EXERCISE TOLERANCE

To achieve a normal exercise tolerance, the body needs to adequately achieve the following:

• Ventilation
• Gas exchange
• Delivery of oxygenated blood to exercising tissues and return of CO₂ to the lungs
• Extraction of O₂ by the muscle and transfer of CO₂ to the blood
• Appropriate use of O₂ within mitochondria to generate energy as adenosine triphosphate (ATP)

This well-known diagram by Wasserman illustrates these 5 stages. VO2 = rate of O₂ uptake, VCO₂ = rate of CO2 production. In reality, the body is not in a steady state. Permission to use image granted by the publisher for Wasserman et al.²

O₂ consumption (VO₂) is the amount of O₂ taken in and used by the body per unit time and is thus the rate of O₂ use. CO₂ production (VCO₂) is the amount of CO₂ exhaled from the body per unit time (see Figure 1).²

Increased VO₂ by the muscles results from increases in the following:

• O₂ extraction from the blood at the exercising muscles
• O₂ delivery, by a decrease in local vascular resistance
• Cardiac output, through increased heart rate and stroke volume
• Pulmonary blood flow
• Linear increase in minute ventilation through increased tidal volume and ventilatory frequency

Figure 2. Normal response to exercise: at rest, our oxygen consumption ( VO2) is approximately 250 mL min 1 with a lower CO2 production
( VCO2) of varying fraction depending on diet.  VO2 increases on light exercise such as slow walking, as does VCO2, proportionally. VO2 and
VCO2 increase linearly with increasing work rate. Anaerobic metabolism then further increases CO₂ production without any further utilisation of
O₂, illustrated here where trendlines cross.

At rest, VO₂ is approximately 3.5 mL kg^-1min^-1. During strenuous exercise, this can increase by more than 10 to 20 times, requiring a large cardiopulmonary response to deliver the required O₂ to the muscles (see Figure 2). Measuring VO₂ is of particular interest during exercise because it reflects the needs of the body in a stressed, perioperative state. It is recognised that patients who are less physically fit are more likely to experience adverse perioperative outcomes.

CPET VARIABLES

A magnetically braked (or similar) cycle ergometer with a predetermined ramp of pedalling resistance provides a reliable, gradual increase in work rate (in Watts). A treadmill or hand ergometer is an alternative. The breath-by-breath expired gas concentrations are commonly measuredusing rapid infrared gas analysers, while flow is measured by pressure differential pneumotachographs. This enables calculation of VO₂ and VCO₂, together with spirometry and respiratory rate. Serial measurements of electrocardiogram (ECG), O₂ saturation (SpO₂) and blood pressure (BP) are also recorded. From the primary values of VO₂, VCO₂, minute ventilation (V_E) and HR, secondary values can be calculated, such as ventilatory equivalents for CO₂ (V_E/VCO₂). These terms are explained below. Trends are represented graphically by computer software and displayed in a ‘9-panel plot’, where the cardiovascular system isrepresented by panels 2, 3 and 5; ventilation is represented by panels 1, 4 and 7; and panels 6, 8 and 9 show ventilation-perfusion (VQ) relationships.

VO₂ Peak

Figure 3. VO₂ peak: a 20-second-averaged maximum oxygen consumption is recorded during the peak of the subject’s work rate. Typically,
this will be the time preceding the transition to recovery or prior to stopping the test prematurely due to patient exhaustion. The VO₂ peak
recorded may be the patient’s ‘best effort’; however, it is not a physiological limit and is therefore not their highest attainable VO₂.  As work
increases, if VO₂ begins to plateau, this represents the highest attainable VO₂ for a subject and is known as maximal VO₂ or VO₂ max. Noting
the linear relationship between work rate and VO₂, the increase in the VO₂ (red squares) should parallel the increase in work (green dash). The
horizontal shading indicates the patient’s 80-100% predicted VO₂ peak given their demographics.

The VO₂ increases linearly at a rate of 10 mL of O₂-min^-1 for every 1-W increase in power.³ Any level significantly lower than this could imply a limitation in the patient’s physiological reserve. The limit of tolerated exercise is reached at a plateau threshold known as the maximum O₂ consumption (VO_2max). In the case of an increasing ramp CPET, where a shorter duration of increasing work rate is used and where we would not be certain of a plateau threshold, we use the peak O₂ consumption (VO_2peak). The VO_2peak is usually measured over a 20-second average of peak O₂ consumption (see Figure 3).

Research has elicited different VO_2peak thresholds of increased risk for different surgery types. In general, a VO_2peak of <15 mL O₂ kg^-1-min^-1 is considered to represent an increased risk of perioperative complications.

Anaerobic Threshold

The anaerobic threshold (AT) is the point at which the cardiopulmonary system is unable to meet the O₂ demand of the muscles. Muscle cellsgenerate ATP by switching to anaerobic metabolism, a process that produces lactic acid. Lactic acid is buffered by our bicarbonate buffer system, and further CO₂ is generated.

Figure 4. The ‘V-slope’ method plotting VO₂ against VCO₂. Initially, there is a steady rise in both parameters. At the anaerobic threshold, the VCO₂ will increase in relation to the VO₂, increasing the gradient of the curve. Wasserman’s method was to plot a straight line of best fit through the initial and final parts of the curve. The intersection of these 2 lines would be the AT. The ‘modified V-slope’ method may also be used (shown). Here, a VO2/VCO2 = 1 gradient line is brought in from the right, and the point at which it touches the curve and the dots pull away from it with increasing gradient is the AT.

CO₂ output will climb in proportion to O₂ consumption until the AT, at which point the change in VCO₂ (&#916;VCO₂) exceeds the change in VO₂ (&#916;VO₂₎. This can be seen on a ‘V-slope’ plot of VCO₂ against VO₂ (see Figure 4).

Values of AT indicating increased risk vary depending on the type of surgery. That said, an AT of <11 mL O₂ kg^-1 min^-1 would put the patient into a higher-risk group.⁴

Ventilatory Equivalents

These are indicators of ventilatory efficiency, representing the ratio of minute ventilation (V_E) to CO₂ output or O₂ uptake. They provide us insight into the efficiency of VQ matching in the lung and that of gas exchange. If we consider the V_E required to support an increase in VO₂ and VCO₂, a lower V_E (and therefore a lower ratio) would represent greater efficiency.

Figure 5. Ventilatory equivalents. AT is at the point at which divergence begins. Increased CO2 production drives minute ventilation up, and
therefore, while oxygen consumption remains constant, the V_E/VO₂ ratio increases with respect to V_E/VCO₂.

Plotting the ventilatory equivalents for VO₂ and VCO₂ against time with increasing exercise intensity, we see a small initial improvement in theventilatory efficiency. This is due to decreased dead space ventilation as the tidal volumes increase at the start of exercise (see Figure 5).

Beyond the AT, lactate produced is buffered by the bicarbonate system generating more CO₂, which acts on chemoreceptors and subsequentlythe respiratory center, increasing V_E. Initially, there is an isocapnic buffering phase in which V_E/ VCO₂ remains the same, but the V_E/VO₂ rises, as relatively no more O₂ is being consumed. The divergence of the V_E/VO₂ and V_E/VCO₂ lines at this point is another way of marking the AT. The V_E/VCO₂ at the AT is the value that is reported and is usually less than 34. The higher the level, the higher the perioperative risk.

INTERPRETATION OF CPET DATA

The test may be too physically demanding for the patient to generate adequate data for interpretation; however, the inability to complete a test is a useful measure in predicting poor surgical outcome.

1.     Was the test terminated prematurely?

Adapted from the American Thoracic Society, POETTS have consensus guidelines on the reasons for premature termination of the CPET.⁵ These include the following:

• Angina: > 2 mm ST depression if symptomatic or 4 mm if asymptomatic or >1 mm ST elevation
• Arrythmia causing symptoms or haemodynamic compromise
• Hypotension: systolic BP drop of >20 mm Hg from the highest value during the test
• Hypertension
  • Systolic BP >250 mm Hg
  • Diastolic BP >120 mm Hg
• Desaturation: SpO2 <80%
• Loss of coordination or mental confusion
• Dizziness or faintness

2.     Is the test maximal?

Figure 7. Markers of a maximal test. Increasing RER to >1.15 within the exercising period is indicative of a maximal test. Achieving >80% maximal HR as indicated by HR within the 80-100% predicted maximal HR reference zone is also indicative of a maximal test.

The patient will usually stop when they are symptom limited and cannot exercise any longer. It is possible to grade their symptoms with a suitable scale, such as the Borg scale, at this point (see Figure 6) ⁶. The reason for stopping must be ascertained, such as tired legs, dyspnoea, or pain. See Figure 7a,b for markers of a maximal test.

The respiratory exchange ratio (RER) is the ratio of VCO₂/VO₂ and corresponds to gas exchange. At a basal metabolic rate, it represents tissue metabolism and equates to the respiratory quotient (RQ). Metabolism of carbohydrate, protein and fat result in RQs of 1, 0.8 and 0.7, respectively. Because extra CO₂ is introduced into the system during anaerobic exercise from bicarbonate buffering of lactic acid, an RER substantially greater than 1 at peak exercise is one marker of maximal effort.

Physiological markers of a maximal test include the following:

• >80% predicted work rate (as per demographics)
• >80% maximal HR (predicted maximum = 220 beats-min^–1 – age)
• Heart rate reserve (HRR) of <15% would indicate a maximal test, where HRR = predicted maximum HR – maximum HR achieved during the test; a raised HRR could represent a submaximal test or chronotropic insufficiency
• Achieving an RER >1.15
• Achieving maximal predicted V_E

COMMON PATTERNS OF PHYSIOLOGIAL LIMITATION

We will now examine 3 common patterns of physiological limitation by exercise-limiting pathology (see Table) ⁷.

Cardiovascular Limitation

In individuals with valvular or ischaemic cardiac pathology, there is a circulatory delivery issue of gases between the muscles and the lungs. An individual with a cardiac limitation may display a normal CPET pattern but with a lower than predicted VO_2peak and an early-onset AT. The typical performance-limiting symptom will be leg fatigue due to O₂ delivery failure and lactic acidosis at the tissue level, rather than dyspnoea. Patients may develop angina.

Figure 8. Cardiac limitation pattern.

The key features are as follows (see Figure 8):

• Reduced VO_2peak to <80% predicted (relative to age, gender and height) with early-onset AT (plots 3, 6).
• HR may be increased during light exercise as the heart tries to increase its cardiac output without the ability to sufficiently recruit SV (plot 2).
• Peak HR commonly does not reach the age-predicted maximum due to impaired chronotropy from disease or b-blockade, causing a raised HRR (>15%).
• Normal linear increase in minute ventilation up to AT with no ventilatory limitation.
• A higher ventilatory equivalent for CO₂ can be a feature where LV failure may cause ‘back up’ or reduced pulmonary flow and worsening of VQ matching (plot 6).
• In severe disease, BP will either not increase normally with exercise or may even fall, requiring immediate abortion of the test.

Respiratory Limitation

Lung disease will result in exercise limitations due to ventilatory failure. Inadequate alveolar ventilation secondary to increased dead space, decreased tidal volumes and loss of alveolar volume causes low O₂ saturations and hypercapnia. With chronic obstructive pulmonary disease (COPD), progressive air trapping causes increased end-expiratory lung volume and extreme dyspnoea before the onset of an AT, which isoften not achieved before terminating the test. With restrictive lung disease, the patient is much more reliant on respiratory rate to increase ventilation.

Figure 9. Respiratory limitation pattern.

The key features are as follows (see Figure 9):

• Reduced VO_2peak –<80% predicted relative to age, gender and height (plot 3)
• Exhaustion due to ventilatory limitation prior to the onset of AT, so measurement is not achieved (plots 3, 5, 6)
• Elevated V_E for VO₂ and VCO₂ at all work rates (plot 6)
• Decreasing tidal volumes on increasing exercise secondary to air trapping in COPD or restriction in restrictive pathologies (plot 7)
• Low O₂ saturations due to VQ mismatch (plot 2)

Pulmonary Vascular Disease

Those with pulmonary vascular disease cannot increase pulmonary blood flow in response to a required rise in cardiac output. This means thatas V_E increases with exercise, the dead-space fraction remains abnormally high as the individual ventilates areas of poorly perfused lungtissue. This causes a VQ mismatch. The elimination of CO₂ becomes inefficient. Patients tend to have a low alveolar partial pressure of CO₂ (PACO₂) and partial pressure of end-tidal CO₂ (pEtCO₂), which decreases further with exercise. (Normally, in the absence of pulmonary vascular disease, the V_E/VCO₂ falls in the first stages of exercise as the VQ matching improves with better lung perfusion.) An echocardiogram is often subsequently requested to evaluate right heart pressures.

Figure 10. Pulmonary vascular disease pattern (plot 7: A, pulmonary vascular; B, interstitial lung disease).

The key features are the following (see Figure 10):

• Reduced VO_2peak to <80% predicted, relative to age, gender and height (plot 3)
• Elevated HR disproportionate to work rate compared with normal individuals (plot 2)
• Desaturation with progressive exercise due to VQ mismatch (SpO₂ may be normal at rest; plot 9)
• Low pEtCO₂, which falls with exercise (plot 9)

• High V_E/VCO₂, which rises with unloaded cycling and continues to rise throughout the test due to increased dead space (plot 4)
• Early-onset AT (plots 3, 6)

APPLICATION OF CPET DATA

Studies evaluating the relationship between CPET performance and surgical outcome have found that VO₂ peak, AT and V_E/VCO₂ are predictors of postoperative morbidity and mortality following noncardiac surgery.^8,9 The inability to complete the test, whether due topoor mobility, poor physiological reserve or inability to follow instructions, is also associated with an increased risk of postoperative morbidity and mortality.¹⁰

Identified physiological limitations may trigger further investigation. For example, a patient with COPD may show a pattern in keeping withcardiac limitation of uncertain cause. An echocardiogram would be required to identify features such as valvular disease and ischaemic cardiomyopathy and for pulmonary artery pressure measurement.

In some centres, CPET data are being used to provide patients with focused prehabilitation programmes.¹⁰

Patients with CPET data showing significant limitation are identified as high risk. This raises an opportunity to discuss the risks and benefits of bothsurgical and nonsurgical options. Multidisciplinary discussion is prompted. The patient’s ideas, concerns and expectations are understood, and a mutually agreed treatment plan is made.

Increasingly, CPET is being used to triage patients to intensive care, high-dependency or ward-based care for their postoperative management.A UK case-control study has shown that patients undergoing open colorectal surgery who are assigned as ‘high risk’ with AT <11 mL kg^-1 min^-1 showed a significantly lower incidence of postoperative major cardiacevents if they were managed in intensive care than those managed on a surgical ward.¹¹