End-tidal to arterial PCO₂ ratio: a bedside meter of the overall gas exchanger performance

Abstract

Background

The physiological dead space is a strong indicator of severity and outcome of acute respiratory distress syndrome (ARDS). The “ideal” alveolar PCO₂, in equilibrium with pulmonary capillary PCO₂, is a central concept in the physiological dead space measurement. As it cannot be measured, it is surrogated by arterial PCO₂ which, unfortunately, may be far higher than ideal alveolar PCO₂, when the right-to-left venous admixture is present. The “ideal” alveolar PCO₂ equals the end-tidal PCO₂ (P_ETCO₂) only in absence of alveolar dead space. Therefore, in the perfect gas exchanger (alveolar dead space = 0, venous admixture = 0), the P_ETCO₂/PaCO₂ is 1, as P_ETCO₂, P_ACO₂ and PaCO₂ are equal. Our aim is to investigate if and at which extent the P_ETCO₂/PaCO₂, a comprehensive meter of the “gas exchanger” performance, is related to the anatomo physiological characteristics in ARDS.

Results

We retrospectively studied 200 patients with ARDS. The source was a database in which we collected since 2003 all the patients enrolled in different CT scan studies. The P_ETCO₂/PaCO₂, measured at 5 cmH₂O airway pressure, significantly decreased from mild to mild–moderate moderate–severe and severe ARDS. The overall populations was divided into four groups (~ 50 patients each) according to the quartiles of the P_ETCO₂/PaCO₂ (lowest ratio, the worst = group 1, highest ratio, the best = group 4). The progressive increase P_ETCO₂/PaCO₂ from quartile 1 to 4 (i.e., the progressive approach to the “perfect” gas exchanger value of 1.0) was associated with a significant decrease of non-aerated tissue, inohomogeneity index and increase of well-aerated tissue. The respiratory system elastance significantly improved from quartile 1 to 4, as well as the PaO₂/FiO₂ and PaCO₂. The improvement of P_ETCO₂/PaCO₂ was also associated with a significant decrease of physiological dead space and venous admixture. When PEEP was increased from 5 to 15 cmH₂O, the greatest improvement of non-aerated tissue, PaO₂ and venous admixture were observed in quartile 1 of P_ETCO₂/PaCO₂ and the worst deterioration of dead space in quartile 4.

Conclusion

The ratio P_ETCO₂/PaCO₂ is highly correlated with CT scan, physiological and clinical variables. It appears as an excellent measure of the overall “gas exchanger” status.

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 (P_ETCO₂) is representative of the actual alveolar gases. In this case, the P_ETCO₂ is lower than the PACO₂ depending on the amount of alveolar dead space.

The measurement of the P_ETCO₂ 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 P_ETCO₂/PaCO₂ ratio may be seen as a direct overall meter of the gas exchanger performance in a scale from 0 to 1. Indeed, a P_ETCO₂/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 P_ETCO₂/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 (P_ETCO₂, PaO₂, PaCO₂, PaO₂/PaCO₂ ratio, SaO₂, venous admixture (Q_s/Q_t), physiological dead space fraction (V_d/V_t)). 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 P_ETCO₂/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 P_ETCO₂/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 P_ETCO₂/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 P_ETCO₂/PaCO₂ ratio.

Table 1.

Baseline characteristics among ARDS groups

ARDS severity	Mild	MM	MS	Severe	P
Number of patients	N = 33	N = 54	N = 70	N = 43
Age	59.0 [43.0; 69.0]	66.0 [53.2; 76.0]	61.0 [45.2; 70.5]	63.0 [52.0; 72.5]	0.382
Sex					0.905
Female	13 (39.4)	16 (29.6)	23 (32.9)	13 (30.2)
Male	20 (60.6)	38 (70.4)	46 (65.7)	30 (69.8)
BMI	25.6 [22.2; 28.0]	25.0 [23.1; 27.8]	24.2 [21.9; 26.7]	26.1 [22.2; 32.0]	0.107
SAPS II	41.5 [27.8; 46.2]	40.0 [31.0; 54.2]	39.0 [33.0; 52.0]	43.0 [35.0; 54.5]	0.416
Tidal volume, ml/kg	540 [500; 600]	550 [480; 600]	502 [432; 560]	500 [428; 590]	0.082
Respiratory Rate, bpm	15.0 [12.0; 18.0]	15.0 [13.0; 18.0]	18.0 [14.0; 20.0]	18.0 [15.0; 20.0]	0.110
Plateau pressure, cmH2O	19.0 [16.1; 21.3]	17.0 [14.5; 20.0]	18.5 [16.3; 21.0]	18.0 [15.9; 21.0]	0.121
Ers, cmH2O/L	23.1 [17.6; 29.2]	22.3 [19.1; 25.6]	26.9 [21.4; 31.7]	26.9 [21.0; 33.2]	0.005
PaO2/FiO2 ratio	230 [218; 255]	173 [160; 183]	122 [108; 139]	79.6 [66.7; 87.4]	< 0.001
PaO2, mmHg	96.2 [83.0; 109]	75.2 [65.8; 81.9]	67.2 [62.0; 71.9]	60.0 [54.0; 71.3]	< 0.001
FiO2	0.40 [0.40; 0.45]	0.40 [0.40; 0.50]	0.55 [0.50; 0.60]	0.85 [0.70; 0.92]	< 0.001
PaCO2, mmHg	40.9 [38.2; 44.2]	42.9 [38.2; 49.8]	44.5 [39.7; 50.3]	52.0 [43.2; 55.0]	< 0.001
Arterial pH	7.39 [7.35; 7.46]	7.39 [7.35; 7.43]	7.38 [7.31; 7.42]	7.36 [7.30; 7.40]	0.024
ARDS causes, no. (%):
Aspiration	1 (3.03)	5 (9.26)	7 (10.0)	2 (4.65)
Other	5 (15.2)	5 (9.26)	11 (15.7)	5 (11.6)
Pneumonia	8 (24.2)	21 (38.9)	35 (50.0)	28 (65.1)
Sepsis	15 (45.5)	18 (33.3)	14 (20.0)	7 (16.3)
Trauma	4 (12.1)	5 (9.26)	3 (4.29)	0 (0.00)

P for one-way Anova and Kruskal–Wallis test. MM mild–moderate, MS moderate–severe, SAPS Simplified Acute Physiology Score, BMI body mass index, E_rs respiratory system elastance

Fig. 1.

Panel A: P_ETCO₂/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

Fig. 2.

Mortality rate observed in the four quartiles of P_ETCO₂/PaCO₂ ratio

Table 2 gives the quantitative CT scan variables obtained at 5 cmH₂O PEEP stratified as quartiles of P_ETCO₂/PaCO₂. As shown, the well-aerated tissue increased with the P_ETCO₂/PaCO₂ ratio. The poorly inflated, non-aerated tissue, the inhomogeneity index [10] and recruitability all significantly decrease throughout the P_ETCO₂/PaCO₂ quartiles. As shown in Table 3, the P_ETCO₂/PaCO₂ ratio was strongly associated with respiratory system elastance, alveolar ventilation and VCO₂. These variables improved when the P_ETCO₂/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 P_ETCO₂/PaCO₂ ratio, while the PaO₂/FiO₂ ratio and saturation increased. Both venous admixture and dead space significantly decreased throughout the P_ETCO2/PaCO₂ quartiles.

Table 2.

Computed tomography quantitative variables at 5 cmH₂O of end-expiratory pressure among the P_ETCO₂/PaCO₂ ratio quartiles

PETCO2/PaCO2 quartiles	I	II	III	IV	p value
Ranges	[0.416,0.709]	[0.709,0.796]	[0.796,0.886]	[0.886,1.16]
Number of patients	N = 52	N = 51	N = 48	N = 49
Not aerated lung tissue, g	864 [534; 1321]	570 [417; 824]	510 [343; 692]	459 [314; 664]	< 0.001
Poorly aerated lung tissue, g	545 [342; 761]	398 [271; 552]	423 [284; 584]	356 [264; 440]	0.001
Normally aerated lung tissue, g	281 [189; 414]	288 [220; 452]	363 [243; 487]	356 [260; 500]	0.021
Hyperinflated lung tissue, g	0.32 [0.02; 2.72]	0.16 [0.01; 1.10]	0.24 [0.02; 2.47]	0.19 [0.01; 1.05]	0.739
Inhomogeneity index	0.20 [0.15; 0.24]	0.16 [0.13; 0.23]	0.15 [0.12; 0.18]	0.14 [0.12; 0.20]	0.007
Possibly recruitable tissue, g	336 [168; 583]	253 [109; 462]	171 [89.8; 295]	117 [54.4; 219]	< 0.001

Data are expressed in medians and IQR. P for Mann–Whitney test

Table 3.

Respiratory mechanics and hemodynamics across P_ETCO₂/PaCO₂ ratio quartiles

PETCO2/PaCO2 quartiles	I	II	III	IV	p value
Range	[0.416,0.709]	(0.709,0.796]	(0.796,0.886]	(0.886,1.16]
Number of patients	N = 52	N = 51	N = 48	N = 49
Respiratory variables
Ers, cmH2O/L	27.9 [21.4; 33.5]	23.6 [20.4; 30.0]	25.7 [20.1; 30.1]	22.3 [18.1; 27.4]	0.015
Tidal volume, mL	480 [420; 550]	520 [455; 598]	510 [451; 600]	540 [485; 598]	0.064
RR, bpm	18.0 [14.8; 20.0]	16.0 [13.0; 19.0]	16.0 [13.0; 18.0]	15.0 [14.0; 18.0]	0.414
MAP, cmH2O	12.0 [10.0; 13.0]	11.0 [9.00; 13.0]	11.0 [10.0; 12.0]	10.0 [9.83; 11.5]	0.130
VA L/min	3.18 [2.74; 4.75]	3.99 [2.86; 5.12]	4.25 [3.44; 5.60]	4.72 [3.33; 5.74]	0.003
VCO2, mL/min	117 [81.2; 137]	144 [112; 174]	164 [129; 189]	180 [144; 200]	< 0.001
Hemodynamics
HR, bpm	87.0 [71.0; 105]	89.0 [70.5; 96.0]	89.0 [81.0; 106]	96.0 [82.0; 108]	0.245
Mean arterial pressure, mmHg	77.0 [69.5; 86.7]	83.0 [73.7; 90.3]	79.0 [72.0; 87.5]	81.7 [73.2; 89.2]	0.210
CVP, mmHg	11.0 [9.00; 14.0]	11.0 [9.00; 13.0]	12.0 [9.50; 14.0]	12.0 [9.00; 14.0]	0.822

Variables are expressed in medians and IQR. P for Mann–Whitney test. E_rs respiratory system elastance, RR respiratory rate, PEEP end-expiratory pressure, MAP mean airway pressure, V_A alveolar ventilation, HR heart rate, CVP central venous pressure

Table 4.

Gas exchange across P_ETCO₂/PaCO₂ ratio quartiles

PETCO2/PaCO2 quartiles	I	II	III	IV	p value
Ranges	[0.416,0.709]	[0.709,0.796]	[0.796,0.886]	[0.886,1.16]
Number of patients	N = 52	N = 51	N = 48	N = 49
PaO2, mmHg	62.6 [55.0; 73.6]	71.0 [63.5; 81.2]	75.0 [65.8; 89.7]	71.8 [65.0; 83.0]	0.001
PaCO2, mmHg	48.1 [43.3; 53.8]	46.0 [41.1; 52.4]	44.7 [40.4; 50.1]	39.9 [36.5; 43.2]	< 0.001
PaO2/FiO2	103 [76.7; 131]	117 [102; 158]	164 [139; 203]	171 [143; 207]	< 0.001
Arterial pH	7.36 (0.07)	7.37 (0.07)	7.38 (0.08)	7.40 (0.07)	0.009
SaO2	90.8 [87.5; 94.0]	92.4 [90.5; 95.3]	94.1 [92.0; 96.2]	94.7 [92.7; 96.8]	< 0.001
Venous pH	7.34 (0.07)	7.35 (0.06)	7.36 (0.07)	7.37 (0.05)	0.141
PvO2, mmHg	42.1 [39.8; 45.6]	42.0 [39.2; 44.1]	40.8 [37.2; 49.0]	42.9 [40.0; 47.7]	0.667
PvCO2, mmHg	50.2 [46.9; 56.9]	52.0 [46.8; 55.3]	49.8 [45.0; 56.5]	45.8 [41.0; 47.3]	< 0.001
SvO2	73.5 [70.1; 76.5]	74.3 [71.4; 77.7]	76.4 [70.0; 80.6]	77.7 [72.6; 81.0]	0.073
v-a difference	2.31 [1.30; 2.83]	2.46 [1.92; 2.83]	2.65 [2.00; 3.26]	2.10 [1.56; 2.53]	0.036
Qs/Qt	0.54 [0.40; 0.66]	0.42 [0.36; 0.48]	0.35 [0.27; 0.43]	0.39 [0.30; 0.46]	< 0.001
Vd/Vt	0.74 [0.67; 0.80]	0.63 [0.60; 0.68]	0.56 [0.51; 0.61]	0.47 [0.44; 0.55]	< 0.001

Variables are expressed in medians and IQR or means ± SD according to distribution. P for Mann–Whitney test or one-way Anova. Q_s/Q_t: shunt fraction; V_d/V_t: dead space fraction

P_ETCO₂/PaCO₂ ratio at different airway pressures

Figure 3 illustrates how lung tissue aeration changed in the different P_ETCO₂/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.

Portions of lung tissue classified as not aerated, poorly aerated, normally aerated and hyperinflated among P_ETCO₂/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 P_ETCO₂/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

In Table 5, we report the changes of CT scan, respiratory mechanics and gas exchange variables through the quartiles of P_ETCO₂/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 P_ETCO₂/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 P_ETCO₂/PaCO₂ ratio quartiles

PETCO2/PaCO2quartiles Δ	I	II	III	IV	p value
Ranges	[0.416,0.709]	[0.709,0.796]	[0.796,0.886]	[0.886,1.16]
Number of patients	N = 52	N = 51	N = 48	N = 49
Δ Lung volume, mL	579 [417; 775]	602 [436; 719]	588 [467; 735]	586 [443; 823]	0.98
Δ Lung gas, mL	546 [451; 816]	598 [413; 711]	551 [456; 700]	564 [395; 810]	0.99
Δ Lung tissue, g	10.9 [− 42; 53]	26 [− 5.1; 53]	20 [6.4; 43.4]	22.6 [− 23; 56]	0.87
Δ Not aerated tissue, mL	− 170 [− 282; − 78]	− 87.7 [− 160; − 42.3]	− 70.1 [− 124.4; − 40.3]	− 23.5 [− 91.5; 0.3]	< 0.001
Δ Poorly aerated tissue, mL	7.3 [− 50; 171]	− 42.4 [− 97.1; 14.1]	− 37.2 [− 105.7; 15]	− 73 [− 112; − 17]	0.02
Δ Normally aerated tissue, mL	140 [82; 241]	153 [68; 226]	143 [94; 197]	134 [87; 199]	0.96
Δ Hyperinflated tissue, mL	1.5 [0.17; 4]	0.85 [0.13; 1.8]	0.5 [0.04; 3.44]	0.5 [0.11; 5.4]	0.92
Δ Qs/Qt	− 0.13 [− 0.2; − 0.08]	− 0.08 [− 0.13; − 0.04]	− 0.08 [− 0.14; − 0.01]	− 0.07 [− 0.13; − 0.03]	0.01
Δ Vd/Vt	0.01 [0.0; 0.03]	0.02 [− 0.01; 0.04]	0.01 [0.0; 0.04]	0.03 [0.02; 0.06]	0.03
Δ PaO2, mmHg	32 [18.5; 46]	23 [10.2; 58.4]	21.2 [4.3; 36]	16 [4.4; 28]	0.01
Δ ERS, cmH2O/L	0.07 [− 4.0; 3.4]	− 0.2 [− 2.2; 4.1]	0.3 [− 4.1; 2.4]	0.0 [− 2.5; 2.2]	0.85

Differences were computed as the variable at PEEP 15 cmH₂O minus the variable at PEEP 5 cmH₂O. Variables are expressed in medians and IQR. P for Mann–Whitney test. Q_s/Q_t: shunt fraction; V_d/V_t: dead space fraction; P/F: PaO₂/FiO₂ ratio; E_RS: respiratory system elastance; SvO₂: central venous oxygen saturation; P_ETCO₂: end-tidal CO₂

Discussion

In this study, we found that the P_ETCO₂/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 P_ETCO₂/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, P_ETCO₂ is equal to PACO₂ (alveolar dead space fraction = 0). Therefore, in this “ideal” setting the ratio of P_ETCO₂ 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 P_ETCO₂/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 P_ETCO₂/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.

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 P_ETCO₂. In turn, the P_ETCO₂ may be diluted into the gas ventilating the airways and the apparatus (anatomical dead space) becoming P_ETCO₂. 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 P_ETCO₂ 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, P_ETCO₂ equals the PACO₂ (no alveolar dead space) and PACO₂ equals PaCO2 (no venous admixture). Therefore P_ETCO₂/PaCO₂ equals 1

This is not really surprising, as almost all variables characterizing the ARDS are related to the P_ETCO₂/PaCO₂ ratio. With regard to the morphological variables, the P_ETCO₂/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 P_ETCO₂/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 P_ETCO₂/PaCO₂ ratio, alveolar dead space and venous admixture accounts for its high sensitivity in detecting an overall impairment in gas exchange. The P_ETCO₂/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 P_ETCO₂/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 P_ETCO₂/PaCO₂ ratio. Therefore, an altered P_ETCO₂/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 P_ETCO₂/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 P_ETCO₂, while a decrease of right-to-left venous admixture would tend to reduce PaCO₂. The P_ETCO₂/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 P_ETCO₂/PaCO₂ ratio had a more favorable response to PEEP.

The P_ETCO₂/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 P_ETCO₂/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 P_ETCO₂/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 P_ETCO₂/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 P_ETCO₂/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.

Authors’ contributions

Conception and design: MB, MQ, DC, LG. Data collection: FR, MB, MMP, IS, SG. Analysis and interpretation: KM, MMQ, DC. Drafting the manuscript for important intellectual content: all authors. All authors read and approved the final manuscript.

Funding

Open Access funding enabled and organized by Projekt DEAL. Institutional.

Availability of data and materials

Dataset available upon reasonable request.

Ethics approval and consent to participate

The ethics committee was notified and permission to use the data was granted (Göttingen Antragsnummer 14/12/12).

Consent for publication

All authors have approved the manuscript.

Competing interests

The authors have no conflict of interest to disclose.

Supplementary Information

The online version contains supplementary material available at 10.1186/s40635-021-00377-9.