Changes in central venous-to-arterial carbon dioxide tension induced by fluid bolus in critically ill patients

Charalampos Pierrakos; David De Bels; Thomas Nguyen; Dimitrios Velissaris; Rachid Attou; Jacques Devriendt; Patrick M. Honore; Fabio Silvio Taccone; Daniel De Backer

doi:10.1371/journal.pone.0257314

Abstract

Background

In this prospective observational study, we evaluated the effects of fluid bolus (FB) on venous-to-arterial carbon dioxide tension (P_vaCO₂) in 42 adult critically ill patients with pre-infusion P_vaCO₂ > 6 mmHg.

Results

FB caused a decrease in P_vaCO₂, from 8.7 [7.6−10.9] mmHg to 6.9 [5.8−8.6] mmHg (p < 0.01). P_vaCO₂ decreased independently of pre-infusion cardiac index and P_vaCO₂ changes during FB were not correlated with changes in central venous oxygen saturation (S_cvO₂) whatever pre-infusion CI. Pre-infusion levels of P_vaCO₂ were inversely correlated with decreases in P_vaCO₂ during FB and a pre-infusion P_vaCO₂ value < 7.7 mmHg could exclude a decrease in P_vaCO₂ during FB (AUC: 0.79, 95%CI 0.64–0.93; Sensitivity, 91%; Specificity, 55%; p < 0.01).

Conclusions

Fluid bolus decreased abnormal P_vaCO₂ levels independently of pre-infusion CI. Low baseline P_vaCO₂ values suggest that a positive response to FB is unlikely.

Citation: Pierrakos C, De Bels D, Nguyen T, Velissaris D, Attou R, Devriendt J, et al. (2021) Changes in central venous-to-arterial carbon dioxide tension induced by fluid bolus in critically ill patients. PLoS ONE 16(9): e0257314. https://doi.org/10.1371/journal.pone.0257314

Editor: Vincenzo Lionetti, Scuola Superiore Sant’Anna, ITALY

Received: May 17, 2021; Accepted: August 28, 2021; Published: September 10, 2021

Copyright: © 2021 Pierrakos et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All relevant data are within the manuscript and its Supporting information files.

Funding: The authors received no specific funding for this work.

Competing interests: The authors have declared that no competing interests exist.

Introduction

The venous-to-arterial carbon dioxide tension difference is an easily-derived metabolic index that can be used to assess the adequacy of tissue perfusion to support the body’s metabolism [1–3]. Applying Fick’s formula for CO₂ shows that the difference between the mixed venous and arterial CO₂ content equals the ratio between CO₂ production (VCO₂) and cardiac output. As CO₂ content is difficult to assess, it can be replaced with the partial pressure of CO₂ in the blood, since there is a linear relationship between these two parameters, at least in a large physiological range [4]. Ideally, venous-to-arterial carbon dioxide tension difference should be derived using pulmonary artery obtained PCO₂. Nevertheless, Swan–Ganz catheter is not used often in contemporary intensive care [5]. Central venous venous-to-arterial carbon dioxide tension (P_vaCO₂) even though is not interchangeable to mixed venous [6] can be used instead as a high P_vaCO₂ (> 6 mmHg) indicates that tissue perfusion is not sufficiently high to remove the CO₂ produced by the tissues [7]. Of note, persistent abnormal P_vaCO₂ levels can be related to poor outcome in critically ill patients [8, 9]. Accordingly, P_vaCO₂ might be an interesting target for resuscitation [10].

Unfortunately, the interventions potentially improving P_vaCO₂ have not yet been adequately evaluated. Observational studies have shown that resuscitation maneuvers improving central venous saturation and arterial pressure might not be related to a decrease in P_vaCO₂ [6, 11, 12]. Dobutamine can cause a decrease in P_vaCO₂ due to an increase in CI, although a paradoxical increase might be observed at higher doses [13, 14]. Fluid bolus (FB) might be another therapeutic option in patients with abnormal P_vaCO₂. Mecher et al. reported that FB decreased high P_vaCO₂ in patients with septic shock, but the authors enrolled only septic patients with low CI [15]. As elevated P_vaCO₂ might also represent microcirculatory alterations in the context of preserved CI [16], one may wonder whether FB decreases P_vaCO₂ independently of the baseline CI.

The aim of this study was to investigate whether FB decreases P_vaCO₂ and to determine their relationships with CI and oxygenation changes.

Methods

Design and setting

In this prospective observational study, we collected data from patients treated in Brugmann University Hospital’s 33-bed intensive care unit in Brussels between January and June 2015. Approval was obtained from the Ethics Committee (CE2014/122) of CHU-Brugmann.

Inclusion and exclusion criteria

Patients with P_vaCO₂ > 6 mmHg in whom the attending physician decided for a FB of either colloids or crystalloids within 30–40 min at any time of their stay in the ICU were considered eligible for this study. We included patients using a deferred informed consent as FB was part of standard treatment and we used not invasive methods for monitoring. Informed consent was obtained from all patients or, when that was not feasible, a consent form was gathered from the next-of-kin as soon as possible after FB but before ICU discharge.

Each patient was assessed once. The exclusion criteria were: 1) patients younger than 18 years old; 2) not equipped with jugular or subclavian venous catheter and arterial catheter; 3) measurement of cardiac output with cardiac ultrasound was not possible due to lack of acoustic window; 4) patients receiving extracorporeal membrane oxygenation (ECMO) support; 5) PCO₂ higher than 75 mmHg in venous or arterial blood gas analysis; 6) atrial fibrillation; 7) other simultaneous interventions (i.e., introduction or increase in inotrope dosage, mode changes, or the introduction of mechanical ventilation) within 30 min prior to fluid administration.

Data and sample collections

Demographics, the type of fluids used for FB, clinical data concerning treatment (mechanical ventilation, inotropic agents), and laboratory data were collected for each patient. The Acute Physiology and Chronic Health Evaluation (APACHE) II score were used to assess the severity of disease at the time of inclusion in the study.

Using Doppler transthoracic echocardiography (GE Healthcare Vivid S5), we measured the left ventricular outflow tract (LVOT) blood velocity time integral (VTI) just prior to the administration of FB. To calculate stroke volume (SV) and CI, LVOT diameter was measured below the aortic valve at the aortic cusp insertion points in the parasternal long-axis view. Immediately after FB, we repeated the measurements. Both measurements were stored and analyzed off-line. Three consecutive velocity curves were measured, and the average VTI was calculated. We used the same value of LVOT diameter to calculate SV and CI before and after FB. Each patient was assessed once. No interventions were allowed during fluid administration.

Arterial and central venous blood gas analysis were simultaneously obtained just before and after FB. We measured the haemoglobin, arterial, and venous oxygen tensions (P_aO₂ and P_vO₂, respectively) and oxygen saturation (S_aO₂ and S_cvO₂). Applying the usual formulas, we calculated the arterial (C_aO₂) and venous (C_vO₂) oxygen content and oxygen delivery (DO₂), and oxygen consumption (VO₂). The P_vaCO₂ and P_vaCO₂/C_avO₂ ratios were calculated before and after FB.

Diagnostic definitions

All the diagnostic definitions were set beforehand. The smallest detectable difference (SDD) of P_vaCO₂ was expected to be ±2.06 mm Hg as it was evaluated in a previous study in critically ill patients [17]. Accordingly, patients were considered as ‘P_vaCO₂ responders’ if they had a decrease in P_vaCO₂ > 2 mmHg. ‘Fluid responders’ were defined as patients who had an increase in CI > 15% [18]. Sepsis was defined according to standard criteria [19]. As changes in P_vaCO₂ may be affected by baseline value and as P_vaCO₂ is inversely related to cardiac index, we separated patients into ‘low’ and ‘high’ cardiac index using a cut-off value of 2.2 L/min/m², similarly to a previous study [15]. Of note, the term ‘low CI’ should not be misinterpreted as in some case the low CI may still be adequate [20].

Primary outcome

The primary endpoint was to evaluate whether FB can decrease P_vaCO₂ by at least 2 mmHg on average.

Secondary outcomes

The secondary endpoint was to investigate changes of P_vaCO₂ during FB in patients with baseline CI less or more 2.2 L/min/m² and its relationship with changes of CI and S_cvO₂. The value of baseline P_vaCO₂ for the prediction of a decrease in P_vaCO₂ during FB will be evaluated.

Statistical analysis

We performed statistical analysis using R through the R-studio interface (www.r-project.org, R version 3.3.1). We used a Kolmogorov-Smirnov test to verify the normality of the distribution of the continuous variables. Normally distributed and non-normally distributed data were compared using a Student’s t-test or Wilcoxon signed-rank test, as appropriate. Categorical variables were compared using Fisher’s exact test. Pearson correlation and scatter diagrams were used to assess correlations between values. Univariate regression analysis was performed to evaluate the association between decrease P_vaCO₂ > 2mmHg and baseline CI, fluid type and mechanical ventilation. Receiver operating characteristics (ROC) analysis was used to derive the prognostic discriminatory performance of baseline P_vaCO₂ in determining a decrease of P_vaCO₂ during FB. The sample size was calculated to aim for an AUC of greater than 0.8, which is usually considered as having a good predictive ability. Assuming a fluid responsiveness rate of 30% in mixed population of critically ill patients [21] 40 patients were required to obtain 90% power (alpha 0.05). The Youden index was used to derive the optimal cut-off. Statistical significance was defined as p < 0.05.

Results

We evaluated 80 patients who received FB during the study period. Two patients refused to give informed consent and were excluded from any further analysis. Forty-two patients (73 years (64−83) and APACHE II score on admission 21(15−29)) met our entry criteria (S1 Fig). Twenty-four of the patients (57%) received colloids (Geloplasma^®, Fresenius-Kabi AG, Bad Homburg, Germany) and 18 (43%) crystalloids (Plasma-Lyte A, Baxter Healthcare, Deerfield, IL) (S1 Table). The median given volume was 6.3 ml/kg [6.3−7.1] for FB with colloids and 14.9 ml/kg [12.1−19.6] for FB with crystalloids within a median time of 33 min [27− 44]. Central venous pressure increased after FB from 8.5 mmHg [4.0−11.2] to 11.1 mmHg [9.2− 13.0] (p<0.01). No differences were observed in the increases in central venous pressure after FB between the patients who received colloids or crystalloids (33% [30–73] vs 22% [9−44], p = 0.07). Fourteen patients (33%) had an increase in CI >15% after FB. No differences were observed in the changes in CI after FB between the patients who received colloids or crystalloids (13% [0−21]vs 12% [2−25], p = 0.22). Nineteen (45%) of the patients were supported with mechanical ventilation during FB, and 11 (26%) were under sedation. No changes in respiratory rate were observed during FB (21 ± 5 resp/min to 21 ± 6 resp/min, p = 0.92). Sixteen patients had a CI ≤ of 2.2 L/min/m² before FB, and 26 had a CI of > 2.2 L/min/m².

Primary outcome

The median P_vaCO₂ before FB was 8.7 [7.6−10.9] and did not differ between intubated and not intubated patients (9.2 [7.7−13.5] mmHg versus 8.4 [7.4−10.2] mmHg; p = 0.23). FB decreased P_vaCO₂ to 6.9 [5.8−8.6] mmHg (p < 0.01) (Fig 1). Twenty-two patients (52%) had a decrease in P_vaCO₂ > 2 mmHg (‘P_vaCO₂ responders’). The hemodynamic and metabolic characteristics of the patients, as well as their changes, are presented in Table 1 and S2 Table. ‘P_vaCO₂ responders’ had a higher relative and absolute increase in CI compared to ‘P_vaCO₂ non-responders’.

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Fig 1. Evolution of central venous-to-arterial carbon dioxide tension difference (P_vaCO₂) during fluid bolus.

https://doi.org/10.1371/journal.pone.0257314.g001

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Table 1. Patients’ baseline hemodynamic and metabolic variables and changes during fluid bolus according to a decrease (or not) in central venous-to-arterial carbon dioxide tension difference (P_vaCO₂) > 2 mmHg (P_vaCO₂ non-responders and responders).

Changes are presented as relative (d, %) and absolute values (Δ). Values are presented either as means with standard deviations (±) or as median values and percentiles 25 and 75.

https://doi.org/10.1371/journal.pone.0257314.t001

There was no association between the decrease of P_vaCO₂ > 2 mmHg after FB and the pre-infusion levels of CI (i.e. ‘low’ or ‘high CI’). Additionally, the type of fluid used for FB and mechanical ventilation were not found to be associated with the likelihood of decreasing P_vaCO₂ > 2 mmHg after FB (S3 Table).

Secondary outcomes

A correlation between changes in CI and P_vaCO₂ was observed only in patients who had a low CI before FB (r = -0.71, p < 0.01). None of the patients who had an increase in CI > 15% (Fig 2) experienced an increase in P_vaCO₂. Because estimation of the area of LVOT represents the major source of error in calculating cardiac output with transthoracic echocardiography [22] we repeated the analysis using only VTI: similar results were found when P_vaCO₂ changes were assessed with changes in VTI (S2 Fig).

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Fig 2. Relationship between absolute changes in P_vaCO₂ (Δ P_vaCO₂) during fluid bolus and absolute changes in cardiac index (Δ CI).

Panel A: Patients with CI ≤ 2.2 L/min/m²; Panel B: Patients with CI > 2.2 L/min/m². d CI: relative to baseline values changes in CI. The horizontal dotted line corresponds to Δ P_vaCO₂−2 mmHg. Triangle points represent “Fluid responders” (d CI > 15%) and circle points “Fluid non-responders” (d CI ≤ 15%).

https://doi.org/10.1371/journal.pone.0257314.g002

We found no statistically significant correlation between P_vaCO₂ and S_cvO₂ changes, independently of the baseline CI. S_cvO₂ could either increase, decrease, or remained unchanged in ‘P_vaCO₂ responders’ (S3 Fig).

A value < 7.7 mmHg could exclude a decrease of P_vaCO₂ during the FB, independently of baseline CI (AUC: 0.79, 95%CI 0.64 ‒ 0.93; Sensitivity, 91%; Specificity, 55%; p < 0.01) (S4 Fig). Baseline P_vaCO₂ was correlated with the changes in P_vaCO₂ during FB in patients with low as well as in patients with high CI before FB (low CI before FB: r = -0.55, p = 0.02, high CI before FB: r = -0.72, p < 0.01) (Fig 3).

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Fig 3. Relationship between baseline P_vaCO₂ and changes in P_vaCO₂ (Δ P_vaCO₂) during fluid bolus.

Panel A: Patients with CI ≤ 2.2 L/min/m²; Panel B: Patients with CI > 2.2 L/min/m². The vertical dotted line corresponds to the baseline P_vaCO₂ 8mmHg. The horizontal dotted line corresponds to Δ P_vaCO₂−2 mmHg.

https://doi.org/10.1371/journal.pone.0257314.g003

Discussion

The results of this study can be summarized as follows: 1) FB can decrease an abnormal high P_vaCO₂ in critically ill patients independently of the before FB CI values, 2) the response of P_vaCO₂ to FB is highly variable, yet low baseline P_vaCO₂ (6 to 8 mmHg) can exclude a positive response.

The clinical implication of the study is that P_vaCO₂ derived from central venous and arterial blood gas analysis can be used in clinical practice for the evaluation of FB response (S5 Fig). ‘P_vaCO₂ responders’ had a significantly higher increase in CI, which confirms that the CI augmentation is implicated in the decrease in P_vaCO₂ during FB. Of note, in theory, FB can cause an increase in P_vaCO₂ due to acute decrease in hemoglobin concentration [23]. The results of our study showed that an increase in P_vaCO₂ is rare after FB. Notwithstanding, given that none of the ‘CI responders’ presented an increase in P_vaCO₂ can be considered as an adverse effect of FB and it can be used as a safety limit for FB in case no CI monitoring is available.

Interestingly, the group of ‘P_vaCO₂ responders’ was not exactly the same as ‘CI responders’: several ‘CI responders’ did not have a decrease in P_vaCO₂, whereas P_vaCO₂ decreases were not always associated with increases in CI >15%. Similar observations were reported by other teams using various measurements related to tissue perfusion [24–26]. Different factors can explain this phenomenon. Increases in CI after FB might not always lead to an improvement in tissue perfusion [27], particularly when CI is not a major contributing factor for microcirculatory abnormalities. Additionally, in patients with high CI changes in P_vaCO₂ are expected to be limited as the relationship between these two variables is curvilinear [28]. Of note, we detected a statistically significant correlation of CI changes with P_vaCO₂ only in the group of patients with low baseline CI. Furthermore, ‘CI responders’ are defined based on relative changes in CI. Accordingly, several patients with increases in CI between 0.4–0.5 L/min/m² were allocated as ‘CI non-responders’. Moreover, evaluation of changes in CI with the method of cardiac echocardiography might not be precise in detecting mild changes [29].

The results of this study add to our knowledge of the optimization of fluid administration in critically ill patients using P_vaCO₂ values. Recognition of the severity of inadequate tissue perfusion based on the levels of P_vaCO₂ can guide the physician to decide fluid administration: a low P_vaCO₂ can be considered as an indication to avoid FB whereas a high level may not always be an indication for FB evaluation of its effects is required. This finding is in line with the results of previous studies, which showed mild microcirculation abnormalities are less likely to be improved after FB [24]. Nevertheless, some patients with high P_vaCO₂ failed to respond to FB, and therefore, the decision for FB administration should not be based only on the P_vaCO₂ levels. Furthermore, whether FB is the more appropriate treatment for the treatment of high P_vaCO₂ levels compared to other interventions aiming to improve tissue perfusion (e.g dobutamine, nitrate) should be further evaluated in future studies.

P_vaCO₂ changes were not found to be correlated to S_cvO₂. The meaning of this finding is dual. First, P_vaCO₂ changes after FB potentially can provide additional information to S_cvO₂. As in other studies, P_vaCO₂ may remain altered when S_cvO₂ is close to normal, so that P_vaCO₂ can be used in addition to S_cvO₂ for evaluating the adequacy of resuscitation in critically ill patients [30–32]. P_vaCO₂ is related to tissue perfusion independently of the presence of tissue hypoxia [3], whereas S_cvO₂ reflects the balance between oxygen delivery and oxygen consumption [33]. In the majority of patients, improvement in tissue perfusion (‘P_vaCO₂ responders’) was associated with an increase in S_cvO₂. However, increases in S_cvO₂ occurred in some ‘P_vaCO₂ non-responders’. As multiple patterns were observed, our study underscores the multiple factors implicated in changes in P_vaCO₂ and S_cvO₂ after FB. Second, the absence of correlation between P_vaCO₂ changes and S_cvO₂ suggests that the Haldane effect has only a minor impact on the changes of P_vaCO₂ during fluid bolus. Given that arterial saturation and PCO₂ did not change in our cohort increases in S_cvO₂ secondary to a positive fluid response could cause an increase in venous partial pressure of CO₂ and consequently an increase in P_vaCO₂ [34].

The strength of this study is that we assessed the effect of FB on P_vaCO₂ in a non-selected critically ill population with abnormal high P_vaCO₂. The high range of the pre-infusion CI permitted the study of P_vaCO₂ changes after FB in a diversity of hemodynamic conditions, whereas no respiratory variations or other interventions can explain these changes. Nevertheless, this study has several limitations. First, we assessed only acute changes in P_vaCO₂ so that we cannot ensure that these beneficial effects were maintained. However, evaluation of P_vaCO₂ over several hours might be challenging as metabolic changes can also occur, especially in non-sedated patients, in addition to other cardiovascular events. Second, metabolic changes independent of FB may have occurred. However, major spontaneous metabolic changes are not expected to occur during the short observational period of the study. Third, only central venous and not mixed venous-to-arterial carbon dioxide tension differences were evaluated. Fourth, we did not investigate thoroughly the effects of other therapeutic interventions (e.g. mechanical ventilation, inotropes) on P_vaCO₂ as well as its changes during FB.

Conclusions

Abnormal high P_vaCO₂ can be decreased with FB independently of the levels of the pre-infusion CI. A decrease in P_vaCO₂ after FB is unlikely in patients with pre-infusion P_vaCO₂ below 7.7 mmHg. Increases in P_vaCO₂ can be considered as an indication of negative response to FB. Decreases in P_vaCO₂can be considered a positive response to FB, even though they might not always be associated with relative increases in CI >15%. Changes in CI can only partially explain decreases in P_vaCO₂. P_vaCO₂ and S_cvO₂ provide complementary information for the effects of FB on tissue perfusion.

Supporting information

S1 Fig. Flowchart of patients selection.

https://doi.org/10.1371/journal.pone.0257314.s001

(PDF)

S2 Fig. Relationship between changes in P_vaCO₂ (Δ P_vaCO₂) during fluid bolus and absolute changes in velocity time integral (Δ VTI).

Panel A: Patients with CI ≤ 2.2 L/min/m2; Panel B: Patients with CI > 2.2 L/min/m2. d VTI: relative to baseline values changes in VTI. Horizontal dotted line corresponds to Δ P_vaCO₂−2 mmHg.

https://doi.org/10.1371/journal.pone.0257314.s002

(PDF)

S3 Fig. Relationship between changes in central venous oxygen saturation (ScvO2) during fluid bolus and absolute changes in P_vaCO₂ (Δ P_vaCO₂).

Panel A: Patients with CI ≤ 2.2 L/min/m2; Panel B: Patients with CI > 2.2 L/min/m2. d CI: relative to baseline values changes in CI. Vertical dotted line corresponds to Δ P_vaCO₂−2 mmHg.

https://doi.org/10.1371/journal.pone.0257314.s003

(PDF)

S4 Fig. ROC curve for baseline values of P_vaCO₂ for prediction of P_vaCO₂ decrease during fluid bolus.

https://doi.org/10.1371/journal.pone.0257314.s004

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S5 Fig. Algorithm of interpretation P_vaCO₂ in relation to decision and appreciation of fluid bolus.

https://doi.org/10.1371/journal.pone.0257314.s005

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S1 Table. Characteristics of the patients received fluid bolus (FB) and included in the study.

https://doi.org/10.1371/journal.pone.0257314.s006

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S2 Table. Blood gas analysis derived parameters before and after fluid bolus.

https://doi.org/10.1371/journal.pone.0257314.s007

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S3 Table. Univariate logistic regression analysis with positive P_vaCO₂ decrease > 2mmHg after fluid bolus as the dependent variable.

https://doi.org/10.1371/journal.pone.0257314.s008

(PDF)

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Figures

Abstract

Background

Results

Conclusions

Introduction

Methods

Design and setting

Inclusion and exclusion criteria

Data and sample collections

Diagnostic definitions

Primary outcome

Secondary outcomes

Statistical analysis

Results

Primary outcome

Secondary outcomes

Discussion

Conclusions

Supporting information

S1 Fig. Flowchart of patients selection.

S2 Fig. Relationship between changes in PvaCO2 (Δ PvaCO2) during fluid bolus and absolute changes in velocity time integral (Δ VTI).

S3 Fig. Relationship between changes in central venous oxygen saturation (ScvO2) during fluid bolus and absolute changes in PvaCO2 (Δ PvaCO2).

S4 Fig. ROC curve for baseline values of PvaCO2 for prediction of PvaCO2 decrease during fluid bolus.

S5 Fig. Algorithm of interpretation PvaCO2 in relation to decision and appreciation of fluid bolus.

S1 Table. Characteristics of the patients received fluid bolus (FB) and included in the study.

S2 Table. Blood gas analysis derived parameters before and after fluid bolus.

S3 Table. Univariate logistic regression analysis with positive PvaCO2 decrease > 2mmHg after fluid bolus as the dependent variable.

References

S2 Fig. Relationship between changes in P_vaCO₂ (Δ P_vaCO₂) during fluid bolus and absolute changes in velocity time integral (Δ VTI).

S3 Fig. Relationship between changes in central venous oxygen saturation (ScvO2) during fluid bolus and absolute changes in P_vaCO₂ (Δ P_vaCO₂).

S4 Fig. ROC curve for baseline values of P_vaCO₂ for prediction of P_vaCO₂ decrease during fluid bolus.

S5 Fig. Algorithm of interpretation P_vaCO₂ in relation to decision and appreciation of fluid bolus.

S3 Table. Univariate logistic regression analysis with positive P_vaCO₂ decrease > 2mmHg after fluid bolus as the dependent variable.