By Richard Kallet, MS, RRT, FCCM
Director of Quality Assurance, Respiratory Care Services, San Francisco General Hospital
Mr. Kallet reports no financial relationships relevant to this field of study.
Over the past several decades, there have been tremendous advances in both the technology and application of bedside capnography that has yet to be fully exploited in the management of critically ill patients. Here are some of the technologic and physiologic aspects of capnography as they relate to dead space ventilation and their application in the management of critically ill patients.
DEAD SPACE PHYSIOLOGY
Dead space can be conceived as both an anatomic space measured from casts taken from cadavers and a “virtual space” identified by gas composition.1 Bohr proposed measuring dead space and alveolar volume based on expired fractional gas concentrations. This led to the discovery that no sharp boundary demarcates atmospheric gases in the airways from that occupying the respiratory zone equilibrated with capillary blood.2,3 Moreover, it was conceded that a true alveolar CO2 (from which dead space is calculated) was a theoretical construct. What can be measured as a practical matter is a mean alveolar CO2 that represents the effect of multiple factors, including diffusion coefficients, tidal fluctuations in alveolar gas composition, the spatial heterogeneity of alveolar architecture, and non-uniform ventilation-perfusion distributions.3
As a solution to this conundrum, Enghoff proposed utilizing arterial carbon dioxide partial pressure (PaCO2) as a “physiological integrator” of alveolar carbon dioxide tension (PACO2) throughout the lungs.4 Enghoff also popularized the clinically useful concept of expressing “ineffective ventilation” as a quotient, VD/VT = (PaCO2 – PECO2)/PaCO2, where PECO2 is the partial pressure of carbon dioxide in expired or exhaled air that is referred to commonly as physiologic dead space fraction. However, in critically ill patients, this method overestimates actual dead space in the presence of anatomic and intrapulmonary shunts.5 Moreover, the antiquated term anatomic dead space has been replaced by the more accurate descriptor airway dead space.
The advent of volumetric capnography into clinical practice is a welcomed advance as it allows for VD/VT to be measured readily at the bedside. Its origin was the single-breath nitrogen washout technique of Fowler3 that was refined for clinical use by Fletcher using CO2 as the tracer gas.6 The waveform produced by plotting the integrated simultaneous measurements of expired CO2 against expired tidal volume (VT) produces a waveform with three distinct phases according to gas composition changes: Phase I (pure airway dead space without CO2), Phase II (transitional period during which airway and alveolar gas mixes and PCO2 rises exponentially), and Phase III (the “alveolar plateau” during which PCO2 becomes relatively stable over the remainder of expired VT (Figure 1).
An in-depth description of volumetric capnography can be found elsewhere.7 What is important to stress is the morphologies of Phases II and III represent clinically significant aspects of pulmonary function. Phase II represents convective gas flow from the lungs and, therefore, reflects expiratory time constant distribution. Phase III represents gas diffusion and, therefore, reflects ventilation-perfusion distribution. Normal physiologic conditions of both relatively homogenous lung emptying and ventilation-perfusion distributions are reflected in a sharp upstroke in Phase II, followed by a clear inflection into Phase III, characterized by a very subtle upward slope (Figure 1). Under pathologic conditions of heterogeneous lung emptying, the slope of Phase II becomes gentle and sometimes obscures the transition into Phase III (Figure 2). In contrast, marked alterations in ventilation-perfusion distribution in the lung parenchyma are characterized by a steep progressive upward slope in Phase III (Figure 3). In extraordinarily severe disease presentations, such as acute respiratory distress syndrome (ARDS) superimposed upon obstructive lung disease, the shape resembles the trajectory of a plane taking off (Figure 4). Thus, important information is available to clinicians immediately from gross inspection of the volumetric capnograph.
DEAD SPACE AND MORTALITY IN CRITICAL ILLNESS
Since ARDS was first described in the late 1960s, it was widely believed that elevated VD/VT occurred late in ARDS and reflected the fibroproliferative phase of the syndrome. However, in 2002, Nuckton et al demonstrated that elevated VD/VT occurred early in ARDS and was associated strongly and independently with hospital mortality.8 For every 0.05 increase in VD/VT, they reported that the mortality risk increased by 45%. This study was conducted prior to the advent of lung protective ventilation, and patients were ventilated with a mean VT of 10 mL/kg. Although not reported, the mean plateau pressure in these patients was 33 cm H2O with a corresponding mean elastic driving pressure of 25 cm H2O. Considering the recent findings on the link between elastic driving pressure and mortality by Amato et al,9 the association between elevated VD/VT and mortality suggests that dead space potentially was a signifier for ventilator-induced lung injury (VILI).
However, numerous subsequent studies conducted with lung protective ventilation confirmed the association between elevated VD/VT and mortality,10-15 suggesting that other mechanisms are in play. One supposition is that the higher diffusibility of CO2 across tissues makes it a uniquely perfusion sensitive marker of pulmonary gas exchange function and is a signifier for the magnitude of endothelial injury and a pro-coagulant state in the lungs. This hypothesis is supported by studies of biomarkers such as activated protein C and angiopoietin levels in ARDS.16-18
As mentioned above, by substituting PaCO2 for PACO2 in the Enghoff modification, VD/VT also represents the contributions of intrapulmonary and intracardiac shunts.5 Thus, along with representing the contributions of endothelial injury and alveolar overdistension, VD/VT provides a more global representation of pulmonary dysfunction in ARDS. However, elevated VD/VT during lung protective ventilation also may reflect an iatrogenic rise in airway dead space when VT is lowered in response to worsening lung function. This is difficult to differentiate clinically because dead space has a U-shaped function, with rises at both extremes of VT. Moreover, what is considered extreme is relative to the fraction of aerated lung tissue represented by functional residual capacity (FRC). In ARDS, the mean values of FRC range between 0.6-1.8 L (25%-75% of normal), depending on the severity of lung injury.19
The strong association between VD/VT and mortality has not led to the wide embrace of measuring dead space as part of routine management of ARDS. This has prompted others to investigate indirect methods of estimating dead space that could be applied to assess mortality risk in large datasets of ARDS.20 The most common of these has been using both the Harris-Benedict and Weir Equations to estimate PECO2. Although indirect estimates are quite capable of assessing mortality risk in ARDS,19 they can be vulnerable to substantial error when these estimates are compared directly with simultaneous measurements of VD/VT.20,21 This likely is explained by the fact that PECO2 is derived from estimates of steady state CO2 production (VCO2). The problem is that even under normal resting conditions, a VCO2 steady state is more an ideal than a reality owing to the body’s vast capacity to store CO2.7 Moreover, when VD/VT is highly elevated (as in severe ARDS and hemodynamic instability), VCO2 represents CO2 excretion, not production. Thus, while indirect estimates of VD/VT appear useful (but flawed) in the context of post-hoc analysis of large data sets, they are not satisfactory for managing critically ill patients.
DEAD SPACE, RECRUITMENT, AND VENTILATOR-INDUCED LUNG INJURY
Because dead space is perfusion-sensitive, several studies have found that measuring VD/VT is particularly useful in assessing both alveolar recruitment and overdistension when titrating positive end-expiratory pressure (PEEP). This was first demonstrated in the seminal study by Suter et al22 during which VD/VT tracked lung recruitment; much more importantly, its deterioration with pulmonary overdistension occurred despite the continued improvement in oxygenation. More recently, in healthy patients undergoing general anesthesia, the lowest VD/VT and maximal respiratory system compliance (CRS) occurred together during the decremental PEEP trial and coincided with elevated values for both FRC and oxygenation.23 Moreover, during both the recruitment maneuver (and at the highest PEEP settings), both FRC and oxygenation reached their apex despite marked deterioration in both VD/VT and CRS. Similar findings have shown that changes in VD/VT reflecting both recruitment as well as de-recruitment tend to occur earlier than changes in both oxygenation and CRS.24,25 Similarly, VD/VT has been found useful in assessing responders to prone position.26
UTILITY OF MEASURING DEAD SPACE BEYOND ARDS
Because it is perfusion-sensitive, dead space also has been utilized in other facets of clinical practice, such as improving the diagnosis of pulmonary embolism and assessing the likelihood for extubation failure. By combining a cutoff of 20% for the presence of abnormal alveolar VD/VT (i.e., substituting end-tidal PaCO2 for PECO2) with D-dimer assay, the specificity improved from 38% to 78%, compared to D-dimer assay alone, while the sensitivity remained 100%.27 It also has been found useful in the emergent diagnosis of and monitoring in the treatment of massive pulmonary embolism.28 Measuring VD/VT prior to extubation is helpful in predicting extubation success and the need for non-invasive ventilation in the pediatric population.29,30
CONCLUSION
In summary, the widespread availability of both volumetric capnography and indirect calorimetry over the past 20 years has allowed clinicians to easily measure VD/VT. From this capability, a wealth of knowledge has been generated, informing our understanding of ARDS and improving clinical practice. Although it remains an underutilized tool, continued progress in its application to various clinical problems will hopefully encourage its wider acceptance into clinical practice.
REFERENCES
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- Gray JS, Grodins FS, Carter ET. Alveolar and total ventilation and the dead-space problem. J Appl Physiol 1956;9:307-320.
- Fowler WS. Lung function studies II. The respiratory dead-space. Am J Physiol 1948;154:405-416.
- Enghoff H. Volumen inefficax: Bemerkungen zur frage des schädlichen raumes. Upsala Lakareforen Forh 1938;44:191-218.
- Kuwabara S, Duncalf D. Effect of anatomic shunt on physiologic deadspace-to-tidal volume ratio – a new equation. Anesthesiol 1969;31:575-577.
- 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;53:77-87.
- Kallet RH. Measuring dead-space in acute lung injury. Minerva Anaesthesiologica 2012;78:1297-1305.
- Nuckton TJ, Alonso JA, Kallet RH, et al. Pulmonary dead-space fraction as a risk factor for death in the acute respiratory distress syndrome. N Engl J Med 2002;346:1281-1286.
- Amato MB, Meade MO, Slutsky AS, et al. Driving pressure and survival in the acute respiratory distress syndrome. N Engl J Med 2015;372:747-755.
- Lucangelo U, Bernabe F, Vatua S, et al. Prognostic value of different dead space indices in mechanically ventilated patients with acute lung injury. Chest 2008;133:62-71.
- Cepkova M, Kapur V, Ren X, et al. Pulmonary dead space fraction and pulmonary artery systolic pressure as early predictors of clinical outcome in acute lung injury. Chest 2007;132:836-842.
- Raurich JM, Vilar M, Colomar A, et al. Prognostic value of the pulmonary dead-space fraction during early and intermediate phases of acute respiratory distress syndrome. Respir Care 2010;55:282-287.
- Ong T, McClintock DE, Kallet RH, et al. Ratio of angiopoietin-2 to angiopoeitin-1 as a predictor of mortality in acute lung injury patients. Crit Care Med 2010;38:1-7.
- Kallet RH, Zhou H, Liu KD, et al. A multi-center observational study of dead-space ventilation during the first week of acute lung injury. Respir Care 2014;59:1611-1618.
- Kallet RH, Ho K, Lipnick M, et al. Pulmonary dead-space fraction and mortality using the Berlin definition of acute respiratory distress syndrome. Respir Care 2016;61:OF-16,2527188. [abstract].
- Liu KD, Levitt J, Zhou H, et al. Randomized clinical trial of activated protein C for the treatment of acute lung injury. Am J Respir Crit Care Med 2008;178:618-623.
- Kallet RH, Jasmer RM, Pittet JF. The effects of activated protein C therapy on alveolar dead-space ventilation in a patient with sepsis-induced acute respiratory distress syndrome. Respir Care 2010;55:617-622.
- Ong T, McClintock DE, Kallet RH, et al. Ratio of angiopoietin-2 to angiopoeitin-1 as a predictor of mortality in acute lung injury patients. Crit Care Med 2010;38:1-7.
- Kallet RH, Katz JA. Respiratory system mechanics in acute respiratory distress syndrome. Respir Care Clin 2003;9:297-319.
- Beitler JR, Thompson BT, Matthay MA, et al. Estimating dead-space fraction for secondary analysis of ARDS clinical trials. Crit Care Med 2015;43:1026-1035.
- Kallet RH, Ho K, Lipnick M, et al. Pulmonary dead-space Fraction (VD/VT) cannot be estimated accurately using the unadjusted Harris-Benedict equation (H-BE) in acute respiratory distress syndrome (ARDS). Respir Care 2016;61:OF-16,2527192.
- Suter PM, Fairley HB, Isenberg MD. Optimum end-expiratory airway pressure in patients with acute pulmonary failure. N Engl J Med 1975;292:284-289.
- Maisch S, Reismann H, Fuellekrug B, et al. Compliance and dead-space fraction indicate an optimal level of positive end-expiratory pressure after recruitment in anesthetized patients. Anesth Analg 2008;106:175-181.
- Tusman G, Suarez-Sipmann F, Bohm SH, et al. Monitoring dead-space during recruitment and PEEP titration in an experimental model. Intensive Care Med 2006;32:1863-1871.
- Fengmei G, Jin C, Songquiao L, et al. Dead-space fraction changes during positive end-expiratory pressure titration following lung recruitment in acute respiratory distress syndrome patients. Respir Care 2012;57:1578-1585.
- Charon C, Repesse X, Bouferrache K, et al. PaCO2 and alveolar dead-space are more relevant than PaO2 / FiO2 ratio in monitoring the respiratory response to prone position in ARDS patients: A physiological study. Crit Care 2011;15:R175.
- Yoon YH, Lee SW, Jung DM, et al. The additional use of end-tidal alveolar dead-space fraction following D-dimer test to improve diagnostic accuracy for pulmonary embolism in the emergency department. Emerg Med J 2010;27:663-667.
- Gazmuri RJ, Patel DJ, Stevens R, Smith S. Circulatory collapse, right ventricular dilation and alveolar dead space: A triad for the rapid diagnosis of massive pulmonary embolism. Am J Emerg Med 2016. [Epub ahead of print].
- Hubble CL, Gentile MA, Tripp DS, et al. Deadspace to tidal volume ratio predicts successful extubation in infants and children. Crit Care Med 2000;28:2034-2040.
- Riou Y, Chaari W, Leteutre S, Leclerc F. Predictive value of the physiological deadspace/tidal volume ratio in the weaning process of mechanical ventilation in children. J Pediatr (Rio J) 2012;88:217-221.
Here are some of the technologic and physiologic aspects of capnography as they relate to dead space ventilation and their application in the management of critically ill patients.
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