# Prognostic Value of Venous-to-Arterial pCO gap During Cardiopulmonary Bypass for Predicting Cardiac Surgery-Associated Kidney Injury: A Bicentric Retrospective Study

T Jeanmougin, X Buzin, A. Mansour, B Duceau, A Carillion, P Dureau, G

Lebreton, Nicolas Nesseler, A Bouglé, Geoffroy Hariri

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T Jeanmougin, X Buzin, A. Mansour, B Duceau, A Carillion, et al.. Prognostic Value of Venous-to-Arterial pCO gap During Cardiopulmonary Bypass for Predicting Cardiac Surgery-Associated Kidney Injury: A Bicentric Retrospective Study. Anaesthesia Critical Care & Pain Medicine, 2025, 45 (2), pp.101639. 10.1016/j.accpm.2025.101639. hal-05341045

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Original Article

# Prognostic value of venous-to-arterial pCO₂ gap during cardiopulmonary bypass for predicting cardiac surgery-associated kidney injury: A bicentric retrospective study

<figure><img src="image_3.png" /></figure>

T. Jeanmougin<sup>a</sup>, X. Buzin<sup>b</sup>, A. Mansour<sup>c</sup>, B. Duceau<sup>a</sup>, A. Carillion<sup>a,d,e</sup>, P. Dureau<sup>a</sup>, G. Lebreton<sup>d,e</sup>, N. Nesseler<sup>f,g,h</sup>, A. Bouglé<sup>a</sup>, G. Hariri<sup>a,*</sup>

ARTICLE INFO

Article history:

Available online 4 October

Keywords:

Cardiopulmonary bypass

Venous-to-arterial pCO₂ difference

Postoperative complications

Cardiac surgery

Acute kidney injury

ABSTRACT

**Background:** Cardiac surgery-associated acute kidney injury (CSA-AKI) is one of the most frequent and severe complications after cardiac surgery. The association between acute kidney injury and the mismatch between oxygen consumption and delivery has been well established during cardiopulmonary bypass (CPB). In this study, we aim to explore the prognostic value of the central venous-to-arterial pCO₂ gap during CPB to predict CSA-AKI.

**Methods:** Bicentric retrospective study conducted in two teaching hospitals. All patients who underwent cardiac surgery requiring CPB in two periods between 2019 and 2023 were screened for inclusion. Patients were divided into 2 groups according to the presence or absence of an elevated pCO₂ gap during CPB, which was defined as greater than 6 mmHg. The primary outcome was the occurrence of CSA-AKI.

**Results:** Among 318 patients included, 213 were in the low pCO₂ gap group and 105 in the elevated pCO₂ gap group. No significant difference in CSA-AKI occurrence was found between groups (32.4% vs. 23.8%; *p* = 0.14). pCO₂ gap was not a good predictor of CSA-AKI, with an area under the curve for the ROC curve of 0.63 (*p* = 0.87). Except for SVO₂ during CPB, we did not find any correlation between pCO₂ gap and other tissue perfusion parameters during or after CPB.

**Conclusion:** We did not find any association between the presence of an elevated pCO₂ gap during CPB and the occurrence of CSA-AKI. This may suggest that a single intraoperative measurement of pCO₂ gap is not a reliable marker of persistent tissue hypoperfusion in this context.

© 2025 The Author(s). Published by Elsevier Masson SAS on behalf of Société Française d'Anesthésie et de Réanimation (SFAR). This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Introduction

Cardiac surgery-associated acute kidney injury (CSA-AKI) is one of the most frequent complications after cardiac surgery, occurring in 15–40% of cases [1]. CSA-AKI is a severe complication associated with increased mortality, hospital length of stay, and the development of chronic kidney disease (CKD) [2,3]. The association between acute kidney injury (AKI) and the mismatch between oxygen consumption (VO₂) and delivery (DO₂) has been well established in cardiac surgery [4,5]. During cardiopulmonary

Abbreviations: CSA-AKI, Cardiac Surgery Associated Acute Kidney Injury; VO₂, Consumption of Oxygen; DO₂, Delivery of Oxygen; AKI, Acute Kidney Injury; CPB, Cardio Pulmonary Bypass; CABG, Coronary Artery Bypass Grafting; GDP, Goal Directed Perfusion; SOFA, Sepsis-related Organ Failure; ICU, Intensive Care Unit; BMI, Body Mass Index; ASA, American Society of Anesthesiologists; LVEF, Left Ventricular Ejection Fraction; ARDS, Acute Respiratory Distress Syndrome; VA-ECMO, Veno-Arterial Extra Corporeal Membrane Oxygenation; LVAD, Left Ventricular Assist Device; RRT, Renal Replacement Therapy.

<footnote><sup>a</sup>Sorbonne Université, GRC 29, Groupe de Recherche Clinique en Anesthésie Réanimation Médecine Périopératoire, ARPE, F-75012 Paris, France</footnote>

<footnote><sup>b</sup>Univ Rennes, CHU Rennes, Department of Anesthesia and Critical Care, F-35000 Rennes, France</footnote>

<footnote><sup>c</sup>Univ Rennes, CHU Rennes, Inserm, Irset - UMR_S 1085, Department of Anesthesia and Critical Care, F-35000 Rennes, France</footnote>

<footnote><sup>d</sup>Sorbonne Université, Inserm, UMR_S 1166-ICAN, Institut de Cardiometabolisme et Nutrition (ICAN), Paris, France</footnote>

<footnote><sup>e</sup>Cardiothoracic Surgery Department, Assistance Publique-Hôpitaux de Paris, Pitié-Salpêtrière Hospital, F-75013 Paris, France</footnote>

<footnote><sup>f</sup>Department of Anesthesia and Critical Care, Pontchaillou, University Hospital of Rennes, Rennes, France</footnote>

<footnote><sup>g</sup>University of Rennes, CHU Rennes, Inserm, CIC 1414 (Centre d'Investigation Clinique de Rennes), Rennes, France</footnote>

<footnote><sup>h</sup>University of Rennes, CHU de Rennes, Inra, Inserm, Institut NUMECAN - UMR_A 1341, UMR_S 1241, Rennes, France</footnote>

<footnote>* Corresponding author.</footnote>

<footnote>E-mail address: geoffroy.hariri@aphp.fr (G. Hariri).</footnote>
bypass (CPB), impaired tissue perfusion is a critical factor contributing to this mismatch and is extensively involved in the development of CSA-AKI [6]. Consequently, studies have demonstrated that achieving optimal tissue perfusion significantly improves patient outcomes [7,8]. Therefore, optimizing tissue perfusion and oxygen delivery is a critical challenge during CPB. Inadequate blood flow relative to CO₂ production leads to an increase in venous pCO₂, and the central venous-to-arterial pCO₂ gap is a widely recognized marker of tissue perfusion in the critical care setting [9]. Commonly referred to as the "pCO₂ gap", this parameter measures the difference between venous and arterial partial pressure of CO₂ and has proven effective as a complementary tool in identifying patients with sub-optimized hemodynamics [10,11]. Beyond tissue perfusion, the pCO₂ gap also integrates the complex interplay between CO₂ content, cardiac output, and oxygen delivery and consumption [12]. In the context of cardiac surgery, the pCO₂ gap may be of interest as a valuable tool for optimizing hemodynamic parameters. However, studies investigating the use of the pCO₂ gap in this setting have yielded inconsistent results. In 2020, Kanzariya H et al. reported a significant association between pCO₂ gap and indicators of hypoperfusion in patients after off-pump coronary artery bypass grafting surgery (CABG) [13]. Similarly, in 2019, Moussa et al. found that a higher pCO₂ gap measured two hours after a cardiac surgery with cardiopulmonary bypass was significantly associated with the occurrence of major post-operative complications [14]. But in contrast, several recent studies have failed to establish any significant correlation between the pCO₂ gap and clinical outcomes such as mortality, SOFA score, or length of Intensive Care Unit (ICU) stay [15-17].

However, all these studies have solely focused on pCO₂ gap levels after surgery, and none have assessed the usefulness of pCO₂ gap during CPB. We hypothesized that the pCO₂ gap could be a marker of tissue hypoperfusion during CPB and, therefore, could be associated with the occurrence of postoperative complications, especially CSA-AKI. The study aimed to explore the use of pCO₂ gap during CPB and to evaluate its association with the occurrence of CSA-AKI during the first 7 postoperative days.

## Methods

### Study subjects

We conducted a bicentric retrospective study with two inclusion periods. The first phase was conducted at the French Teaching Hospital of Rennes, where we retrospectively included all consecutive adult patients who underwent cardiac surgery requiring CPB between March 1 and October 30, 2019, provided that pCO₂ gap data during CPB were available. The study was later extended to the Teaching Hospital of La Pitié-Salpêtrière in Paris, following the same retrospective design. All consecutive adult patients who underwent cardiac surgery at this hospital between February 28 and April 7, 2023, were included. Patients without available pCO₂ gap measurement during CPB, as well as those undergoing cardiac transplantation or implantation of a long-term mechanical circulatory support device, were excluded.

### Ethics approval

This study was approved by the ethical committee of the French Society of Anesthesia and Intensive Care (IRB 00010254 - 2024 - 094) and registered at [ClinicalTrials.gov](http://ClinicalTrials.gov) (ID NCT06710275). In accordance with actual recommendations, as this retrospective observational study did not modify existing diagnostic or therapeutic strategies, written consent was not required. The

manuscript was drafted in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology checklist for cohort study [18].

### Patient management

As recommended for cardiac surgery, a central venous catheter and an arterial line were placed before starting the surgery. No specific hemodynamics protocol was used, and anesthesia, surgical procedure, and post-operative care were performed in accordance with local standards and international guidelines. Briefly, mean arterial pressure was maintained between 50 and 80 mmHg during CPB, and between 65 and 80 mmHg otherwise. Vasopressors were used when required. Unfractionated heparin was administered to achieve an Activated Clotting Time over 400 ms. During CPB, pump flow was adjusted following a Goal-Directed Perfusion (GDP) strategy, guided by the continuous monitoring of DO₂. Adjustment in pump blood flow and hematocrit was made if necessary to reach and maintain a DO₂ value above 270 mL/min/m² [19]. Red blood cell transfusion was only performed if the hematocrit dropped below a critical value (ranging from 21% to 24% depending on the patient's comorbidities), and was associated with low DO₂. For most cases, CPB was performed under normothermic conditions, but at the discretion of the attending physician, it could also be conducted under moderate hypothermic conditions, targeting a temperature above 34 °C. Concerning the ventilation settings, ultra-protective ventilation was used during CPB. This included a very low tidal volume, a low respiratory rate, and maintenance of PEEP. Venous and arterial blood gases during the CPB were performed at the discretion of the medical team in charge of the patient. All patients were admitted to a post-cardiac surgery intensive care unit [20].

### Data collection

For all patients who underwent cardiac surgery at both institutions, multiple preoperative, intraoperative, and postoperative variables were recorded from the medical records. Subsequently, using a standardized data collection form, we retrospectively extracted additional data, including the pCO₂ gap during CPB, along with the following variables:

- Baseline characteristics: age, body mass index (BMI), sex, ASA score, EUROSCORE II, pre-operative Left Ventricular Ejection Fraction (LVEF)

- Surgery details: type of surgery, CPB, aortic cross-clamp time, and transfusion requirements.

- Hemodynamics intra-operative parameters: need, type, and maximum dose of catecholamines, fluid administration, arterial blood lactate, and hemoglobin level

- Postoperative outcomes: incidence of CSA-AKI, maximum dose of catecholamines, duration of catecholamines, duration of mechanical ventilation, Acute Respiratory Distress Syndrome (ARDS), atrial fibrillation, stroke, need for Renal Replacement Therapy (RRT), need for Veno-Arterial ExtraCorporeal Membrane Oxygenation (VA-ECMO), length of ICU and hospital stay, mortality within the first 28 days.

All biologic parameters during CPB were measured on arterial and central venous blood gas with an automated analyser.

### Outcomes & definitions

The primary outcome was the occurrence of CSA-AKI, as defined in the KDIGO guidelines, within the first seven days, considering all patients with KDIGO stage ≥1 [21].
Secondary outcomes included other post-operative complications within the first seven days: occurrence of atrial fibrillation, defined as the absence of discernible and regular P waves, with irregular activation of the ventricles; occurrence of stroke confirmed by brain imaging; occurrence of mild ARDS, defined as PaO₂/FiO₂ ratio < 200 under mechanical ventilation; onset of severe AKI requiring RRT; need for VA-ECMO implantation and occurrence of cardiac arrest. Additionally, the length of stay in ICU, in hospital, and the mortality rate within the first 28 days were also assessed as secondary outcomes.

pCO₂ gap was calculated as $PvCO₂-PaCO₂$, using the first set of arterial and venous blood gas measurements obtained after the initiation of CPB, most commonly at the time of calibration and verification of CPB parameters, and was defined as elevated when greater than six mmHg [10].

## Statistical analysis

A descriptive analysis was first performed, with quantitative data presented as mean (± standard deviation) or median [interquartile range], and qualitative data as absolute value (%).

In a secondary phase, patients were divided into a low and a high pCO₂ gap group. All data were censored on day 28 after surgery. We used the chi-square test, Mann-Whitney U test, or independent t-test, depending on the type and distribution of the variable, to compare groups using two-tailed tests. Variables known to be associated with postoperative AKI, along with those showing a potential association in univariate analysis (*p* < 0.15), were included in a multivariate logistic regression model incorporating the pCO₂ gap during CPB. In addition to the pCO₂ gap, the following variables were entered into the model: age, presence of diabetes, preoperative LVEF, preoperative hemoglobin level, duration of CPB, intraoperative transfusion requirement, use of dobutamine, and the maximum dose of norepinephrine administered during surgery. Multivariate analysis was performed using the Wald test.

Third, to further investigate whether the pCO₂ gap during CPB can serve as a reliable predictor of post-operative AKI, we performed a separate logistic regression analysis using only the pCO₂ gap values during CPB as the explanatory variable to predict AKI. Subsequently, the performance of this model was evaluated by calculating the Area Under the Curve (AUC) of the associated ROC curve.

We also assessed reliability between pCO₂ gap, perfusion parameters (arterial blood lactate, SvO₂), and mean DO₂ during surgery by using Pearson's rank method.

Finally, in a post hoc exploratory analysis, we assessed the association between the ratio of the pCO₂ gap to the arteriovenous oxygen content difference [$C(a-v)O₂$], and the occurrence of CSA-AKI. $C(a-v)O₂$ was calculated using the following formula: $C(a-v)O₂ = (Hb \times SaO₂ \times 1.34 + PaO₂ \times 0.003) - (Hb \times SvO₂ \times 1.34 + PvO₂ \times 0.003)$.

Python (v.3.11.4) was used for statistical analysis, and no imputation was made for missing data. We consider *p*-value < 0.05 for significance.

## Results

### Baseline patient characteristics

A total of 876 patients underwent cardiac surgery during the study inclusion period. Among them, pCO₂ gap data during CPB were unavailable for 550 patients, and 8 patients underwent cardiac transplantation or left ventricular assist device (LVAD) implantation. Consequently, 318 patients were included in the

final analysis (Supplementary Fig. 1). Median age was 67 [59-73] years, with 73.2% of them being male (n = 233). Nearly half of patients (n = 187, 58%) presented comorbidities, the most frequent being arterial hypertension (n = 160, 50.3%), followed by ischemic cardiomyopathy (n = 125, 39%). The surgical procedures consisted of valve replacement or repair in 29.2% (n = 93), coronary artery bypass grafting (CABG) in 25.8% (n = 82), intervention on the ascending aorta in 14.8% (n = 47), and combined procedure in 30.2% (n = 96). Median time of CPB was 115 min [94-148] and median time of aortic cross-clamp was 91 min [75-116]. Catecholamines were used during surgery in 278 (87.4%) patients, mostly norepinephrine (n = 271, 85.2%) and dobutamine (n = 80, 25.2%). Median maximum dose of catecholamines during intervention was respectively 0.13 [0.05-0.25] and 5 [3.8-8] µg/kg/min for norepinephrine and dobutamine (Table 1). For all patients, the median pCO₂ gap during CPB was 5.3 [4.2-6.3]. As shown in Supplementary Table 1, some baseline characteristics and perioperative variables differed between the two centers, reflecting the heterogeneity of the two recruitment periods and settings.

### Association between pCO₂ gap and CSA-AKI

A total of 213 patients with a pCO₂ gap lower than six mmHg were included in the low pCO₂ gap group; the remaining 105 patients constituted the elevated pCO₂ gap group. The incidence of CSA-AKI was lower in the elevated pCO₂ gap group, although the difference was not statistically significant (-8.4%, 95% CI [-18.4 to 1.7], *p* = 0.14). (Table 2). Most CSA-AKI cases were classified as stage 1 according to the KDIGO classification (n = 65/84, 77.3%). In the same way, we did not find any association between the incidence of CSA-AKI and the pCO₂ gap level during CPB. The distribution of the pCO₂ gap level according to the occurrence of CSA-AKI is presented in Fig. 1. Subgroup analyses restricted to CABG and valve procedures (due to the small number of other surgeries) showed no difference in CSA-AKI incidence. Finally, we found that a logistic regression model based on pCO₂ gap during CPB to predict the occurrence of CSA-AKI within the first seven postoperative days showed poor performance, with an AUC for the ROC curve of 0.63 (95% CI: [0.46-0.79], *p* = 0.87) (Fig. 2).

### Association between pCO₂ gap and other post-operative complications

Other postoperative complications, including the occurrence of stroke, ARDS, and the need for RRT or VA ECMO, did not differ between the two groups. The length of ICU stay was one day longer in the low pCO₂ gap group (4.0 [3.0-6.0] vs. 3.0 [2.0-6.0] days; *p* = 0.04), but without a significant difference in the duration of mechanical ventilation, catecholamine support, or overall hospital stay (Table 2). Apart from the SvO₂ value during CPB, significantly higher in the low pCO₂ gap group (81.7 vs. 79.2%, *p* < 0.01), no differences were found in other hemodynamic parameters during or after CPB (Table 3). In our multivariate analysis, age, preoperative LVEF, preoperative hemoglobin level, CPB duration, and the maximum dose of norepinephrine during CPB were significantly associated with the occurrence of CSA-AKI, whereas the presence of an elevated pCO₂ gap was not (S. Table 2).

### pCO₂ gap, variation, and relation with other parameters

We found a weak correlation between pCO₂ gap and SvO₂ during CPB (Pearson correlation coefficient -0.19 [-0.29 to -0.08], *p* < 0.01), but no correlation with other parameters such as arterial blood lactate level during or after CPB (-0.01 [-0.12 to 0.10]) and (-0.03 [-0.14 to 0.09]), arterial pump flow during CPB (0.06 [-0.05 to 0.17]) or DO₂ during CPB (0.09 [-0.08 to 0.26]) (Fig. 3). In a
<table><caption>**Table 1**
Baseline characteristics.</caption><thead><tr><th></th><th>Total (n = 318)</th><th>Low pCO<sub>2</sub> gap group (n = 213)</th><th>Elevated pCO<sub>2</sub> gap group (n = 105)</th><th>p</th></tr></thead><tbody><tr><td>Pre-operative characteristics</td><td></td><td></td><td></td><td></td></tr><tr><td>Men</td><td>233 (73.2)</td><td>145 (68.1)</td><td>88 (83.8)</td><td><strong>&lt;0.01</strong></td></tr><tr><td>Age, years</td><td>67 [59.25-73]</td><td>68 [59-74]</td><td>67 [60-72]</td><td>0.45</td></tr><tr><td>BMI, kg/m<sup>2</sup></td><td>26 [24-29]</td><td>26 [24-30]</td><td>26 [23-29]</td><td>0.58</td></tr><tr><td>Medical history</td><td></td><td></td><td></td><td></td></tr><tr><td>- Diabetes mellitus</td><td>61 (19)</td><td>38 (18)</td><td>23 (21)</td><td>0.47</td></tr><tr><td>- Coronary artery disease</td><td>125 (39)</td><td>75 (35)</td><td>50 (48)</td><td>0.04</td></tr><tr><td>- Arterial hypertension</td><td>160 (50)</td><td>106 (49)</td><td>54 (51)</td><td>0.96</td></tr><tr><td>- Chronic kidney disease</td><td>34 (10)</td><td>21 (9)</td><td>13 (12)</td><td>0.65</td></tr><tr><td>Pre-operative LVEF, %</td><td>60 [55-65]</td><td>60 [55-65]</td><td>60 [55-65]</td><td>0.97</td></tr><tr><td>Pre-operative LVEF &lt; 45%</td><td>31 (9.7)</td><td>20 (9.3)</td><td>11 (10.5)</td><td>0.96</td></tr><tr><td>Euroscore II</td><td>1.6 [0.94-3.2]</td><td>1.7 [0.93-3.2]</td><td>1.37 [0.96-2.5]</td><td>0.16</td></tr><tr><td>Per operative characteristics</td><td></td><td></td><td></td><td></td></tr><tr><td>Surgery</td><td></td><td></td><td></td><td></td></tr><tr><td>- Valvular</td><td>93 (29.2)</td><td>66 (31)</td><td>27 (25.7)</td><td>0.40</td></tr><tr><td>- CABG</td><td>82 (25.8)</td><td>48 (22.5)</td><td>34 (32.3)</td><td>0.07</td></tr><tr><td>- Aortic</td><td>47 (14.8)</td><td>33 (15.5)</td><td>14 (13.3)</td><td>0.73</td></tr><tr><td>- Multiple</td><td>96 (30.2)</td><td>66 (30.9)</td><td>30 (28.6)</td><td>0.75</td></tr><tr><td>CPB time, minutes</td><td>115 [94-148]</td><td>117 [94-151]</td><td>112 [95-148]</td><td>0.56</td></tr><tr><td>ACC time, minutes</td><td>91 [75-116]</td><td>91 [76-113]</td><td>89.5 [75-116]</td><td>0.96</td></tr><tr><td>Catecholamines support</td><td></td><td></td><td></td><td></td></tr><tr><td>- Norepinephrine</td><td>271(85)</td><td>181 (85)</td><td>90 (85.7)</td><td>0.99</td></tr><tr><td>- Dobutamine</td><td>80 (25)</td><td>60 (28.1)</td><td>20 (19)</td><td>0.11</td></tr><tr><td>Catecholamines maximum dose, µg/kg/min</td><td></td><td></td><td></td><td></td></tr><tr><td>- Norepinephrine</td><td>0.13 [0.05 - 0.25]</td><td>0.12 [0.05-0.25]</td><td>0.12 [0.05-0.26]</td><td>0.82</td></tr><tr><td>- Dobutamine</td><td>5 [3.8-8]</td><td>5 [3.9-8.1]</td><td>5 [4.4-6.4]</td><td>0.37</td></tr><tr><td>Transfusion</td><td>119 (37.4)</td><td>84 (39.4)</td><td>35 (33.3)</td><td>0.30</td></tr></tbody></table>

Data are presented as median and interquartile range [IQR] or number and percentages (%) according to type of variable. ACC: Aortic Cross Clamp Time BMI: Body Mass Index, LVEF: Left Ventricular Ejection Fraction, CABG: Coronary Artery Bypass Graft, CPB: Cardio Pulmonary Bypass.
Bold text indicates a significant p value.

multivariate linear regression model, the pCO₂ gap was influenced by hemoglobin level, SvO₂, and the arterial oxygen content (S. Fig. 2). During CPB, the pCO₂ gap/C(a-v)O₂ ratio was significantly lower in the low pCO₂ gap group (1.8 [1.3-2.4]) compared to the high pCO₂ gap group (2.7 [2.2-3.5]; *p* < 0.001). However, this ratio was not significantly different between patients who developed CSA-AKI (1.9 [1.4-3.0]) and those who did not (2.2 [1.5-2.8]; *p* = 0.17). The ratio also failed to reliably predict the occurrence of CSA-AKI, with an AUC of 0.45 (95% CI: [0.37-0.53]).

pCO₂ gap measurement after surgery, measured upon arrival in the intensive care unit, was available in 59 patients. pCO₂ gap decreased compared to CPB for 25 patients (42%) and increased for the remaining 34 patients (58%). Incidence of CSA-AKI was not different in patients who decreased their pCO₂ gap compared to those who increased their pCO₂ gap (n = 12/25, 50% vs. n = 16/34, 47%; *p* = 1).

Discussion

We conducted a bicentric retrospective study to explore the relationship between the presence of an elevated pCO₂ gap during CPB and the occurrence of CSA-AKI. Our study did not find an association between elevated pCO₂ gap levels during CPB and the incidence of CSA-AKI. Furthermore, a pCO₂ gap greater than six

mmHg did not appear to correlate with other postoperative complications such as atrial fibrillation, need for RRT, VA-ECMO, or mortality. In complementary analysis, we found that the pCO₂ gap during CPB was not correlated with other usual hemodynamic parameters, and that the variation in pCO₂ gap from CPB to the post-operative period did not appear to be associated with the incidence of CSA-AKI.

In contrast to Kanzariya *et al.* [13], we found no variation in the duration of mechanical ventilation according to pCO₂ gap levels, while ICU stay was longer in the low pCO₂ gap group. In this study involving 100 patients after off-pump CABG, the authors defined a high pCO₂ gap as greater than 8 mmHg. In contrast, we selected a threshold of 6 mmHg, based on previous findings identifying this cutoff as optimal for detecting patients at risk of complications following high-risk surgery [10], and on the assumption that arterial blood flow is tightly controlled during CPB, which supports the expectation of lower pCO₂ gap levels. Other recent studies have explored the use of the pCO₂ gap in cardiac surgery [15-17]. Despite differences in study design – where they categorized patients based on the occurrence of complications, while we based ours on the presence of an elevated pCO₂ gap – their findings were similar to ours, showing no significant difference in pCO₂ gap between groups. However, their focus was on the pCO₂ gap after the surgery, while we focused on the pCO₂ gap during CPB, which can explain the difference in mean pCO₂ gap observed in our study
<table><caption>**Table 2**
Postoperative outcomes.</caption><thead><tr><th></th><th>Low pCO<sub>2</sub> gap group (n = 213)</th><th>Elevated pCO<sub>2</sub> gap group (n = 105)</th><th>p</th></tr></thead><tbody><tr><td>AKI</td><td>69 (32.4)</td><td>25 (23.8)</td><td>0.14</td></tr><tr><td>– KDIGO1</td><td>48 (22.5)</td><td>17 (16.1)</td><td>0.33</td></tr><tr><td>– KDIGO2</td><td>9 (4.2)</td><td>3 (2.9)</td><td>0.77</td></tr><tr><td>– KDIGO3</td><td>12 (5.6)</td><td>5 (4.7)</td><td>0.95</td></tr><tr><td>Need for RRT</td><td>7 (3.3)</td><td>5 (4.8)</td><td>0.76</td></tr><tr><td>AF</td><td>54 (26.3)</td><td>32 (31)</td><td>0.46</td></tr><tr><td>Stroke</td><td>9 (4.4)</td><td>5 (4.8)</td><td>1.00</td></tr><tr><td>ARDS</td><td>8 (3.7)</td><td>2 (1.9)</td><td>0.59</td></tr><tr><td>Cardiac arrest</td><td>9 (4.3)</td><td>3 (2.9)</td><td>0.86</td></tr><tr><td>Postoperative VA-ECMO</td><td>8 (3.8)</td><td>2 (1.9)</td><td>0.57</td></tr><tr><td>Length of catecholamine support, days</td><td>1.0 [1.0–2.0]</td><td>1.0 [1.0–2.0]</td><td>0.49</td></tr><tr><td>Catecholamines maximum dose, µg/kg/min</td><td></td><td></td><td></td></tr><tr><td>– Norepinephrine</td><td>0.07 [0.0–0.16]</td><td>0.08 [0.02–0.12]</td><td>0.89</td></tr><tr><td>– Dobutamine</td><td>5.6 [4.5–9.4]</td><td>5.0 [5.0–6.63]</td><td>0.21</td></tr><tr><td>Length of MV duration, days</td><td>1.0 [1.0–1.0]</td><td>1.0 [1.0–1.0]</td><td>0.20</td></tr><tr><td>Length of ICU stay, days</td><td>4.0 [3.0–6.0]</td><td>3 [2.0–6.0]</td><td>0.04</td></tr><tr><td>Length of hospital stay, days</td><td>10.0 [8.0–15.0]</td><td>9.0 [8.0–14.0]</td><td>0.12</td></tr><tr><td>Death</td><td>8 (3.8)</td><td>3 (2.8)</td><td>0.93</td></tr></tbody></table>

<figure><img src="image_4.png" /><figcaption>**Fig. 1.** CSA-AKI incidence according to the level of pCO₂ gap during CPB.
Legend: AKI: Acute Kidney Injury. CPB: Cardio-Pulmonary Bypass. KDIGO: Kidney Disease: Improving Global Outcomes.</figcaption></figure>

(5 mmHg) compared to theirs (8 mmHg). Additionally, while they investigated overall complications, we specifically focused on CSA-AKI. We made this choice firstly to limit misclassification bias and secondly because of the significant role of microcirculatory alterations in the development of AKI [22,23], especially following cardiac surgery [1,24], and even when systemic hemodynamics are adequately managed [25,26].

Our hypothesis was that an elevated pCO₂ gap would reflect impaired tissue perfusion [27] and therefore be associated with CSA-AKI. Several factors may explain the negative results observed in our study. First, it is important to acknowledge that CSA-AKI likely results from a multifactorial process involving several mechanisms beyond impaired tissue perfusion. Among these, mechanical stress, leading to hemolysis, may play a significant role. Hemolysis is linked to CPB blood flow and is implicated in the

development of CSA-AKI [28]. As a higher pump flow may increase hemolysis and simultaneously decrease pCO₂ gap, this could explain the trend towards a higher incidence of CSA-AKI and a longer ICU stay in the low pCO₂ gap group. Although pump flow was similar between groups, this does not imply that it was optimal for every patient, as individual perfusion needs may vary. These highlight the importance of a more personalized, patient-tailored CPB management strategy rather than relying solely on standardized flow targets.

Second, a significant heterogeneity in organ perfusion may exist during CPB, particularly with respect to renal perfusion [29]. As suggested by Horsdal *et al.* [30], the pCO₂ gap may not be sensitive enough to detect such regional alterations in tissue perfusion.

Third, the pCO₂ gap may not be a reliable marker of impaired tissue perfusion during CPB. Physiologically, the relationship
<figure><img src="image_5.png" /><figcaption>**Fig. 2.** ROC Curve of the pCO₂ gap model as a tool for predicting the occurrence of CSA-AKI.</figcaption></figure>

<table><caption>**Table 3**

Hemodynamics parameters during and after CPB.</caption><thead><tr><th></th><th>Low pCO<sub>2</sub> gap group (n = 213)</th><th>Elevated pCO<sub>2</sub> gap group (n = 105)</th><th>p</th></tr></thead><tbody><tr><td>Parameters during CPB</td><td></td><td></td><td></td></tr><tr><td>pCO<sub>2</sub> gap, mmHg</td><td>4.6 [3.6–5.3]</td><td>6.9 [6.3–8]</td><td>&lt;0.01</td></tr><tr><td>Arterial lactate, mmol/L</td><td>1.2 [1–1.6]</td><td>1.3 [1–1.6]</td><td>0.82</td></tr><tr><td>SvO<sub>2</sub>, %</td><td>81.7 [77–84.6]</td><td>79.2 [74.3–83]</td><td>&lt;0.01</td></tr><tr><td>CPB pump flow, L/min,</td><td>4.8 [4.3–5.2]</td><td>4.8 [4.4–5.2]</td><td>0.25</td></tr><tr><td>DO<sub>2</sub>, mL/min/m<sup>2</sup></td><td>390 [350–428]</td><td>380 [352–422]</td><td>0.59</td></tr><tr><td>Parameters after CPB</td><td></td><td></td><td></td></tr><tr><td>pCO<sub>2</sub> gap, mmHg</td><td>7.1 [4.5–8.9]</td><td>8.9 [6.7–9.6]</td><td>0.16</td></tr><tr><td>Arterial lactate, mmol/L</td><td>1.5 [1.2–2.2]</td><td>1.6 [1.2–2.2]</td><td>0.53</td></tr><tr><td>SvO<sub>2</sub>, %</td><td>68.3 [60.5–76.6]</td><td>71 [61.4–75.2]</td><td>0.94</td></tr></tbody></table>

Data are presented as median and interquartile range [IQR]. SvO₂: venous saturation in oxygen, CPB: Cardio Pulmonary Bypass. Bold text indicates a significant p value.

<figure><img src="image_6.png" /><figcaption>**Fig. 3.** Correlation between DO₂ and pCO₂ gap (a.), SvO₂ and pCO₂ gap (b.) and arterial blood flow and pCO₂ gap (c.) during CPB.
Legend: DO₂: Oxygen delivery. SvO₂: venous oxygen saturation. CPB: Cardio-Pulmonary Bypass. AKI: Acute Kidney Injury.</figcaption></figure>

between the pCO₂ gap and cardiac output relies on two main mechanisms: first, low blood flow leads to CO₂ stagnation in the tissues, and second, a reduced cardiac output promotes anaerobic metabolism, generating hydrogen ions that are buffered by intracellular bicarbonate, thereby increasing CO₂ production. This relationship can be described by the Fick equation, where total CO₂ production (VCO₂) is linked to cardiac output (CO) and the

arteriovenous difference in CO₂ content (CvCO₂ – CaCO₂) [VCO₂ = CO × (CvCO₂ – CaCO₂)]. Under normal physiological conditions, the relationship between CO₂ content (CCO₂) and pCO₂ is approximately linear and can be expressed using a proportionality constant k [pCO₂ = k × CCO₂]. Based on this assumption, the pCO₂ gap can be approximated as pCO₂ gap = VCO₂/CO. However, during CPB, several factors can modify the value of k, including
anemia, changes in temperature, or alterations in base excess [27]. Moreover, the Haldane effect implies that oxygen saturation influences the CO2-CCO2 relationship, adding another layer of complexity. In addition, the gas-exchange membranes used during CPB are considerably more efficient at removing CO2 from venous blood than the native lungs [31], which may lower venous CO2 levels independently of tissue perfusion. Taken together, these factors may explain why, in contrast to previous studies conducted in the postoperative setting, we did not observe any correlation between the pCO2 gap measured during CPB and other hemodynamic parameters such as arterial lactate, DO2, or arterial blood flow.

Although the correlation between pCO₂ gap and cardiac output has been well documented in sepsis [32], it has more recently been demonstrated to be a good marker of low cardiac output in other situations such as cardiogenic shock [30,33]. Even in more specific situations, where arterial blood flow is supported by mechanical assistance such as ECMO [34] or Impella [35], it has been shown that an elevated pCO₂ gap is associated with worsened outcomes, which the authors interpret as a consequence of persistent tissular dysoxia. Our findings differ, and several factors may explain this discrepancy. CPB differs from these circulatory support devices in several ways: it simultaneously provides oxygenation and decarboxylation, whereas Impella does not; the flow rates and patterns are not comparable; both ECMO and Impella maintain some degree of pulsatility, unlike CPB; ECMO delivers retrograde flow; and, finally, CPB is systematically performed under general anesthesia, while ECMO or Impella support may occur in less deeply sedated patients. These physiological and technical differences, as well as the shorter duration of CPB and the higher frequency of AKI in patients requiring ECMO or Impella, may contribute to the different associations observed. Another explanation has been proposed by Bakker et al. [36], who suggested that the pCO₂ gap may be useful primarily in situations where conventional hemodynamic parameters fail to detect tissue hypoperfusion, such as in sepsis, where SvO₂ often remains normal despite ongoing anaerobic metabolism due to impaired tissue oxygen extraction [10,37]. In contrast, during CPB, and as we used a goal-directed perfusion strategy, arterial blood flow was strictly monitored and maintained, making it unlikely that patients experienced significant hypoperfusion. As no studies have yet demonstrated that the relationship between pCO₂ gap and blood flow persists at higher flow rates, this could further explain our negative findings. Moreover, if the pCO₂ gap did not seem to correlate with arterial blood flow during CPB, some authors have suggested pCO₂ gap could also reflect tissue hypoxia. This assumption is still debated, and, for instance, Vallet et al. [27] showed that the pCO₂ gap did not increase in situations of hypoxia when cardiac output was maintained and oxygen delivery was artificially reduced in a porcine model. Interestingly, in our study, the pCO₂ gap showed a weak correlation with SvO₂, prompting us to perform a post hoc analysis using the pCO₂ gap/C(a-v)O₂ ratio. This ratio has been shown to be a more sensitive indicator of anaerobic metabolism and tissue hypoxia and may provide additional insight into tissue perfusion status during CPB [38]. Although this ratio has shown significant associations with outcomes in conditions such as sepsis [39,40] and cardiogenic shock [41], our findings suggest that in the specific context of CPB, it offers no stronger association with postoperative outcomes than the pCO₂ gap alone.

Our study has several limitations. First, besides the retrospective design of our study, patients included were from only two centers, which may limit generalizability. Furthermore, although 318 patients were included, a number similar to other studies in this field [13–16], we cannot exclude the possibility that the study lacked sufficient power to detect small differences in the

occurrence of the primary outcome, as reflected by the relatively wide confidence intervals. Second, the pCO₂ gap was measured using central venous blood rather than mixed venous blood, due to the absence of a systematic arterial pulmonary catheter. While the correlation between these two values appears acceptable, it is not perfect, and the pCO₂ gap from central venous blood might have underestimated perfusion from splanchnic circulation [10]. In a similar way, data concerning pH and bicarbonate levels were not collected as part of our initial study protocol and were therefore not available for analysis. These variables could have represented potential confounders, as previously discussed. Third, because of the observational nature of the study, and because repeated measurement of the pCO₂ gap during CPB was not part of routine care, the pCO₂ gap was typically measured only once, usually after the beginning of CPB when venous and arterial blood gases were used to calibrate the GDP monitor. This single measurement may not accurately reflect the evolution of the pCO₂ gap throughout CPB. Finally, as post-operative pCO₂ gap was not routinely collected, we lack these data for all our patients, limiting the power of our secondary analysis. Moreover, postoperative time points might be more relevant, as suggested by Moussa et al., who reported that pCO₂ gap measured two hours after ICU admission was significantly associated with adverse outcomes [14]. Consequently, we cannot exclude the possibility that variations in the pCO₂ gap between the CPB and postoperative periods could be an interesting parameter for predicting complications after cardiac surgery, and this remains to be explored in future studies. Similarly, our study was not designed to assess the use of pCO₂ gap after CPB, therefore we cannot draw conclusions about its postoperative relevance.

We demonstrated that measuring of pCO₂ gap during CPB was feasible. However, the lack of correlation with hemodynamic parameters and the absence of an association with postoperative outcomes, in conjunction with the results of existing literature, suggest that a single intraoperative measurement has limited clinical utility in cardiac surgery. Future studies may consider pCO₂ gap as a time-sensitive parameter and explore its variation rather than relying on a single value.

## Conclusion

In our study, an elevated pCO₂ gap during CPB was not associated with the occurrence of CSA-AKI or postoperative complications. Although future studies incorporating multiple pCO₂ gap measurements during CPB are warranted, the absence of correlation with other tissue perfusion parameters suggests that a single intraoperative measurement of pCO₂ gap is not a reliable marker of persistent tissue hypoperfusion in this context.

## CRediT authorship contribution statement

Study concept and design, all authors. Acquisitions of data, TJ, XB. Drafting of the manuscript, TJ, GH, AB. Critical revision of manuscript, all authors. Statistical analysis, G.H

## Ethics approval

This study was approved by the ethical committee of the French Society of Anesthesia and Intensive Care (IRB 00010254 - 2024 - 094) and registered at [ClinicalTrials.gov](http://ClinicalTrials.gov) (ID NCT06710275).

## Funding

None.
## Availability of data and material

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

## Declaration of competing interest

The authors declare that they have no competing interests

## Acknowledgements

The authors are particularly grateful to T. Richard and V. Pauchet for their substantial contributions to data collection, and to Drs. Hirwe, Bourouchaki, and Campeanu for their contributions to this study.

## Appendix A. Supplementary data

Supplementary material related to this article can be found, in the online version, at doi:https://doi.org/10.1016/j.accpm.2025.101639.

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