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Abstract Background The selection of adequate indicators of tissue hypoxia for guiding the resuscitation process of septic patients is a highly relevant issue. Current guidelines advocate for the use of lactate as sole metabolic marker, which may be markedly limited, and the integration of different variables seems more adequate. In this study, we explored the metabolic profile and its implications in the response to the administration of a fluid challenge in early septic shock patients. Methods Observational study including septic shock patients within 24 h of ICU admission, monitored with a cardiac output estimation system, with ongoing resuscitation. Hemodynamic and metabolic variables were measured before and after a fluid challenge (FC). A two-step cluster analysis was used to define the baseline metabolic profile, including lactate, central venous oxygen saturation (ScvO2), central venous-to-arterial carbon dioxide difference (PcvaCO2), and PcvaCO2 corrected by the difference in arterial-to-venous oxygen content (PcvaCO2/CavO2). Results Seventy-seven fluid challenges were analyzed. Cluster analysis revealed two distinct metabolic profiles at baseline. Cluster A exhibited lower ScvO2, higher PcvaCO2, and lower PcvaCO2/CavO2. Increases in cardiac output (CO) were associated with increases in VO2 exclusively in cluster A. Baseline isolated metabolic variables did not correlate with VO2 response, and changes in ScvO2 and PcvaCO2 were associated to VO2 increase only in cluster A. Conclusions In a population of early septic shock patients, two distinct metabolic profiles were identified, suggesting tissue hypoxia or dysoxia. Integrating metabolic variables enhances the ability to detect those patients whose VO2 might increase as results of fluid administration.

Background: The selection of adequate indicators of tissue hypoxia for guiding the resuscitation process of septic patients is a highly relevant issue. Current guidelines advocate for the use of lactate as sole metabolic marker, which may be markedly limited, and the integration of different variables seems more adequate. In this study, we explored the metabolic profile and its implications in the response to the administration of a fluid challenge in early septic shock patients. Methods: Observational study including septic shock patients within 24 h of ICU admission, monitored with a cardiac output estimation system, with ongoing resuscitation. Hemodynamic and metabolic variables were measured before and after a fluid challenge (FC). A two-step cluster analysis was used to define the baseline metabolic profile, including lactate, central venous oxygen saturation (ScvO2), central venous-to-arterial carbon dioxide difference (PcvaCO2), and PcvaCO2 corrected by the difference in arterial-to-venous oxygen content (PcvaCO2/CavO2). Results: Seventy-seven fluid challenges were analyzed. Cluster analysis revealed two distinct metabolic profiles at baseline. Cluster A exhibited lower ScvO2, higher PcvaCO2, and lower PcvaCO2/CavO2. Increases in cardiac output (CO) were associated with increases in VO2 exclusively in cluster A. Baseline isolated metabolic variables did not correlate with VO2 response, and changes in ScvO2 and PcvaCO2 were associated to VO2 increase only in cluster A. Conclusions: In a population of early septic shock patients, two distinct metabolic profiles were identified, suggesting tissue hypoxia or dysoxia. Integrating metabolic variables enhances the ability to detect those patients whose VO2 might increase as results of fluid administration. [ABSTRACT FROM AUTHOR]

Background: Cardiac surgery is associated with a substantial risk of major adverse events. Although carbon dioxide (CO2)-derived variables such as venous-to-arterial CO2 difference (ΔPCO2), and PCO2 gap to arterial–venous O2 content difference ratio (ΔPCO2/C(a−cv)O2) have been successfully used to predict the prognosis of non-cardiac surgery, their prognostic value after cardiopulmonary bypass (CPB) remains controversial. This hospital-based study explored the relationship between ΔPCO2, ΔPCO2/C(a−cv)O2 and organ dysfunction after CPB.Methods: We prospectively enrolled 114 intensive care unit patients after elective cardiac surgery with CPB. Patients were divided into the organ dysfunction group (OI) and non-organ dysfunction group (n-OI) depending on whether organ dysfunction occurred or not at 48 h after CPB. ΔPCO2 was defined as the difference between central venous and arterial CO2 partial pressure.Results: The OI group has 37 (32.5%) patients, 27 of which (23.7%) had one organ dysfunction and 10 (8.8%) had two or more organ dysfunctions. No statistical significance was found (P = 0.84) for ΔPCO2 in the n-OI group at intensive care unit (ICU) admission (9.0, 7.0–11.0 mmHg), and at 4 (9.0, 7.0–11.0 mmHg), 8 (9.0, 7.0–11.0 mmHg), and 12 h post admission (9.0, 7.0–11.0 mmHg). In the OI group, ΔPCO2 also showed the same trend [ICU admission (9.0, 8.0–12.8 mmHg) and 4 (10.0, 7.0–11.0 mmHg), 8 (10.0, 8.5–12.5 mmHg), and 12 h post admission (9.0, 7.3–11.0 mmHg), P = 0.37]. No statistical difference was found for ΔPCO2/C(a−cv)O2 in the n-OI group (P = 0.46) and OI group (P = 0.39). No difference was detected in ΔPCO2, ΔPCO2/C(a−cv)O2 between groups during the first 12 h after admission (P > 0.05). Subgroup analysis of the patients with two or more failing organs compared to the n-OI group showed that the predictive performance of lactate and Base excess (BE) improved, but not of ΔPCO2 and ΔPCO2/C(a−cv)O2. Regression analysis showed that the BE at 8 h after admission (odds ratio = 1.37, 95%CI: 1.08–1.74, P = 0.009) was a risk factor for organ dysfunction 48 h after CBP.Conclusion : ΔPCO2 and ΔPCO2/C(a−cv)O2 cannot be used as reliable indicators to predict the occurrence of organ dysfunction at 48 h after CBP due to the pathophysiological process that occurs after CBP.

Central venous-to-arterial carbon dioxide difference (PcvaCO2), and its correction by the arterial-to-venous oxygen content difference (PcvaCO2/CavO2) have been proposed as additional tools to evaluate tissue hypoxia. Since the relationship between pressure and content of CO2 (CCO2) might be affected by several factors, some authors advocate for the use of CcvaCO2/CavO2. The aim of the present study was to explore the factors that might intervene in the difference between PcvaCO2/CavO2 and CcvaCO2/CavO2, and to analyze their association with mortality. Observational study in a 30-bed mixed ICU. Fifty-two septic shock patients within the first 24 h of ICU admission were studied. After restoration of mean arterial pressure, hemodynamic and metabolic parameters were evaluated. A total of 110 sets of measurements were performed. Simultaneous PcvaCO2/CavO2 and CcvaCO2/CavO2 values were correlated, but agreement analysis showed a significant proportional bias. The difference between PcvaCO2/CavO2 and CcvaCO2/CavO2 was independently associated with pH, ScvO2, baseline CcvaCO2/CavO2 and hemoglobin. A stepwise regression analysis showed that pH was the single best predictor for the magnitude of such difference, with very limited effect of other variables. At inclusion, variables associated with ICU-mortality were lactate, pH, PcvaCO2/CavO2, and the difference between PcvaCO2/CavO2 and CcvaCO2/CavO2. Initial ScvO2, PcvaCO2, CcvaCO2/CavO2, and cardiac index were not different in survivors and non-survivors. In a population of early septic shock patients, simultaneous values of PcvaCO2/CavO2 and CcvaCO2/CavO2 were not equivalent, and the main determinant of the magnitude of the difference between these two parameters was pH. The PcvaCO2/CavO2 ratio was associated with ICU mortality, whereas CcvaCO2/CavO2 was not. [ABSTRACT FROM AUTHOR]

Central venous-to-arterial carbon dioxide difference (PcvaCO2) has demonstrated its prognostic value in critically ill patients suffering from shock, and current expert recommendations advocate for further resuscitation interventions when PcvaCO2 is elevated. PcvaCO2 combination with arterial-venous oxygen content difference (PcvaCO2/CavO2) seems to enhance its performance when assessing anaerobic metabolism. However, the fact that PCO2 values might be altered by changes in blood O2 content (the Haldane effect), has been presented as a limitation of PCO2-derived variables. The present study aimed at exploring the impact of hyperoxia on PcvaCO2 and PcvaCO2/CavO2 during the early phase of shock. Prospective interventional study. Ventilated patients suffering from shock within the first 24 h of ICU admission. Patients requiring FiO2 ≥ 0.5 were excluded. At inclusion, simultaneous arterial and central venous blood samples were collected. Patients underwent a hyperoxygenation test (5 min of FiO2 100%), and arterial and central venous blood samples were repeated. Oxygenation and CO2 variables were calculated at both time points. Twenty patients were studied. The main cause of shock was septic shock (70%). The hyperoxygenation trial increased oxygenation parameters in arterial and venous blood, whereas PCO2 only changed at the venous site. Resulting PcvaCO2 and PcvaCO2/CavO2 significantly increased [6.8 (4.9, 8.1) vs. 7.6 (6.7, 8.5) mmHg, p 0.001; and 1.9 (1.4, 2.2) vs. 2.3 (1.8, 3), p < 0.001, respectively]. Baseline PcvaCO2, PcvaCO2/CavO2 and ScvO2 correlated with the magnitude of PO2 augmentation at the venous site within the trial (ρ -0.46, p 0.04; ρ 0.6, p < 0.01; and ρ 0.7, p < 0.001, respectively). Increased PcvaCO2/CavO2 values were associated with higher mortality in our sample [1.46 (1.21, 1.89) survivors vs. 2.23 (1.86, 2.8) non-survivors, p < 0.01]. PcvaCO2 and PcvaCO2/CavO2 are influenced by oxygenation changes not related to flow. Elevated PcvaCO2 and PcvaCO2/CavO2 values might not only derive from cardiac output inadequacy, but also from venous hyperoxia. Elevated PcvaCO2/CavO2 values were associated with higher PO2 transmission to the venous compartment, suggesting higher shunting phenomena. [ABSTRACT FROM AUTHOR]

Background: To evaluate the ability of the central venous-to-arterial CO content and tension differences to arteriovenous oxygen content difference ratios (∆ContCO/∆ContO and ∆PCO/∆ContO, respectively), blood lactate concentration, and central venous oxygen saturation (ScvO) to detect the presence of global anaerobic metabolism through the increase in oxygen consumption (VO) after an acute increase in oxygen supply (DO) induced by volume expansion (VO/DO dependence). Methods: We prospectively studied 98 critically ill mechanically ventilated patients in whom a fluid challenge was decided due to acute circulatory failure related to septic shock. Before and after volume expansion (500 mL of colloid solution), we measured cardiac index, VO, DO, ∆ContCO/∆ContO and ∆PCO/∆ContO ratios, lactate, and ScvO. Fluid-responders were defined as a ≥15 % increase in cardiac index. Areas under the receiver operating characteristic curves (AUC) were determined for these variables. Results: Fifty-one patients were fluid-responders (52 %). DO increased significantly (31 ± 12 %) in these patients. An increase in VO ≥ 15 % ('VO-responders') concurrently occurred in 57 % of the 51 fluid-responders (45 ± 16 %). Compared with VO-non-responders, VO-responders were characterized by higher lactate levels and higher ∆ContCO/∆ContO and ∆PCO/∆ContO ratios. At baseline, lactate predicted a fluid-induced increase in VO ≥ 15 % with AUC of 0.745. Baseline ∆ContCO/∆ContO and ∆PCO/∆ContO ratios predicted an increase of VO ≥ 15 % with AUCs of 0.965 and 0.962, respectively. Baseline ScvO was not able to predict an increase of VO ≥ 15 % (AUC = 0.624). Conclusions: ∆ContCO/∆ContO and ∆PCO/∆ContO ratios are more reliable markers of global anaerobic metabolism than lactate. ScvO failed to predict the presence of global tissue hypoxia. [ABSTRACT FROM AUTHOR]

Purpose: Septic shock has been associated with microvascular alterations and these in turn with the development of organ dysfunction. Despite advances in video microscopic techniques, evaluation of microcirculation at the bedside is still limited. Venous-to-arterial carbon dioxide difference (Pv-aCO2) may be increased even when venous O2 saturation (SvO2) and cardiac output look normal, which could suggests microvascular derangements. We sought to evaluate whether Pv-aCO2 can reflect the adequacy of microvascular perfusion during the early stages of resuscitation of septic shock.Methods: Prospective observational study including 75 patients with septic shock in a 60-bed mixed ICU. Arterial and mixed-venous blood gases and hemodynamic variables were obtained at catheter insertion (T0) and 6 h after (T6). Using a sidestream dark-field device, we simultaneously acquired sublingual microcirculatory images for blinded semiquantitative analysis. Pv-aCO2 was defined as the difference between mixed-venous and arterial CO2 partial pressures.Results: Progressively lower percentages of small perfused vessels (PPV), lower functional capillary density, and higher heterogeneity of microvascular blood flow were observed at higher Pv-aCO2 values at both T0 and T6. Pv-aCO2 was significantly correlated to PPV (T0: coefficient -5.35, 95 % CI -6.41 to -4.29, p < 0.001; T6: coefficient, -3.49, 95 % CI -4.43 to -2.55, p < 0.001) and changes in Pv-aCO2 between T0 and T6 were significantly related to changes in PPV (R (2) = 0.42, p < 0.001). Absolute values and changes in Pv-aCO2 were not related to global hemodynamic variables. Good agreement between venous-to-arterial CO2 and PPV was maintained even after corrections for the Haldane effect.Conclusions: During early phases of resuscitation of septic shock, Pv-aCO2 could reflect the adequacy of microvascular blood flow. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the prognostic value of the Cv-aCO/Da-vO ratio combined with lactate levels during the early phases of resuscitation in septic shock. Methods: Prospective observational study in a 60-bed mixed ICU. One hundred and thirty-five patients with septic shock were included. The resuscitation protocol targeted mean arterial pressure, pulse pressure variations or central venous pressure, mixed venous oxygen saturation, and lactate levels. Patients were classified into four groups according to lactate levels and Cv-aCO/Da-vO ratio at 6 h of resuscitation (T6): group 1, lactate ≥2.0 mmol/L and Cv-aCO/Da-vO >1.0; group 2, lactate ≥2.0 mmol/L and Cv-aCO/Da-vO ≤1.0; group 3, lactate <2.0 mmol/L and Cv-aCO/Da-vO >1.0; and group 4, lactate <2.0 mmol/L and Cv-aCO/Da-vO ≤1.0. Results: Combination of hyperlactatemia and high Cv-aCO/Da-vO ratio was associated with the worst SOFA scores and lower survival rates at day 28 [log rank (Mantel-Cox) = 31.39, p < 0.0001]. Normalization of both variables was associated with the best outcomes. Patients with a high Cv-aCO/Da-vO ratio and lactate <2.0 mmol/L had similar outcomes to hyperlactatemic patients with low Cv-aCO/Da-vO ratio. The multivariate analysis revealed that Cv-aCO/Da-vO ratio at both T0 (RR 3.85; 95 % CI 1.60-9.27) and T6 (RR 3.97; 95 % CI 1.54-10.24) was an independent predictor for mortality at day 28, as well as lactate levels at T6 (RR 1.58; 95 % CI 1.13-2.22). Conclusion: Complementing lactate assessment with Cv-aCO/Da-vO ratio during early stages of resuscitation of septic shock can better identify patients at high risk of adverse outcomes. The Cv-aCO/Da-vO ratio may become a potential resuscitation goal in patients with septic shock. [ABSTRACT FROM AUTHOR]

Purpose: To explore the relationship between central venous-to-arterial carbon dioxide difference (P cva CO 2 ), P cva CO 2 /arterial-venous oxygen content difference ratio (P cva CO 2 /C av O 2 ) and the microcirculatory status, evaluated by using near-infrared spectroscopy, in septic shock patients., Methods: Observational study in a 30-bed mixed ICU. Fifty septic shock patients within the first 24 h of ICU admission were studied. After restoration of mean arterial pressure, hemodynamic, metabolic and microcirculatory parameters were simultaneously evaluated. Local tissue oxygen saturation (StO 2 ), and local hemoglobin index (THI) were measured on the thenar eminence by means of near-infrared spectroscopy. A transient vascular occlusion test was performed in order to obtain StO 2 deoxygenation rate (DeO 2 ), local oxygen consumption (nirVO 2 ), and reoxgenation rate (ReO 2 )., Results: At inclusion, increased P cva CO 2 values were associated with lower StO 2 and THI, whereas increased P cva CO 2 /C av O 2 values were associated with lower DeO 2 , nirVO 2 , and ReO 2 . Multiple regression models confirmed the association between P cva CO 2 /C av O 2 and nirVO 2 , while P cva CO 2 was only related to CI, and not to microcirculatory parameters., Conclusions: In a population of early septic shock patients, increases in P cva CO 2 and P cva CO 2 /C av O 2 reflected different alterations at the microcirculatory level. While P cva CO 2 was related to global flow, the P cva CO 2 /C av O 2 ratio was associated to impaired local oxygen utilization and diminished microvascular reactivity., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Oxygen-derived parameters have been traditionally used to guide resuscitation during shock states. Nevertheless, normalization of venous oxygen saturation does not exclude the persistence of tissue hypoperfusion and tissue hypoxia. Combination of O 2 and CO 2 -derived variables has consistently demonstrated to be related with clinical outcomes and its variations could anticipate changes in lactate and also predict fluid responsiveness in terms of oxygen consumption. Here we discuss the potential mechanisms leading to increase the venous-to-arterial CO 2 (Cv-aCO 2 ) to arterial-to-venous O 2 content difference (Ca-vO 2 ), i.e., the Cv-aCO 2 /Ca-vO 2 ratio, its potential clinical application, limitations and uncertainties. Finally, although biologically plausible, the potential applications of the Cv-aCO 2 /Ca-vO 2 ratio in the clinical practice require to be confirmed., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.