Cardiopulmonary Exercise Testing (CPET) is a safe, non-invasive assessment of cardiorespiratory function. It allows the determination of crucial prognostic variables and can distinguish pathophysiology not apparent at rest. It can discriminate cardiovascular, ventilatory, and musculoskeletal limitations during exercise by monitoring disturbances in key variable responses such as: oxygen, carbon dioxide, minute ventilation, and heart rate.  It offers additional interpretive power over conventional stress testing and thus can lead to improved clinical decision-making and risk stratification in patients with cardiometabolic and respiratory disease.
The ability to perform physical exercise is dependent on the cardiovascular system's ability to deliver oxygen to the tissues, and eliminate the metabolic by-products produced. The transport of O2 and CO2 in and out of the human body is a sequential phenomenon. Three processes occur in the body that assists with the ability to supply O2 and remove CO2.
Ventilation-Perfusion Matching: In healthy individuals, exercise causes blood flow to the apex of the lung to increase, due to increased recruitment of previously unused capillaries (increase in tidal volume) along with decreased pulmonary vascular resistance. This results in increased flow to the pulmonary circuit during exercise with relatively small increases in pulmonary arterial pressure. The increase in tidal volume is seen early in exercise and is a contributing factor to increased minute ventilation. The ideal Ventilation (V) - Perfusion (Q) ratio to sustain exercise is ~1.0. Progressive exercise will ultimately end in a V/Q mismatch because cardiac output cannot keep up with the demand of the skeletal muscles. Certain disease states initiate the V/Q mismatch early, contributing to the exercise intolerance commonly observed. In patients with poor cardiac function, perfusion to the lungs is reduced, leading to a high V/Q ratio. Conversely, in patients with respiratory disease ventilation is impaired, causing a low V/Q ratio.
Per the AHA scientific statement for Cardiopulmonary Exercise Testing .
Class 1 indication:
Class 2a indication:
Class 2b indication:
Contraindications per AHA guidelines:
A metabolic cart is used to accurately measure the variables of metabolic gas exchange. To interpret the values accurately, adhering to the calibration standards and quality assurance procedures is essential. There may be slight differences in calibration techniques as there are a variety of metabolic carts available. Following the instructions provided by the manufacturer, in conjunction with the recommendation that is described in detail in the AHA scientific statement by Balady et al.  is vital.
Additionally, emergency equipment should be readily available. This includes:
Choosing an appropriate exercise protocol is essential in increasing the validity of the results. Although there are multiple study protocols available for use, the clinician should tailor the protocol to the patient such that it can yield a fatigue-limited exercise in approximately 8 to 12 minutes. The most commonly used methodology is incremental or constant work protocols. Ramp protocols are a type of incremental protocol where there is a gradual increase in work rate at specified time intervals of each minute of different exercise phases.
Peak VO2: Maximal Oxygen Uptake
Maximal VO2 is the measure of one’s aerobic capacity representing the amount of oxygen taken in by the skeletal muscle during exercise. There is a linear relationship between exercise intensity and oxygen uptake until the cardiovascular system can no longer met the demands of the exercising muscle. This is known as an oxygen uptake plateau and achieved following progressive exercise.
VO2 is derived using the Fick equation where maximal oxygen uptake equals cardiac output x the arteriovenous difference (VO2 = CO x (CaO2 – CvO2). Higher VO2 values represent greater aerobic fitness. Men have higher peak VO2 due to increased levels of hemoglobin, increased stroke volume and greater muscle mass. 
Declines in VO2 happen with age, there is approximately a 10% decrease every ten years after 30 years of age. This is due to decreases noted in stroke volume and maximal heart rate.  Any pathophysiologic state can impair peak VO2 as seen in heart failure or chronic obstructive pulmonary disease (COPD) and even in deconditioning . Values below 80% of predicted (based on age, gender and anthropometric data) are considered abnormal. VO2 is the most important parameter, as it can quantitatively measure disease severity.
O2 pulse is the amount of oxygen consumed by the tissues at any given heart rate (VO/HR). This value is used as a surrogate for stroke volume. Decreased O2 pulse often points to a cardiac limitation to exercise.
There is a physiologic max for heart rate based on age. The generally accepted equation is: 220-age. The normal heart rate response to progressive exercise is linear. Peak exercise HR that is 20 bpm below (<85%) age-predicted max for subjects limited by volitional fatigue is considered chronotropic incompetence.
Exercise is a state of increased sympathetic tone which is overridden by local vaso-regulatory mechanisms. The metabolic byproducts produced by exercise all favor vaso-regulation which all lower systemic vascular resistance. Additionally, blood shunting occurs where any nonworking muscles/organs remain in a vaso-constricted state in order to promote more blood flow to the working muscles. The initial phase of progressive exercise CO is mainly increased due to the increased LV stroke volume in response to blood filling (frank-starling). Around 50% of the VO2 max, further increases in CO are augmented due to increased heart rate.
Ventilatory Anaerobic Threshold (VAT)
VAT is the point in exercise where there is a supply /demand imbalance of oxygen being delivered to working muscles activating anaerobic metabolism. Minute ventilation increases disproportionately to the workload, where for any increases in VO2, VCO2 increases out of proportion. When a plot is drawn with VCO2 as X-axis and VO2 as Y-axis, the point at which the slope of VCO2/VO2 changes from less than 1 to more than 1 is the ventilatory threshold (V-slope method).  At this point in exercise, there are rising blood lactate levels and intracellular bicarbonate levels are not adequate to counteract cellular acidosis. As a compensatory measure, hyperventilation sets in, to dump off the excess VCO2 formed.
Ventilatory Efficiency (VE/VCO2)
The Ventilatory Efficiency slope is demonstrative of how hard a subject must breathe in order to eliminate CO2. It is the major link between the circulatory and ventilatory response to exercise. During exercise initiation, VE/VCO2 typically decreases due to improved ventilation perfusion matching. Throughout exercise, both minute ventilation and CO2 increase in order to maintain acid base status.
Respiratory Exchange Ratio: RER
Represents the metabolic exchange of gases in the tissues and is dependent on fuel utilization used for cellular metabolism. It is the ratio of CO2 elimination over O2 consumption. RER is mainly used as part of the criteria to measure a maximal effort.
Oxygen Uptake Efficiency Slope (OUES)
Slope of the logarithmic relationship between VO2 and minute Ventilation during exercise for any given VO2. The OUES is fairly linear throughout progressive exercise.
Etiologic Categorization of CPET parameters:
Subject deconditioning is apparent from the following responses:
The most dangerous complications include: exercise-induced life-threatening arrhythmias (ventricular tachycardia, ventricular fibrillation, or marked bradycardia), orthopedic injury, hemodynamic instability, or acute myocardial infarction; all requiring immediate medical assessment and subsequent treatment. Other complications include arrhythmias like atrial fibrillation, supraventricular tachycardia, non-sustained ventricular tachycardia, syncope (including vasovagal syncope), stroke, or transient ischemic attack.
Multiple health conditions can contribute to exercise intolerance in both healthy and unhealthy people with various known and unknown comorbidities; cardiopulmonary fitness testing helps in establishing the etiology and also gives prognostic importance, thus playing a significant role in alleviating the diagnostic challenge for clinicians.  When combined with the standard tools of clinical investigation, the cardiopulmonary exercise test is the “gold standard” method for objectively assessing cardiorespiratory physiology.
Cardiopulmonary fitness testing requires an interprofessional team effort, including exercise physiologists, physician assistants, nurses, physical therapists under the supervision of a cardiologist. When a patient is considered high risk for testing (example: in patients within seven days of myocardial ischemia, patients with malignant arrhythmia, severe pulmonary arterial hypertension), the recommendation is that direct supervision of the procedure and immediate availability of a cardiologist is needed to improve patient safety.
We thank Ms. Angela Romme, MS for her insightful comments.
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