Research Article29th Annual New Horizons Symposium: Back to Basics—Respiratory Physiology in Critically Ill Patients

The Physiology of Ventilation

Gaston Murias, Lluís Blanch and Umberto Lucangelo
Respiratory Care November 2014, 59 (11) 1795-1807; DOI: https://doi.org/10.4187/respcare.03377

Introduction

The diffusion of gases brings the partial pressures of O2 and CO2 in blood and alveolar gas to an equilibrium at the pulmonary blood-gas barrier. Alveolar PCO2 (PACO2) depends on the balance between the amount of CO2 being added by pulmonary blood and the amount being eliminated by alveolar ventilation (V̇A). In steady-state conditions, CO2 output equals CO2 elimination, but during non-steady-state conditions, phase issues and impaired tissue CO2 clearance make CO2 output less predictable. Lung heterogeneity creates regional differences in CO2 concentration, and sequential emptying raises the alveolar plateau and steepens the expired CO2 slope in expiratory capnograms. Lung areas that are ventilated but not perfused form part of the dead space. Alveolar dead space is potentially large in pulmonary embolism, COPD, and all forms of ARDS. When PEEP recruits collapsed lung units, resulting in improved oxygenation, alveolar dead space may decrease; however, when PEEP induces overdistention, alveolar dead space tends to increase. Measuring physiologic dead space and alveolar ejection volume at admission or examining the trend during mechanical ventilation might provide useful information on outcomes of critically ill patients with ARDS.

Physiology of Carbon Dioxide

In normal conditions, CO2 is produced at the tissue level during pyruvate oxidation as a result of aerobic metabolism. The respiratory quotient shows the relationship between oxygen consumption (V̇O2) and CO2 production (V̇CO2): respiratory quotient = V̇CO2/V̇O2. In aerobic metabolism, the respiratory quotient varies from 0.7 to 1 as a function of the substrate being burned to produce energy. Tissue PCO2 can also increase as a consequence of bicarbonate (HCO3−) buffering of non-volatile acids (eg, lactate) during tissue dysoxia,1,2 which can result in a respiratory quotient of > 13; lipogenesis can also produce a respiratory quotient of > 1 under aerobic conditions.4 Regardless of its origin, CO2 has to leave the tissues, be transported in blood, and be eliminated in the lungs, or respiratory acidosis will develop.

CO2 transport in blood is complex. Tissue CO2 enters capillary blood by simple diffusion resulting from a pressure gradient. Thus, CO2 capillary pressure must remain low for diffusion to continue. The 2 main mechanisms that keep CO2 capillary pressure low are continuous capillary flow and the low proportion of CO2 in solution. Blood flow is the main determinant of tissue CO2 clearance, and low flow increases the tissue PCO2-venous PCO2 difference.5,6 Various mechanisms maintain the proportion of CO2 at low levels in solution in plasma (∼5%). Figure 1 shows the ways CO2 is transported. Once in blood, CO2 easily diffuses into red cells, where carbonic anhydrase catalyzes the reaction with water to form carbonic acid, which rapidly dissociates into HCO3− and H+. Although no carbonic anhydrases are present in plasma, it seems that their presence in endothelial cells in pulmonary capillaries enables some activity in plasma.7 Even though carbonic acid is almost completely dissociated within red cells, the accumulation of HCO3− and H+ would limit the amount of CO2 that blood can transport. However, H+ is buffered by hemoglobin, and HCO3− is exchanged for Cl− by Band 3 (anion exchanger 1 [AE1]), a membrane transport protein.8 As a consequence, bicarbonate is the main form of CO2 transport, accounting for ≈95% of the total (mainly in plasma).

Fig. 1.
Fig. 1.

Carbon dioxide transport in blood. CO2 produced during cell metabolism reaches the blood by simple diffusion driven by a partial pressure gradient (higher in tissue, lower in blood). To allow CO2 to be cleared from tissues, this gradient must remain high. A series of reactions keeps CO2 in solution low. Once in plasma, CO2 diffuses into red cells, where carbon anhydrase catalyzes the reaction with water to produce carbonic acid (H2CO3), which subsequently dissociates into hydrogen (H+) and bicarbonate (HCO3−). Once again, the accumulation of either H+ or HCO3− would stop those reactions. However, protons are buffered by hemoglobin, and bicarbonate is exchanged for extracellular chloride (Cl−) by AE1 (Band 3). For more details, see text.

In normal conditions, a negligible amount of CO2 is transported as carbamino compounds, but this mechanism can be markedly increased by inhibition of carbonic anhydrase (eg, by acetazolamide). CO2 binds mainly to α-amino groups at the ends of both α- and β-chains of hemoglobin. Reduced hemoglobin is 3.5 times more effective than oxyhemoglobin as a CO2 carrier, so the release of oxygen at the tissue level increases the amount of CO2 that hemoglobin can carry. This is the major component of the Haldane effect. The other component is related to H+ buffering: as hemoglobin releases oxygen, it becomes more basic, and its buffering capacity increases (see Fig. 1).9

PACO2

PACO2 depends on the balance between the amount of CO2 being added by pulmonary blood and the amount eliminated by V̇A. As the former is nearly continuous and the latter is not, PACO2 varies during the ventilatory cycle (Fig. 2). PACO2 can be calculated (when inspired gas is free from CO2) as CO2 output/V̇A. V̇A is the difference between tidal volume (VT) and dead-space volume (VD).

Fig. 2.
Fig. 2.

Alveolar and airway CO2 during the ventilatory cycle: flow (upper graph) and mean alveolar and airway CO2 pressure scalars (lower graph). Alveolar PCO2 (PACO2) is lower at end inspiration (as far as fresh air dilutes alveolar gas) and higher at end expiration (because blood keeps releasing CO2 into the alveolus). PACO2 varies between alveoli: it is higher (A) in units with lower V̇A/Q̇ ratios (closer to mixed venous PCO2) and lower (B) in units with higher V̇A/Q̇ ratios (closer to inspired PCO2). Airway CO2 is zero during inspiration (provided there is no rebreathing, phase I of the capnogram). At the very beginning of expiration, CO2 remains zero as long as the gas comes purely from airway dead space; it then increases progressively (phase II) when units start to empty (low time constant units first, high time constant units later). Phase III is considered to represent alveolar gas, and the end of phase III (end-tidal PCO2 [PETCO2]) is used as a reference of mean alveolar gas composition. Phase IV of the capnogram shows the sudden fall in PCO2 at the start of inspiration.

In steady-state conditions, CO2 output equals V̇CO2; during non-steady-state conditions, phase issues and impaired tissue CO2 clearance make CO2 output less predictable.10 So, the equation can be re-written as: PACO2 = V̇CO2/V̇A. However, the magnitude of these variables varies in different conditions, so corrections have to be made. V̇A measurements are expressed in body temperature and pressure saturated with vapor (BTPS); V̇CO2 is expressed in standard temperature and pressure dry (STPD) conditions; and PACO2 measurements are expressed in body temperature and pressure dry (BTPD) conditions. So the above equation must be used in the form: PACO2 (BTPD) = 0.863 × V̇CO2 (STPD)/V̇A (BTPS), where 0.863 is a constant that summarizes the corrections when V̇CO2 and V̇A measurements are not provided in the same units.

Figure 3 (constructed from the adjusted equation) shows the relationship between PACO2 and V̇A for 2 different V̇CO2 values. This relationship is not linear: as PACO2 decreases, the increase in alveolar ventilation necessary to reduce PACO2 increases.

Fig. 3.
Fig. 3.

Nonlinear relationship between alveolar ventilation (V̇A) and alveolar PCO2 (PACO2). The effects of changes in V̇A on PACO2 are far more evident when basal V̇A is lower. Higher CO2 production (V̇CO2) = 200 mL/min, and lower V̇CO2 = 100 mL/min.

PaCO2

When venous blood arrives at pulmonary capillaries, the events illustrated in Figure 1 occur in the opposite order. The fall in plasma PCO2 resulting from CO2 diffusion to the alveolus results in CO2 being released from red cells, so carbonic acid is converted to CO2 and H2O (carbonic anhydrase facilitates the reaction in both directions). The drop in carbonic acid concentration leads to new formation of H2CO3 from bicarbonate (from the cytoplasm and plasma through Band 3) and protons (free and from hemoglobin). CO2 is also free from carbamates. As the environment becomes more basic, hemoglobin's affinity for O2 increases (Bohr effect).

PCO2 depends on CO2 concentration and the solubility coefficient in blood (SCB): PCO2 = CO2 × SCB. SCB varies with temperature; at 37°C, it is 0.0308 mmol/L/mm Hg.11

At the pulmonary blood-gas barrier, the diffusion of gases brings the PO2 and PCO2 of blood and alveolar gas to an equilibrium, and when blood leaves the pulmonary capillaries, it has the same PO2 and PCO2 as alveolar gas. However, the blood that arrives at the left atrium has lower PO2 and higher PCO2 because venous admixture and shunt (both physiologic and large) contaminates it with venous blood. Likewise, exhaled gas has higher PO2 and lower PCO2 than alveolar air because dead space pollutes it with fresh air (Fig. 4).

Fig. 4.
Fig. 4.

Model of relationship between ventilation and perfusion. Even when the gases at the blood-gas barrier are in complete equilibrium, the composition of effluent (expiratory) gas differs from that of alveolar gas because effluent gas also contains gas from the alveolar dead space (whose composition is that of the inspired gas). Similarly, the composition of arterial blood differs from that of capillary blood to the extent that it is mixed with shunt blood (whose composition is that of mixed venous blood). This concept (the calculation of the difference between expected composition and actual composition of the effluent media) is the basis for calculating both alveolar dead space and shunt.

The Concept of Dead Space

The concept of dead space accounts for those lung areas that are ventilated but not perfused. The VD is the sum of 2 separate components of lung volume. One is the nose, pharynx, and conduction airways, which do not contribute to gas exchange and are often referred to as anatomic or airway VD. The mean volume of the airway VD in adults is 2.2 mL/kg,12 but the measured amount varies with body13 and neck/jaw12 position. The second component consists of well-ventilated alveoli that receive minimum blood flow, which is referred to as alveolar VD. In mechanical ventilation, the ventilator's endotracheal tube, humidification devices, and connectors add mechanical dead space, which is considered part of the airway VD. Physiologic VD consists of airway VD (mechanical and anatomic) and alveolar VD; in mechanical ventilation, physiologic VD is usually reported as the fraction of VT that does not participate in gas exchange.14–16 Alveolar VD can result from an increase in ventilation or a decrease in perfusion.10 The gas from the alveolar VD behaves in parallel with the gas from perfused alveoli, exiting the lungs at the same time as the gas that effectively participates in gas exchange and diluting it; this is evident as the difference between PaCO2 and end-tidal PCO2 (PETCO2).15,16 Beyond that, if the amount of gas that reaches the exchange areas surpasses the areas' capacity for perfusion (high V̇A/Q̇ ratio), the excess gas supplied by ventilation behaves like alveolar VD (functional concept) (Fig. 5).

Fig. 5.
Fig. 5.

Alveolar dead space. A: An ideal unit (top) receives nearly equal amounts of ventilation and perfusion. B: When perfusion drops (and ventilation is kept constant) (top), a fraction of the ventilation the unit is receiving (gray area) does not adequately participate in gas exchange and behaves like parallel dead space (it leaves the lungs at the same time as alveolar ventilation [V̇A]). Bottom: histograms for ventilation and perfusion for each situation. For clarity, only units with V̇A/Q̇ > 0 and lower than infinite are plotted (neither shunt nor serial dead space is shown).

Measurement of Dead Space

In critical patients, correct measurement and calculation of dead space provides valuable information about ventilatory support and can also be a valuable diagnostic tool. Nuckton et al17 demonstrated that a high physiologic VD/VT was independently associated with an increased risk of death in subjects diagnosed with ARDS. Changes in the shape of the capnographic curve often indicate ventilatory maldistribution, and several indices have been developed to quantify maldistribution based on the geometrical analysis of the volumetric capnographic curve.18,19

Bohr

Bohr's dead-space fraction (VD/VT) is calculated as (PETCO2 − PĒCO2)/PETCO2,15 where PĒCO2 is the mean expired PCO2 per breath, calculated as V̇CO2/VT × (Pb − PH2O), where Pb is barometric pressure and PH2O is water-vapor pressure. It is simple but cumbersome to collect PĒCO2 using a Douglas bag.

In certain situations, the Bohr equation's use of PETCO2 can be problematic. In exercise, in acute hyperventilation, or in presence of different alveolar time constants, PACO2 rises, often steeply, during expiration of alveolar gas, so PETCO2 will depend on the duration of expiration. The dead space so derived will not necessarily correspond to any of the compartments of the dead space (instrumental, anatomic, and alveolar).15,16,20

Enghoff

In 1931, Enghoff first demonstrated that the physiologic dead space remained a fairly constant fraction of VT over a wide range of VT. Physiologic VD/VT calculated from the Enghoff modification of the Bohr equation15 uses PaCO2 with the assumption that PaCO2 is similar to PACO2: physiologic VD/VT = (PaCO2 − PĒCO2)/PaCO2.

Langley

Langley et al21 plotted the volume of CO2 elimination per breath (V̇eCO2) against the total expired volume to contrive an alternative method of calculating airway dead space. This curvilinear graph is shown in Figure 6. A straight best-fit line is extrapolated from the linear portion of the graph, and the intercept of this line on the volume axis (X axis) represents the dead space. This method correlates with Fowler's method for calculating airway VD (Fig. 7) but has the added advantage that it does not rely on visual interpretation to determine equal areas. Although several factors can influence airway VD, in the critical care setting, this volume remains relatively unchanged. Any changes in measured physiologic VD/VT, without added equipment dead space, are mostly a result of changes in alveolar VD. It is clearly alveolar VD and its inherent interaction with physiologic VD that are most important clinically.

Fig. 6.
Fig. 6.

Langley's method for calculating airway dead-space volume (VDAW). Single-breath expiratory carbon dioxide volume (V̇eCO2) is plotted versus expired volume. Airway VD can be calculated from the value obtained on the volume axis by back-extrapolation from the first linear part of the V̇eCO2 versus volume curve (solid line).

Fig. 7.
Fig. 7.

Single-breath expiratory volumetric capnogram recorded in a mechanically ventilated subject with COPD. PETCO2 = end-tidal PCO2; PĒCO2 = mixed exhaled PCO2; PACO2 = mean alveolar PCO2. The solid lines indicate Fowler's geometric method of equivalent areas to calculate airway dead space. Airway dead space is measured from the beginning of expiration to the point where the vertical line crosses the volume axis.

Alveolar Ejection Volume

The advanced technology combination of airway flow monitoring and mainstream capnography allows noninvasive breath-by-breath bedside calculation of V̇eCO2 and the ratio between alveolar ejection volume (VAE) and VT independent of ventilatory settings.22,23 VAE can be defined as the fraction of VT with minimum VD contamination, which may be inferred from the asymptote of the V̇eCO2/VT curve at end of expiration, whereby VD is equal to zero. VAE is defined as the volume that characterizes this relationship, up to a 5% variation.23

Using the V̇eCO2/VT curve, the fraction of volume flow corresponding to alveolar gas exhalation can be calculated. After a given volume has been exhaled, V̇eCO2 progressively increases to reach a total amount of V̇eCO2 elimination in a single expiration. The increase in V̇eCO2 is slightly nonlinear because of alveolar inhomogeneity, in other words, because of the presence of a certain amount of alveolar gas contaminated by parallel VD. At the very end of expiration, the gas exhaled comes only from the alveoli, so it is pure alveolar gas. From this curve, the last 50 points of every cycle are back-extrapolated by least-squares linear regression analysis. Assuming a fixed amount of VD contamination (dead-space allowance), a point on the V̇eCO2/VT curve representing the beginning of the VAE is obtained. The VAE is then obtained as the value of the volume at the intersection between the V̇eCO2/VT curve and a straight line having the maximum value at end of expiration and a slope equal to 0.95 (1 − dead-space allowance) times the calculated slope (Fig. 8). VAE is expressed as a fraction of expired VT (VAE/VT).24

Fig. 8.
Fig. 8.

Determination of alveolar ejection volume (VAE) in a healthy subject. CO2 production (V̇CO2) is plotted as a function of expired volume. From this curve, the last 50 points of every cycle are back-extrapolated to represent the ideal lung behavior (straight dashed line). Assuming a fixed amount of dead-space contamination of 5% (red arrow), a straight line is plotted. Alveolar ejection begins at the intersection between the sampled curve and the straight line (black arrow). The volume between this point and end of expiration is the VAE (shaded area).

The VAE/VT ratio, an index of alveolar inhomogeneity, correlates with the severity of lung injury and is not influenced by the set ventilatory pattern in acute lung injury (ALI) or ARDS patients receiving mechanical ventilation.23 It follows that VAE/VT might have clinical applications in lung disorders characterized by marked alveolar inhomogeneity, and indeed, measurement of VAE/VT at ICU admission and after 48 h of mechanical ventilation, together with PaO2/FIO2, provided useful information on outcome in critically ill patients with ALI or ARDS.25

Causes of Elevated Dead Space in Mechanically Ventilated Patients

In patients with lung disease, VD can be large. Patients with unevenly distributed ventilation and perfusion have lung units in which the amount of ventilation is high relative to the amount of blood flow. The PCO2 in gas coming from these units is lower than PaCO2. During expiration, this gas mixes with gas coming from other lung areas in which ventilation and perfusion are more closely matched, diluting it so that expired PCO2, including PETCO2, can be greatly different from PaCO2. In addition, the PCO2 of expired gas in patients with obstructive airway disease may increase steeply during expiration because lung units that empty late are poorly ventilated and contain gas with higher CO2 concentrations. The effect of these late-emptying lung units on expired PCO2 leads to a difference between PaCO2 and PETCO2 (Fig. 9).26

Fig. 9.
Fig. 9.

Three single-breath volumetric capnograms during mechanical ventilation in different scenarios: a subject with normal lungs and 2 subjects with COPD with and without hypercapnia.

Pulmonary Embolism

Pulmonary embolism is most commonly due to blood clots that travel through the venous system and lodge in the pulmonary arterial tree. Spatial differences in blood flow between respiratory units in the lung cause inefficient gas exchange that is reflected as increased alveolar VD. Occlusion of the pulmonary vasculature by an embolism will result in a lack of CO2 flux to the alveoli in the affected vascular distribution. The mechanical properties may not be greatly affected, so these alveoli empty in parallel with other respiratory units with similar time constants. Because ventilation to the affected alveoli continues unabated, PCO2 in these alveoli decreases.27

In patients with sudden pulmonary vascular occlusion due to pulmonary embolism, the resultant high V̇/Q̇ mismatch produces an increase in alveolar VD. This effect enables volumetric capnography to be used as a diagnostic tool at the bedside: in the context of a normal D-dimer assay, a normal alveolar VD is highly reliable to rule out pulmonary embolism.28 In patients with clinical suspicion of pulmonary embolism and elevated D-dimer levels, calculations derived from volumetric capnography such as late dead-space fraction had a statistically better diagnostic performance in suspected pulmonary embolism than the traditional measurement of the P(a-ET)CO2 difference.28 Moreover, a normal physiologic VD/VT ratio makes pulmonary embolism unlikely. Finally, volumetric capnography is an excellent tool for monitoring thrombolytic efficacy in patients with major pulmonary embolism.29

COPD

Mismatch of the distribution of ventilation and perfusion within any single acinus results from spatial differences in gas-flow distribution due to the differences in the time constants of the respiratory units. PACO2 will vary between respiratory units. In this situation, individual respiratory units will empty sequentially at differing rates and times dependent upon mechanical properties.

Pulmonary heterogeneity is, together with airway obstruction, a cardinal feature in the functional impairment of COPD. Heterogeneity, mostly dependent on peripheral involvement, increases with the severity of the disease; therefore, volumetric capnography, a technique that basically explores regional distribution, can be a good tool to determine the degree of functional involvement in patients with COPD (see Fig. 9).30,31

Ventilation to regions with little or no blood flow (low PACO2) affects pulmonary dead space. In patients with air-flow obstruction, inhomogeneities in ventilation are responsible for the increase in VD. Shunt increases physiologic VD/VT as the mixed venous PCO2 from shunted blood elevates the PaCO2, increasing physiologic VD/VT by the fraction that PaCO2 exceeds the non-shunted pulmonary capillary PCO2. The accuracy of physiologic VD/VT measurement can be improved with a forced maximum exhalation, which reduces the P(a-ET)CO2 difference and physiologic VD/VT because of more complete emptying of the lungs, including peripheral alveoli that have a higher PCO2 level. Furthermore, maximum exhalation is generally preceded by maximum inhalation, resulting in a more even distribution of gases within the alveoli.32,33

ARDS

Even mild forms of ARDS can severely alter respiratory system mechanics.34,35 Most of these changes affect peripheral structures beyond the conducting airways: the interstitium, alveolar spaces, and small airways. The main consequence of peripheral lung injury is the development of heterogeneities that affect the efficacy of respiratory gas exchange and ventilatory distribution.34,35

Patients with ARDS have lung regions with low V̇/Q̇ (and high PACO2) that usually coexist with others having high V̇/Q̇ (and low PACO2). The combination of these 2 conditions secondary to severe alveolar and vascular damage results in increased pulmonary dead space. Moreover, pulmonary dead space is increased by shock states, systemic and pulmonary hypotension, and obstruction of pulmonary vessels (massive pulmonary embolus and microthrombosis). Dead space accounts for most of the increase in the minute ventilation requirement and CO2 retention that occur in severe ARDS,34 and the extent of lung inhomogeneities increased with the severity of ARDS and correlated with physiologic VD/VT.36 Mechanical ventilation can substantially affect dead-space measurements, making the variations in dead space more complex.37

Effects of Mechanical Ventilation on Dead Space

Mechanical ventilation makes it more difficult to understand variations in dead space at the bedside. On the one hand, PEEP levels that recruit collapsed lung can reduce dead space, primarily by reducing intrapulmonary shunt. On the other hand, overdistention promotes the development of high V̇/Q̇ regions with increased dead space.38 Therefore, a number of pulmonary and non-pulmonary factors might affect interpretation of dead-space variations at the bedside.

Several studies in subjects with ARDS have shown that hypoxemia is due to intrapulmonary shunt and regions with very low V̇/Q̇.39 The multiple inert gas elimination technique has also shown that patients with ARDS have a large percentage of ventilation distributed to unperfused or poorly perfused regions.39 Coffey et al38 found that oleic acid-induced ARDS in dogs resulted in high VD/VT by increasing shunt, inert gas dead space, and mid-range V̇/Q̇ heterogeneity. Capnographic findings in patients with ALI and ARDS are consistent with a high degree of ventilatory maldistribution and poor ventilatory efficiency. Blanch and co-workers25 reported that indices obtained from volumetric capnography (Bohr's VD/VT, phase 3 slope, and VAE/VT) were markedly different in subjects with ALI and ARDS than in control subjects. Bohr's dead space and phase 3 slope were higher in subjects with ALI than in control subjects and higher in subjects with ARDS than in both control and ALI subjects. Moreover, VAE/VT was lower in subjects with ALI than in control subjects and lower in subjects with ARDS than in both control and ALI subjects.

Effect of VT

In recumbent, anesthetized, normal subjects, increasing VT increases ventilatory efficiency. Studies in normal subjects40 have shown that the convection-dependent non-homogeneity of ventilation increases with relatively small increases in VT, whereas non-homogeneity due to interaction of convection and diffusion in the lung periphery decreases. In an earlier study, Romero et al23 found that VAE/VT changed significantly with volume in normal subjects but not in subjects with ARDS. Even earlier, Paiva et al41 showed that phase 3 slope decreases with increased VT in normal subjects. It might seem reasonable to expect that the increase in VT in subjects with ARDS would recruit some alveolar units and thus improve the degree of alveolar homogeneity to some extent.42 In fact, however, recruited units would contribute to improvement in ventilatory and mechanical efficiency only if they were strictly normal and homogeneous. We can reasonably suppose that the reason that VAE/VT does not increase with VT in patients with ARDS is that recruited alveoli are mostly diseased or that increased VT does not effectively recruit new lung areas. Nowadays, VT is no longer used to increase oxygenation because it causes injuries to lungs and distant organs and poor outcome.34,35,43 Currently, the use of a lung-protective ventilation strategy has also been extended to intermediate-risk and high-risk patients undergoing major surgical procedures because it was associated with improved clinical outcomes and reduced health-care utilization.44 This brings us to the current hypotheses that elevated physiologic VD/VT and decreased VAE/VT are signs of poor prognosis in ARDS, and their evolution during treatment has an impact on final outcome.17,25,45,46

Effect of PEEP

Alveolar VD is significantly increased in ARDS and does not vary with PEEP. However, when PEEP is administered to recruit collapsed lung units (resulting in improved oxygenation), alveolar VD decreases unless overdistention impairs alveolar perfusion. Breen and Mazumdar47 found that the application of PEEP at 11 cm H2O to anesthetized, mechanically ventilated, open-chested dogs increased physiologic VD, reduced V̇eCO2, and resulted in a poorly defined alveolar plateau. These changes were mainly produced by a significant decrease in cardiac output due to PEEP. In dogs with oleic acid-induced ARDS, Coffey et al38 found that low PEEP reduced physiologic VD/VT and intrapulmonary shunt. Conversely, in the same animals, high PEEP increased the fraction of ventilation delivered to areas with high V̇/Q̇, resulting in increased physiologic VD/VT. When Tusman et al48 tested the usefulness of alveolar VD for determining open-lung PEEP in eight lung-lavaged pigs, they observed 2 interesting physiologic effects. First, alveolar VD showed a good correlation with PaO2 and with normally aerated and non-aerated areas on computed tomography in all animals, yielding a sensitivity of 0.89 and a specificity of 0.90 for detecting lung collapse. However, PEEP also induced airway dilation and increased airway VD, thus affecting the global effect of both on physiologic VD/VT. Finally, variations in dead space with the application of PEEP largely depend on the type, degree, and stage of lung injury. Experimental ARDS induced by lung lavage potentially allows for much greater recruitment at increasing increments of PEEP49–51 than experimental ARDS models induced by oleic acid injury or pneumonia, and comparisons with human ARDS remains speculative.

Blanch et al37 studied the relationship between the effects of PEEP on volumetric capnography and respiratory system mechanics in subjects with normal lungs, with moderate ALI, and with severe ARDS. Compared with control subjects, subjects with ARDS had markedly decreased respiratory system compliance (CRS) and increased total respiratory system resistance. Increasing PEEP improved respiratory mechanics in normal subjects and worsened lung tissue resistance in subjects with respiratory failure; however, it did not affect volumetric capnography indices. Other authors have corroborated these findings. Smith and Fletcher52 found that PEEP did not modify CO2 elimination in subjects immediately after heart surgery. Beydon et al53 studied the effect of PEEP on dead space in subjects with ALI. They found a large physiologic VD/VT that remained unchanged after PEEP was raised from 0 to 15 cm H2O. In healthy anesthetized subjects, Maisch et al54 found that physiologic VD/VT and maximum CRS during a decremental PEEP trial were lowest after a recruitment maneuver. However, at the highest PEEP level during the incremental PEEP trial when PaO2 and the increase in lung volume induced by PEEP peaked, physiologic VD/VT deteriorated. Therefore, physiologic VD/VT and CRS are more sensitive than PaO2 measurements for detecting lung overdistention.19,40,54 Seminal studies on the effect of PEEP in P(a-ET)CO2 difference showed similar results.55 Finally, Fengmei et al56 evaluated the effect of PEEP titration following lung recruitment in subjects with ARDS on physiologic VD/VT, arterial oxygenation, and CRS. Interestingly, they found that optimal PEEP in these subjects was 12 cm H2O because, at this pressure, the highest CRS in conjunction with the lowest physiologic VD/VT indicated a maximum number of effectively expanded alveoli.

Variations in dead space and its partitions resulting from PEEP largely depend on the type, degree, and stage of lung injury. When PEEP results in global lung recruitment, physiologic VD and alveolar VD decrease; when PEEP results in lung overdistention, physiologic VD and alveolar VD increase. Therefore, volumetric capnography may be helpful to identify overdistention or better alveolar gas diffusion in patients with ARDS.

Effect of Inspiratory Flow Waveforms and End-Inspiratory Pause

Patients receiving pressure controlled inverse-ratio ventilation had lower PaCO2 than those receiving the normal inspiratory/expiratory ratio.57 Several studies have reported that an exponentially decreasing inspiratory flow pattern results in modest improvements in PaCO2 and dead space. These phenomena are explained by an increased mean distribution time for gas mixing, during which fresh gas from the VT is present in the respiratory zone and is available for distribution in the lung periphery. The mean distribution time of inspired gas is the mean time during which fractions of fresh gas are present in the respiratory zone.19,58,59 It was recently proposed that setting the ventilator to a pattern that enhances CO2 exchange can reduce dead space and significantly increase CO2 elimination or alternatively reduce VT. This option is especially interesting when lung-protective ventilation results in hypercapnia. In particular, doubling the proportion of the inspiratory cycle from 20 to 40% (without creating auto-PEEP),59 increasing end-inspiratory pause up to 30% of the inspiratory cycle,58 or both60 markedly reduced PaCO2 and physiologic VD/VT, allowing the use of protective ventilation with low VT and enhancing lung protection.

Prone Position, PaCO2, and Dead Space

In patients with severe ARDS, prone positioning improves survival.61 In the prone position, recruitment in dorsal areas usually prevails over ventral derecruitment because of the need for the lung and its confining chest wall to conform to the same volume, with more homogeneous overall dorsal-to-ventral lung inflation and more homogeneously distributed stress and strain than in the supine position.62 Because the distribution of perfusion remains nearly constant in both postures, prone positioning usually improves oxygenation and may be associated with a decrease in PaCO2, an indirect reflection of the reduction in alveolar VD.63 Gattinoni et al64 also reported improved prognosis in subjects in whom PaCO2 declined after an initial prone position session. Charron et al65 showed that prone positioning induced a decrease in plateau pressure, PaCO2, and alveolar VD/VT ratio and an increase in PaO2/FIO2 and CRS; these changes peaked after 6–9 h. In fact, the respiratory response to prone positioning appeared more relevant when PaCO2 rather than PaO2/FIO2 was used. Protti et al66 investigated the gas exchange response to prone positioning as a function of lung recruitability, measured by computed tomography in a supine position. Interestingly, changes in PaCO2, but not in oxygenation, were associated with lung recruitability, which was in turn associated with the severity of lung injury.

Prognostic Value of Dead-Space Measurement

Alterations in the pulmonary microcirculation due to epithelial and endothelial lung cell injuries are characteristic of most forms of ARDS. Consequently, pulmonary ventilation and pulmonary and bronchial circulation are compromised, and pulmonary artery pressure and dead space increase. A high physiologic VD/VT fraction represents an impaired ability to excrete CO2 due to any kind of V̇/Q̇.38 Traditionally, pulmonary hypertension in the course of ARDS was considered a predictor of poor outcome.67 However, in the era of lung-protective ventilation using low VT, elevated systolic pulmonary artery pressure early in the course of ARDS is not necessarily predictive of poor outcome, although a persistently large dead space in early ARDS remains associated with increased mortality and fewer ventilator-free days.68

Several studies have demonstrated this association. Nuckton et al17 demonstrated that a high physiologic VD/VT was independently associated with an increased risk of death in subjects with ARDS. The mean physiologic VD/VT was 0.58 early in the course of ARDS and was higher in subjects who died than in those who survived. The dead space was an independent risk factor for death (for every 0.05 increase in physiologic VD/VT, the odds of death increased by 45%). Raurich et al45 studied mortality and dead-space fraction in 80 subjects with early-stage ARDS and 49 subjects with intermediate-stage ARDS. In both stages, the dead-space fraction was higher in subjects who died than in those who survived and was independently associated with a greater risk of death. Similar results were reported by Lucangelo et al25 regarding measuring the VAE/VT fraction at admission and after 48 h of mechanical ventilation in subjects with ALI or ARDS and by Siddiki et al69 regarding estimating physiologic VD/VT from the calculation of V̇CO2 using the Harris-Benedict equation. Finally, Kallet et al70 tested the association between the VD/VT fraction and mortality in subjects with ARDS diagnosed using the Berlin Definition34 who were enrolled in a clinical trial incorporating lung-protective ventilation and found that markedly elevated physiologic VD/VT (> 0.60) in early ARDS was associated with higher mortality. In the clinical arena, measuring or estimating physiologic VD/VT at bedside is an easy method to predict outcome in ARDS and should be routinely incorporated to monitor respiratory function in patients receiving mechanical ventilation.71

Conclusions

Understanding the physiology of ventilation and measuring the dead-space fraction at bedside in patients receiving mechanical ventilation may provide important physiologic, clinical, and prognostic information. Further studies are warranted to assess whether the continuous measurement of different derived capnographic indices is useful for risk identification and stratification and for tracking the effects of therapeutic interventions and mechanical ventilation modes and settings in critically ill patients.

Acknowledgments

We thank Mr John Giba for editing and language revision and Ms Merce Ruiz for administrative work related to this paper.

Footnotes

  • Correspondence: Lluís Blanch MD PhD, Critical Care Center, Hospital de Sabadell, Corporació Sanitària Universitària Parc Taulí, Universitat Autònoma de Barcelona, Parc Taulí 1, 08208 Sabadell, Spain. E-mail: lblanch{at}tauli.cat.

  • Dr Blanch presented a version of this paper at the 29th New Horizons in Respiratory Care Symposium: Back to the Basics: Respiratory Physiology in Critically Ill Patients of the AARC Congress 2013, held November 16–19, 2013, in Anaheim, California.

  • The authors have disclosed relationships with Corporació Sanitària Parc Taulí (Spain) and Better Care SL. This work was partially supported by ISCIII PI09/91074, Centro de Investigación Biomédica en Red de Enfermedades Respiratorias, Fundación Mapfre, and Fundació Parc Taulí.

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