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Home , Dead space (physiology), Haldane Effect, Respiratory quotient, Respiratory system

The Physiology of Ventilation

Gaston Murias MD, Lluís Blanch MD PhD, and Umberto Lucangelo MD

Introduction Physiology of Dioxide P ACO2 P aCO2 The Concept of Measurement of Dead Space Bohr Enghoff Langley Alveolar Ejection Volume Causes of Elevated Dead Space in Mechanically Ventilated Patients Pulmonary COPD ARDS Effects of on Dead Space

Effect of VT Effect of PEEP Effect of Inspiratory Flow Waveforms and End-Inspiratory Pause Prone Position, P , and Dead Space aCO2 Prognostic Value of Dead-Space Measurement Conclusions

Introduction added by pulmonary and the amount being elimi- ˙ nated by alveolar ventilation (VA). In steady-state condi- The of gases brings the partial of O2 tions, CO2 output equals CO2 elimination, but during non- and CO2 in blood and alveolar gas to an equilibrium at the steady-state conditions, phase issues and impaired pulmonary blood-gas barrier. Alveolar P (P ) de- CO clearance make CO output less predictable. CO2 ACO2 2 2 pends on the balance between the amount of CO2 being heterogeneity creates regional differences in CO2 concen- tration, and sequential emptying raises the alveolar plateau

and steepens the expired CO2 slope in expiratory capno- Dr Murias is affiliated with the Critical Care Center, Clínica Bazterrica y Clínica Santa Isabel, Buenos Aires, . Dr Blanch is affiliated with the Critical Care Center, Hospital de Sabadell, and the Fundacio´ Parc Taulí, Corporacio´ Sanita`ria Parc Taulí, Universitat Auto`noma de The authors have disclosed relationships with Corporacio´ Sanita`ria Parc Barcelona, Sabadell, Spain and Centro de Investigacio´n Biome´dica en Taulí (Spain) and Better Care SL. This work was partially supported by Red de Enfermedades Respiratorias, ISCIII, Madrid, Spain. Dr Lucan- ISCIII PI09/91074, Centro de Investigacio´n Biome´dica en Red de En- gelo is affiliated with the Department of Perioperative , Inten- fermedades Respiratorias, Fundacio´n Mapfre, and Fundacio´ Parc Taulí. sive Care and Emergency, Cattinara Hospital, University of Trieste, Trieste, Italy. Correspondence: Lluís Blanch MD PhD, Critical Care Center, Hospital de Sabadell, Corporacio´ Sanita`ria Universita`ria Parc Taulí, Universitat Dr Blanch presented a version of this paper at the 29th New Horizons in Auto`noma de Barcelona, Parc Taulí 1, 08208 Sabadell, Spain. E-mail: Respiratory Care Symposium: Back to the Basics: Respiratory Physiol- [email protected]. ogy in Critically Ill Patients of the AARC Congress 2013, held Novem- ber 16–19, 2013, in Anaheim, California. DOI: 10.4187/respcare.03377

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Fig. 1. transport in blood. CO2 produced during cell reaches the blood by simple diffusion driven by a partial 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 low. Once in plasma, CO2 diffuses into red cells, where carbon anhydrase catalyzes the reaction with water ϩ Ϫ to produce carbonic acid (H2CO3), which subsequently dissociates into (H ) and (HCO3 ). Once again, the accu- ϩ Ϫ mulation of either H or HCO3 would stop those reactions. However, protons are buffered by , and bicarbonate is exchanged for extracellular chloride (ClϪ) by AE1 (Band 3). For more details, see text. grams. Lung areas that are ventilated but not perfused ratory quotient of Ͼ 13; can also produce a form part of the dead space. Alveolar dead space is po- of Ͼ 1 under aerobic conditions.4 Re- tentially large in , COPD, and all gardless of its origin, CO2 has to leave the tissues, be forms of ARDS. When PEEP recruits collapsed lung units, transported in blood, and be eliminated in the , or resulting in improved oxygenation, alveolar dead space will develop. may decrease; however, when PEEP induces overdisten- CO2 transport in blood is complex. Tissue CO2 enters tion, alveolar dead space tends to increase. Measuring phys- blood by simple diffusion resulting from a pres- iologic dead space and alveolar ejection volume at admis- sure gradient. Thus, CO2 capillary pressure must remain sion or examining the trend during mechanical ventilation low for diffusion to continue. The 2 main mechanisms that might provide useful information on outcomes of critically keep CO2 capillary pressure low are continuous capillary ill patients with ARDS. flow and the low proportion of CO2 in solution. Blood flow is the main determinant of tissue CO2 clearance, and Physiology of Carbon Dioxide low flow increases the tissue P -venous P differ- CO2 CO2 ence.5,6 Various mechanisms maintain the proportion of CO at low levels in solution in plasma (ϳ5%). Figure 1 In normal conditions, CO2 is produced at the tissue level 2 during pyruvate oxidation as a result of aerobic metabo- shows the ways CO2 is transported. Once in blood, CO2 lism. The respiratory quotient shows the relationship be- easily diffuses into red cells, where tween consumption (V˙ ) and CO production catalyzes the reaction with water to form carbonic acid, O2 2 Ϫ ϩ (V˙ ): respiratory quotient ϭ V˙ /V˙ . In aerobic me- which rapidly dissociates into HCO3 and H . Although CO2 CO2 O2 tabolism, the respiratory quotient varies from 0.7 to 1 as a no carbonic anhydrases are present in plasma, it seems that function of the substrate being burned to produce energy. their presence in endothelial cells in pulmonary 7 Tissue PCO can also increase as a consequence of bicar- enables some activity in plasma. Even though carbonic 2 Ϫ bonate (HCO3 ) buffering of non-volatile acids (eg, lac- acid is almost completely dissociated within red cells, the 1,2 Ϫ ϩ tate) during tissue dysoxia, which can result in a respi- accumulation of HCO3 and H would limit the amount

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Fig. 2. Alveolar and airway CO2 during the ventilatory cycle: flow (upper graph) and mean alveolar and airway CO2 pressure scalars (lower graph). Alveolar P (P ) is lower at end inspiration (as far as fresh air dilutes alveolar gas) and higher at end expiration (because blood CO2 ACO2 keeps releasing CO into the alveolus). P varies between alveoli: it is higher (A) in units with lower V˙ /Q˙ ratios (closer to mixed venous 2 ACO2 A P ) and lower (B) in units with higher V˙ /Q˙ ratios (closer to inspired P ). Airway CO is zero during inspiration (provided there is no CO2 A CO2 2 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 P [P ]) is used as a reference of mean alveolar CO2 ETCO2 gas composition. Phase IV of the capnogram shows the sudden fall in P at the start of inspiration. CO2

ϩ of CO2 that blood can transport. However, H is buffered comes more basic, and its buffering capacity increases (see Ϫ Ϫ 9 by hemoglobin, and HCO3 is exchanged for Cl by Band Fig. 1). 3 (anion exchanger 1 [AE1]), a membrane transport pro- 8 tein. As a consequence, bicarbonate is the main form of PACO Ϸ 2 CO2 transport, accounting for 95% of the total (mainly in plasma). P depends on the balance between the amount of ACO2 In normal conditions, a negligible amount of CO2 is CO2 being added by pulmonary blood and the amount ˙ transported as carbamino compounds, but this mechanism eliminated by VA. As the former is nearly continuous and can be markedly increased by inhibition of carbonic an- the latter is not, P varies during the ventilatory cycle ACO2 hydrase (eg, by acetazolamide). CO2 binds mainly to (Fig. 2). PACO can be calculated (when inspired gas is free ␣ ␣ ␤ 2 ˙ ˙ -amino groups at the ends of both - and -chains of from CO2)asCO2 output/VA.VA is the difference be- hemoglobin. Reduced hemoglobin is 3.5 times more ef- tween (VT) and dead-space volume (VD). fective than oxyhemoglobin as a CO carrier, so the re- In steady-state conditions, CO output equals V˙ ; dur- 2 2 CO2 lease of oxygen at the tissue level increases the amount of ing non-steady-state conditions, phase issues and impaired 10 CO2 that hemoglobin can carry. This is the major compo- tissue CO2 clearance make CO2 output less predictable. nent of the . The other component is related So, the equation can be re-written as: P ϭ V˙ /V˙ . ACO2 CO2 A to Hϩ buffering: as hemoglobin releases oxygen, it be- However, the magnitude of these variables varies in dif-

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P depends on CO and the co- CO2 2 efficient in blood (SC ): P ϭ CO ϫ SC .SC varies B CO2 2 B B with ; at 37°C, it is 0.0308 mmol/L/mm Hg.11 At the pulmonary blood-gas barrier, the diffusion of gases brings the P and P of blood and alveolar gas to O2 CO2 an equilibrium, and when blood the pulmonary cap- illaries, it has the same P and P as alveolar gas. O2 CO2 However, the blood that arrives at the left atrium has lower P and higher P because venous admixture and shunt O2 CO2 (both physiologic and large) contaminates it with venous blood. Likewise, exhaled gas has higher P and lower O2 P than alveolar air because dead space pollutes it with CO2 fresh air (Fig. 4).

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 ˙ Fig. 3. Nonlinear relationship between alveolar ventilation (VA) and 2 separate components of lung volume. One is the , alveolar P (P ). The effects of changes in V˙ on P are far CO2 ACO2 A ACO2 ˙ , and conduction airways, which do not contribute more evident when basal VA is lower. Higher CO2 production (V˙ ) ϭ 200 mL/min, and lower V˙ ϭ 100 mL/min. to and are often referred to as anatomic or CO2 CO2 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 /jaw12 position. The second component consists ferent conditions, so corrections have to be made. VA mea- surements are expressed in body temperature and pressure of well-ventilated alveoli that receive minimum blood flow, saturated with vapor (BTPS); V˙ is expressed in stan- which is referred to as alveolar VD. In mechanical venti- CO2 dard temperature and pressure dry (STPD) conditions; lation, the ’s endotracheal tube, humidification and P measurements are expressed in body tempera- devices, and connectors add mechanical dead space, which ACO2 ture and pressure dry (BTPD) conditions. So the above is considered part of the airway VD. Physiologic VD con- equation must be used in the form: P (BTPD) ϭ 0.863 sists of airway VD (mechanical and anatomic) and alveolar ACO2 ϫ V˙ (STPD)/V˙ (BTPS), where 0.863 is a constant VD; in mechanical ventilation, physiologic VD is usually CO2 A that summarizes the corrections when V˙ and V˙ mea- reported as the fraction of VT that does not participate in CO2 A 14-16 surements are not provided in the same units. gas exchange. Alveolar VD can result from an increase 10 Figure 3 (constructed from the adjusted equation) shows in ventilation or a decrease in . The gas from the relationship between P and V˙ for 2 different the alveolar VD behaves in parallel with the gas from ACO2 A V˙ values. This relationship is not linear: as P de- perfused alveoli, exiting the lungs at the same time as the CO2 ACO2 creases, the increase in alveolar ventilation necessary to gas that effectively participates in gas exchange and dilut- ing it; this is evident as the difference between PaCO and reduce PACO increases. 2 2 end-tidal P (P ).15,16 Beyond that, if the amount of CO2 ETCO2 gas that reaches the exchange areas surpasses the areas’ PaCO ˙ ˙ 2 capacity for perfusion (high VA/Q ratio), the excess gas supplied by ventilation behaves like alveolar VD (func- When venous blood arrives at pulmonary capillaries, the tional concept) (Fig. 5). events illustrated in Figure 1 occur in the opposite order. The fall in plasma P resulting from CO diffusion to the Measurement of Dead Space CO2 2 alveolus results in CO2 being released from red cells, so carbonic acid is converted to CO2 and H2O (carbonic an- In critical patients, correct measurement and calculation hydrase facilitates the reaction in both directions). The of dead space provides valuable information about venti- drop in carbonic acid concentration leads to new formation latory support and can also be a valuable diagnostic tool. 17 of H2CO3 from bicarbonate (from the cytoplasm and plasma Nuckton et al demonstrated that a high physiologic VD/VT through Band 3) and protons (free and from hemoglobin). was independently associated with an increased risk of

CO2 is also free from carbamates. As the environment death in subjects diagnosed with ARDS. Changes in the becomes more basic, hemoglobin’s affinity for O2 increases shape of the capnographic curve often indicate ventilatory (). maldistribution, and several indices have been developed

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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 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. to quantify maldistribution based on the geometrical anal- with the assumption that P is similar to P : phys- aCO2 ACO2 ysis of the volumetric capnographic curve.18,19 iologic V /V ϭ (P Ϫ P ៮ )/P . D T aCO2 ECO2 aCO2

Bohr Langley

21 Bohr’s dead-space fraction (VD/VT) is calculated as Langley et al plotted the volume of CO2 elimination (P Ϫ P ៮ )/P ,15 where P ៮ is the mean ex- per breath (V˙ ) against the total expired volume to con- ETCO2 ECO2 ETCO2 ECO2 eCO2 pired P per breath, calculated as V˙ /V ϫ (P Ϫ trive an alternative method of calculating airway dead space. CO2 CO2 T b P O), where P is barometric pressure and P O is water- This curvilinear graph is shown in Figure 6. A straight H2 b H2 vapor pressure. It is simple but cumbersome to collect best-fit line is extrapolated from the linear portion of the P ៮ using a Douglas bag. graph, and the intercept of this line on the volume axis (X ECO2 In certain situations, the Bohr equation’s use of P axis) represents the dead space. This method correlates ETCO2 can be problematic. In , in acute , with Fowler’s method for calculating airway VD (Fig. 7) or in presence of different alveolar time constants, P but has the added advantage that it does not rely on visual ACO2 rises, often steeply, during expiration of alveolar gas, so interpretation to determine equal areas. Although several P will depend on the duration of expiration. The dead factors can influence airway V , in the critical care setting, ETCO2 D space so derived will not necessarily correspond to any of this volume remains relatively unchanged. Any changes in the compartments of the dead space (instrumental, ana- measured physiologic VD/VT, without added equipment 15,16,20 tomic, and alveolar). dead space, are mostly a result of changes in alveolar VD. It is clearly alveolar VD and its inherent interaction with Enghoff physiologic VD that are most important clinically.

In 1931, Enghoff first demonstrated that the physiologic Alveolar Ejection Volume dead space remained a fairly constant fraction of VT over a wide range of VT. Physiologic VD/VT calculated from The advanced technology combination of airway flow the Enghoff modification of the Bohr equation15 uses P and mainstream allows noninva- aCO2

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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 [VA]). Bottom: histograms for ventilation ˙ ˙ Ͼ and perfusion for each situation. For clarity, only units with VA/Q 0 and lower than infinite are plotted (neither shunt nor serial dead space is shown).

sive breath-by-breath bedside calculation of V˙ and the alveolar gas contaminated by parallel V . At the very end eCO2 D ratio between alveolar ejection volume (VAE) and VT in- of expiration, the gas exhaled comes only from the alveoli, 22,23 dependent of ventilatory settings. VAE can be defined so it is pure alveolar gas. From this curve, the last 50 as the fraction of VT with minimum VD contamination, points of every cycle are back-extrapolated by least-squares which may be inferred from the asymptote of the V˙ /V linear regression analysis. Assuming a fixed amount of V eCO2 T D curve at end of expiration, whereby VD is equal to zero. contamination (dead-space allowance), a point on the V is defined as the volume that characterizes this rela- V˙ /V curve representing the beginning of the V is AE eCO2 T AE 23 tionship, up to a 5% variation. obtained. The VAE is then obtained as the value of the Using the V˙ /V curve, the fraction of volume flow volume at the intersection between the V˙ /V curve and eCO2 T eCO2 T corresponding to alveolar gas can be calculated. a straight line having the maximum value at end of expi- After a given volume has been exhaled, V˙ progres- ration and a slope equal to 0.95 (1 Ϫ dead-space allow- eCO2 sively increases to reach a total amount of V˙ elimina- ance) times the calculated slope (Fig. 8). V is expressed eCO2 AE tion in a single expiration. The increase in V˙ is slightly as a fraction of expired V (V /V ).24 eCO2 T AE T nonlinear because of alveolar inhomogeneity, in other The VAE/VT ratio, an index of alveolar inhomogeneity, words, because of the presence of a certain amount of correlates with the severity of lung injury and is not in-

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Fig. 6. Langley’s method for calculating airway dead-space vol- Fig. 7. Single-breath expiratory volumetric capnogram recorded in ume (V ). Single-breath expiratory carbon dioxide volume (V˙ ) a mechanically ventilated subject with COPD. P ϭ end-tidal DAW eCO2 ETCO2 is plotted versus expired volume. Airway V can be calculated P ;P៮ ϭ mixed exhaled P ;P ϭ mean alveolar P . D CO2 ECO2 CO2 ACO2 CO2 from the value obtained on the volume axis by back-extrapolation The solid lines indicate Fowler’s geometric method of equivalent from the first linear part of the V˙ versus volume curve (solid areas to calculate airway dead space. Airway dead space is mea- eCO2 line). sured from the beginning of expiration to the point where the vertical line crosses the volume axis. fluenced by the set ventilatory pattern in acute lung injury (ALI) or ARDS patients receiving mechanical ventilation.23 the pulmonary arterial tree. Spatial differences in blood

It follows that VAE/VT might have clinical applications in flow between respiratory units in the lung cause inefficient lung disorders characterized by marked alveolar inhomo- gas exchange that is reflected as increased alveolar VD. geneity, and indeed, measurement of VAE/VT at ICU ad- Occlusion of the pulmonary vasculature by an embolism mission and after 48 h of mechanical ventilation, together will result in a lack of CO2 flux to the alveoli in the with P /F , provided useful information on outcome in affected vascular distribution. The mechanical properties aO2 IO2 critically ill patients with ALI or ARDS.25 may not be greatly affected, so these alveoli empty in parallel with other respiratory units with similar time con- Causes of Elevated Dead Space in Mechanically stants. Because ventilation to the affected alveoli contin- Ventilated Patients ues unabated, P in these alveoli decreases.27 CO2 In patients with sudden pulmonary vascular occlusion ˙ ˙ In patients with lung disease, VD can be large. Patients due to pulmonary embolism, the resultant high V/Q mis- with unevenly distributed ventilation and perfusion have match produces an increase in alveolar VD. This effect lung units in which the amount of ventilation is high rel- enables volumetric capnography to be used as a diagnostic ative to the amount of blood flow. The P in gas coming tool at the bedside: in the context of a normal D-dimer CO2 from these units is lower than P . During expiration, assay, a normal alveolar V is highly reliable to rule out aCO2 D this gas mixes with gas coming from other lung areas in pulmonary embolism.28 In patients with clinical suspicion which ventilation and perfusion are more closely matched, of pulmonary embolism and elevated D-dimer levels, cal- diluting it so that expired P , including P , can be culations derived from volumetric capnography such as CO2 ETCO2 greatly different from P . In addition, the P of ex- late dead-space fraction had a statistically better diagnostic aCO2 CO2 pired gas in patients with obstructive airway disease may performance in suspected pulmonary embolism than the increase steeply during expiration because lung units that traditional measurement of the P difference.28 (a-ET)CO2 empty late are poorly ventilated and contain gas with higher Moreover, a normal physiologic VD/VT ratio makes pul- CO2 . The effect of these late-emptying lung monary embolism unlikely. Finally, volumetric capnogra- units on expired P leads to a difference between P phy is an excellent tool for monitoring thrombolytic effi- CO2 aCO2 and P (Fig. 9).26 cacy in patients with major pulmonary embolism.29 ETCO2

Pulmonary Embolism COPD

Pulmonary embolism is most commonly due to blood Mismatch of the distribution of ventilation and perfu- clots that travel through the venous system and lodge in sion within any single acinus results from spatial differ-

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Fig. 8. Determination of alveolar ejection volume (VAE) in a healthy Fig. 9. Three single-breath volumetric capnograms during mechan- subject. CO production (V˙ ) is plotted as a function of expired ical ventilation in different scenarios: a subject with normal lungs 2 CO2 volume. From this curve, the last 50 points of every cycle are and 2 subjects with COPD with and without . back-extrapolated to represent the ideal lung behavior (straight dashed line). Assuming a fixed amount of dead-space contami- nation of 5% (red arrow), a straight line is plotted. Alveolar ejection begins at the intersection between the sampled curve and the ARDS straight line (black arrow). The volume between this point and end of expiration is the VAE (shaded area). Even mild forms of ARDS can severely alter mechanics.34,35 Most of these changes affect pe- ripheral structures beyond the conducting airways: the in- ences in gas-flow distribution due to the differences in the terstitium, alveolar spaces, and small airways. The main time constants of the respiratory units. P will vary consequence of peripheral lung injury is the development ACO2 between respiratory units. In this situation, individual re- of heterogeneities that affect the efficacy of respiratory gas spiratory units will empty sequentially at differing rates exchange and ventilatory distribution.34,35 and times dependent upon mechanical properties. Patients with ARDS have lung regions with low V˙ /Q˙ (and high P ) that usually coexist with others having Pulmonary heterogeneity is, together with airway ob- ACO2 high V˙ /Q˙ (and low P ). The combination of these 2 struction, a cardinal feature in the functional impairment ACO2 of COPD. Heterogeneity, mostly dependent on peripheral conditions secondary to severe alveolar and vascular dam- involvement, increases with the severity of the disease; age results in increased pulmonary dead space. Moreover, therefore, volumetric capnography, a technique that basi- pulmonary dead space is increased by shock states, sys- cally explores regional distribution, can be a good tool to temic and pulmonary hypotension, and obstruction of pul- monary vessels (massive pulmonary embolus and micro- determine the degree of functional involvement in patients thrombosis). Dead space accounts for most of the increase with COPD (see Fig. 9).30,31 in the requirement and CO retention Ventilation to regions with little or no blood flow (low 2 that occur in severe ARDS,34 and the extent of lung inho- PACO ) affects pulmonary dead space. In patients with air- 2 mogeneities increased with the severity of ARDS and cor- flow obstruction, inhomogeneities in ventilation are re- 36 related with physiologic VD/VT. Mechanical ventilation sponsible for the increase in VD. Shunt increases physio- can substantially affect dead-space measurements, making logic V /V as the mixed venous P from shunted blood 37 D T CO2 the variations in dead space more complex. elevates the P , increasing physiologic V /V by the aCO2 D T fraction that P exceeds the non-shunted pulmonary aCO2 Effects of Mechanical Ventilation on Dead Space capillary P . The accuracy of physiologic V /V mea- CO2 D T surement can be improved with a forced maximum exha- Mechanical ventilation makes it more difficult to un- lation, which reduces the P difference and physi- (a-ET)CO2 derstand variations in dead space at the bedside. On the ologic VD/VT because of more complete emptying of the one hand, PEEP levels that recruit collapsed lung can re- lungs, including peripheral alveoli that have a higher P CO2 duce dead space, primarily by reducing intrapulmonary level. Furthermore, maximum exhalation is generally pre- shunt. On the other hand, overdistention promotes the de- ceded by maximum , resulting in a more even velopment of high V˙ /Q˙ regions with increased dead space.38 distribution of gases within the alveoli.32,33 Therefore, a number of pulmonary and non-pulmonary

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factors might affect interpretation of dead-space variations elevated physiologic VD/VT and decreased VAE/VT are at the bedside. signs of poor prognosis in ARDS, and their dur- Several studies in subjects with ARDS have shown that ing treatment has an impact on final outcome.17,25,45,46 is due to intrapulmonary shunt and regions with very low V˙ /Q˙ .39 The multiple inert gas elimination Effect of PEEP technique has also shown that patients with ARDS have a large percentage of ventilation distributed to unperfused or Alveolar VD is significantly increased in ARDS and poorly perfused regions.39 Coffey et al38 found that oleic does not vary with PEEP. However, when PEEP is admin- acid-induced ARDS in dogs resulted in high VD/VT by istered to recruit collapsed lung units (resulting in im- ˙ ˙ increasing shunt, inert gas dead space, and mid-range V/Q proved oxygenation), alveolar VD decreases unless over- heterogeneity. Capnographic findings in patients with ALI distention impairs alveolar perfusion. Breen and and ARDS are consistent with a high degree of ventilatory Mazumdar47 found that the application of PEEP at maldistribution and poor ventilatory efficiency. Blanch and 11 cm H2O to anesthetized, mechanically ventilated, open- co-workers25 reported that indices obtained from volumet- chested dogs increased physiologic V , reduced V˙ , D eCO2 ric capnography (Bohr’s VD/VT, phase 3 slope, and and resulted in a poorly defined alveolar plateau. These VAE/VT) were markedly different in subjects with ALI and changes were mainly produced by a significant decrease in ARDS than in control subjects. Bohr’s dead space and cardiac output due to PEEP. In dogs with -in- phase 3 slope were higher in subjects with ALI than in duced ARDS, Coffey et al38 found that low PEEP reduced control subjects and higher in subjects with ARDS than in physiologic VD/VT and intrapulmonary shunt. Conversely, both control and ALI subjects. Moreover, VAE/VT was in the same , high PEEP increased the fraction of lower in subjects with ALI than in control subjects and ventilation delivered to areas with high V˙ /Q˙ , resulting in 48 lower in subjects with ARDS than in both control and ALI increased physiologic VD/VT. When Tusman et al tested subjects. the usefulness of alveolar VD for determining open-lung PEEP in eight lung-lavaged pigs, they observed 2 inter-

Effect of VT esting physiologic effects. First, alveolar VD showed a good correlation with P and with normally aerated and aO2 In recumbent, anesthetized, normal subjects, increasing non-aerated areas on computed tomography in all animals,

VT increases ventilatory efficiency. Studies in normal sub- yielding a sensitivity of 0.89 and a specificity of 0.90 for jects40 have shown that the convection-dependent non- detecting lung collapse. However, PEEP also induced air- homogeneity of ventilation increases with relatively small way dilation and increased airway VD, thus affecting the increases in VT, whereas non-homogeneity due to interac- global effect of both on physiologic VD/VT. Finally, vari- tion of convection and diffusion in the lung periphery ations in dead space with the application of PEEP largely decreases. In an earlier study, Romero et al23 found that depend on the type, degree, and stage of lung injury. Ex-

VAE/VT changed significantly with volume in normal sub- perimental ARDS induced by lung lavage potentially al- jects but not in subjects with ARDS. Even earlier, Paiva lows for much greater recruitment at increasing increments et al41 showed that phase 3 slope decreases with increased of PEEP49-51 than experimental ARDS models induced by

VT in normal subjects. It might seem reasonable to expect oleic acid injury or , and comparisons with hu- that the increase in VT in subjects with ARDS would re- man ARDS remains speculative. cruit some alveolar units and thus improve the degree of Blanch et al37 studied the relationship between the ef- alveolar homogeneity to some extent.42 In fact, however, fects of PEEP on volumetric capnography and respiratory recruited units would contribute to improvement in venti- system mechanics in subjects with normal lungs, with mod- latory and mechanical efficiency only if they were strictly erate ALI, and with severe ARDS. Compared with control normal and homogeneous. We can reasonably suppose subjects, subjects with ARDS had markedly decreased re- that the reason that VAE/VT does not increase with VT in spiratory system compliance (CRS) and increased total re- patients with ARDS is that recruited alveoli are mostly spiratory system resistance. Increasing PEEP improved re- diseased or that increased VT does not effectively recruit spiratory mechanics in normal subjects and worsened lung new lung areas. Nowadays, VT is no longer used to in- tissue resistance in subjects with ; how- crease oxygenation because it causes injuries to lungs and ever, it did not affect volumetric capnography indices. distant organs and poor outcome.34,35,43 Currently, the use Other authors have corroborated these findings. Smith and 52 of a lung-protective ventilation strategy has also been ex- Fletcher found that PEEP did not modify CO2 elimina- tended to intermediate-risk and high-risk patients under- tion in subjects immediately after surgery. Beydon going major surgical procedures because it was associated et al53 studied the effect of PEEP on dead space in subjects with improved clinical outcomes and reduced health-care with ALI. They found a large physiologic VD/VT that utilization.44 This brings us to the hypotheses that remained unchanged after PEEP was raised from 0 to

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15 cm H O. In healthy anesthetized subjects, Maisch et al54 Prone Position, P , and Dead Space 2 aCO2 found that physiologic VD/VT and maximum CRS during a decremental PEEP trial were lowest after a recruitment In patients with severe ARDS, prone positioning im- maneuver. However, at the highest PEEP level during the proves survival.61 In the prone position, recruitment in dorsal areas usually prevails over ventral derecruitment incremental PEEP trial when PaO and the increase in lung 2 because of the need for the lung and its confining chest volume induced by PEEP peaked, physiologic VD/VT de- wall to conform to the same volume, with more homoge- teriorated. Therefore, physiologic VD/VT and CRS are more sensitive than P measurements for detecting lung over- neous overall dorsal-to-ventral lung inflation and more aO2 distention.19,40,54 Seminal studies on the effect of PEEP in homogeneously distributed stress and strain than in the 62 55 supine position. Because the distribution of perfusion P(a-ET)CO difference showed similar results. Finally, 2 remains nearly constant in both postures, prone position- Fengmei et al56 evaluated the effect of PEEP titration fol- ing usually improves oxygenation and may be associated lowing lung recruitment in subjects with ARDS on phys- with a decrease in PaCO , an indirect reflection of the re- iologic V /V , arterial oxygenation, and C . Interestingly, 2 D T RS duction in alveolar V .63 Gattinoni et al64 also reported they found that optimal PEEP in these subjects was D improved prognosis in subjects in whom PaCO declined 12 cm H O because, at this pressure, the highest C in 2 2 RS after an initial prone position session. Charron et al65 conjunction with the lowest physiologic VD/VT indicated a showed that prone positioning induced a decrease in pla- maximum number of effectively expanded alveoli. teau pressure, P , and alveolar V /V ratio and an in- aCO2 D T Variations in dead space and its partitions resulting from crease in P /F and C ; these changes peaked after aO2 IO2 RS PEEP largely depend on the type, degree, and stage of 6–9 h. In fact, the respiratory response to prone position- lung injury. When PEEP results in global lung recruit- ing appeared more relevant when P rather than P /F aCO2 aO2 IO2 ment, physiologic VD and alveolar VD decrease; when was used. Protti et al66 investigated the gas exchange re- PEEP results in lung overdistention, physiologic VD and sponse to prone positioning as a function of lung recruitabil- alveolar VD increase. Therefore, volumetric capnography ity, measured by computed tomography in a supine posi- may be helpful to identify overdistention or better alveolar tion. Interestingly, changes in P , but not in oxygenation, aCO2 gas diffusion in patients with ARDS. were associated with lung recruitability, which was in turn associated with the severity of lung injury. Effect of Inspiratory Flow Waveforms and Prognostic Value of Dead-Space Measurement End-Inspiratory Pause Alterations in the pulmonary microcirculation due to Patients receiving pressure controlled inverse-ratio ven- epithelial and endothelial lung cell injuries are character- tilation had lower P than those receiving the normal istic of most forms of ARDS. Consequently, pulmonary aCO2 inspiratory/expiratory ratio.57 Several studies have reported ventilation and pulmonary and bronchial circulation are that an exponentially decreasing inspiratory flow pattern compromised, and pulmonary pressure and dead results in modest improvements in P and dead space. space increase. A high physiologic VD/VT fraction repre- aCO2 These phenomena are explained by an increased mean sents an impaired ability to excrete CO2 due to any kind of ˙ ˙ 38 distribution time for gas mixing, during which fresh gas V/Q. Traditionally, in the course of ARDS was considered a predictor of poor outcome.67 from the V is present in the respiratory zone and is avail- T However, in the era of lung-protective ventilation using able for distribution in the lung periphery. The mean dis- low V , elevated systolic pressure early tribution time of inspired gas is the mean time during T in the course of ARDS is not necessarily predictive of poor which fractions of fresh gas are present in the respiratory outcome, although a persistently large dead space in early zone.19,58,59 It was recently proposed that setting the ven- ARDS remains associated with increased mortality and tilator to a pattern that enhances CO2 exchange can reduce fewer ventilator-free days.68 dead space and significantly increase CO2 elimination or Several studies have demonstrated this association. alternatively reduce VT. This option is especially interest- 17 Nuckton et al demonstrated that a high physiologic VD/VT ing when lung-protective ventilation results in hypercap- was independently associated with an increased risk of nia. In particular, doubling the proportion of the inspira- death in subjects with ARDS. The mean physiologic VD/VT tory cycle from 20 to 40% (without creating auto-PEEP),59 was 0.58 early in the course of ARDS and was higher in increasing end-inspiratory pause up to 30% of the inspira- subjects who died than in those who survived. The dead tory cycle,58 or both60 markedly reduced P and phys- aCO2 space was an independent risk factor for death (for every iologic VD/VT, allowing the use of protective ventilation 0.05 increase in physiologic VD/VT, the odds of death 45 with low VT and enhancing lung protection. increased by 45%). Raurich et al studied mortality and

1804 RESPIRATORY CARE • NOVEMBER 2014 VOL 59 NO 11 THE PHYSIOLOGY OF VENTILATION dead-space fraction in 80 subjects with early-stage ARDS 7. Bidani A, Mathew SJ, Crandall ED. Pulmonary vascular carbonic and 49 subjects with intermediate-stage ARDS. In both anhydrase activity. J Appl Physiol Respir Environ Exerc Physiol stages, the dead-space fraction was higher in subjects who 1983;55(1 Pt 1):75-83. 8. Cabantchik ZI, Knauf PA, Ostwald T, Markus H, Davidson L, Breuer died than in those who survived and was independently W, Rothstein A. The interaction of an anionic photoreactive probe associated with a greater risk of death. Similar results were with the anion transport system of the . Biochim reported by Lucangelo et al25 regarding measuring the Biophys Acta 1976;455(2):526-537.

VAE/VT fraction at admission and after 48 h of mechanical 9. Jensen FB. Red blood cell pH, the Bohr effect, and other oxygen- ventilation in subjects with ALI or ARDS and by Siddiki ation-linked phenomena in blood O and CO transport. Acta Physiol 69 Scand 2004;182(3):215-227. et al regarding estimating physiologic VD/VT from the ˙ 10. Dubin A, Murias G, Estenssoro E, Canales H, Sottile P, Badie J, et calculation of VCO using the Harris-Benedict equation. 2 al. End-tidal CO2 pressure determinants during hemorrhagic shock. 70 Finally, Kallet et al tested the association between the Intensive Care Med 2000;26(11):1619-1623. VD/VT fraction and mortality in subjects with ARDS di- 11. Bradley AF, Severinghaus JW, Stupfel M. Effect of temperature on 34 agnosed using the Berlin Definition who were enrolled PCO2 and PO2 of blood in vitro. J Appl Physiol 1956;9(2):201-204. in a clinical trial incorporating lung-protective ventilation 12. Nunn JF, Campbell EJ, Peckett BW. Anatomical subdivisions of the volume of respiratory dead space and effect of position of the jaw. and found that markedly elevated physiologic VD/VT Ͼ J Appl Physiol 1959;14(2):174-176. ( 0.60) in early ARDS was associated with higher mor- 13. Fowler WS. Lung function studies. IV. Postural changes in respira- tality. In the clinical arena, measuring or estimating phys- tory dead space and functional residual capacity. J Clin Invest 1950; iologic VD/VT at bedside is an easy method to predict 29(11):1437-1438. outcome in ARDS and should be routinely incorporated to 14. Fowler WS. Lung function studies II: the respiratory dead-space. monitor respiratory function in patients receiving mechan- Am J Physiol 1948;154(3):405-416. ical ventilation.71 15. Fletcher R, Jonson B, Cumming G, Brew J. The concept of dead space with special reference to the single breath test for carbon dioxide. Br J Anaesth 1981;53(1):77-88. Conclusions 16. Lucangelo U, Blanch L. Dead space. Intensive Care Med 2004; 30(4):576-579. Understanding the physiology of ventilation and mea- 17. Nuckton TJ, Alonso JA, Kallet RH, Daniel BM, Pittet JF, Eisner suring the dead-space fraction at bedside in patients re- MD, Matthay MA. Pulmonary dead-space fraction as a risk factor for ceiving mechanical ventilation may provide important death in the acute respiratory distress syndrome. N Engl J Med 2002;346(17):1281-1286. physiologic, clinical, and prognostic information. Further 18. Hedenstierna G, Sandhagen B. Assessing dead space. A meaningful studies are warranted to assess whether the continuous variable? Minerva Anestesiol 2006;72(6):521-528. measurement of different derived capnographic indices is 19. Kallet RH. Measuring dead-space in acute lung injury. Minerva Anes- useful for risk identification and stratification and for track- tesiol 2012;78(11):1297-1305. ing the effects of therapeutic interventions and mechanical 20. Lumb AB. Nunn’s applied respiratory physiology, 5th edition. Ox- ford: Butterworth-Heinemann; 2000:163-199. ventilation modes and settings in critically ill patients. 21. Langley FE, Duroux P, Nicolas RL, Cumming G. Ventilatory con- sequences of unilateral pulmonary artery occlusion. Colloques IN- ACKNOWLEDGMENTS SERM 1975;51:209-212. 22. Blanch L, Romero PV, Lucangelo U. Volumetric capnography in the We thank Mr John Giba for editing and language revision and Ms Merce mechanically ventilated patient. Minerva Anestesiol 2006;72(6):577- Ruiz for administrative work related to this paper. 585. 23. Romero PV, Lucangelo U, Lopez Aguilar J, Fernandez R, Blanch L. REFERENCES Physiologically based indices of volumetric capnography in patients receiving mechanical ventilation. Eur Respir J 1997;10(6):1309-1315. 1. Schlichtig R, Bowles SA. Distinguishing between aerobic and an- 24. Lucangelo U, Gullo A, Bernabe` F, Blanch L. Capnographic mea- aerobic appearance of dissolved CO2 in intestine during low flow. J Appl Physiol 1994;76(6):2443-2451. sures. In: Gravenstein JS, Jaffe MB, Paulus DA. Capnography clin- 2. Dubin A, Estenssoro E. Mechanisms of tissue hypercarbia in sepsis. ical aspects, 2nd edition. Cambridge: Cambridge University Press; Front Biosci 2008;13(1):1340-1351. 2004:309-319. 3. Cohen IL, Sheikh FM, Perkins RJ, Feustel PJ, Foster ED. Effect of 25. Lucangelo U, Bernabe` F, Vatua S, Degrassi G, Villagra` A, Fernan- hemorrhagic shock and reperfusion on the respiratory quotient in dez R, et al. Prognostic value of different dead space indices in swine. Crit Care Med 1995;23(3):545-552. mechanically ventilated patients with acute lung injury and ARDS. 4. Silberman H, Silberman AW. Parenteral nutrition, biochemistry and Chest 2008;133(1):62-71.

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