulation, such as observed in peripheral vascular disease (PVD) has been shown to produce a drop in oxygen saturation of skeletal muscle tissue relative to workload or exercise performance, and delays in reoxygenation kinetics after exercise and ischemic vascular occlusion tests (VOT). Consequently, NIRS may be able to detect alterations in oxygenation that are associated with the level of arterial insufficiency. We recently reported proof of concept studies regarding the potential diagnostic role of both power output and NIRS in patients with diagnosed sport-related FLIA. Complaints reported in the early stages of FLIA are powerlessness and pain in the leg muscles when cycling near maximal exertion, which rapidly disappear with rest. Traditionally, incremental ramp cycling exercise to maximal exercise tolerance has been used as a provocative functional test, after which clinical outcome measures including ABI are tested. As the condition progresses however, symptoms can occur earlier during exercise at a lower intensity and take longer to resolve during recovery. Multi-stage exercise protocols are commonly used to understand metabolic responses related to submaximal exercise intensity. Therefore, a progressive multi-stage cycling protocol with brief recovery intervals between work intervals will be introduced. This protocol is designed to allow for multiple opportunities to evaluate work and recovery responses in an intensity-dependent manner. Subjective symptoms, performance impairments (including limitations to cycling power output) and muscle oxygenation kinetic delays will be evaluated across submaximal workloads including after maximal intensity. Understanding the onset of symptoms and objective signs of flow limitation with progressive exercise intensity will improve understanding of severity and progression of this condition. These outcome measures will be compared to healthy subjects, in order to develop normative values related to healthy performance, compared to pathological impairment. The use of a common multi-stage performance assessment protocol will improve the applicability of using this approach for screening and early detection of FLIA outside of a specialised vascular clinic. It has been suggested that altered vascular function and structure may contribute to the appearance of symptoms in patients in which obvious stenosis or intraluminal disease is not apparent on imaging. In addition to standard clinical evaluation of the aortoiliac tract with echo-Doppler ultrasound, vascular flow velocity will be recorded for later offline analysis of pulse wave velocity as a measurement of arterial stiffness.

Official Title
-----------------
A Non-invasive Exercise Test for Evaluating Sport-related Arterial Blood Flow Limitation in the Leg: an Exploratory Study (NIRS and Cycling Power in Patients With FLIA)

Conditions
-----------------
Near-Infrared Spectroscopy, Iliac Artery Stenosis, Iliac Artery Disease, Iliac Artery Occlusion

Intervention / Treatment
-----------------
* Other: Cycling test
* Other: Occlusion tests
* Device: NIRS during cycling
* Device: CPET
* Device: Echo-Doppler examination


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Aged ≥ 18 years and ≤ 40 years Trained cyclist or triathlete regularly training at least  3/week for at least five years and identifying with a particular cycle-sport Exclusion Criteria: Earlier vascular iliac surgery Microvascular abnormalities (e.g. diabetes), Vascular abnormalities outside of the iliac region, Heart failure (New York Heart Association class >I), Orthopedic/neurological entities potentially limiting exercise capacity, Obesity. Adipose tissue thickness > 7.5 mm These excluding conditions are considered as medical safety precautions to maximal exercise or as risk of unexpected pathophysiological effects confounding our primary outcome measures. It is known that a high level of adipose tissue thickness (ATT) influences the accuracy of NIRS measurement of underlying muscular tissue. A > 7.5 mm ATT cut-off point at the site of NIRS measurement determined with a skinfold caliper (Harpenden, Baty International West Sussex, UK) was chosen. The ATT is calculated as half the skinfold thickness.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 40 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Healthy subjects<br>Subjects without FLIA | Other: Cycling test<br>* RAMP and MULTI-STAGE test<br>Other: Occlusion tests<br>* Occlusion test before and after exercise<br>Device: NIRS during cycling<br>* NIRS devices measuring oxygenation during exercise<br>Device: CPET<br>* Cardiopulmonary exercise testing (heart rate, pulmonary gas exchange) during exercise<br>Device: Echo-Doppler examination<br>* Peak systolic velocity and vascular stiffness measurements in the iliac-aortic tract<br>|
| Patient subjects<br>Subjects with FLIA | Other: Cycling test<br>* RAMP and MULTI-STAGE test<br>Other: Occlusion tests<br>* Occlusion test before and after exercise<br>Device: NIRS during cycling<br>* NIRS devices measuring oxygenation during exercise<br>Device: CPET<br>* Cardiopulmonary exercise testing (heart rate, pulmonary gas exchange) during exercise<br>Device: Echo-Doppler examination<br>* Peak systolic velocity and vascular stiffness measurements in the iliac-aortic tract<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Power-deoxygenation (PD) profile | Power-deoxygenation (PD) profile: The ratio of power output to deoxygenation (eg. power/deoxy[heme]) as a proxy for the metabolic disturbance at the working muscle relative to the workload. | During cyclingtest day 1 | 
| Near Infrared Spectroscopy (NIRS) deoxygenation parameters | Baseline: Average 60-second value before the start of exercise. min: the minimum 5-second mean value attained during exercise. max: the maximum 5-second mean value attained typically during the recovery after exercise. Δexercise amplitude: the difference between baseline and minimum values. | During cyclingtest day 1 | 
| Near Infrared Spectroscopy (NIRS) deoxygenation parameters | Baseline: Average 60-second value before the start of exercise. min: the minimum 5-second mean value attained during exercise. max: the maximum 5-second mean value attained typically during the recovery after exercise. Δexercise amplitude: the difference between baseline and minimum values. | During cyclingtest day 2 | 
| NIRS delta_recovery amplitude | The difference between minimum and maximum value. | During cyclingtest day 1 | 
| NIRS delta_recovery amplitude | The difference between minimum and maximum value. | During cyclingtest day 2 | 
| NIRS reoxygenation kinetics: tau | Time constant (tau, in seconds): the time constant parameter of a monoexponential curve fit to the reoxygenation profile after each work stage. | Immediately after exercise day 1 | 
| NIRS reoxygenation kinetics: Time delay | Time delay (TD, in seconds): the delay before systematic rise in oxygenation after each work stage. | Immediately after exercise day 1 | 
| NIRS reoxygenation kinetics: Mean Response Time | Mean response time (MRT, in seconds): the sum of TD and tau. | Immediately after exercise day 1 | 
| NIRS reoxygenation kinetics: Half value time | Half value recovery time (HVT, in seconds): the time required to reoxygenate half of the total amplitude during recovery after each work stage. | Immediately after exercise day 1 | 
| NIRS reoxygenation kinetics: Peak reoxygenation rate | Peak reoxygenation rate (SmO2/sec): a linear estimation of the peak resaturation slope, representing the magnitude of greatest mismatch between oxygen supply and utilization at the tissue during recovery kinetics, after each work stage. | Immediately after exercise day 1 | 
| NIRS reoxygenation kinetics: Peak reoxygenation MRT | Peak reoxygenation MRT: an estimate of the time to occurrence of the peak reoxygenation rate, analogous to the MRT in a monoexponential curve, and representing the balance of recovery kinetics of oxygen supply and utilization in the tissue after each work stage. | Immediately after exercise day 1 | 
| NIRS reoxygenation kinetics: tau | Time constant (tau, in seconds): the time constant parameter of a monoexponential curve fit to the reoxygenation profile after each work stage. | Immediately after exercise day 2 | 
| NIRS reoxygenation kinetics: Time delay | Time delay (TD, in seconds): the delay before systematic rise in oxygenation after each work stage. | Immediately after exercise day 2 | 
| NIRS reoxygenation kinetics: Mean response time | Mean response time (MRT, in seconds): the sum of TD and tau. | Immediately after exercise day 2 | 
| NIRS reoxygenation kinetics: Half Value time | Half value recovery time (HVT, in seconds): the time required to reoxygenate half of the total amplitude during recovery after each work stage. | Immediately after exercise day 2 | 
| NIRS reoxygenation kinetics: Peak reoxygenation rate | Peak reoxygenation rate (SmO2/sec): a linear estimation of the peak resaturation slope, representing the magnitude of greatest mismatch between oxygen supply and utilization at the tissue during recovery kinetics, after each work stage. | Immediately after exercise day 2 | 
| NIRS reoxygenation kinetics: Peak reoxygenation MRT | Peak reoxygenation MRT: an estimate of the time to occurrence of the peak reoxygenation rate, analogous to the MRT in a monoexponential curve, and representing the balance of recovery kinetics of oxygen supply and utilization in the tissue after each work stage. | Immediately after exercise day 2 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recovery kinetics VO2/NIRS comparison | To describe skeletal muscle oxygenation kinetics vs pulmonary oxygen uptake kinetics in both healthy cyclists and patients with FLIA | After stages/maximal exercise. This is an offline analyses and therefore takes the time of the stage (1 minute for in between blocks; 5 minutes for maximal exercise) | 
| Vascular Occlusion Test - Reactive Hyperemia Area Under The Curve | Reactive Hyperemia area under the curve: the area of the NIRS signal (eg. SmO2⋅sec) will be calculated during the recovery from occlusion, as the total area under the curve and above the baseline value before cuff inflation during the first 4-minutes of recovery. (This will be calculated from the same VOT for Outcome 1 | Before cycling test day 1 | 
| Multiple reoxygenation kinetics - Primary Component Time constant tau | Primary component time constant (tau): the time constant parameter of a monoexponential curve fit to the rise in VO2 at the start of each work stage. | Between intervention day 1 (1-minute stages of block-protocol) and immediately after the intervention day 2 (ramp maximal test) | 
| Multiple reoxygenation kinetics - Cardiodynamic component time delay | Cardiodynamic component time delay (TD): the delay before systematic rise in VO2 at the start of each work stage. | Between intervention day 1 (1 minustages of block-protocol) and immediately after the intervention day 2 (ramp maximal test) | 
| Multiple reoxygenation kinetics - Δdeoxy[heme] / ΔVO2 onset kinetics | Δdeoxy[heme] / ΔVO2 onset kinetics: The oxygenation and VO2 curves will be normalized at the start of each work stage to a starting baseline and the eventual steady-state, as 0-100% of the response profile. The relative overshoot of Δdeoxy[heme] vs ΔVO2 can then be used to describe the matching of perfusive O2 delivery to O2 extraction. | During intervention day 1 (stages of block-protocol) | 
| Multiple reoxygenation kinetics - Δdeoxy[heme] / ΔVO2 recovery kinetics | Δdeoxy[heme] / ΔVO2 recovery kinetics: The same comparison of the response profiles of deoxy[heme] and VO2 will be performed during recovery after work stages. | Between intervention day 1 (stages of block-protocol) and immediately after the intervention day 2 (ramp maximal test) | 
| Vascular Occlusion Test (VOT): Microvascular Responsiveness | Microvascular Responsiveness (peak reoxygenation rate, eg. SmO2/sec): the linear slope of reoxygenation when the occlusion cuff is removed will be taken as the rate of reperfusion, representing microvascular responsiveness, a proxy for vasodilatory capacity and vascular function. | Before and after cycling test day 1 | 
| Vascular Occlusion Test (VOT): Reactive Hyperemia | Reactive Hyperemia area under the curve: the area of the NIRS signal (eg. SmO2⋅sec) will be calculated during the recovery from occlusion, as the total area under the curve and above the baseline value before cuff inflation during the first 4-minutes of recovery. Calculated from same in VOT (Outcome 7) | Before and after cycling test day 1 | 
| Clinical Assessment | Peak systolic velocity (PSV): Measurement of PSV at the external iliac artery with echo-Doppler ultrasound, before and after exercise, and with and without provocative maneuvers can be discriminative for FLIA. | During the same examination-appointment. The PSV will be measured following measurments of the arterial stiffness. This takes about 10 minutes for both sides. | 
| Clinical Assessment | Ankle brachial index (ABI): Blood pressures will be taken at bilateral ankles and from the arm both before and after exercise. The ratio of ankle and brachial pressures adjusted for height, and a bilateral difference can be discriminative for FLIA. | Immediately after maximal exercise day 1 | 
| Clinical Assessment | Ankle brachial index (ABI): Blood pressures will be taken at bilateral ankles and from the arm both before and after exercise. The ratio of ankle and brachial pressures adjusted for height, and a bilateral difference can be discriminative for FLIA. | Immediately after maximal exercise day 2 | 
| Clinical Assessment | Arterial stiffness with echo-Doppler: Arterial pulse wave velocities will be measured at the carotid and external iliac/femoral arteries with echo-Doppler ultrasound, before and after exercise. The velocity of propagation of the pulse wave is taken as an index of arterial stiffness. | Before exercise day 1, the arterial stiffness will be measured by the vascular technician. While this will be analyzed offline, this takes a few minutes. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
FLIA, NIRS, Endofibrosis