Transfer coefficient of the lung for carbon monoxide and the accessible alveolar volume: clinically useful if used wisely

Discussion

The transfer of any inspired gas with the ability of binding to haemoglobin (e.g. O₂) in the red blood cells (RBCs) crossing the pulmonary capillaries depends on [14]:

• the pre-haemoglobin resistance to gas flow (literally from the mouth to the interior of the RBCs), collectively called the “membrane” component; and

• the concentration and binding properties of haemoglobin.

When carbon monoxide (CO) is used instead of O₂ to assess the integrity of this complex process (haemoglobin's affinity for CO is 230 times that of O₂), it has been shown that ∼80% of the T_LCO signal comes from the blood phase, i.e. the number of RBCs and/or the number of open capillary vessels (capillary volume, VC) [15]. It is therefore understandable that T_LCO is considered a “window to the pulmonary microcirculation” [16]. It may also partially explain why a low T_LCO is associated with increased areas of high ventilation–perfusion relationship [17]. It follows that patients with chronic obstructive pulmonary disease presenting with a low T_LCO need to ventilate in excess to a given metabolic load (i.e. poor exertional ventilatory efficiency) to overcome an enlarged physiological dead space [18]. Patients with low T_LCO (<50% predicted) are also at higher risk of presenting with another source of increased ventilatory stimuli: hypoxaemia [19]. Thus, a low T_LCO may be associated with a high respiratory neural drive on exertion, a key correlate of exertional dyspnoea [20]. It is not surprising, therefore, that a low T_LCO is an independent predictor of decreased physical activity in this patient population [21].

The clinical interpretation of T_LCO, however, might be confounded by the fact that it is critically dependent on:

1) the lung volume at which it is measured and, importantly,

2) “how many” gas exchanging unities at a given lung volume have received the inhaled gas mixture [22, 23].

Regarding the first point, T_LCO increases as the alveoli are distended because the surface area for gas exchange increases and because the alveolar–capillary membrane may become thinner. Conversely, as the lung deflates T_LCO decreases because the surface area decreases while it may become progressively thicker [24]. However, alveolar distension also compresses the lung capillaries, whereas alveolar emptying gives more space to capillary filling [25] (although this is partially compensated by a squeezing effect on the total intra-thoracic blood volume at very low lung volumes) [26]. It follows that [24–26]: from mid-lung volumes upwards, T_LCO increases less than it would be expected from the increase in V_A because the latter effect is partially counterbalanced by a (small) decrease in VC; and from mid-lung volumes downwards, T_LCO decreases less than it would be expected from the decrease in V_A because VC decreases less than the V_A [23]. The final result is a curvilinear, exponential-like increase in the VC/V_A ratio as the V_A diminishes. Translating those concepts to T_LCO measurements, they imply an essentially linear decrease in T_LCO but an exponential increase in K_CO (T_LCO/V_A) as V_A decreases (figure 2) [23]. These considerations carry important messages:

• they might lead to a “pseudo-normal” K_CO in a restrictive defect that decreases both T_LCO and V_A [27]; and

• 1 “unit” change in V_A does not lead to 1 “unit” change in T_LCO across all possible V_A values, i.e. it is highly misleading to state that “the T_LCO/V_A ratio represents T_LCO corrected by lung volume”.

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Figure 2

The linear decrease in T_LCO as the accessible V_A decreases is associated with an exponential increase in K_CO. For instance, T_LCO decreases ∼25% while K_CO increases by ∼90% from TLC to FRC. It follows that at a given V_A below TLC, K_CO (% predicted) will always be a higher value than T_LCO (% predicted). See the text for further elaboration on the clinical interpretation of those measurements. V_A/V_A TLC%: accessible V_A as a percentage of the V_A found at TLC. Modified from [23] with permission from the publisher.

Concerning the second point, it should be remembered that during the T_LCO manoeuvre we measure only the fraction of TLC which can be accessed by the inhaled mixture (which is provided by V_A), a volume that depends on how well the peripheral units connect with the large airways [10, 28]. In most healthy subjects, the V_A/TLC ratio is ≥0.85 [8, 29] or ≥0.80 [9] provided that the subject performed a maximal inspiratory manoeuvre. However, in the presence of airway disease and extensive maldistribution of ventilation, V_A will be a poor representation of the lungs as a whole (TLC) and V_A/TLC ratio is <0.80–0.85 [28]. This might lead to a “pseudo-normal” K_CO in an obstructive defect that decreases V_A [27].

How to deal with these potential pitfalls in V_A and K_CO interpretation? We suggest the following simplified interpretation algorithm when T_LCO is reduced (figure 3) [23].

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Figure 3

A simplified algorithm for the differential diagnosis of a low T_LCO taking into consideration the potential pitfalls involved in interpretation of the accessible V_A and K_CO. Symbols ↑, ↓ and ↔ represent values above, below and within the normal range, respectively. See the text for further elaboration.

When V_A is normal there is a high negative predictive value for restriction (because V_A is always a fraction of TLC; thus, if V_A is normal so is TLC in the great majority of subjects) [30]. If obstruction with maldistribution of ventilation were present, it would decrease V_A secondary to a low V_A/TLC [31]. It follows that a normal V_A, when associated with a low K_CO (provided there is no anaemia or recent smoking), suggests pulmonary vascular disease (e.g. PH or vasculitis), intrapulmonary right-to-left shunting or early emphysema, i.e. mild enough to not (yet) be associated with a low V_A/TLC.

When V_A is low the next step is to check the V_A/TLC ratio.

• If the V_A/TLC ratio is low (<0.8) indicating obstruction with ventilation distribution abnormalities [10, 28], the K_CO might turn “normal”. In this scenario, no further valid inferences can be made regarding K_CO; however, if K_CO is low despite those caveats (which, as mentioned, would otherwise tend to increase the T_LCO/V_A ratio), there is extensive impairment in pulmonary gas exchange efficiency, e.g. severe emphysema [32].

• If the V_A/TLC ratio is normal (≥0.8), the only explanation for a low V_A is a low TLC, i.e. restriction [30]. Thus:

  • 1) A high K_CO indicates a predominance of VC over V_A due to: a) incomplete alveolar expansion but preserved gas exchange unities frequently leading to K_CO >120–140% or even higher, i.e. extra-parenchymal restriction (e.g. pleural, chest wall or neuromuscular disease) [11]; b) an increase in pulmonary blood flow from areas of diffuse (pneumonectomy) or localised (local destructive lesions/atelectasis) loss of gas exchange units to areas with preserved parenchyma frequently leading to more modest increases in K_CO (although a high K_CO can also be seen with normal or near-normal V_A when there is increased pulmonary blood flow or redistribution such as left-to-right shunt and asthma); and c) extra-vascular haemoglobin, i.e. alveolar haemorrhage.

  • 2) A low K_CO points towards intra-parenchymal restriction with impaired gas exchange efficiency as in some interstitial lung diseases (ILD) [33].

  • 3) A normal K_CO is consistent with intra-parenchymal restriction with preserved K_CO. This is the most common finding in patients with HRCT abnormalities showing a pattern consistent with idiopathic interstitial pneumonia [33]. Thus, a normal K_CO should not be misinterpreted as indicative of “no ILD” [34, 35]. In this context, a normal K_CO may either indicate that the main mechanism underlying the low T_LCO is loss of lung volume (e.g. fibrotic ILD) or the low V_A led to a normalisation of K_CO due to the curvilinear increase in K_CO as V_A decreases (figure 2).

Owing to the trend for K_CO to be higher than T_LCO regardless the underlying reason(s), the severity of functional impairment should always be gradated based on T_LCO based on the European Respiratory Society recommendations: mild (less than lower limit of normal, but above 60% predicted according to the recently published Global Lung Initiative equations [36]), moderate (40–60% predicted) and severe (>40% predicted) [6].

In the present case, a low V_A but normal V_A/TLC (coupled with the absence of obstruction on spirometry, gas trapping or high specific airway resistance) is not consistent with maldistribution of ventilation due to small airway disease. Thus, V_A decreased in proportion to a low TLC, i.e. secondary to the patient's morbid obesity and/or to the known trend for CTEPH patients to present with mild restriction due to microatelectasis and fibrotic changes [37]. As shown in figure 2, K_CO should increase as V_A decreases if there was no impairment in gas exchange efficiency; in fact, this is one of the justifications as to why obesity is associated with a high K_CO [38]. It follows that the only plausible explanation for a low K_CO in the present case is a low VC, i.e. a pulmonary vascular disease. Some key interpretative issues regarding T_LCO and its derived measurements are provided in table 2.