Abstract Background The CO2 gap is the difference between mixed venous and arterial CO2, and can be estimated by the difference in partial pressure in CO2 (Pv-aCO2 or ∆PCO2). ∆PCO2 is affected by cardiac output (CO), CO2 production and solubility. The central venous-to-arterial CO2 gap has been proposed as a less invasive surrogate for P(v-a)CO2 and has been investigated as a measure of adequacy of resuscitation, and to guide sepsis management. Nevertheless, the CO2-gap as determinant of CO has never been thoroughly investigated in large cohort of critically ill ICU-patients. This study aims to investigate the relationship between ∆PCO2 and cardiac index (CI) in a retrospective cohort of critically ill patients in a large quaternary cardiothoracic intensive care unit. Methods Over 62 months, pulmonary artery catheter monitored critically ill patients were identified and their case files reviewed in retrospect. Extracorporeal membrane oxygenation (ECMO) patients were excluded. P(v-a)CO2 measurements were defined as mixed venous and arterial pCO2 measurements drawn simultaneously or within maximum 30 minutes together with PA-measurements. Correlation coefficients were calculated between P(v-a)CO2 and CI, serum lactate, mixed venous saturations (SvO2), cardiac power index (CPI), inotropic score (IS), central venous pressure (CVP) and minute expiratory volume (MV)(Table 1). We used receiver operator characteristic (ROC) curves to assess the diagnostic performance of P(v-a)CO2 as a surrogate for CI lower than 2,2L/min/m2. Multivariate linear regression analysis was performed with P(v-a)CO2 as an dependent variable. Results 4414 P(v-a)CO2 measurements were identified from 1526 patients. Median P(v-a)CO2 was 0,86 kPa (0,66-1,1) or 6.45 mmHg (4.95-8.25), and mean CI was 2.7l/min/m2 (2.2-3.2). Correlation coefficients of P(v-a)CO2 with the other variables remained poor (> 0,35). The area under the ROC curve for P(v-a)CO2 as a predictor of CI<2.2l/min/m2 was 0.65, p<0.0001 (Fig. 1B). A value of P(v-a)CO2 > 6.9 mmHg was found to have the highest sensitivity and specificity, with a poor performance of 61.21% sensitivity and 62.73% specificity. Conclusion This large retrospective study in 1526 critically ill cardiac ICU-patients did not demonstrate a strong relationship between P(v-a)CO2 and CI, nor with any other hemodynamic variable found in the ICU patient cohort studied (Table 1). This raises scepticism regarding the efficacy of P(v-a)CO2 as a physiological goal in guiding resuscitation and management of this precarious patient group. Therefore, we argue that the PA-catheter remains the cornerstone in assessing critically ill (cardiothoracic) ICU patients.