SPECIAL ARTICLE CME

Rationale of Dead Space Measurement by Volumetric Capnography

Gerardo Tusman, MD,* Fernando Suarez Sipmann, MD, PhD, and Stephan H. Bohm, MD
Dead space is the portion of a tidal volume that does not participate in gas exchange because it does not get in contact with blood flowing through the pulmonary capillaries. It is commonly calculated using volumetric capnography, the plot of expired carbon dioxide (CO2) versus tidal volume, which is an easy bedside assessment of the inefficiency of a particular ventilatory setting. Today, Bohrs original dead space can be calculated in an entirely noninvasive and breath-by-breath manner as the mean alveolar partial pressure of CO2 (Paco2) which can now be determined directly from the capnogram. The value derived from Enghoffs modification of Bohrs formula (using Paco2 instead of Paco2) is a global index of the inefficiency of gas exchange rather than a true dead space because it is influenced by all causes of ventilation/perfusion mismatching, from real dead space to shunt. Therefore, the results obtained by Bohrs and Enghoffs formulas have different physiological meanings and clinicians must be conscious of such differences when interpreting patient data. In this article, we describe the rationale of dead space measurements by volumetric capnography and discuss its main clinical implications and the misconceptions surrounding it. (Anesth Analg 2012;114:866 74)

ulmonary diseases impair gas exchange by inducing a ventilation/perfusion (V/Q) mismatch that may require ventilatory support.13 Such treatment aims to minimize lung areas of low V/Q and shunt but often at the expense of increasing the zones of high V/Q and dead 4,5 space. Thus, the way a mechanical ventilator delivers gas during inspiration determines gas exchange. Given the above scenario, detailed monitoring of ventilation should help in adjusting the ventilator settings to an individual patients needs. A simple approach to this monitoring is the breath-wise analysis of carbon dioxide (CO2) kinetics applying the concept of dead space or wasted ventilation.6,7 The most popular technique for assessing dead space at the bedside is volumetric capnography (VCap) or the representation of expired CO2 over a tidal breath.7,8 In this article, we describe the rationale of dead space measurement by VCap and discuss its main clinical implications and the misconceptions surrounding it.

THE CONCEPT OF DEAD SPACE

A simple depiction of lung physiology is provided by Rileys 3-compartment model that helps in obtaining a
From the *Department of Anesthesiology, Hospital Privado de Comunidad, Mar del Plata, Argentina; Department of Surgical Sciences, Section of Anesthesiology & Critical Care, Uppsala University, Uppsala, Sweden; Instituto de Investigacion Sanitaria, Fundacion Jimenez Daz, IIS-FJD, Madrid, Spain; CIBERES; and Swisstom AG, Landquart, Switzerland. Accepted for publication December 7, 2011. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journals Web site (www.anesthesia-analgesia.org). Conflicts of Interest: See Disclosures at the end of the article. Reprints will not be available from the authors. Address correspondence to Gerardo Tusman, MD, Department of Anesthesiology, Hospital Privado de Comunidad, Mar del Plata, Argentina. Address e-mail to gtusman@hotmail.com. Copyright 2012 International Anesthesia Research Society
DOI: 10.1213/ANE.0b013e318247f6cc

basic understanding of the problem of dead space ventilation (Fig. 1).9,10 This model groups alveoli according to their V/Q ratios ranging from a normally perfused but not ventilated unit called shunt (unit A with a V/Q of 0) to a normally ventilated but not perfused unit called dead space (unit C with a V/Q of ). A normally ventilated and perfused alveolus called ideal unit (unit B with a V/Q of 1) can be found between the above extremes. It is important that certain amounts of high V/Q areas (similar to unit C, but with V/Q 1 but ) and low V/Q areas (similar to unit A, but with V/Q 0 but 1) can also be found in mechanically ventilated patients.1,2,4 Gas exchange will depend on the overall quantitative balance of all these different subpopulations of alveoli. Dead space is the portion of ventilation that is not participating in gas exchange because it does not come in contact with the pulmonary capillary blood flow.6,7,11 Therefore, ventilation per unit of time, such as minute ventilation (Ve), is formed by an effective portion called alveolar ventilation (Va) and an ineffective portion called dead space ventilation (Vd)6,11:

Ve

Va

Vd

(1)

Because dead space units are not perfused, their gas composition is not much different from inspired gases containing no CO2. This volume of gas free of CO2 is mixed with gases that come from ideal units with CO2, diluting the latter to decrease expired concentrations of CO2. The rationale of dead space analysis is to measure the degree of dilution.6 Dead space can be clinically expressed as an amount of breathing volume per unit of time (Vd), as a fraction of a tidal volume (Vd/Vt), or as an absolute volume value contributing to 1 breath known as the physiological dead space (Vdphys). Vdphys is composed of 2 portions: the dead space of the conducting airways (Vdaw) and the one within the alveolar compartment represented by the lung units C (Vdalv).7,1214 Table 1 describes the main features of Vdphys and its subcomponents.
April 2012 Volume 114 Number 4

866

www.anesthesia-analgesia.org

Dead Space Measured by Volumetric Capnography

THE TOOL TO MEASURE DEAD SPACE

VCaps are generated by specific capnography apparatuses that measure flow and CO2 with mainstream or sidestream sensors placed at the airway opening. The most frequently used clinical VCap device is the COSMO2 Plus and its newest version, the NICO (Philips Respironics, Wallingford, CT). The main difference between VCap and time-based capnography is that CO2 raw data are related point by point, not to time but to expiratory flow, which is then integrated to obtain volume. Using volume instead of time has the advantage of being able to directly derive volume-based variables

such as dead space or the amount of CO2 eliminated per tidal breath. Figure 2 shows the main features of VCaps. VCap is the breath-wise tidal elimination of CO2 by measuring the area under the curve or Vtco2,br (Fig. 2A). Petco2, Paco2, and Peco2 are defined as end-tidal, mean alveolar, and mixed expired partial pressures of CO2, respectively (Fig. 2B). The capnogram is divided into 3 phases: phase I, or the portion of tidal volume free of CO2; phase II, representing the CO2 coming from lung units with different rates of ventilation and perfusion; and phase III, the pure alveolar gas. The slopes of phases II and III contain important physiological information mainly related to the distribution of ventilation within the lungs7,15,16 (Fig. 2A). It is important to address here the difference in the slope of phase III

Figure 1. Rileys model of the lungs and volumetric capnography (VCap). Adaptation of Rileys 3-compartment model of the lungs with (A) representing shunt, (B) an ideal unit, and (C) dead space. During inspiration, physiological dead space (VDphys) is lled with air containing no CO2 shown as white area. VDphys is constituted by the sum of airway (VDaw) and alveolar dead space (VDalv or unit C), which are delimited by the airway-alveolar interface (dotted line). VCap (top) is collected by proper sensors placed at the airways opening. PETCO2, PACO2, and PECO2 are the end-tidal, mean alveolar, and mixed expired partial pressures of CO2, respectively.

Figure 2. Volumetric capnography (VCap) and derived variables. VCap is the plot of expired carbon dioxide (CO2) on the y-axis versus the expired volume on the x-axis. A, VCap is divided into phases I, II, and III. SII and SIII are the lines following the slopes of phase II and III, respectively. The area under the curve in gray is the VTCO2,br. B, VCap represents the transport of CO2 by convection (Conv) within main airways and by diffusion (Diff) within alveoli. The black dot in phase II is the inection point of the whole VCap that marks the airway-alveolar interface (Aw-alv). According to Fowlers concept, a tidal volume is divided into an airway dead space (VDaw) and an alveolar tidal volume (VTalv). PaCO2, PACO2, PETCO2, and PECO2 are the arterial, mean alveolar, end-tidal, and mixed expired partial pressures of CO2, respectively.

Table 1. Dead Space Components

Abbreviation Name Physiological dead VDphys space VDalv Limits Measurement Clinical presentation Factors that change it From ETT to the alveolarBohrs formula Absolute value or VD/VT It is affected by factors that capillary membrane of change both VDalv and VDaw (Eq. 7) units C Alveolar or parallel From airway-alveolar interface Bohrs and Fowlers Absolute value, VDalv/VT Increases with high PEEP and/ or VDalv/VTalv dead space until the alveolar-capillary or VT, hypovolemia, lung methodologies hypoperfusion, pulmonary membrane of units C together (Eq. 10) hypotension. Decreases with adequate treatment of the above conditions Airway, anatomical, or From ETT to the airwayAny method using Absolute value or Increases with increased body series dead space alveolar interface Fowlers concept VDaw/VT size, VT, PEEP, and FRC. Decreases with inspiratory pause Instrumental or Its clinical effect depends on Any gadget between ETT and Water displacement Included in the apparatus dead the size of gadget and the the Y piece (humidiers, of gadget calculation of VDaw space size of VT applied. Very connectors, mainstream important in pediatric sensors, etc.) patients

VDaw

VDinst

ETT endotracheal tube; PEEP positive end-expiratory pressure; FRC functional residual capacity; VD/VT measured by Bohrs formula (VDBohr); VDphys physiological dead space; VDaw airway dead space and VDalv alveolar dead space. Dead space values are commonly normalized by tidal volume (VT) to allow comparison among patients with different VT size: VDaw/VT airway dead space to tidal volume ratio and VDalv/VTalv alveolar dead space to alveolar tidal volume ratio.

April 2012 Volume 114 Number 4

www.anesthesia-analgesia.org

867

SPECIAL ARTICLE

between time-based and volume-based capnography. Because of the exponential passive nature of the expiratory flow, VCap shows a steeper alveolar slope than the corresponding time-based capnogram because most of the volume is exhaled early during expiration. The shallower alveolar slope of time-based capnography may lead to the erroneous assumptions of a relative equivalence of the Paco2 and Petco2 values. VCap separates the volume of gas that belongs to main airways from the one located within the alveolar compartment (Fig. 2B).7,12 Thus, VCap contains all of the information needed to calculate dead space on a breath-by-breath basis. A brief explanation of our systematic analysis of VCap17 can be found in the Online Supplement (see Supplemental Digital Content 1, http://links.lww.com/AA/A363).

it resolves a key limitation of the past.19 This implies that reliable and physiologically meaningful breath-by-breath dead space values can be obtained noninvasively using standard VCap. Below, we describe how Paco2 and Peco2, the 2 key constituents of Bohrs formula, can be determined from VCap.

The Measurement of PACO2

Paco2 is the mean value of CO2 within the alveolar compartment, which depends on the balance between pulmonary perfusion and Va. The classic alveolar air equation describes such relationship as:

Paco2

Vco2/Va

(8)

THE CALCULATION OF DEAD SPACE

Following the above reasoning, dead space must be calculated by considering both gas from Rileys units C and the gas within the conducting airways. This is what Christian Bohr proposed in 1891 using a formula based on the principle of conservation of mass of CO2.6 Bohrs dead space (VdBohr)11 was thus calculated in the following way6,18:

Feco2

Vt

Faco2

Va

Fico2

Vd

(2)

Va in Equation 1 can also be expressed as the difference between Vt and Vd:

Feco2

Vt

Faco2(Vt

Vd)

Fico2

Vd

(3)

A simple rearrangement delivers:

Vd/Vt

(Faco2

Feco2)/(Faco2

Fico2)

(4)

Because inspired gases usually do not contain CO2 (Fico2 0), then the Bohrs formula can be simplified as:

Vd/Vt

(Faco2

Feco2)/Faco2

(5)

In Bohrs equation, fractions or partial pressures of CO2 can be used interchangeably:

VdBohr or Vd/Vt

(Paco2

Peco2)/Paco2

(6)

VdBohr constitutes the Vd/Vt ratio representing the dilution of the CO2 concentration by dead air stemming from both the main airways and from ventilated but not perfused alveoli. The absolute volume of dead space, however, is expressed as Vdphys, which is calculated as:

Vdphys

VdBohr

Vt

(7)

VdBohr was originally obtained noninvasively using a Douglas bag.6 Because this technique is time-consuming, bothersome, and prone to handling errors, it has never reached broad clinical acceptance and has therefore rarely been applied systematically in mechanically ventilated patients. Currently, fast CO2 sensors and pneumotachographs placed at the airway opening allow VCap to be determined on a breath-by-breath basis.7,8,16 The recently validated noninvasive determination of Paco2 from VCap marks a turning point in the monitoring of VdBohr because

where K is a constant and Vco2 is the amount of CO2 delivered to the lungs by the pulmonary circulation, which is then to be eliminated by Va. By definition, Paco2 must be measured within the alveolar compartment, which in VCap is represented by the alveolar tidal volume (Vtalv). Thus, Paco2 can be determined from VCap as the value located at the midpoint on the slope of phase III within Vtalv.17,19 (Fig. 2B; for more details see Online Supplement, http://links.lww.com/AA/A363). Two factors should be considered when measuring Paco2: (1) Any single lung unit has its own Paco2 depend ing on its individual V/Q ratio, meaning that a heterogeneous lung is represented by a broad spectrum of Paco2 values; and (2) Paco2 changes cyclically with the respiratory cycle. Experimental and theoretical studies showed that in normal lungs at rest, these tidal swings in alveolar Pco2 are in the order of 2 to 3 mm Hg and 4 to 5 mm Hg during exercise.20 22 Therefore, the precise moment during a breath at which a sample of alveolar CO2 is taken is crucial for the determination of representative dead space values, as seen in Figure 3. The calculated values differ depending on whether the alveolar sample is obtained at end-inspiration or at end-expiration. To avoid errors in dead space calculation because of these factors, one intuitive solution is to use the mean Paco2 for a respiratory cycle. Therefore, before reliable Paco2-dependent calculations such as the one for dead space can be conducted, it is imperative to first agree on a standardized method to measure mean Paco2. In the past, this measurement of Paco2 has been the cause of intense debates.23 DuBois et al.20,24 showed similar mean Paco2 values for inspiration and expiration despite the fluctuation of CO2 during the respiratory cycle (Fig. 3). Because the CO2 sensor is placed at the airway opening, mean Paco2 can only be determined from expiratory gases because Pico2 is zero. Fortunately, mean Paco2 has been shown to be represented most reliably by an alveolar sample taken shortly after mid-expiration time.24,25 Fletcher and Jonson7 extended the above concept by suggesting that mean Paco2 could theoretically be measured as the Pco2 value found at the midpoint of phase III of VCap. Later, Breen et al.26 confirmed that the mean Paco2 will correspond to the midpoint of phase III in volumebased but not in time-based capnography.

868

www.anesthesia-analgesia.org

ANESTHESIA & ANALGESIA

Dead Space Measured by Volumetric Capnography

Figure 3. Alveolar CO2 during the respiratory cycle and its relationship with volumetric capnography. Changes in the partial pressure of CO2 within the alveolar compartment during the respiratory cycle are represented by the dotted line. Point a represents the reinhalation of CO2 at the beginning of inspiration coming from the airways and from instrumental dead spaces. Point b is the lowest PCO2 found at the end of inspiration, which is the result of the dilution by the CO2-free inhaled tidal volume. Point c is the highest PCO2 found at the end of expiration. Black dots represent the mean PACO2 during both inspiration and expiration. As the CO2 sensor is placed at the airway opening, it does not measure any CO2 in the inspired fresh gas (PICO2 0). Once the gas in the airway dead space has been washed out during expiration, alveolar gas is sampled and PACO2 can be measured directly in capnograms at the middle point of phase III (modied from DuBois et al.20).

These rather theoretical ideas about the true mean value of Paco2 in VCap have recently been confirmed and validated in an experimental model of lung injury for a broad range of V/Q conditions.19 A strong correlation between mean Paco2 as measured by VCap and the one calculated by the alveolar air equation (Equation 8) using Vco2 values obtained from the multiple inert gas technique (MIGET) algorithms was found (r 0.99, P 0.0001). Pearson correlation between Vco2 from capnograms and MIGET was also good (r 0.96, P 0.0001). These data show that mean Paco2 can be calculated with accuracy even under conditions of high V/Q dispersion and irrespective of the resultant deformations of the shape of the capnogram.

best done following Fowlers concept.12 Fowler described a concept based on the analysis of expired gases (irrespective of the tracer gas used)28 representing the mechanisms of gas transport within lungs. Thus, capnograms represent the way CO2 travels, either by convection within the main airways or by diffusion within the wide cross-sectional areas of the lung periphery29,30 (Fig. 2B). A limit or stationary interface between these 2 mechanisms of CO2 transport is found in each bronchiole, which, because of airway asymmetry, is located at the end of inspiration at different depths within the lungs. During expiration, these interfaces move mouthward and reach the gas sensor at different times, thereby causing the typical wide spread in gas concentrations of phase II. The mean value of these many individual interfaces defines the so-called airway-alveolar interface that allows the differentiation between main airway and the alveolar compartment.12,17,31 According to theoretical and experimental calculations, this mean interface is found at the midpoint of phase II.3134 Several techniques to measure Vdaw by means of VCap have been published.7,19,25,35 40 All of them use Fowlers original concept to determine the position of the airwayalveolar interface.12 The limitations of these methodologies were highlighted by Wolff et al.39 and Tang et al.41 Most approaches are based in a geometric calculation and their performances are affected by changes in the shape of VCap as observed in pulmonary diseases. Wolff et al.39 and our group17 have published methodologies that show a more stable and robust measurement of Vdaw even in deformed capnograms. Once Vdphys and Vdaw have been obtained sequentially by Bohrs equation and Fowlers concept, the next step is to calculate Vdalv as follow:

Vdalv

Vdphys

Vdaw

(10)

How PACO2 Has Been Approximated in the Past

The direct measurement of Paco2 by VCap has not been validated until very recently. To create a feasible approximation of dead space, in the past clinicians have replaced the lacking Paco2 in Bohrs equation by the surrogates Petco2 or arterial Pco2 (Paco2).9,10,42 Both of these substitutes, however, lead to erroneous values for Vdphys, especially under pathological lung conditions. Using Petco2 instead of Paco2 in Bohrs formula will increase the calculated value for Vdphys. Whereas Paco2 is the average value for all ventilated alveoli, Petco2 represents only those alveoli with the highest Pco2 resulting from ventilatory inhomogeneities within the lungs as witnessed by the positive sloping of phase III.29,30 Because Petco2 is the value at the very top end of this slope, its value is higher than the value of Paco2 located at the middle of such slope (Figs. 2B and 3).19 Additionally, because these lung units have a longer expiratory time constant than the remainder of the alveoli, they have more time to equilibrate with the higher CO2 values of the incoming blood, thereby increasing the CO2 concentration within these units.43 From the above explanation, it becomes obvious that using Petco2 in Bohrs formula will systematically overestimate Vdphys in sicker lungs. Only in those healthy patients with flat slopes of phase III will the

Measurement of PECO2
Peco2 is determined by the dilution effect that the inspired Vt, a volume normally free of CO2, has on the CO2 residing within the lungs. Peco2 is influenced not only by Vdalv but also by Vdaw and therefore, it is used in Bohrs equation to calculate Vdphys.6 Peco2 is measured using VCap as:

Peco2

Feco2

barometric pressure

(9)

This measurement has been validated comparing it against reference values derived either from indirect calorimetry27 or from MIGET.19

The Calculation of VDaw and VDalv

A complete dead space analysis requires a separation of Vdphys into the airway and alveolar components. This is

April 2012 Volume 114 Number 4

www.anesthesia-analgesia.org

869

SPECIAL ARTICLE

Figure 4. Graphical representation of the approaches of Bohr and Enghoff. VDaw airway dead space and VDalv alveolar dead space. PaCO2, PETCO2, and PACO2 are the arterial, endtidal, and mean alveolar partial pressures of carbon dioxide, respectively.

Table 2. Differences Between the Approaches of Bohr and Enghoff

Formula Origin of PACO2 Type of V/Q analyzed Bohrs approach VDBohr (PACO2 PECO2)/PACO2 Mean PACO2 as the average PCO2 coming from all lung units V/Q of (units C) High V/Q 1 but Enghoffs approach VDB-E (PaCO2 PECO2)/PaCO2 PaCO2 replaces PACO2 following Rileys concept of an ideal lung V/Q of (units C) High V/Q 1 but V/Q of 0 (unit A) Low V/Q 1 but 0 Invasive, discontinuous provides information only when arterial blood samples are obtained Idem Bohrs approach plus all causes of shunt and low V/Q: atelectasis, pneumonia, COPD, asthma, etc.

Type of measurement Physiological factors having an inuence on parameter

Noninvasive, continuous, breath by breath Alveolar overdistension by excessive PEEP and/ or VT, pulmonary embolism, hypovolemia, pulmonary hypotension

VDBohr VD/VT measured by Bohrs formula; VT tidal volume; PEEP positive end-expiratory pressure; V/Q ventilation/perfusion ratio; PaCO2, PETCO2, PACO2, and PECO2 the arterial, end-tidal, mean alveolar, and mixed expired partial pressures of carbon dioxide, respectively; COPD chronic obstructive pulmonary disease.

use of Petco2 in Bohrs formula deliver dead space values similar to those where Paco2 is used. Using Paco2 instead of Paco2 in Bohrs formula also overestimates the true value of Vdphys. Riley and Cournand9,10 proposed the concept of ideal lungs where Paco2 was considered identical with Paco2 assuming that all lung units have a perfect V/Q matching. Subsequently, Enghoff ingeniously modified Bohrs equation applying this concept by rewriting the formula as44:

used the term apparent dead space. Following the same line of reasoning, Wagner47 highlighted the effect that low V/Q areas have on Paco2. These facts support the idea that VdB-E must be consid ered an index of global V/Q mismatching rather than a dead space.

COMMON MISCONCEPTIONS ABOUT DEAD SPACE

Having introduced the rationale for a meaningful dead space analysis, we discuss below the main misconceptions and misunderstandings around the topic.

VdB-E or Vd/Vt

(Paco2

Peco2)/Paco2

(11)

Any increase in the Bohr-Enghoff value (VdB-E) beyond normal reflects the degree by which a patients lung deviates from the assumed ideal condition. Such deviation has long been thought to be attributable to dead space only. However, the main drawback of this concept of an ideal lung is that even perfectly healthy lungs are never ideal but always show certain amounts of anatomical shunt and dead space.1,4,45 The VdB-E equation not only measures the real Vdalv but also includes all other causes of venous admixture because it considers arterial blood.7,18 This effect is easy to understand in Figure 1: if pulmonary artery blood with its high Pco2 bypasses the lungs via shunt pathways, Paco2 will exceed that of Paco2, which in turn leads to an overestimation of dead space. Using Bohrs true dead space as a reference, Figure 4 shows how venous admixture increases dead space if Enghoffs approach is used. This was the reason why Suter et al.46 called this fictitious type of Vdalv shunt dead space or why Fletcher and Jonson7

Should Values Derived from Enghoffs Formula Be Called Dead Space?

We believe the main source of misconception is the use of the term dead space for the variables derived from Enghoffs modification of Bohrs original formula. By definition, only Bohrs formula is measuring true dead space (units C) because it is viewing the dilution of CO2 from only the alveolar side of the alveolar-capillary membrane.6 As we already stated above, because VdB-E includes information from both the blood and the alveolar gas side, it must not be called dead space (Table 2). Although these differences seem to be nothing more than simple semantic problems, the clinical implications, however, of the differences between VdBohr and VdB-E may be enormous (see below).

870

www.anesthesia-analgesia.org

ANESTHESIA & ANALGESIA

Dead Space Measured by Volumetric Capnography

Does Bohrs Formula Measure Only Dead Space?

Alveoli with an excess of ventilation relative to perfusion (high V/Q areas) generate a Vdalv-like effect and will contribute to the calculation of Vdalv performed by VCap. It was postulated that this effect is caused by the intermediate solubility of CO2 in blood, making it impossible to differ entiate high V/Q from pure dead space areas.14,18 From the physiological point of view, both V/Q mismatches have a similar diminishing effect on CO2 clearance and can thus be considered part of the same problem. Therefore, for clinical purposes, it seems legitimate to assume that dead space and high V/Q are the same thing, no matter which one of these V/Q mismatches prevails.

approximately one-third of the Vdphys (personal unpublished data). Third, to provide even stronger support for this point of view, we have reanalyzed part of our data from an animal model of acute lung injury and details of this analysis are given in the Online Supplement, http://links.lww.com/AA/A363. We hypothesized that Vphys obtained by Bohrs formula would be the same as the one obtained using Enghoffs approach, provided the latter was corrected for shunt effects using the formula described by Kuwabara and Duncalf49 as follow:

PvCO2 Vd/Vt

PvCO2 1

PaCO2 Qs/Qt

PECO2

Does Bohrs Original Formula Measure VDalv or VDphys?

Until the end of the 19th century, the concept of alveolar dead space was ignored and VdBohr was thought to be related only to the anatomical dead space measured in cadavers. Ever since the work of Haldane and Priestley48 in the first years of the next century, alveolar gas could be clearly differentiated from the one within the Vdaw. Consequently, using the Bohr-Enghoff formula, Fletcher found that VdBohr was always higher than Vdaw but lower than Vdphys.11 Hence he concluded, similar to many other researchers, that VdBohr had limited clinical value because it was not adequately representing the Vdalv component. In other words, VdBohr was considered neither representative of Vdaw nor of Vdphys. Therefore, the question arises what VdBohr really is. The answer to this key question can be found in the definition of Paco2. Because Fletcher and others used the ideal Paco2 in their dead space calculations, they overestimated Vdphys because of the inadvertent addition of a fictitious Vdalv from other sources. Today, we understand that these pioneers erroneously thought that VdBohr underestimated Vdphys. Following this reasoning, we firmly believe that VdBohr encompasses a well-defined airway as well as an alveolar component provided that the mean Paco2 is used to calculate it. The following facts support this point of view. First, it must be highlighted that the rationales behind the methodologies of both Fowler and Bohr have been clearly described and that the physiological meaning of Vdaw and VdBohr have been clearly differentiated from one another.6,12 Fowlers concept determines Vdaw, making use of phase II and thus detects the gas interface that marks the limit between conducting and gas-exchanging airways (Fig. 2B).12,31,33 Bohrs formula, however, measures Vdphys based on the dilution effect of inspired gases on CO2 of the entire tidal breath, using phase III of the capnograms.6,19 Thus, it would not be plausible to confuse Vdaw with VdBohr neither from a theoretical nor from a clinical point of view. Second, data from MIGET calculations showed that the zones of dead space and high V/Q develop even in healthy patients undergoing anesthesia or mechanical ventilation.4 Using VCap and Bohrs formula, we found in 70 anesthetized patients with healthy lungs that Vdalv constituted

PvCO2

PvCO2 1

PaCO2 Qs/Qt (12)

where Pvco2 is the partial pressure of CO2 in mixed venous blood and Qs/Qt the right-to-left shunt. Correcting our experimental data this way revealed a Pearson correlation of r2 0.93 (P 0.0001) between VdBohr and the corrected VdB-E. The corresponding BlandAltman plot showed a mean bias of 0.0025 and limits of agreement between 0.0375 and 0.0425 (Fig. 5). These results confirm that, by removing the effects of venous admixture from Enghoffs formula, Vdphys becomes similar to the one obtained by Bohrs original equation. Thus, VdBohr comprises a true Vdalv component and Vdphys is not underestimated by this formula.

Issues Related to the Calculation of VA

The opposing twin concept of dead space is the effective part of ventilation within the alveolar compartment that is in close contact with the capillary blood (Va). The formula to calculate Va is a direct derivative of Equation (1)6,11:

Va

Ve

Vd

(13)

Fletcher proposed that Va should be measured by Enghoffs approach and not by Bohrs original equation because he postulated that VdBohr underestimated Vdphys.7,11 As has been pointed out above, we now know that VdBohr measures Vdphys accurately and that VdB-E underestimates Va because of the addition of a shunt-related apparent or fictitious Vdalv.18,19 Conceptually but also practically, Va is a real volume that can be adjusted on the ventilator whereas the fictitious volume is not. Therefore, the calculation of Va suffers from the same problem as dead space whenever the concept of ideal lung is included in the formula.

CLINICAL IMPLICATIONS OF THE APPROACHES OF BOHR AND ENGHOFF

Table 2 shows the main differences between the formulas of Bohr and Enghoff that are of clinical relevance. The intention of this report is to highlight these important differences but not to judge whether Bohrs equation is better than Enghoffs or vice versa. What we are trying to convey is the simple fact that true dead space can only be determined by

April 2012 Volume 114 Number 4

www.anesthesia-analgesia.org

871

SPECIAL ARTICLE

Figure 5. Relationship between VDBohr and VDB-E corrected for shunt fraction of a tidal volume (VD/VT) measured by Bohrs formula (VDBohr) versus the one calculated by the Enghoff approach but corrected for the effect of shunt using the formula described by Kuwabara and Duncalf49 (VDB-Ecorr). (A) Pearson correlation and (B) Bland-Altman plot showing the mean bias and limit of agreement between variables. Data were obtained in an experimental model of acute lung injury (n 12 pigs, 144 data points).

Bohrs formula. However, it is obvious why Enghoffs approach is clinically useful because it provides a good global estimate of a lungs state of V/Q. Therefore, the question of which formula we must use at the bedside deserves an answer. This answer is, both, depending on the clinical problem or disease to be addressed. On the one hand, Bohrs approach is useful to determine the balance between effective and wasted ventilation. It will detect an excess of ventilation caused by large Vt and/or too much positive end-expiratory pressure (PEEP) or at a fixed ventilatory setting a respective deficit in lung perfusion caused by hypovolemia, pulmonary hypotension, or embolism.50 Enghoffs approach includes a similar but less specific calculation, i.e., it can give a false-positive diagnosis of an increment in dead space or type C units. This is the case, for example, in atelectatic lungs where the fictitious Vdalv is increased by high shunt and low V/Q. If clinicians misinterpret such a scenario as PEEP-induced lung overdistension, they might want to decrease the level of PEEP while in fact more PEEP is needed to overcome the atelectatic and shunting state. Bohrs formula cannot detect what is happening at the capillary side of the alveolar-capillary membrane. Enghoffs approach has a notable clinical advantage because it provides a good idea of the global state of gas exchange from using just one single arterial blood sample. Thus, Enghoffs approach has important clinical applications: it has been used to diagnose pulmonary embolism,51,52 to guide the weaning process and to predict tracheal extubation,53 to adjust PEEP,54 to detect lung collapse,55 or to predict survival in acute respiratory distress syndrome patients.56 Despite these ample publications, we encourage caution and a critical reappraisal of some of these results. For example, Nuckton et al.56 demonstrated that Vd/Vt obtained by Enghoffs approach seems to be a predictor of mortality in acute respiratory distress syndrome patients. Was mortality really related to dead space or was it more related to the amount of shunt? What would happen if we determined true dead space using Bohrs equation? Can a link between overdistension and mortality be established?

In future studies, all of these questions need to be addressed by appropriate methodologies considering that the clinical role of VCap in monitoring lung function is grossly enriched if both Bohrs and Enghoffs approaches are used synergistically.

CONCLUSIONS
VCap is clinically useful to monitor the V/Q relationship in mechanically ventilated patients. Although this technique may not be as precise and detailed as the investigational gold standard of MIGET, it can easily be applied at the bedside. Currently, the novel direct determination of Paco2 by VCap allows the calculation of wasted ventilation (true dead space together with areas of high V/Q) using Bohrs equation on a breath-by-breath basis. Contrarily, Enghoffs approach uses an arterial blood sample and delivers an index of global V/Q matching considering both, wasted ventilation and wasted perfusion (shunt plus low V/Q areas). Therefore, to avoid misunderstanding using dead space as a descriptor of the output of Enghoffs formula is no longer justified. Following both approaches separately provides the clinician with useful complementary information when monitoring mechanically ventilated patients at the bedside. We think it is time to call these important physiological variables by their appropriate names.
DISCLOSURES

Name: Gerardo Tusman, MD. Contribution: This author helped prepare the manuscript, figures, and tables. Conflicts of Interest: Gerardo Tusman is the inventor and applicant of patent EP 04007355.3: non-invasive method and apparatus for optimizing the respiration of atelectatic lungs. Name: Fernando Suarez Sipmann, MD, PhD. Contribution: This author helped prepare the manuscript. Conflicts of Interest: This author has no conflicts of interest to declare.

872

www.anesthesia-analgesia.org

ANESTHESIA & ANALGESIA

Dead Space Measured by Volumetric Capnography

Name: Stephan H. Bohm, MD. Contribution: This author helped prepare the manuscript. Conflicts of Interest: Stephan H. Bohm is the inventor and applicant of patent EP 04007355.3: non-invasive method and apparatus for optimizing the respiration of atelectatic lungs. This manuscript was handled by: Steven L. Shafer, MD.
REFERENCES 1. Wagner PD, Saltzman HA, West JB. Measurement of continuous distributions of ventilation-perfusion ratios: theory. J Appl Physiol 1974;36:588 99 2. Melot C. Ventilation-perfusion relationship in acute respiratory failure. Thorax 1994;49:1251 8 3. Batchinsky AI, Weiss WB, Jordan BS, Dick EJ, Cancelada DA, Cancio LC. Ventilation-perfusion relationships following experimental pulmonary contusion. J Appl Physiol 2007;103: 895902 4. Hedenstierna G. Ventilation-perfusion relationships during anaesthesia. Thorax 1995;50:8591 5. Terragni PP, Rosboch G, Tealdi A, Corno E, Menaldo E, Davini O, Gandini G, Herrman P, Mascia L, Quintal M, Slutsky AS, Gattinoni L, Ranieri VM. Tidal hyperinflation during low tidal volume ventilation in acute respiratory distress syndrome. Am J Respir Crit Care Med 2007;175:160 6 6. Bohr C. Uber die Lungeatmung. Skand Arch Physiol 1891;2:236 8 7. Fletcher R, Jonson B. The concept of deadspace with special reference to the single breath test for carbon dioxide. Br J Anaesth 1981;53:77 88 8. Breen PH, Isserles SA, Harrison BA, Roizen MF. Simple computer measurement of pulmonary VCO2 per breath. J Appl Physiol 1992;72:2029 35 9. Riley RL, Cournand A. Ideal alveolar air and the analysis of ventilation-perfusion relationships in the lungs. J Appl Physiol 1949;1:825 47 10. Riley RL, Cournand A. Analysis of factors affecting partial pressures of oxygen and carbon dioxide in gas and blood of the lungs: theory. J Appl Physiol 1951;4:77101 11. Fletcher R. Deadspace, invasive and non-invasive. Br J Anaesth 1985;57:2459 12. Fowler WS. Lung function studies. II. The respiratory dead space. Am J Physiol 1948;154:40516 13. Folkow B, Pappenheimer IR. Components of the respiratory dead space and their variation with pressure breathing and with bronchoactive drugs. J Appl Physiol 1955;8:10210 14. Severinghaus JW, Stupfel M. Alveolar deadspace as an index of distribution of blood flow in pulmonary capillaries. J Appl Physiol 1957;10:335 48 15. Tusman G, Bohm SH, Suarez Sipmann F, Turchetto E. Alveolar recruitment improves ventilatory efficiency of the lungs during anesthesia. Can J Anaesth 2004;51:7237 16. Tusman G, Areta M, Climente C, Plit R, Suarez Sipmann F, Rodrguez-Nieto MJ. Effect of pulmonary perfusion on the slopes of single-breath test of CO2. J Appl Physiol 2005; 99:650 5 17. Tusman G, Scandurra A, Bohm SH, Suarez Sipmann F, Clara F. Model fitting of volumetric capnograms improves calculations of airway dead space and slope of phase III. J Clin Monit Comput 2009;23:197206 18. Hedenstierna G, Sandhagen B. Assessing dead space: a meaningful variable? Minerva Anestesiol 2006;72:521 8 19. Tusman G, Suarez Sipmann F, Borges JB, Hedenstierna G, Bohm SH. Validation of Bohr dead space measured by volumetric capnography. Intensive Care Med 2011;37:870 4 20. Dubois AB, Britt AG, Fenn WO. Alveolar CO2 during the respiratory cycle. J Appl Physiol 1951;4:535 48 21. Krogh A, Lindhard J. On the average composition of the alveolar air and its variations during the respiratory cycle. J Physiol 1913;47:431 45 22. Paiva M, Engel LA. Model analysis of intra-acinar gas exchange. Respir Physiol 1985;62:25772

23. Bannister RG, Cunningham DJC, Douglas CG. The carbon dioxide stimulus to breathing in severe exercise. J Physiol 1954;125:90 117 24. DuBois AB. Alveolar CO2 and O2 during breath holding, expiration and inspiration. J Physiol 1952;5:112 25. Aitken RS, Clack-Kennedy AE. On the fluctuation in the composition of the alveolar air during the respiratory cycle in muscular exercise. J Physiol 1928;65:389 411 26. Breen PH, Mazumdar B, Skinner SC. Comparison of end-tidal PCO2 and average alveolar expired PCO2 during positive end-expiratory pressure. Anesth Analg 1996;82:368 73 27. Kallet RH, Daniel BM, Garcia O, Matthay MA. Accuracy of physiologic dead space measurements in patients with ARDS using volumetric capnography: comparison with the metabolic monitor method. Respir Care 2005;50:4627 28. Bartels J, Severinghaus JW, Forster RE, Briscoe WA, Bates DV. The respiratory dead space measured by single breath analysis of oxygen, carbon dioxide, nitrogen or helium. J Clin Invest 1954;33:41 8 29. Crawford ABH, Makowska M, Paiva M, Engel LA. Convection- and diffusion-dependent ventilation misdistribution in normal subjects. J Appl Physiol 1985;59:838 46 30. Verbank S, Paiva M. Model simulations of gas mixing and ventilation distribution in the human lung. J Appl Physiol 1990;69:2269 79 31. Horsfield K, Cumming G. Functional consequences of airway morphology. J Appl Physiol 1968;24:384 90 32. Gomez DM. A physico-mathematical study of lung function in normal subjects and in patients with obstructive pulmonary diseases. Med Thorac 1965;22:27594 33. Paiva M. Computation of the boundary conditions for diffusion in the human lung. Comput Biomed Res 1972;5:58595 34. Engel LA. Gas mixing within acinus of the lung. J Appl Physiol 1983;54:609 18 35. Hatch T, Cook KM, Palm PE. Respiratory dead space. J Appl Physiol 1953;5:3417 36. Langley F, Even P, Duroux P, Nicolas RL, Cumming G. Ventilatory consequences of unilateral pulmonary artery occlusion. Colloques Inst Natl Sante Recherche Med 1975;51: 209 14 37. Olsson SG, Fletcher R, Jonson B, Nordstroem L, Prakash O. Clinical studies of gas exchange during ventilatory support: a method using the Siemens-Elema CO2 analyzer. Br J Anaesth 1980;52:491 8 38. Cumming G, Guyatt AR. Alveolar gas mixing efficiency in the human lung. Clin Sci (Lond) 1982;62:5417 39. Wolff G, Brunner JX, Weibel W, Bowes CL, Muchenberger R, Bertschmann W. Anatomical and series dead space volume: concept and measurement in clinical praxis. Appl Cardiopul Pathophysiol 1989;2:299 307 40. Bowes CL, Richardson JD, Cumming G, Horsfield K. Effect of breathing pattern on gas mixing in a model of asymmetrical alveolar ducts. J Appl Physiol 1985;58:18 26 41. Tang Y, Turner MJ, Baker AB. Systematic errors and susceptibility to noise of four methods for calculating anatomical dead space from the CO2 expirogram. Br J Anaesth 2007;98:828 34 42. Hedenstierna G, McCarthy G. The effect of anaesthesia and intermittent positive pressure ventilation with different frequencies on the anatomical and alveolar deadspace. Br J Anaesth 1975;47:84752 43. Gronlund J, Swenson ER, Ohlsson J, Hlastala MP. Contribution of continuing gas exchange to phase III exhaled PCO2 and PO2 profiles. J Appl Physiol 1987;62:246776 44. Enghoff H. Volumen inefficax. Bemerkungen zur Frage des schadlichen Raumes. Uppsala Lakareforen Forh 1938;44:191 218 45. Altemeier WA, McKinney S, Glenny RW. Fractal nature of regional ventilation distribution. J Appl Physiol 2000;88:15517 46. Suter PM, Fairley HB, Isenberg MD. Optimum end-expiratory airway pressure in patients with acute pulmonary failure. N Engl J Med 1975;292:284 9 47. Wagner P. Causes of high physiological dead space in critically ill patients. Crit Care 2008;12:148 9

April 2012 Volume 114 Number 4

www.anesthesia-analgesia.org

873

SPECIAL ARTICLE

48. Haldane JS, Priestley JG. The regulation of the lung-ventilation. J Physiol 1905;32:225 66 49. Kuwabara S, Duncalf D. Effect of anatomic shunt on physiological dead space o ratio: a new equation. Anesthesiology 1969;31:5757 50. Burki NK. The dead space to tidal volume ratio in the diagnosis of pulmonary embolism. Am Rev Respir Dis 1986;133:679 85 51. Kline JA, Israel EG, Michelson EA, ONeil BJ, Plewa MC, Portelli DC. Diagnosis accuracy of a bedside D-dimer assay and alveolar dead space measurement for rapid exclusion of pulmonary embolism: a multicenter study. JAMA 2001;285: 761 8 52. Verschuren F, Listro G, Coffeng R, Thys F, Roeseler J, Zech F, Reynaert M. Volumetric capnography as a screening test for pulmonary embolism in the emergency department. Chest 2004;125:84150

53. Hubble CL, Gentile MA, Tripp DS, Craig DM, Meliones JN, Cheifetz IM. Deadspace to tidal volume ratio predicts successful extubation in infants and children. Crit Care Med 2000;28:2034 40 54. Tusman G, Suarez Sipmann F, Bohm SH, Pech T, Reissmann H, Meschino G, Scandurra A, Hedenstierna G. Monitoring dead space during recruitment and PEEP titration in an experimental model. Intensive Care Med 2006;32:186371 55. Maisch S, Reissmann H, Fuellekrug B, Weismann D, Rutkowski T, Tusman G, Bohm SH. Compliance and dead space fraction indicate an optimal level of positive end-expiratory pressure after recruitment in anesthetized patients. Anesth Analg 2008;106:175 81 56. Nuckton TJ, Alonso JA, Kallet RH, Daniel BM, Pittet JF, Eisner MD, Matthay MA. Pulmonary dead-space fraction as a risk factor for death in the acute respiratory distress syndrome. N Engl J Med 2002;346:1281 6

874

www.anesthesia-analgesia.org

ANESTHESIA & ANALGESIA