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Intensive care and perioperative medicine

Central venous-to-arterial carbon dioxide partial pressure difference in early resuscitation from septic shock

A prospective observational study

Mallat, Jihad; Pepy, Florent; Lemyze, Malcolm; Gasan, Gaëlle; Vangrunderbeeck, Nicolas; Tronchon, Laurent; Vallet, Benoit; Thevenin, Didier

Author Information
European Journal of Anaesthesiology: July 2014 - Volume 31 - Issue 7 - p 371-380
doi: 10.1097/EJA.0000000000000064


This article is accompanied by the following Invited Commentary:

Sheehan A, Columb M. Two goals, one shot at survival: ΔPCO2 and ScvO2. Eur J Anaesthesiol 2014; 31:361–362.


The haemodynamic profile of septic shock is composed of components of hypovolaemic, cardiogenic and distributive shock.1 Aggressive fluid therapy usually results in a hyperdynamic state with a high normal or elevated cardiac output (CO). At the onset of septic shock in unresuscitated patients, there is evidence of low CO with tissue hypoperfusion, which is a crucial factor in the development of multiple organ failure. The mixed venous-to-arterial blood carbon dioxide partial pressure difference () has already been shown to be inversely related to CO in nonseptic2–7 and septic8–10 low flow states. Previous reports8,9 found that patients in septic shock with high (>0.8 kPa) had a lower CO than those with normal . Opposing changes in P[ and cardiac index (CI) during the course of septic shock were observed.9 The major role of low blood flow in the widening of P[ was first demonstrated by Vallet et al.11 using a model of isolated dog hind limb. P[ could serve as an indicator of how venous blood flow was performing in the removal of total CO2 produced by peripheral tissues.12


The measurement of P[ needs the insertion of a pulmonary artery catheter, which is seldom used today. As a central venous catheter is inserted in most patients with septic shock, the use of central venous-arterial carbon dioxide partial pressure difference (ΔPCO2) is considerably simpler and equally useful. Cuschieri et al.13 have shown that P[ can be substituted by ΔPCO2 in critically ill patients. Vallée et al.14 have shown that, in resuscitated septic shock patients in whom central venous saturation (ScvO2) was already greater than 70%, the subgroup with normal ΔPCO2 (≤0.8 kPa) had a higher CO with a lower lactate concentration and a greater lactate decrease than those who presented with an initial ΔPCO2 exceeding 0.8 kPa. In a recent retrospective study, septic shock patients who achieved both normal ScvO2 and ΔPCO2 after resuscitation had a greater lactate decrease than those who achieved only a normal ScvO2.15 The mean baseline of ScvO2 in that study was more than 70%. There are no conclusive reports on the relationship between ΔPCO2 and blood lactate concentrations during the early resuscitation phase of septic shock when normal ScvO2 (≥70%) has not yet been achieved. Therefore, the aim of our study was to examine the behaviour of ΔPCO2 and its relationship to CO, lactate decrease and 28-day mortality during resuscitation in the very early phase of septic shock. We also hypothesised that patients who normalise both their ΔPCO2 and ScvO2 during the early resuscitation period would have a greater lactate decrease than those who achieve only a normal ScvO2.


Materials and methods

Ethical approval for this prospective observational study (Ethical Committee N° 03.03.09-2) was provided by the Ethical Committee (comité d’éthique du centre hospitalier du Dr Shaffner de Lens) of Lens Hospital, Lens, France on 3 March 2009. As no intervention was required and all measurements were part of routine care of septic shock, the requirement for written informed consent was waived, and only oral consent was obtained. If the patient or next of kin refused, the data were not entered into the analysis.

The study was conducted in a single, mixed medical and surgical adult Intensive Care Unit (ICU) with 15 beds. All patients were screened for eligibility, and were included if they met the following criteria:

  1. Presence of septic shock defined by the criteria of the American College of Chest Physicians/ Society of Critical Care Medicine Consensus Conference;16
  2. Mechanically ventilated with tracheal intubation;
  3. Monitored by a transpulmonary thermodilution device (PiCCO; Pulsion Medical System, Munich, Germany) for measurement of CI.

Exclusion criteria were pregnancy, age less than 18 years and irreversible underlying disease such as end-stage neoplasm.

Within 3 h after the diagnosis of septic shock, a 5-Fr arterial catheter (Pulsiocath PV2015L20; Pulsion Medical Systems) was inserted into the descending aorta via the femoral artery using the Seldinger technique. A temperature sensor was connected to the distal port of a standard central venous catheter in either the internal jugular or subclavian vein. The femoral arterial and central venous catheters were connected to pressure transducers and also to an integrated bedside monitor (PiCCO; Pulsion Medical Systems). The time of inclusion in this study (T0) began with the first set of measurements after insertion of the PiCCO device. Patients were resuscitated to achieve the following goals as recommended by the Surviving Sepsis Campaign:17 mean arterial pressure at least 65 mmHg; urine output at least 0.5 ml kg−1 h−1; ScvO2 at least 70%; and normalisation of serum lactate concentration. Our standard septic shock resuscitation protocol is described in the supplemental digital content ( Treatment of septic shock included the eradication of the septic focus with large early doses of empirical antibiotics, and surgery when needed.

Data collection

The severity of disease and organ dysfunction at study entry were quantified using the Acute Physiology and Chronic Health Evaluation (APACHE) II18 and Sequential Organ Failure Assessment (SOFA) scores.19CI was measured with the PiCCO monitor by triplicate central venous injections of 20 ml of iced (<6°C) 0.9 % wt/vol isotonic saline solution and recorded as the average of the three measurements. Blood gas analysis and blood lactate concentration were determined using the GEM Premier 3000 (Instrumentation Laboratory Co., Paris, France). Lactate decrease was defined by the equation: [(lactateT0 − lactateT6)/lactateT0] × 100,20 for which lactate T0 was the measurement at the start of the study and lactate T6 was another measurement performed 6 h after inclusion. ScvO2 was determined in a sample taken from the central venous catheter with the tip confirmed to be in the superior vena cava near or at the right atrium by radiograph. ΔPCO2 was calculated as the difference between central venous carbon dioxide (PcvCO2) and arterial carbon dioxide (PaCO2) pressures. The threshold prognostic value for ΔPCO2 is 0.8 kPa;9,21,22 therefore, we chose ΔPCO2 0.8 kPa as the upper limit of ‘normal’. Oxygen extraction ratio surrogate (O2ER) was calculated by the formula: (SaO2 − ScvO2)/SaO2, where SaO2 is the arterial oxygen saturation. Oxygen delivery (DO2) was calculated using the standard formula.23

Blood lactate concentrations, and haemodynamic and oxygen-derived variables, were recorded at T0 and T6. Treatment received during the first 6 h of the study was also recorded. SOFA score was measured at T0 and 24 h after enrolment (T24). The time between the diagnosis of septic shock and inclusion in the study was recorded. The survival was followed up to 28 days. Patients were separated into several groups according to their ΔPCO2 values (normal, high) at T0 and T6.

Statistical analysis

The primary outcome variable was the difference in lactate decrease between patients who reached a normal ΔPCO2 (≤0.8 kPa) at T6 and those who did not. With a two-sided α of 0.05, a power of 80% and an allocation ratio of sample sizes in patients with normal ΔPCO2 to high ΔPCO2 of 1.5 at T6, a total of 75 patients were required to detect a significant difference of 20% between the means of two groups, with a common standard deviation of 30%.

Data are presented as mean ± SD or median (interquartile range). Proportions were used as descriptive statistics for categorical variables. The normality of data distribution was assessed using the Kolmogorov–Smirnov test. Continuous data that were normally distributed were compared using the two-tailed Student's t-test or, if not, by the Mann–Whitney U-test. Pairwise comparisons between different study times were performed using paired Student's t-test or Wilcoxon test as appropriate. The Bonferroni method was used to adjust for multiple comparisons. One-way analysis of variance was used to determine the overall effect between different subgroups. Analysis of categorical data was performed using the χ2 and Fisher's exact tests. Pearson and Spearman correlation coefficients were estimated. Forward stepwise multivariate logistic regression (entry P < 0.10) was used to identify significant independent predictors of 28-day mortality. Goodness-of-fit of the model was assessed using the Hosmer–Lemeshow test. The potential problem of co-linearity was evaluated before running the analysis. Nonlinear regression was used to determine the best fit curves for CI, ΔPCO2 and ScvO2. Statistical analyses were performed using Statistical Package for Social Sciences (SPSS for Windows release 17.0, Chicago, Illinois, USA) and Prism 5 for Windows (GraphPad Prism 5.00, San Diego, California, USA). P < 0.05 (two-sided) was considered statistically significant.


From April 2009 to December 2011, 1200 patients were admitted to the ICU and 88 of these met the criteria for septic shock. Eight of these met the predetermined exclusion criteria (five patients had contraindications to femoral arterial catheterisation, and the three others had end-stage neoplasm). Eighty patients were, therefore, included in this observational study. The median time between septic shock diagnosis and enrolment was 1.5 (1 to 2) h. The main characteristics of the cohort are summarised in Table 1. The majority of patients (80%) were admitted to the ICU through the emergency unit. The overall 28-day mortality was 55% (44/80).

Table 1:
Characteristics of the patients (n = 80)

Comparisons between patients with high and normal ΔPCO2 values at T0

Forty-four patients had a ΔPCO2 more than 0.8 kPa at T0 after insertion of the PiCCO device (Table 2). They had significantly lower CI, ScvO2, and DO2 and a higher O2ER. PaCO2 in patients with high ΔPCO2 was not significantly different from that in those with normal ΔPCO2. Conversely, PcvCO2 was significantly higher in the group of patients with high vs. normal ΔPCO2. No significant difference was found in mean arterial pressure, lactate concentrations, SOFA and APACHE II scores between groups.

Table 2:
Comparisons of illness severity, haemodynamic and acid–base data between normal and high ΔPCO2 groups at T0

Comparisons between patients according to their ΔPCO2 values at T6

During the early resuscitation phase (between T0 and T6) in patients who had normalised ΔPCO2 by T6 (n = 48), CI, ScvO2 and DO2 significantly increased, whereas lactate concentrations, O2ER and ΔPCO2 significantly decreased (Fig. 1). Patients (n = 32) with a high ΔPCO2 at T6 had significantly lower CI and ScvO2, and higher O2ER, ΔPCO2 and lactate concentrations (Fig. 1). During the first 6 h, all patients received 3.7 (2.8 to 4.8) l of colloid and crystalloid fluid loading. At T6, patients with a normal ΔPCO2 had received significantly more fluid than those with a high ΔPCO2 [4.2 (3.1 to 5.2) vs. 3.0 (2.4 to 4.3) l, respectively, P = 0.011]. There was no significant difference regarding norepinephrine and dobutamine infusion rates (Table 3). Also, similar proportions in the two groups required inotropic support (P = 0.84), renal replacement therapy (P = 0.36) and red blood cell transfusion (P = 0.75) (Table 3).

Fig. 1:
No captions available.
Table 3:
Comparisons of haemodynamic, acid–base and clinical data between normal and high ΔPCO2 groups at T6

From T0 to T6, lactate decrease was significantly greater for patients who reached a normal ΔPCO2 at T6 (28.3 ± 31 vs. −0.20 ± 34.5%, P < 0.0001). The decrease in lactate was also significantly greater in patients who had ScvO2 at least 70% at T6 (26.4 ± 34.1 vs. −0.82 ± 31%, P = 0.001). However at T6, lactate decrease was the greatest in the subgroup achieving the goals of both ScvO2 at least 70% and ΔPCO2 0.8 kPa or less (33.3 ± 28.9%, n = 38) compared with the subgroups of ScvO2 at least 70% and ΔPCO2 more than 0.8 kPa (7.8 ± 41.2%, n = 14, P = 0.016), ScvO2 less than 70% and ΔPCO2 0.8 kPa or less (9.3 ± 34.9%, n = 10, P = 0.03) and ScvO2 less than 70% and ΔPCO2 more than 0.8 kPa (−6.5 ± 28%, n = 18, P < 0.0001) (Table 4).

Table 4:
Comparisons of clinical data between patients who achieved the goals of both normal ScvO2 and ΔPCO2 values and those who achieved only normal ScvO2 values at T6

Correlation analysis

At T0 and T6, significant correlations were found for CI with ΔPCO2 (T0: r = −0.69, P < 0.0001; T6: r = −0.54, P < 0.0001) and CI with ScvO2 (T0: r = 0.55, P < 0.0001; T6: r = 0.59, P < 0.0001) (Fig. 2). The changes in CI between T0 and T6 were also correlated with changes in ΔPCO2 (r = −0.62, P < 0.0001) and with changes in ScvO2 (r = 0.48, P < 0.0001). At T0, there was no correlation between ΔPCO2 and lactate concentrations (r = 0.13, P = 0.25). Nevertheless, at T6, there was a moderate correlation (r = 0.42, P < 0.0001) for ΔPCO2 with lactate concentrations.

Fig. 2:
No captions available.

ΔPCO2 and outcome

At T0, APACHE II score (P = 0.001) was significantly higher with increasing age (P = 0.065) with nonsurvivors older than survivors, whereas the SOFA score (P = 0.72) was not significantly different. The characteristics of the survivors and nonsurvivors are presented in Table 5. At T0, there were no significant differences between survivors and nonsurvivors in their haemodynamic and oxygen-derived variables. Only in the survivors, CI, ScvO2 and DO2 significantly increased, whereas ΔPCO2, blood lactate and O2ER significantly decreased from T0 to T6 (Table 5). At T6, ΔPCO2 and lactate concentrations were significantly higher and ScvO2 significantly lower in nonsurvivors. Conversely, there was no significant difference between survivors and nonsurvivors regarding fluid administered [4.0 (3.0 to 5.5) vs. 3.5 (2.5 to 4.5) l, P = 0.14], norepinephrine infusion rate [0.39 (0.17 to 0.73) vs. 0.32 (0.04 to 0.79) μg kg−1 min−1, P = 0.20] and dobutamine infusion rate [0.0 (0.0 to 5.0) vs. 0.3 (0.0 to 7.5) μg kg−1 min−1, P = 0.10]. Nevertheless, lactate decrease was significantly greater in survivors than in nonsurvivors (38.4 ± 24.7 vs. −0.7 ± 33%, P < 0.0001). At T6, survival was higher in patients who had a normal compared with high ΔPCO2 (28/48 vs. 8/32; χ2 = 8.62, P = 0.003). From T0 to T24, the decrease in SOFA score was significantly greater for patients who achieved a normal compared with high ΔPCO2 at T6 [29.3 (9.3 to 46.5) vs. 0.0% (0.0 to 9.6), P < 0.0001]. Also, the patients with a normal ΔPCO2 at T6 had a significantly lower SOFA score at T24 [7 (6 to 10) vs. 12 (10 to 13), P < 0.0001].

Table 5:
Characteristics and clinical data of survivors and nonsurvivors over the first 6 h of septic shock

In the univariate analyses, 10 variables were associated with increased mortality at P < 0.10 for entry into multivariate models. These included age, APACHE II score, lactate decrease and the T6 values for lactate concentration, CI, ScvO2, ΔPCO2, O2ER, SaO2, PaO2/FiO2 ratio and arterial pH. Multivariate logistic regression analysis with 28-day mortality as the dependent variable was then performed. For reasons of co-linearity between SaO2 and PaO2/FiO2, pH and lactate concentration, and ScvO2 and ΔPCO2, eight variables were finally included in the model (age, APACHE II score, lactate decrease, lactate concentration, CI, O2ER, SaO2, and ΔPCO2 or ScvO2). Among theses variables, only lactate decrease and lactate levels at T6 were significant independent predictors of mortality with odds ratios (OR) of 0.96 (95% confidence interval 0.94 to 0.98, P = 0.001) and 1.50 (95% confidence interval 1.08 to 2.08, P = 0.015), respectively. When the same analysis was performed with four independent variables (APACHE II, lactate decrease, lactate concentration and ΔPCO2 or ScvO2), the OR did not change, indicating that the final OR in the regression analysis is minimally affected by the number of independent variables.


The main findings of our study are as follows: ΔPCO2 correlated negatively with CI during the initial resuscitation period of septic shock; during the very early phase of septic shock, patients who achieved a normal ΔPCO2 after 6 h of resuscitation had a larger decrease in SOFA score on day 1, a lower blood lactate at T6 and a greater 6 h lactate decrease than those who failed to normalise ΔPCO2; patients who reached the goals of both ΔPCO2 0.8 kPa or less and ScvO2 at least 70% at T6 had the greatest lactate decrease; lactate decrease and lactate concentrations at T6 were found to be independent predictors of 28-day mortality. We believe these are new findings.

Tissue hypoperfusion during circulatory failure is associated with increased tissue PCO2.24 The resulting mixed venous hypercapnia reflects the inadequate clearance of CO2 produced by cellular oxidative and buffering systems24 and translates into an increase of mixed venous-to-arterial carbon dioxide (P[) gradient. An increase in P[ that was directly related to a decrease in CO has been identified in various forms of circulatory failure including septic shock.8,9 Several authors11,25,26 have demonstrated, in experimental studies, the major role of decreased tissue blood flow (ischaemic hypoxia) in the widening of P[. Also, a mathematical model analysis has confirmed that CO represents the major determinant in the elevation of P[.27 Therefore, P[ can be used as a marker of how well the CO removes the total CO2 produced by the peripheral tissues.12,28 Unfortunately, the P[ is rarely obtained at the bedside as pulmonary artery catheters are now seldom used in critically ill patients.29 Interestingly, there is a good agreement between P[ and ΔPCO213,30 and CI correlates strongly with ΔPCO2 in critically ill patients.13 Not all authors agree. Van Beest et al.30 found wide limits of agreement for P[ with ΔPCO2 and a weak correlation (r = −0.26) for ΔPCO2 with CI, but they, and Vallée et al.,30,14 conducted their studies in septic shock in patients already resuscitated when a ScvO2 of at least 70% had been achieved. Recently, in a retrospective study, Du et al.15 showed that achieving normal ScvO2 and ΔPCO2 appears to be a better predictor of mortality following resuscitation from septic shock than ScvO2 alone. But because they took a mean baseline (at T0) of ScvO2 at more than 70%, provided no information on the relationship between CI and ΔPCO2 without a multivariate analysis, we believed that understanding would be improved by investigating ΔPCO2 and its relationship to CI and clinical outcome during the early resuscitation phase of septic shock before normalisation of ScvO2.


In our study, patients were recruited in the very early period of septic shock; the time between diagnosis and enrolment was only 90 min. Within this period, septic shock is rather a hypodynamic state and as a consequence an increased ΔPCO2 is observed more frequently. In the present study, we found that most patients (44/80) had increased ΔPCO2 at the time of the first assessments. These patients had a lower CI and a higher PcvCO2 compared with those with a normal ΔPCO2. There was no difference between the two groups regarding PaCO2. Venous hypercapnia was, therefore, responsible for the observed increase in ΔPCO2. The higher ΔPCO2 seen initially appeared to result from impaired CO2 elimination secondary to critical reductions in systemic and pulmonary blood flow. We noted during the course of septic shock that patients who achieved a normal ΔPCO2 at T6 experienced a decrease in ΔPCO2 and O2ER while DO2 and ScvO2 increased, in parallel with a significant increase in CI (Fig. 1). We also found a significant negative correlation between the changes in CI and in ΔPCO2 (Fig. 2). This establishes that a strong relationship between ΔPCO2 and CI exists in the very early period of septic shock while normal ScvO2 is being achieved. Our findings are in agreement with previous studies that measured mixed venous-to-arterial carbon dioxide partial pressure differences in septic shock.8,9 Bakker et al.9 studied 64 patients with septic shock on admission to ICU. They found that patients with high P[ had a lower CI and a higher PvCO2 with opposing changes in P[ and CI during the course of septic shock. Further corroboration comes from Mecher et al.8 who reported that fluid challenge resulted in a decrease in P[, which was associated with an increase in CI only in the subgroup of septic patients with initially high P[. After fluid resuscitation, they found a significant negative correlation between the changes in CI and in P[.


In our study, patients who had a normal ΔPCO2 6 h after their inclusion received significantly greater fluid volumes, had a greater lactate decrease with lower lactate concentrations and a larger decrease in SOFA score on day 1. The decrease in lactate over the first 6 h was highest in the subgroup achieving both ScvO2 at least 70% and ΔPCO2 0.8 kPa or less, and this matches the findings of a recent retrospective study.15 ScvO2 reflects the balance between oxygen demand and supply and ΔPCO2 reflects the ability of CO to wash out the total CO2 produced by the tissues. Our results suggest that giving these two factors equal weight during the early resuscitation period may be more beneficial in improving tissue oxygenation than considering either in isolation. Interestingly, we found that ΔPCO2 at T6 was greater in the nonsurvivors to the extent that patients with an increased ΔPCO2 at T6 had a significantly (P = 0.003) higher mortality rate (75.0 vs. 41.7%). Despite this, multivariate logistic regression analysis showed only blood lactate at T6 and lactate decrease, not ΔPCO2, to be significantly related to mortality. The reduction in lactate concentration following normalisation of ΔPCO2 can probably be explained not only by improvements in tissue perfusion but also by attenuation of the stress response and an increase in lactate elimination. This agrees with previous studies.20,31 Blood lactate decrease in the first 6 h of resuscitation has already been found to be an independent predictor of in-hospital survival in severe sepsis,31 and lactate decrease-guided therapy at this time appeared as efficient as ScvO2 for the management of septic shock.20

It has been recently suggested that ΔPCO2 could be useful in identifying patients who remain inadequately resuscitated after they have achieved a ScvO2 larger than 70% with an apparently normal O2 supply/consumption ratio.14,32 We believe that the addition of ΔPCO2 to the ‘Surviving Sepsis Campaign’ resuscitation bundle during the first 6 h of resuscitation would be a useful extra tool. In patients with low ScvO2, an increased ΔPCO2 is indicative of the contribution of low CO, and measuring ΔPCO2 could help in speeding up therapies aimed at improving CO, as opposed to the SaO2 or haemoglobin concentration. When ScvO2 is high (≥70%), persisting increases in ΔPCO2 account for the remaining impaired perfusion. ΔPCO2 offers additional help in making the appropriate decisions regarding fluids and inotropes. Further studies, however, are needed to confirm this hypothesis.

The 28-day mortality rate in this study was high in comparison with previous studies.31,33 The patients in our cohort had higher APACHE II scores at baseline compared with other studies and our mortality rate is consistent with the predicted death rate using the APACHE II scoring system (Table 1).

Our study has several limitations. First, it was an observational study without randomisation, and ΔPCO2 was not used as a therapeutic goal. Second, the study was performed in a sample of septic shock patients from a single centre with internal practices as reference. Third, nonsurvivors had a significantly lower ScvO2 at T6 with no significant differences in the amounts of fluid volume and vasoactive drugs administered (Table 5). This finding suggests that some nonsurvivor patients were not fully resuscitated, which is surprising as our standard septic shock resuscitation management is in accordance with the recommendations of the Surviving Sepsis Campaign guidelines. ‘Real life’ differences in practice can be considered as a weakness in the study protocol. It could be that some clinicians might not have performed ScvO2 and lactate measurements frequently enough before T6 to check on the effectiveness of the resuscitation.

Our data demonstrate a strong relationship between ΔPCO2 and CI at the very early phase of resuscitation in septic shock. Monitoring the ΔPCO2 from the beginning of the resuscitation may be a useful tool to assess the adequacy of CO in tissue perfusion. Achieving normal values for both ΔPCO2 and ScvO2 during the early resuscitation period of septic shock seems to be better than only targeting a normal ScvO2. The two variables together result in a greater decrease in lactate concentration, which is independently associated with reduced 28-day mortality. Further clinical trials are required to assess the usefulness of this measure during the early resuscitation period in patients with septic shock.

Acknowledgements relating to this article

Assistance with the study: the authors are deeply indebted to the nursing staff of the ICU for their help in this study.

Financial support and sponsorship: none.

Conflicts of interest: none.

Presentation: none.


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