Introduction

The physiological dead space, which includes both the anatomical and alveolar dead space, is a strong indicator of severity and outcome of acute respiratory distress syndrome (ARDS) [1, 2]. The computation of the physiological dead space is based on the dilution of the ideal alveolar PCO2 (PACO2). This ideal PCO2, introduced by Riley, cannot be measured directly and it is assumed to be equal to the capillary PCO2 (PcCO2) [3] which leaves the ventilated/perfused pulmonary units [4]. As the PcCO2 cannot be measured directly, the arterial PCO2 (PaCO2) is assumed to be its surrogate. Therefore, the assumption on which the physiological dead space is computed is that PACO2, PcCO2 and PaCO2 have identical values. While this is nearly correct in the normal lung, in the diseased lung, as in ARDS, the PaCO2 is higher than PcCO2 and PACO2 due to the presence of venous admixture (in Riley’s model, the fraction of blood which flows through “non-aerated lung regions” maintaining the same PO2 and PCO2 of the mixed venous blood). Consequently, PaCO2 is the result of the weighted average of blood coming from the ideal compartment (PcCO2) and of mixed venous PCO2 (PvCO2) [5]. , It is therefore easy to understand why the venous admixture, i.e., a variable which measures the oxygenation impairment, has an effect on variables which describe the wasted ventilation. To compute the alveolar dead space, we may assume that the end-tidal CO2 (PETCO2) is representative of the actual alveolar gases. In this case, the PETCO2 is lower than the PACO2 depending on the amount of alveolar dead space.

The measurement of the PETCO2 is easily performed in intensive care. Therefore, the alveolar dead space may be derived as follows:

$$\mathrm{Alveolar}\;\mathrm{dead}\;\mathrm{space}=1-\frac{{\mathrm{EtCO}}_2}{{\mathrm{PaCO}}_2}.$$

As the alveolar dead space, as measured by the equation above, depends both on the “true” alveolar dead space and on the extent of the venous admixture, the PETCO2/PaCO2 ratio may be seen as a direct overall meter of the gas exchanger performance in a scale from 0 to 1. Indeed, a PETCO2/PaCO2 ratio equal to 1 represents the perfect gas exchanger, being, in this condition, the alveolar dead space and the venous admixture equal to 0. The presence of alveolar dead space and/or venous admixture at different extent would progressively decrease this ratio from the unity, reflecting the progressive deterioration of the gas exchanger in its two components, oxygenation and CO2 removal.

The aim of this study is to investigate whether the PETCO2/PaCO2, easily measurable at the bedside, can be an adequate tool to assess the physio-anatomical condition of the gas exchanger.

Materials and methods

Study population

This study population consisted of 200 patients, studied from 2003 and 2016 in two university hospitals (Policlinico Milano, Milan, Italy and University Medical Center Göttingen, Göttingen, Germany). All patients suffered from ARDS according to the Berlin criteria [6]. The ethics committee was notified and permission to use the data was granted (Göttingen Antragsnummer 14/12/12).

Recorded variables

For each patient, the CT scans were acquired at 5, 15 and 45 cmH2O of airway pressure. We reported the anatomical variables derived from the CT quantitative analysis: namely, hyperinflated (− 1000/− 900 HU), well aerated (− 900/− 500 HU), poorly inflated (− 500/− 200 HU) and non-aerated (− 100/ + 100 HU) tissues [7, 8]. Recruitability was computed as the fraction of non-aerated tissue at 5 cmH2O minus the fraction of non-aerated tissue at 45 cmH2O [9]. Lung inhomogeneity was computed on a voxel-by-voxel basis, as the ratio of gas content between acinar size lung units and surrounding lung units [10]. A ratio equal to 1 would indicate perfect homogeneity, a ratio of 2 would indicate an inflation of the central lung unit double than the surrounding units. At 5 and 15 cmH2O of airway pressure, we collected the mechanical ventilation settings and respiratory mechanics variables (tidal volume, respiratory rate, alveolar ventilation, and respiratory system elastance), hemodynamics (systolic and diastolic arterial blood pressures, central venous pressure, heart rate, ScvO2 and arteriovenous O2 content difference) and gas exchange variables (PETCO2, PaO2, PaCO2, PaO2/PaCO2 ratio, SaO2, venous admixture (Qs/Qt), physiological dead space fraction (Vd/Vt)). Tidal volume and FiO2 were kept constant at these two PEEP levels. The volumetric capnography measurements were performed with COSMO (Respironics Novametrix, Wallingford, USA).

The first analysis was done grouping the patients according to the their ARDS severity (mild, moderate–mild, moderate–severe, severe) [11]. An additional analysis was performed dividing the patients into four groups (~ 50 patients per group) based on the equal-count quartiles of their PETCO2/PaCO2 ratios determined during ventilation at 5 cmH2O of PEEP. For details regarding the calculated variables, please refer to Additional File 1.

Statistical methods

The normal distribution of the data was assessed by the Shapiro–Wilk test. Physiological, CT scan variables and PETCO2/PaCO2 ratio were compared among groups with one-way analysis of variance or Kruskal–Wallis test as appropriate. Multiple comparisons were performed with Bonferroni correction. Two tailed, p values < 0.05 were considered statistically significant. These statistical analyses were performed with R (R Foundation for Statistical Computing version 3.7).

Results

The main anthropometric and the physiological characteristics of the study population obtained at 5 cmH2O of PEEP are presented in Table 1. Figure 1, panel A shows the PETCO2/PaCO2 ratio as a function of ARDS severity. The ratio decreased linearly with increasing severity. In Fig. 2, we report the mortality rate observed in the quartiles of PETCO2/PaCO2 ratio.

Table 1 Baseline characteristics among ARDS groups
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Fig. 1
figure 1

Panel A: PETCO2/PaCO2 ratio among acute respiratory distress syndrome (ARDS) groups divided in Severe, Moderate–Severe (MS), Moderate–Mild (MM) and Mild groups at 5 cmH2O of positive end-expiratory pressure (PEEP). *p < 0.001, Mann–Whitney test

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Fig. 2
figure 2

Mortality rate observed in the four quartiles of PETCO2/PaCO2 ratio

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Table 2 gives the quantitative CT scan variables obtained at 5 cmH2O PEEP stratified as quartiles of PETCO2/PaCO2. As shown, the well-aerated tissue increased with the PETCO2/PaCO2 ratio. The poorly inflated, non-aerated tissue, the inhomogeneity index [10] and recruitability all significantly decrease throughout the PETCO2/PaCO2 quartiles. As shown in Table 3, the PETCO2/PaCO2 ratio was strongly associated with respiratory system elastance, alveolar ventilation and VCO2. These variables improved when the PETCO2/PaCO2 ratio approached unity. The gas exchange variables under the same conditions are presented in Table 4. As shown, the PaCO2 progressively decreased with the concurrent increase of PETCO2/PaCO2 ratio, while the PaO2/FiO2 ratio and saturation increased. Both venous admixture and dead space significantly decreased throughout the PETCO2/PaCO2 quartiles.

Table 2 Computed tomography quantitative variables at 5 cmH2O of end-expiratory pressure among the PETCO2/PaCO2 ratio quartiles
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Table 3 Respiratory mechanics and hemodynamics across PETCO2/PaCO2 ratio quartiles
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Table 4 Gas exchange across PETCO2/PaCO2 ratio quartiles
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PETCO2/PaCO2 ratio at different airway pressures

Figure 3 illustrates how lung tissue aeration changed in the different PETCO2/PaCO2 ratio quartiles when airway pressure was increased from 5 to 15 and 45 cmH2O. The amount of non-aerated tissue decreased steadily from 5 to 45 cmH2O in all quartiles, while the amount of normally aerated tissue increased.

Fig. 3
figure 3

Portions of lung tissue classified as not aerated, poorly aerated, normally aerated and hyperinflated among PETCO2/PaCO2 ratio quartiles to the response of step increase of PEEP at 5, 15 and 45 cmH2O. The asterisk denotes p < 0.001 among the portions of tissue throughout PETCO2/PaCO2 ratio quartiles for Mann–Whitney test. The dollar denotes p < 0.001 among portions of lung tissue to the response to PEEP for Wilcoxon test

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In Table 5, we report the changes of CT scan, respiratory mechanics and gas exchange variables through the quartiles of PETCO2/PaCO2 when PEEP was increased from 5 to 15 cmH2O. As shown, the greatest improvement of non-aerated tissue, PaO2 and venous admixture were observed in quartile 1 of PETCO2/PaCO2 and the worst deterioration of dead space in quartile 4.

Table 5 Changes in CT scan, respiratory mechanics and gas exchange variables in response to PEEP increase from 5 to 15 cmH2O among PETCO2/PaCO2 ratio quartiles
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Discussion

In this study, we found that the PETCO2/PaCO2 ratio is strongly associated with most of the morphological and physiological characteristics of ARDS, resulting as an easy and appealing measure of the status and the performance of the lung.

The physiological meaning of the PETCO2/PaCO2 ratio may be easily understood when one considers CO2 kinetics through the anatomical space from the pulmonary capillaries to the airway opening. Figure 4 shows that, in the ideal lung, PaCO2 is equal to PcCO2 (venous admixture fraction = 0). Similarly, PETCO2 is equal to PACO2 (alveolar dead space fraction = 0). Therefore, in this “ideal” setting the ratio of PETCO2 to PaCO2 would be 1. This ratio will depart progressively from 1 in the presence of a venous admixture and/or alveolar dead space. Consequently, the PETCO2/PaCO2 ratio is a rather unspecific variable, as it is linked to both CO2 and O2 exchange impairment, but for the same reason it may give an immediate warning of an overall impairment of gas exchange. The potential role of monitoring the PETCO2/PaCO2 ratio in order to follow and understand the disease course is emphasized by its close association with the overall severity of ARDS and the mortality.

Fig. 4
figure 4

The PvCO2 decreases to PcCO2 (the capillary PCO2 pressure) after releasing CO2 in the alveolar space. The partial pressure of CO2 in the alveoli (PACO2) which are perfused is equal to PcCO2. This pressure represents the “ideal” alveolar gas, as it derives from pulmonary units which are both perfused and ventilated. This model ignores other factors possibly affecting the CO2 dynamics, such as the CO2 production from the inflammatory cells residing in the inflamed lung. Actually, this ideal PACO2 may be “diluted” by the gas coming from unperfused but ventilated alveoli (alveolar dead space). The PACO2 then becomes PETCO2. In turn, the PETCO2 may be diluted into the gas ventilating the airways and the apparatus (anatomical dead space) becoming PETCO2. It must be realized that the number of molecules of CO2 involved are exactly the same, but their concentration (and partial pressure) depends on the progressive dilution with alveolar gases and “anatomical” gases. In normal individual, PACO2 and PETCO2 differ only of 1–2 mmHg, being the alveolar dead space negligible. The PvCO2 may also reach the arterial circulation without any modification in presence of venous admixture. In this case, PaCO2 is the result of mixing between PcCO2 and PvCO2. Greater is the venous admixture, greater is the difference between PaCO2 (higher) and PcCO2. In the perfect gas exchanger, PETCO2 equals the PACO2 (no alveolar dead space) and PACO2 equals PaCO2 (no venous admixture). Therefore PETCO2/PaCO2 equals 1

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This is not really surprising, as almost all variables characterizing the ARDS are related to the PETCO2/PaCO2 ratio. With regard to the morphological variables, the PETCO2/PaCO2 ratio is related to the extent of non-aerated and aerated tissue, the size of the baby lung as well as to the extent of recruitability. No other gas exchange variable exhibits such a large number of correlations with lung morphology. Indeed, venous admixture and physiological dead space were only related to the non-aerated tissue and to the normally aerated tissues, respectively. Therefore, the relative nonspecificity of the PETCO2/PaCO2 ratio, which reflects the overall gas exchange (both for oxygen and carbon dioxide), explains its correlation with all the morphological components of the lungs, of which some are more related to oxygen while others are more related to CO2 exchange. On the other hand, the linkage between the PETCO2/PaCO2 ratio, alveolar dead space and venous admixture accounts for its high sensitivity in detecting an overall impairment in gas exchange. The PETCO2/PaCO2 ratio was inversely associated with respiratory system elastance and directly correlated with alveolar ventilation, while no relationship was found with hemodynamic variables. The low specificity but high sensitivity of the PETCO2/PaCO2 ratio to reflect an overall impairment of gas exchange is strikingly shown by the correlation we found with the gas exchange variables. Indeed, as shown in Table 4, all measured or computed variables related either with oxygenation or carbon dioxide clearance were strongly associated with the PETCO2/PaCO2 ratio. Therefore, an altered PETCO2/PaCO2 ratio, as such, is associated both with the morphology and, the function of gas exchange, suggesting it as a sensitive, easily available marker, of changes in lung conditions. Interestingly, we found that the VCO2 significantly increased throughout the quartiles. We believe that this is due to an improved alveolar ventilation, with greater elimination of carbon dioxide. Indeed, the low VCO2 measured in quartile 1 possibly represents only a fraction of the metabolic CO2 production which is partly retained. Increased alveolar ventilation throughout the quartiles leads to a normalization or even a higher than normal (metabolic) CO2 clearance [12].

The PETCO2/PaCO2 ratio may be also considered to anticipate the PEEP response. The PEEP response in gas exchange is a balance between the decrease of venous admixture and increase in alveolar dead space. The venous admixture decrease could either be due to recruitment, better mechanical conditions of pulmonary units already open, or to a decrease in cardiac output, while the alveolar dead space increase may be due to an overdistention of pulmonary units relative to their perfusion. An increase in alveolar dead space would tend to reduce PETCO2, while a decrease of right-to-left venous admixture would tend to reduce PaCO2. The PETCO2/PaCO2 ratio is related to the two variables, and its changes may reflect these physiopathological mechanisms. Moreover, we showed that patients starting with a lower PETCO2/PaCO2 ratio had a more favorable response to PEEP.

The PETCO2/PaCO2 ratio is obviously related to the physiological dead space, although it may be considered a “positive variable” (greater the ratio, better the gas exchange) rather than “negative” (greater the dead space, worse the gas exchange). Indeed, any change of the PETCO2/PaCO2 ratio toward the value of 1 indicates an improvement of the whole gas exchanger condition, which may then be easily monitored after any maneuvre on the respiratory system, change of ventilator setting and pharmacological intervention. Indeed, the daily monitoring of this easy to use variable may show a progressive increase towards the unity, giving some evidence that the lung conditions are improving. In contrast, any change of this ratio towards lower values immediately indicates an overall decrease of the gas exchange performances. The PETCO2/PaCO2 ratio also helps the clinician to be more aware of the dynamics of CO2. Too often oxygenation represents the concern at the bedside of an ARDS patient, but it is only considering also PaCO2 that one can have a more complete picture of the lung structure and function [13]. Finally, the PETCO2/PaCO2 ratio finds in its strength as an overall meter of gas exchange impairment also its weakness. Indeed, to fully understand the various components of the of the gas exchange alteration, both dead space and venous admixture must be be measured.

Conclusions

In this study, we evaluated the PETCO2/PaCO2 ratio as a clinical tool to comprehensively evaluate the gas exchange lung function. The ratio was associated with most of the physiological variables that can be measured at the bedside and, therefore, it can represent a useful parameter for the daily monitoring of the ARDS patient.