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Diffusing capacity
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Diffusing capacity
MeSHD011653
Other codesCPT: 94720

Diffusing capacity of the lung (DL) (also known as transfer factor) measures the transfer of gas from air in the lung, to the red blood cells in lung blood vessels. It is part of a comprehensive series of pulmonary function tests to determine the overall ability of the lung to transport gas into and out of the blood. DL, especially DLCO, is reduced in certain diseases of the lung and heart. DLCO measurement has been standardized according to a position paper[1] by a task force of the European Respiratory and American Thoracic Societies.

In respiratory physiology, the diffusing capacity has a long history of great utility, representing conductance of gas across the alveolar-capillary membrane and also takes into account factors affecting the behaviour of a given gas with hemoglobin.[citation needed]

The term may be considered a misnomer as it represents neither diffusion nor a capacity (as it is typically measured under submaximal conditions) nor capacitance. In addition, gas transport is only diffusion limited in extreme cases, such as for oxygen uptake at very low ambient oxygen or very high pulmonary blood flow.[citation needed]

The diffusing capacity does not directly measure the primary cause of hypoxemia, or low blood oxygen, namely mismatch of ventilation to perfusion:[2]

  • Not all pulmonary arterial blood goes to areas of the lung where gas exchange can occur (the anatomic or physiologic shunts), and this poorly oxygenated blood rejoins the well oxygenated blood from healthy lung in the pulmonary vein. Together, the mixture has less oxygen than that blood from the healthy lung alone, and so is hypoxemic.
  • Similarly, not all inspired air goes to areas of the lung where gas exchange can occur (the anatomic and the physiological dead spaces), and so is wasted.

Testing

[edit]

The single-breath diffusing capacity test is the most common way to determine .[1] The test is performed by having the subject blow out all of the air that they can, leaving only the residual lung volume of gas. The person then inhales a test gas mixture rapidly and completely, reaching the total lung capacity as nearly as possible. This test gas mixture contains a small amount of carbon monoxide (usually 0.3%) and a tracer gas that is freely distributed throughout the alveolar space but which doesn't cross the alveolar-capillary membrane. Helium and methane are two such gasses. The test gas is held in the lung for about 10 seconds during which time the CO (but not the tracer gas) continuously moves from the alveoli into the blood. Then the subject exhales.

The anatomy of the airways means inspired air must pass through the mouth, trachea, bronchi and bronchioles (anatomical dead space) before it gets to the alveoli where gas exchange will occur; on exhalation, alveolar gas must return along the same path, and so the exhaled sample will be purely alveolar only after a 500 to 1,000 ml of gas has been breathed out.[citation needed] While it is algebraically possible to approximate the effects of anatomy (the three-equation method[3]), disease states introduce considerable uncertainty to this approach. Instead, the first 500 to 1,000 ml of the expired gas is disregarded and the next portion which contain gas that has been in the alveoli is analyzed.[1] By analyzing the concentrations of carbon monoxide and inert gas in the inspired gas and in the exhaled gas, it is possible to calculate according to Equation 2. First, the rate at which CO is taken up by the lung is calculated according to:

The pulmonary function equipment monitors the change in the concentration of CO that occurred during the breath hold, , and also records the time .
The volume of the alveoli, , is determined by the degree to which the tracer gas has been diluted by inhaling it into the lung.

Similarly,

where

is the initial alveolar fractional CO concentration, as calculated by the dilution of the tracer gas.
is the barometric pressure

Other methods that are not so widely used at present can measure the diffusing capacity. These include the steady state diffusing capacity that is performed during regular tidal breathing, or the rebreathing method that requires rebreathing from a reservoir of gas mixtures.

Calculation

[edit]

The diffusion capacity for oxygen is the proportionality factor relating the rate of oxygen uptake into the lung to the oxygen gradient between the capillary blood and the alveoli (per Fick's laws of diffusion). In respiratory physiology, it is convenient to express the transport of gas molecules as changes in volume, since (i.e., in a gas, a volume is proportional to the number of molecules in it). Further, the oxygen concentration (partial pressure) in the pulmonary artery is taken to be representative of capillary blood. Thus, can be calculated as the rate that oxygen is taken up by the lung divided by the oxygen gradient between the alveoli ("A") and the pulmonary artery ("a").

(For , say "V dot". This is the notation of Isaac Newton for a first derivative (or rate) and is commonly used in respiratory physiology for this purpose.)
is the rate that oxygen is taken up by the lung (ml/min).
is the partial pressure of oxygen in the alveoli.
is the partial pressure of oxygen in the pulmonary artery.
is the partial pressure of oxygen in the systemic veins (where it can actually be measured).

Thus, the higher the diffusing capacity , the more gas will be transferred into the lung per unit time for a given gradient in partial pressure (or concentration) of the gas. Since it can be possible to know the alveolar oxygen concentration and the rate of oxygen uptake - but not the oxygen concentration in the pulmonary artery - it is the venous oxygen concentration that is generally employed as a useful approximation in a clinical setting.

Sampling the oxygen concentration in the pulmonary artery is a highly invasive procedure, but fortunately another similar gas can be used instead that obviates this need (DLCO). Carbon monoxide (CO) is tightly and rapidly bound to hemoglobin in the blood, so the partial pressure of CO in the capillaries is negligible and the second term in the denominator can be ignored. For this reason, CO is generally the test gas used to measure the diffusing capacity and the equation simplifies to:

Interpretation

[edit]

In general, a healthy individual has a value of between 75% and 125% of the average.[4] However, individuals vary according to age, sex, height and a variety of other parameters. For this reason, reference values have been published, based on populations of healthy subjects[5][6][7] as well as measurements made at altitude,[8] for children[9] and some specific population groups.[10][11][12]

Blood CO levels may not be negligible

[edit]

In heavy smokers, blood CO is great enough to influence the measurement of , and requires an adjustment of the calculation when COHb is greater than 2% of the whole.

The two components of

While is of great practical importance, being the overall measure of gas transport, the interpretation of this measurement is complicated by the fact that it does not measure any one part of a multi-step process. So as a conceptual aid in interpreting the results of this test, the time needed to transfer CO from the air to the blood can be divided into two parts. First CO crosses the alveolar capillary membrane (represented by ) and then CO combines with the hemoglobin in capillary red blood cells at a rate times the volume of capillary blood present ().[13] Since the steps are in series, the conductances add as the sum of the reciprocals:

Any change in alters

The volume of blood in the lung capillaries, , changes appreciably during ordinary activities such as exercise. Simply breathing in brings some additional blood into the lung because of the negative intrathoracic pressure required for inspiration. At the extreme, inspiring against a closed glottis, the Müller's maneuver, pulls blood into the chest. The opposite is also true, as exhaling increases the pressure within the thorax and so tends to push blood out; the Valsalva maneuver is an exhalation against a closed airway which can move blood out of the lung. So breathing hard during exercise will bring extra blood into the lung during inspiration and push blood out during expiration. But during exercise (or more rarely when there is a structural defect in the heart that allows blood to be shunted from the high pressure, systemic circulation to the low pressure, pulmonary circulation) there is also increased blood flow throughout the body, and the lung adapts by recruiting extra capillaries to carry the increased output of the heart, further increasing the quantity of blood in the lung. Thus will appear to increase when the subject is not at rest, particularly during inspiration.

In disease, hemorrhage into the lung will increase the number of haemoglobin molecules in contact with air, and so measured will increase. In this case, the carbon monoxide used in the test will bind to haemoglobin that has bled into the lung. This does not reflect an increase in diffusing capacity of the lung to transfer oxygen to the systemic circulation.

Finally, is increased in obesity and when the subject lies down, both of which increase the blood in the lung by compression and by gravity and thus both increase .

Reasons why varies

The rate of CO uptake into the blood, , depends on the concentration of hemoglobin in that blood, abbreviated Hb in the CBC (Complete Blood Count). More hemoglobin is present in polycythemia, and so is elevated. In anemia, the opposite is true. In environments with high levels of CO in the inhaled air (such as smoking), a fraction of the blood's hemoglobin is rendered ineffective by its tight binding to CO, and so is analogous to anemia. It is recommended that be adjusted when blood CO is high.[1]

The lung blood volume is also reduced when blood flow is interrupted by blood clots (pulmonary emboli) or reduced by bone deformities of the thorax, for instance scoliosis and kyphosis.

Varying the ambient concentration of oxygen also alters . At high altitude, inspired oxygen is low and more of the blood's hemoglobin is free to bind CO; thus is increased and appears to be increased. Conversely, supplemental oxygen increases Hb saturation, decreasing and .

Lung diseases that reduce and

Diseases that alter lung tissue reduce both and to a variable extent, and so decrease .

  1. Loss of lung parenchyma in diseases like emphysema.
  2. Diseases that scar the lung (the interstitial lung disease), such as idiopathic pulmonary fibrosis, or sarcoidosis
  3. Swelling of lung tissue (pulmonary edema) due to heart failure, or due to an acute inflammatory response to allergens (acute interstitial pneumonitis).
  4. Diseases of the blood vessels in the lung, either inflammatory (pulmonary vasculitis) or hypertrophic (pulmonary hypertension).
Lung conditions that increase .
  1. Alveolar hemorrhage Goodpasture's syndrome,[14] polycythemia,[15] left to right intracardiac shunts,[16] due increase in volume of blood exposed to inspired gas.
  2. Asthma due to better perfusion of apices of lung. This is caused by increase in pulmonary arterial pressure and/or due to more negative pleural pressure generated during inspiration due to bronchial narrowing.[17]

History

[edit]

In one sense, it is remarkable that DLCO has retained such clinical utility. The technique was invented to settle one of the great controversies of pulmonary physiology a century ago, namely the question of whether oxygen and the other gases were actively transported into and out of the blood by the lung, or whether gas molecules diffused passively.[18] Remarkable too is the fact that both sides used the technique to gain evidence for their respective hypotheses. To begin with, Christian Bohr invented the technique, using a protocol analogous to the steady state diffusion capacity for carbon monoxide, and concluded that oxygen was actively transported into the lung. His student, August Krogh developed the single breath diffusion capacity technique along with his wife Marie, and convincingly demonstrated that gasses diffuse passively,[19][20][21][22][23][24][25] a finding that led to the demonstration that capillaries in the blood were recruited into use as needed – a Nobel Prize–winning idea.[26]

See also

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References

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Further reading

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Revisions and contributorsEdit on WikipediaRead on Wikipedia

Diffusing capacity

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Diffusing capacity, also known as the diffusing capacity of the (DL), quantifies the ability of the to transfer gas from inhaled air in the alveoli to the red blood cells in pulmonary capillaries, primarily assessed using as a surrogate for oxygen transfer. It is a key component of that evaluates the efficiency of across the alveolar-capillary membrane. Physiologically, diffusing capacity follows Fick's law of diffusion, depending on the surface area available for , the thickness of the diffusion barrier, and the gradient of the gas; is used because its high affinity for minimizes the influence of limitations, isolating the diffusive properties of the . The overall diffusing capacity (DLCO) is mathematically expressed as the product of the membrane diffusing capacity (Dm) and the conductance of blood for (θVc), where DLCO = 1 / (1/Dm + 1/θVc), reflecting both structural integrity of the alveolar-capillary interface and the reaction rate of gas with . Factors such as volume, concentration, and alveolar oxygen tension influence DLCO; for instance, it increases with or due to enhanced blood carrying capacity, while or high altitudes reduce it by altering availability or gas gradients. The standard measurement of diffusing capacity employs the single-breath technique, in which the patient inhales a dilute gas mixture containing 0.3% and a tracer gas like , holds their breath for approximately 10 seconds at total lung capacity, and then exhales for analysis of residual CO uptake and alveolar volume (Va). This method, standardized by the American Thoracic Society and European Respiratory Society, calculates DLCO as the rate of CO transfer per minute per mm Hg difference, typically requiring at least two acceptable tests with results within 2 mL/min/mm Hg of each other. Normal values range from 75% to 140% of predicted norms, adjusted for age, sex, height, ethnicity, and levels, with severity graded by z-scores (e.g., z-score ≤ -2 indicating moderate impairment). Clinically, diffusing capacity is essential for diagnosing and monitoring diseases affecting , such as , , , and , where reduced DLCO (<60% predicted) signals alveolar-capillary damage or loss of surface area. Elevated DLCO can occur in conditions like or early , while isolated analysis of components like the transfer coefficient (KCO = DLCO/Va) helps differentiate between membrane defects and vascular issues. Beyond diagnosis, low DLCO values (<40% predicted) are prognostic indicators of increased mortality in chronic lung diseases and inform treatment decisions, including eligibility for or disability evaluations. The test carries minimal risks, primarily transient , and requires simple preparations like avoiding for 4-6 hours beforehand.

Definition and Physiology

Definition

Diffusing capacity (DL) refers to the ability of the to transfer gas from alveolar air to pulmonary capillary blood across the alveolar-capillary membrane. It is primarily measured as the diffusing capacity of the lung for (DLCO), which quantifies the transfer of CO under standardized conditions to assess overall efficiency. This measure distinguishes itself from other pulmonary function tests, such as , by focusing specifically on the diffusive component of gas transport rather than ventilatory mechanics or lung volumes. The overall diffusing capacity (DL) is determined by two key components in series: the alveolar-capillary membrane conductance (DM), which reflects the permeability and surface area of the membrane, and the pulmonary capillary blood volume adjusted for the reaction rate with hemoglobin (θVc), where θ represents the rate of gas uptake by red blood cells and Vc is the capillary blood volume. These components combine according to the equation DL = 1 / (1/DM + 1/(θVc)), originally derived from the Roughton-Forster model, which separates membrane diffusion resistance from blood reaction resistance. Carbon monoxide is used as the test gas because its high affinity for hemoglobin (approximately 250 times that of oxygen) ensures that uptake is primarily diffusion-limited rather than perfusion-limited, providing a reliable estimate of lung diffusing properties. DLCO is typically expressed in units of milliliters of CO per minute per millimeter of mercury (mL/min/mmHg) at body temperature and pressure, saturated with (STPD). The term "diffusing capacity" was first introduced by Marie Krogh in 1910 to describe the lung's capacity for oxygen , later adapted for CO measurements in clinical practice. Standardization of terminology and measurement, including the use of DLCO over the synonymous transfer factor (TLCO), follows guidelines from the American Thoracic Society (ATS) and European Respiratory Society (ERS), ensuring consistent reporting across laboratories.

Physiological Basis

The diffusing capacity of the lung reflects the rate at which gases, such as (CO) or oxygen, transfer from alveolar air to pulmonary capillary blood, governed by the physical principles of across the alveolar-capillary . This process is fundamentally described by Fick's law of , which quantifies the flux of gas (V_gas) as proportional to the surface area available for (A), the of the gas (D), and the gradient across the (P_1 - P_2), inversely proportional to the thickness of the barrier (T). Mathematically, this is expressed as: Vgas=A⋅D⋅(P1−P2)TV_{\text{gas}} = A \cdot D \cdot \frac{(P_1 - P_2)}{T} In the lungs, this law applies to where the thin alveolar , interstitial space, and capillary endothelium form the diffusive barrier, enabling efficient equilibration of gases during the brief transit of blood through the pulmonary capillaries. For CO, commonly used to measure diffusing capacity, the process involves not only diffusion across the but also the chemical reaction with in red cells, which avidly binds CO and maintains a favorable concentration . The θ represents the rate of CO uptake by whole (in ml CO/min/mmHg/ml ), influenced heavily by concentration, as higher levels increase binding sites and thus enhance θ. The overall diffusing capacity (DL) can be conceptualized as the series combination of diffusing capacity (DM), reflecting conductance across the alveolar-capillary barrier, and the reaction component (θVc), where Vc is the pulmonary capillary volume. Resistance to diffusion is additive, with 1/DL = 1/DM + 1/(θVc); in healthy lungs, the reaction often contributes more significantly to total resistance for CO than the alone. reduces θ by decreasing availability, thereby lowering DL, while elevated competes for binding sites on , further diminishing θ and impairing CO uptake. Anatomically, these processes occur across an alveolar surface area of approximately 70 in adults, providing ample interface for , with a pulmonary of about 75 ml containing the red cells that react with incoming gases. The transit time of blood through these capillaries averages 0.75 seconds at rest, sufficient for near-complete equilibration under normal conditions, though it can shorten during exercise, potentially stressing diffusive limits.

Measurement Methods

Single-Breath Technique

The single-breath technique, also known as the single-breath uptake method (DLCO_SB), is the most widely adopted approach for measuring diffusing capacity of the for (DLCO). In this method, the patient inhales a dilute test gas mixture containing 0.3% (CO), 0.3% or 10% as an inert tracer gas, 21% oxygen, and the balance , to determine both alveolar volume (VA) and CO uptake during a brief breath-hold maneuver. The procedure simulates a single, deep inspiration to total capacity (TLC), allowing CO to diffuse across the alveolar-capillary membrane into the pulmonary blood while the tracer gas helps estimate VA by assuming uniform dilution. The step-by-step procedure begins with the patient exhaling fully to residual volume (RV) through a mouthpiece while wearing a nose clip. They then rapidly inhale the test gas mixture to TLC, achieving at least 85% of (VC) within 4 seconds to ensure adequate distribution. The breath is held uniformly for 10 ± 2 seconds (typically 8-12 seconds), during which CO uptake occurs, followed by a smooth to RV within 12 seconds. The initial 0.75-1.0 L of exhaled gas (or 0.5 L if VC < 2 L) is discarded as dead space, and the subsequent alveolar sample (0.5-1 L in classical systems or a virtual sample of 85-500 mL in rapid gas analyzer systems) is analyzed for CO and tracer gas concentrations. At least two acceptable maneuvers are performed, with a minimum 4-minute interval between tests to allow CO elimination, and results are averaged if within 2 mL·min⁻¹·mmHg (0.67 mmol·min⁻¹·kPa). Equipment for the single-breath technique includes a delivery system for the test gas (often from a or ), a closed-circuit or flowmeter for volume measurement, and gas analyzers to detect CO and the inert tracer. Modern systems employ rapid-response gas analyzers (RGA) with a 0-90% response time of ≤150 ms, ±1% accuracy for gas concentrations, and ±2% flow accuracy across ±10 L/s, enabling continuous online monitoring during and . Classical systems collect discrete samples for offline analysis, but both require with a 3-L and must meet volume accuracy of ±75 mL. Patient preparation is essential to minimize variability and ensure safety. Individuals should avoid for at least 4-24 hours prior to testing, refrain from supplemental oxygen for 10-15 minutes, and abstain from heavy exercise or on the test day. Testing is conducted in a seated position after 5 minutes of rest in a comfortable environment, with the patient wearing a clip and mouthpiece; recent heavy meals are discouraged to avoid discomfort, though is not strictly required. Technicians demonstrate the maneuver, and patients practice tidal breathing beforehand to familiarize themselves. Contraindications include recent (within 1 month) or severe CO exposure. Standardization follows the 2017 American Thoracic Society (ATS)/European Respiratory Society (ERS) guidelines to ensure reproducibility across laboratories. Acceptable tests require an inspiratory volume (VI) of ≥85% VC (ideally ≥90%), uniform breath-holding without glottic adjustments, and exhalation flow rates of 0.5-3 L/s to avoid . Quality grading ranges from A (all criteria met, including ) to F (unusable due to leaks or non-compliance); at least two grade A or B tests are needed for reporting. These criteria address issues like slow inspiration or heterogeneous ventilation, which can underestimate VA. The single-breath technique offers advantages in simplicity and high reproducibility when performed correctly, making it suitable for routine clinical use in pulmonary function laboratories. It requires minimal equipment and patient effort beyond breath-holding, with low risk and the ability to integrate with . However, limitations include dependence on patient compliance for breath-holding, potential errors from leaks, incomplete lung filling, or ventilation inhomogeneity (e.g., in , leading to 8-15% underestimation of DLCO), and the need for adjustments in conditions like or high carboxyhemoglobin levels. No more than five tests per session are recommended to prevent CO accumulation effects.

Alternative Techniques

The rebreathing method for measuring diffusing capacity involves the patient rapidly rebreating a gas mixture containing 0.3% (CO) and 10% for 30 to 90 seconds, typically at a rate of 30 breaths per minute, without a breath-holding period; alveolar volume and CO uptake are calculated from sampled gas concentrations to derive DLCO. This technique is particularly useful for patients unable to perform breath-holding maneuvers, such as children or those with neuromuscular disorders, and during exercise testing where continuous breathing must be maintained, as in protocols. The steady-state method requires the patient to inhale a low-concentration CO mixture (around 0.3%) continuously for several minutes until equilibrium is reached, with exhaled gas collected in a bag for analysis and CO uptake estimated using the alveolar gas equation; accurate assessment often necessitates sampling to measure and oxygen content. It is preferred in scenarios where alveolar volume estimation is challenging, such as in patients with severe airflow obstruction, or during exercise when dynamic needs evaluation without breath interruption. Historically, this approach predates the standardization of single-breath techniques and was among the earliest methods for steady assessment of gas transfer. Measurement of membrane diffusing capacity using nitric oxide (DLNO) employs a single-breath inhalation of a mixture containing (NO), often simultaneously with CO, leveraging NO's faster reaction kinetics with —due to its higher (approximately twice that of CO) and negligible resistance at the level—to isolate the membrane component (DM) without significant influence from capillary blood volume (θVc). DLNO values are typically 4 to 4.5 times higher than DLCO, providing a direct surrogate for DM and enabling research into alveolar-capillary barrier properties in conditions like or pulmonary . Comparisons among these methods reveal variations relative to the single-breath gold standard; the rebreathing approach can overestimate DLCO by 5 to 13% owing to ventilation inhomogeneities and cardiac output influences that enhance CO mixing, while steady-state measurements demand blood sampling for precision and may underestimate in low-output states. DLNO, by contrast, offers superior sensitivity to membrane alterations but is more volume-dependent, with DLNO declining up to 43% from total lung capacity to residual volume compared to 29% for DLCO. Niche applications include DLNO for dissecting membrane versus vascular contributions in experimental settings, and rebreathing or steady-state for specialized pediatric or exercise contexts where the single-breath method is impractical.

Calculation and Interpretation

Formulas and Derivations

The diffusing capacity for carbon monoxide (DLCO) is derived from Fick's principle of diffusion, which states that the rate of gas uptake (V̇_CO) across the alveolar-capillary membrane equals the diffusing capacity multiplied by the partial pressure gradient of the gas: V̇_CO = DLCO × (P_{A_{CO}} - P_{c_{CO}}). In the single-breath method, P_{c_{CO}} (capillary blood CO partial pressure) is assumed to be approximately zero due to the rapid binding of CO to hemoglobin, simplifying the equation to V̇_CO ≈ DLCO × P_{A_{CO}}. Here, P_{A_{CO}} is the alveolar partial pressure of CO, calculated as F_{A_{CO}} × (P_B - P_{H_2O}), where F_{A_{CO}} is the alveolar CO fraction, P_B is barometric pressure, and P_{H_2O} is water vapor pressure at body temperature. During the breath-hold phase of the test, the change in alveolar CO content over time reflects the uptake rate. Assuming constant alveolar volume (V_A) during the breath hold, the governing CO disappearance is: d(VA⋅FACO)dt=−DLCO⋅FACO⋅(PB−PH2O)\frac{d(V_A \cdot F_{A_{CO}})}{dt} = -DLCO \cdot F_{A_{CO}} \cdot (P_B - P_{H_2O}) This simplifies to: dFACOFACO=−DLCO⋅(PB−PH2O)VA dt\frac{d F_{A_{CO}}}{F_{A_{CO}}} = -\frac{DLCO \cdot (P_B - P_{H_2O})}{V_A} \, dt Integrating from initial (t=0) to final (t = t_{BH}) conditions yields the standard single-breath DLCO formula: DLCO=VAtBH⋅(PB−PH2O)⋅ln⁡(FACO,0FACO,t)DLCO = \frac{V_A}{t_{BH}} \cdot (P_B - P_{H_2O}) \cdot \ln\left(\frac{F_{A_{CO},0}}{F_{A_{CO},t}}\right) where t_{BH} is the breath-hold time in minutes (typically ~10 seconds or 0.167 minutes), F_{A_{CO},0} is the initial alveolar CO fraction (approximated from inspired CO fraction adjusted for dead space), and F_{A_{CO},t} is the final alveolar CO fraction. If t_{BH} is measured in seconds, multiply the right-hand side by 60 to obtain units in mL/min/mmHg. Units are typically reported as mL·min⁻¹·mmHg⁻¹ (STPD) in ATS conventions or mmol·min⁻¹·kPa⁻¹ in ERS conventions, with conversion by multiplying the former by 0.334. For low CO concentrations (as used in testing, ~0.3%), a linear approximation may sometimes be applied, but the logarithmic form accounts for the exponential decay of alveolar CO. V_A is typically in mL at BTPS, with full standards incorporating STPD conversion for gas volumes. Alveolar volume (V_A) is estimated concurrently using an inert tracer gas like helium (He) via dilution. The amount of tracer inhaled equals the amount diluted in V_A, leading to: VA=VI⋅FIHeFAHeV_A = V_I \cdot \frac{F_{I_{He}}}{F_{A_{He}}} where V_I is the inspired volume (BTPS) and F_{I_{He}}, F_{A_{He}} are the inspired and alveolar helium fractions, respectively. This form approximates without dead-space correction; full methods subtract dead-space volume V_D: V_A = (V_I - V_D) \cdot \frac{F_{I_{He}}}{F_{A_{He}}}. Adjustments for barometric pressure and water vapor ensure V_A is expressed at body temperature and pressure saturated (BTPS): V_A (BTPS) incorporates (P_B - P_{H_2O}) factors in volume conversions from ambient to body conditions. Key assumptions underlying these derivations include uniform distribution of CO and tracer gas throughout the alveoli, negligible initial CO stores in lung tissue or blood (justifying P_{c_{CO}} ≈ 0), instantaneous mixing upon inhalation and exhalation, constant V_A during breath hold, and a linear partial pressure gradient across the membrane without significant diffusion limitation from reaction rates. Violations, such as uneven ventilation, can introduce errors, but the model provides a robust estimate of overall gas transfer conductance.

Clinical Interpretation

Normal values for diffusing capacity of the lung for (DLCO) in healthy adults typically range from 20 to 30 mL/min/mmHg, with adjustments required for age, , , and to determine predicted values. For instance, DLCO values are approximately 10-15% lower in individuals of African descent compared to Caucasians after adjusting for age, , and , reflecting differences in lung and function. These reference values are standardized globally using the (GLI) 2017 equations, which provide z-scores to assess deviation from the mean and the lower limit of normal (LLN, typically the 5th or z-score of -1.645) for precise interpretation across diverse populations. Clinical patterns of DLCO abnormalities aid in differentiating underlying . An isolated reduction in DLCO, with preserved alveolar volume (VA), often indicates due to loss of alveolar-capillary surface area for . In contrast, a low DLCO accompanied by reduced VA suggests (ILD), where both diffusion impairment and restricted lung volumes reflect parenchymal or inflammation. Elevated DLCO values may occur in conditions such as , which increases pulmonary blood volume, or , which enhances hemoglobin-mediated CO uptake. Adjustments to measured DLCO are essential for accurate interpretation, particularly for anemia and carboxyhemoglobin (COHb) levels. For anemia, the 2017 ERS/ATS standards recommend correction using the formula DLCOc = DLCO × \frac{1.7 \times \mathrm{Hb}}{10.22 + \mathrm{Hb}} for adult males (g/dL), or DLCOc = DLCO × \frac{1.7 \times \mathrm{Hb}}{9.38 + \mathrm{Hb}} for adult females, with Hb_ref = 14.6 g/dL (males) or 13.4 g/dL (females); for children under 15 years, use 9.38 + Hb. This accounts for the effect of hemoglobin on blood conductance for CO (θVc). COHb effects, often from smoking, require correction for competitive binding and back pressure, with adjustments increasing DLCO by approximately 1% for every 1% rise in COHb (e.g., 11% correction for 10% COHb) to reflect the true diffusing capacity. Prognostically, DLCO provides critical insight, especially in (IPF), where values below 40% of predicted are associated with significantly reduced survival, serving as a key threshold for risk stratification beyond symptom assessment. DLCOc=DLCO×1.7×Hb10.22+Hb\mathrm{DLCO_c = DLCO} \times \frac{1.7 \times \mathrm{Hb}}{10.22 + \mathrm{Hb}} This equation adjusts for anemia in adult males, derived from physiological models of gas transfer.

Clinical Applications and Factors

Diagnostic Uses

Diffusing capacity of the for (DLCO) plays a key role in evaluating patients presenting with unexplained dyspnea or , as it provides insights into efficiency that may precede overt radiographic or symptomatic changes. In interstitial diseases (ILDs) such as (IPF) and , DLCO often declines early, serving as a sensitive marker for detecting subclinical or progression before significant forced (FVC) impairment or symptoms manifest. Disease-specific patterns of DLCO help differentiate underlying pathologies. In (COPD), particularly , DLCO is typically reduced due to alveolar surface area loss, often accompanying an obstructive spirometric pattern. and also commonly lower DLCO, reflecting impaired oxygen-carrying capacity or vascular limitations, respectively. In contrast, DLCO remains normal or mildly elevated in , distinguishing it from other obstructive diseases like . Serial DLCO measurements are valuable for monitoring treatment responses in progressive conditions. In IPF patients on antifibrotic therapies such as or , a stabilization or improvement in DLCO over 6-12 months correlates with slowed disease progression and better survival outcomes. Similarly, in cases of chemotherapy-induced lung toxicity, repeated DLCO assessments aid in detecting and quantifying drug-related interstitial changes, guiding dose adjustments or discontinuation. DLCO integrates effectively with other pulmonary function tests (PFTs) for comprehensive assessment. The DLCO adjusted for alveolar volume (DLCO/VA, or KCO) evaluates alveolar-capillary membrane integrity per unit volume, helping isolate true defects from volume-related reductions. When combined with the six-minute walk test (6MWT), low DLCO/VA predicts exertional desaturation in , enhancing risk stratification. Despite its utility, DLCO has limitations in diagnostic specificity, as reductions can arise from multiple etiologies without pinpointing the exact cause, necessitating correlation with and history. Additionally, apparently low DLCO values may occur in without intrinsic lung disease, often due to reduced alveolar volume, though DLCO/VA typically remains preserved or elevated in such cases.

Influencing Factors

Diffusing capacity of the for (DLCO) is influenced by several physiological variables that can alter measurements in healthy individuals. Age is a key determinant, with DLCO declining gradually after the third of life due to reductions in alveolar surface area and pulmonary ; studies indicate an approximate decline of 5-10% per after age 30, though the rate accelerates in later years. Body size also plays a role, as taller individuals exhibit higher DLCO values owing to larger lung volumes and greater alveolar-capillary interface area; reference equations incorporate as a positive predictor alongside age and . Posture affects DLCO through changes in pulmonary blood distribution, with measurements typically 10-15% higher in the compared to sitting due to increased and gravitational redistribution of blood to the bases. Exercise induces acute elevations in DLCO, primarily via and distension of pulmonary capillaries to enhance oxygen delivery, with increases of up to 50-100% observed during moderate to maximal effort in healthy subjects. Environmental factors further modify DLCO outside of disease states. At high altitudes, DLCO effects are complex, with chronic exposure often increasing it by 10% or more due to vascular adaptations, though acute changes may vary; sea-level reference values overestimate predicted DLCO, potentially indicating spurious reductions without barometric pressure adjustments per ATS/ERS guidelines. Acute elevates (COHb) levels to 5-15%, creating a back-pressure effect that reduces measured DLCO by approximately 10% immediately after , independent of chronic lung damage. Variations in ambient and influence gas and analyzer calibration, with changes exceeding 3°C in or 15% in relative potentially altering DLCO readings by 5-10% due to effects on uptake kinetics. Technical aspects of testing impact DLCO results. The lung volume at which the test is performed, specifically the alveolar volume (VA), is directly proportional to DLCO, as larger VA reflects greater for ; DLCO is calculated as the product of the carbon monoxide uptake coefficient (KCO) and VA. The fraction of inspiratory inhaled during the single-breath maneuver, ideally 85-90% of total , ensures optimal VA measurement; suboptimal inhalation reduces effective VA and thus underestimates DLCO. Standardized corrections are applied to account for these influences and ensure comparability. (Hb) concentration affects oxygen-carrying capacity, necessitating adjustment using formulas such as DLCO_corrected = DLCO_observed × [1.7 × Hb / (10.22 + Hb)] for males to normalize to a standard Hb of 14.6 g/dL. COHb corrections mitigate back-pressure by dividing observed DLCO by (1 - COHb fraction), while VA is inherently incorporated into the primary but may require verification against total lung capacity for validity. Ethnic adjustments in reference equations address baseline differences, such as 6-15% lower predicted DLCO in individuals compared to counterparts of similar age, height, and sex, to avoid misclassification. Emerging data post-2020 highlight chronic effects from modern exposures. Vaping, particularly in cases of e-cigarette or vaping product use-associated (EVALI), has been linked to persistent reductions in DLCO, with follow-up studies showing 10-20% deficits persisting months after acute resolution due to alveolar damage and impaired capillary recruitment. Similarly, long-term exposure to , including particulate matter and , correlates with accelerated DLCO decline in non-diseased populations, with recent cohort analyses indicating 5-10% lower values in high-pollution areas, potentially through on the alveolar-capillary membrane.

Historical Development

Early Concepts

The concept of diffusing capacity emerged in the early 20th century amid debates on pulmonary gas exchange, particularly whether oxygen transfer from alveoli to blood relied on passive diffusion or active secretion. In 1910, August and Marie Krogh introduced the single-breath technique using carbon monoxide to assess lung diffusion. In 1915, Marie Krogh published foundational work demonstrating that oxygen diffusion through the lungs of humans could adequately explain observed uptake rates without invoking secretion, building on Christian Bohr's 1909 integration method to estimate alveolar-arterial oxygen gradients from integrated blood samples during exercise. Krogh adapted Bohr's approach to quantify diffusing capacity (DL) for oxygen (DLO2), reporting values around 56 ml/min/mmHg at rest, which increased by 20-40% during exercise, thus resolving a long-standing controversy initiated by Bohr and August Krogh in the 1900s. Prior to widespread DLCO measurements, early assessments of lung function used (CO) absorption as a proxy, with conducting rebreathing tests in the early to evaluate CO uptake and elimination in relation to overall respiratory efficiency. These experiments highlighted CO's utility due to its strong binding to , allowing indirect inferences about limitations, though they did not formally compute DL. Haldane's work, including critiques of pure diffusion models based on high-altitude data from Pike's Peak expeditions, underscored challenges in reconciling measured oxygen uptake with low alveolar tensions. The shift toward routine CO-based diffusing capacity measurements accelerated in the mid-20th century for its simpler kinetics compared to oxygen, avoiding variable saturation effects. In 1946, Lilienthal et al. revived interest by developing a steady-state method to directly measure DLO2 under hypoxic conditions (13% O2), validating CO as a surrogate and reporting DL values that aligned with Krogh's estimates while revealing diffusion impairments in . This paved the way for CO adoption; by 1957, Roughton and Forster introduced a key separation of diffusing capacity into membrane conductance (DM) and blood reaction components (θVc), addressing earlier limitations by incorporating in vitro CO- kinetics to refine calculations. Concurrently, Ogilvie et al. standardized the single-breath CO technique, incorporating helium dilution for accurate alveolar volume measurement and improving reproducibility over Krogh's original method. Early estimates often overestimated diffusing capacity due to neglect of the finite rate of CO reaction with blood (θ), leading to assumptions of instantaneous equilibration that inflated apparent membrane diffusion; this was particularly evident in steady-state approaches before Roughton's corrections. Such challenges highlighted the need for integrated models distinguishing physical diffusion from chemical binding, setting the stage for more precise clinical applications.

Modern Advancements

Standardization efforts in diffusing capacity measurement began with the 1995 American Thoracic Society (ATS) guidelines, which established protocols for the single-breath diffusing capacity of the for (DLCO) to ensure reproducibility and accuracy in clinical settings. These were updated in 2005 by the joint ATS/European Respiratory Society (ERS) statement, emphasizing measures such as equipment calibration, patient positioning, and breath-hold techniques to minimize variability in DLCO testing. Further advancements came in 2017 with the Global Lung Function Initiative (GLI) multi-ethnic reference equations for DLCO, derived from over 5,000 healthy individuals across diverse ethnic groups, enabling more precise interpretation by accounting for age, sex, height, ethnicity, and levels. Technological progress in the introduced automated analyzers for DLCO, which streamlined gas mixing and measurement processes, reducing operator-dependent errors compared to manual systems. By the , online gas monitoring systems emerged, allowing real-time analysis of exhaled and tracer gases, which decreased sampling delays and improved precision in DLCO calculations. Concurrently, the use of (DLNO) alongside DLCO gained traction from the onward, with the DLNO/DLCO ratio providing a non-invasive estimate of pulmonary diffusing capacity (DM) by isolating the effects of alveolar-capillary conductance from contributions. Research in the 2000s highlighted DLCO's role in , with studies showing reduced DLCO due to alveolar-capillary membrane dysfunction and decreased pulmonary capillary blood volume, correlating with disease severity and prognosis in chronic patients. In the 2010s, integration of DLCO with (HRCT) advanced emphysema phenotyping in (COPD), where low DLCO combined with HRCT-detected extent predicted worse outcomes and distinguished emphysema-dominant from airway-dominant phenotypes. Post-2020 developments include AI-assisted interpretation of pulmonary function tests (PFTs), where models analyze DLCO alongside and imaging to enhance diagnostic accuracy for interstitial lung diseases, achieving up to 82% agreement with expert pulmonologists. The spurred research on DLCO in long-haulers, revealing persistent impairment in 30-50% of survivors at 6-12 months post-infection, with incomplete recovery linked to initial disease severity and vascular . Updated corrections for have refined DLCO interpretation, as higher often elevates DLCO due to increased pulmonary , necessitating BMI-adjusted reference values to avoid misclassification in epidemic-era cohorts. Future directions emphasize non-invasive alternatives like the multiple inert gas elimination technique (MIGET), which infuses six inert gases to precisely quantify pulmonary capillary (Vc) and ventilation-perfusion mismatch, offering potential enhancements to DLCO by addressing limitations in complex pathologies.

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