Journal of Pediatric Cardiology and Cardiac Surgery

In our everyday clinical practices of pediatric cardiology, various clinical tests at rest, (e.g., chest X-ray, electrocardiogram, echocardiography, blood gas analysis, serum biochemical tests), are essential and indispensable for their evaluation. These tests can only observe, in a sense, physiological functions of the patients in an extraordinarily sedentary and unloaded circumstance; not at all their status during daily activities such as playing, exercising, standing, or sleeping. Therefore, appropriate evaluations of their physiological and cardiopulmonary responses to various stresses are essential in our clinical practices.

Cardiopulmonary exercise testing (CPET) is a test indispensable for the evaluation of functional reserve in subjects with cardiorespiratory diseases, predicting their prognosis, and effectiveness of treatment.¹⁾ Therefore, this review overviews the basics of measurements obtained from CPET sessions, that is, maximal oxygen uptake (V̇O₂max), anaerobic threshold (AT), the minute ventilation (V̇E)-carbon dioxide output (V̇CO₂) regression slope (V̇E/V̇CO₂ slope), and the oxygen uptake efficiency slope (OUES), mainly in pediatric population.

The V̇O₂max shows the “maximal power output” of an examinee, which is determined comprehensively by the reserve functions of the circulatory system, respiratory system, and the skeletal muscles.²⁾ This is one of the important and accurate prognostic indices of patients with heart failure.

When one mole of glucose is aerobically metabolized, a total of 6 moles of oxygen is used and 36 moles of adenosine triphosphate (ATP) is produced; namely, $${\text{C}}_{\text{6}}{\text{H}}_{\text{12}}{\text{O}}_{\text{6}}+{\text{6O}}_{\text{2}}+\text{36ADP}+\text{36Pi}\to {\text{6CO}}_{\text{2}}+{\text{42H}}_{\text{2}}\text{O}\text{+}\text{36ATP}\text{.}$$ ATP is called as “currency of energy” which produces certain amount of energy (30.5 kJ/mol) when it is hydrolyzed to ADP. The proportional relationship addressed in this chemical formula tells us that measuring the amount of oxygen utilized in (or taken into) the body in a certain duration of time (usually per minute) is proportional to the amount of energy produced in the body during the period. In other words, this represents the work rate (power output) of the subject. Although we cannot directly measure the power produced by the body, we can do so indirectly by measuring the amount of oxygen taken into the body in a certain duration of time, that is, the oxygen uptake (V̇O₂). Therefore, measuring the maximal amount of oxygen an examinee can take into the body per a unit of time (V̇O₂max) is nothing other than indicating the maximal energy output the person can produce.

With the Fick’s law, VO₂ is described as: $${\dot{\text{V}}\text{O}}_{\text{2}}=\text{C}\text{.O}\text{.}\times \left({\text{CaO}}_{\text{2}}–{\text{C}}_{\text{V}}{\text{O}}_{\text{2}}\right)=\text{C}\text{.O}\text{.}\times \left({\text{C}}_{\text{PV}}–{\text{C}}_{\text{PA}}\right)$$ where C.O. is cardiac output, and CaO₂, C_VO₂, C_PV and C_PA, are oxygen contents in arterial, mixed venous, pulmonary venous, and pulmonary arterial blood, respectively. The C.O. indicates the function of the heart. The product CaO₂–C_VO₂ represents efficiency of oxygen utility by the skeletal muscles, and the C_PV–C_PA the function of oxygen intake by the lungs. Thus, V̇O₂max can be considered as an index of comprehensive reserves of cardiac, skeletal muscular, and respiratory functions. A normal value of V̇O₂max for a male subject who does not regularly exercise is about 30–40 mL/min/kg, and the value is slightly lower in a woman.

The V̇O₂max is only a “conceptual gold standard”. Maximal exercise is often difficult and sometimes dangerous because it may lead to myocardial ischemia.^3, 4) The physicians therefore have to compromise by using submaximal measurements. The most frequently used measurement in this respect is the peak V̇O₂, the value at the end of incremental exercise testing. The following 3 indices do not need maximal exercise, either; namely, anaerobic threshold (AT), the slope of the minute ventilation (V̇E)/ carbon dioxide production (V̇CO₂) regression, and the oxygen uptake efficiency slope (OUES).

Since the 1920s, the phenomenon that serum lactate concentration rises during strenuous exercise has been known. Lactate is produced in the working skeletal muscles. In the 1960s, Wasserman and coworkers hypothesized that the production of lactate was associated with the ischemia of the muscles above a certain level of exercise intensity. They named the phenomenon as AT.⁵⁾ This hypothesis was so persuasive that many researchers and clinicians believed it. Then, researchers reported that the threshold can be determined non-invasively by analyzing expired gas during incremental exercise testing. This was named as ventilatory threshold (VT). These studies have made the AT the mainstream of the exercise physiology and exercise cardiology during the 1980s and 1990s. However, studies afterwards have proved that 1) any level of exercise intensity cannot cause ischemia of mitochondria of the skeletal muscle which leads to anaerobic energy production,⁶⁾ 2) lactate is produced from the skeletal muscles at any level of exercise intensity,^7–9) 3) the serum lactate levels are determined by the balance between its production and clearance,^10, 11) and 4) accordingly, there is not any “threshold” of the serum lactate levels.^12, 13) These studies have brought a tide of “abandon faith” for AT to most researchers today.

Although they believe that the AT theory that Wasserman advocated has been disproven, the AT is still widely used in our clinical practices. It is because AT represents the exercise intensity that is not too strenuous but not too mild, either. In fact, significant lactate accumulation in the blood does not occur under the exercise intensity below the AT levels. Cardiac ischemia hardly occurs below the AT levels; that is why exercise intensity at the AT level is often set for cardiac rehabilitation. Also, the AT is still widely utilized in the practices of athletic training, because appropriate training can suppress the blood level of lactate under the same exercise intensity. For example, Hurley and coauthors have shown that a 12-week exercise program elicited significantly lower lactate concentrations after training at the relative exercise intensities of the 55–75% of V̇O₂max.¹⁴⁾

Usually, AT (VT) can be determined by the CPET.¹⁵⁾ Most commonly, it is determined as the level of exercise intensity (or V̇O₂) at which the ventilatory equivalent of the oxygen (V̇E/V̇O₂) begins to increase during incremental exercise.¹⁵⁾ Similarly, AT is the point at which the end-expiratory partial pressure of oxygen begins to increase,¹⁵⁾ or the first point of departure from linearity of V̇CO₂ plotted against V̇O₂.¹⁶⁾

The alveolar ventilation equation concisely addresses the relation among the minute alveolar ventilation (V̇A), V̇CO₂, and the arterial partial pressure of carbon dioxide (PaCO₂), namely: $$\dot{\text{V}}\text{A}=\text{863}\times {\dot{\text{V}}\text{CO}}_{\text{2}}/{\text{PaCO}}_{\text{2}}$$ When we replace V̇A with a more easily measurable parameter V̇E, this equation can be rewritten as: $$\dot{\text{V}}\text{E}=863\times {\dot{\text{V}}\text{CO}}_{\text{2}}/\left({\text{PaCO}}_{\text{2}}\text{.}\times \left(\text{1}-\text{Vd}/\text{Vt}\right)\right)$$ where Vd and Vt represent dead space ventilation and tidal volume, respectively.

We can consider that V̇E is expressed as a linear equation of V̇CO₂, as PaCO₂, Vd and Vt are relatively stable during exercise. In reality, the relation between V̇E and V̇CO₂ during incremental exercise testing is linear from just before maximal exercise until the respiratory compensation point (Fig. 1). The slope of the regression equation shows the efficiency of ventilation during exercise. In patients with heart failure, pulmonary blood flow cannot distribute evenly to their alveoli, causing greater values of Vd, which leads to steeper linear relation between V̇E and V̇CO₂. Therefore, the slope of the V̇E/V̇CO₂ regression shows the ventilatory response to exercise. Also, there have been many studies that show the relation of the regression slope and the prognosis of patients with heart failure.^17–19)

Fig. 1 Relationship between minute ventilation (V̇E, the vertical axis) and carbon dioxide production (V̇CO₂, the horizontal axis) during incremental exercise obtained from a 12-year-old girl

Fig. 2 shows the relation between V̇O₂ and V̇E during incremental exercise. Note that the x-axis is logarithmically plotted. Therefore, their relation can be described as: $${\dot{\text{V}}\text{O}}_{\text{2}}=a\log \dot{\text{V}}\text{E}+b$$ where a and b are constants.

Fig. 2 Relationship between minute ventilation (V̇E, the horizontal axis) and oxygen uptake (V̇O₂, the vertical axis) during incremental exercise (the same examinee as in Fig. 1). The horizontal line is logarithmically plotted. The slope of the regression curve (2699 in this figure) is defined as the oxygen uptake efficiency slope (OUES)

The relation can be observed with high values of regression coefficients regardless of subjects or exercise protocol.²⁰⁾ When the equation above is differentiated by V̇E on both sides: $$d{\dot{\text{V}}\text{O}}_{\text{2}}/d\dot{\text{V}}\text{E}=a\left(\text{1}/\text{ln10}\right)/\dot{\text{V}}\text{E}$$

This equation shows that the increment of V̇O₂ against V̇E is determined by V̇E and the constant ‘a’ (1/ln10 ≈ 0.4343). Therefore, the constant ‘a’ indicates the rate of the increase in V̇O₂ at a certain minute ventilation VE. We have named the slope ‘a’ as the oxygen uptake efficiency slope (OUES).²⁰⁾ The OUES is a measure of the ability to increase V̇O₂ per 10-fold rise in minute ventilation. In other words, a steeper slope (or, a greater value of the OUES) shows that the subject can take oxygen into the body without excessively increasing ventilation, i.e., without causing shortness of breath.

One of the prominent features of the OUES is the fact that this index strongly correlates with V̇O₂max.^20–25) Another feature is that this can be accurately calculated without imposing maximal exercise on the examinee. The OUES is defined as the slope of the logarithmic relation between V̇O₂ and V̇E during incremental exercise. This means that submaximal exercise data is theoretically sufficient for its calculation.^20, 26) Also, the OUES can be used as prognostic indicators of patients with heart failure.^27–31)

The clinical application of the OUES in the pediatric population has also been reported. Bongers and coauthors have provided sex- and age-related normative values for OUES which facilitates the interpretation of the OUES in children.³²⁾ Hossri and coauthors also have published reference values of the OUES and concluded that the OUES is a marker when differentiating preserved functional capacity from abnormal one in children and adolescents even at the submaximal level of exercise, regardless of with and without congenital heart disease.³³⁾ Recently, several studies have shown the prognostic values of the OUES in patients with congenital heart diseases. Chen and coauthors have reported that submaximal exercise parameters including the OUES provide superior prognostic information to maximal exercise data for predicting cardiac morbidity in patients with the Fontan circulation.³⁴⁾ The association between the OUES and cardiac morbidity was independent of relevant baseline clinical information.³⁴⁾ Moreover, Tsai and coauthors showed, in forty post-surgical patients with tetralogy of Fallot younger than 12 years old, that the OUES normalized by body surface area, as well as peak V̇O₂, are useful predictors of cardiac-related hospitalization.³⁵⁾