Venous Minus Arterial Carbon Dioxide Gradients in the Monitoring of Tissue Perfusion and Oxygenation: A Narrative Review.

According to Fick's principle, the total uptake of (or release of) a substance by tissues is the product of blood flow and the difference between the arterial and the venous concentration of the substance. Therefore, the mixed or central venous minus arterial CO2 content difference depends on cardiac output (CO). Assuming a linear relationship between CO2 content and partial pressure, central or mixed venous minus arterial PCO2 differences (Pcv-aCO2 and Pmv-aCO2) are directly related to CO. Nevertheless, this relationship is affected by alterations in the CO2Hb dissociation curve induced by metabolic acidosis, hemodilution, the Haldane effect, and changes in CO2 production (VCO2). In addition, Pcv-aCO2 and Pmv-aCO2 are not interchangeable. Despite these confounders, CO is a main determinant of Pcv-aCO2. Since in a study performed in septic shock patients, Pmv-aCO2 was correlated with changes in sublingual microcirculation but not with those in CO, it has been proposed as a monitor for microcirculation. The respiratory quotient (RQ)-RQ = VCO2/O2 consumption-sharply increases in anaerobic situations induced by exercise or critical reductions in O2 transport. This results from anaerobic VCO2 secondary to bicarbonate buffering of anaerobically generated protons. The measurement of RQ requires expired gas analysis by a metabolic cart, which is not usually available. Thus, some studies have suggested that the ratio of Pcv-aCO2 to arterial minus central venous O2 content (Pcv-aCO2/Ca-cvO2) might be a surrogate for RQ and tissue oxygenation. In this review, we analyze the physiologic determinants of Pcv-aCO2 and Pcv-aCO2/Ca-cvO2 and their potential usefulness and limitations for the monitoring of critically ill patients. We discuss compelling evidence showing that they are misleading surrogates for tissue perfusion and oxygenation, mainly because they are systemic variables that fail to track regional changes. In addition, they are strongly dependent on changes in the CO2Hb dissociation curve, regardless of changes in systemic and microvascular perfusion and oxygenation.

Health inequities in the diagnosis and outcome of sepsis in Argentina: a prospective cohort study.

BACKGROUND: Socioeconomic variables impact health outcomes but have rarely been evaluated in critical illness. Low- and middle-income countries bear the highest burden of sepsis and also have significant health inequities. In Argentina, public hospitals serve the poorest segment of the population, while private institutions serve patients with health coverage. Our objective was to analyze differences in mortality between public and private hospitals, using Sepsis-3 definitions. METHODS: This is a multicenter, prospective cohort study including patients with sepsis admitted to 49 Argentine ICUs lasting 3 months, beginning on July 1, 2016. Epidemiological, clinical, and socioeconomic status variables and hospital characteristics were compared between patients admitted to both types of institutions. RESULTS: Of the 809 patients included, 367 (45%) and 442 (55%) were admitted to public and private hospitals, respectively. Those in public institutions were younger (56 ± 18 vs. 64 ± 18; p < 0.01), with more comorbidities (Charlson score 2 [0-4] vs. 1 [0-3]; p < 0.01), fewer education years (7 [7-12] vs. 12 [10-16]; p < 0.01), more frequently unemployed/informally employed (30% vs. 7%; p < 0.01), had similar previous self-rated health status (70 [50-90] vs. 70 [50-90] points; p = 0.30), longer pre-admission symptoms (48 [24-96] vs. 24 [12-48] h; p < 0.01), had been previously evaluated more frequently in any healthcare venue (28 vs. 20%; p < 0.01), and had higher APACHE II, SOFA, lactate levels, and mechanical ventilation utilization. ICU admission as septic shock was more frequent in patients admitted to public hospitals (47 vs. 35%; p < 0.01), as were infections caused by multiresistant microorganisms. Sepsis management in the ICU showed no differences. Twenty-eight-day mortality was higher in public hospitals (42% vs. 24%; p < 0.01) as was hospital mortality (47% vs. 30%; p < 0.01). Admission to a public hospital was an independent predictor of mortality together with comorbidities, lactate, SOFA, and mechanical ventilation; in an alternative prediction model, it acted as a correlate of pre-hospital symptom duration and infections caused by multiresistant microorganisms. CONCLUSIONS: Patients in public hospitals belonged to a socially disadvantaged group and were sicker at admission, had septic shock more frequently, and had higher mortality. Unawareness of disease severity and delays in the health system might be associated with late admission. This marked difference in outcome between patients served by public and private institutions constitutes a state of health inequity.

Poor agreement in the calculation of venoarterial PCO2 to arteriovenous O2 content difference ratio using central and mixed venous blood samples in septic patients.

PURPOSE: Central venous minus arterial PCO2 to arterial minus central venous O2 content difference ratio (Pcv-aCO2/Ca-cvO2) has been proposed as a clinical surrogate for respiratory quotient. Our goal was to assess its interchangeability with mixed venous minus arterial PCO2 to arterial minus mixed venous O2 content difference ratio (Pmv-aCO2/Ca-mvO2). MATERIALS AND METHODS: This is a subanalysis of a previously published study. We studied 23 septic patients who had an indwelling Swan-Ganz catheter. The agreement between Pcv-aCO2/Ca-cvO2 and Pmv-aCO2/Ca-mvO2 was evaluated by Bland and Altman analysis. We also performed linear regression analysis with Pmv-aCO2/Ca-mvO2 as the dependent variable. RESULTS: 95% limits of agreement between Pcv-aCO2/Ca-cvO2 and Pmv-aCO2/Ca-mvO2 were 1.48. Pmv-aCO2/Ca-mvO2 was significantly correlated with hemoglobin and lactate (R2 = 0.48 and 0.31, respectively, P < 0.01 for both). CONCLUSIONS: In this study, Pcv-aCO2/Ca-cvO2 and Pmv-aCO2/Ca-mvO2 were not interchangeable. In addition, Pmv-aCO2/Ca-mvO2 is a composite variable, which depends on several determinants. Values of Pcv-aCO2/Ca-cvO2 should be cautiously interpreted in the assessment of critically ill patients.

Predictive Validity of Sepsis-3 Definitions and Sepsis Outcomes in Critically Ill Patients: A Cohort Study in 49 ICUs in Argentina.

OBJECTIVES: The new Sepsis-3 definitions have been scarcely assessed in low- and middle-income countries; besides, regional information of sepsis outcomes is sparse. Our objective was to evaluate Sepsis-3 definition performance in Argentina. DESIGN: Cohort study of 3-month duration beginning on July 1, 2016. SETTINGS: Forty-nine ICUs. PATIENTS: Consecutive patients admitted to the ICU with suspected infection that triggered blood cultures and antibiotic administration. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patients were classified as having infection, sepsis (infection + change in Sequential Organ Failure Assessment ≥ 2 points), and septic shock (vasopressors + lactate > 2 mmol/L). Patients on vasopressors and lactate less than or equal to 2 mmol/L (cardiovascular dysfunction) were analyzed separately, as those on vasopressors without serum lactate measurement. Systemic inflammatory response syndrome was also recorded. Main outcome was hospital mortality. Of 809 patients, 6% had infection, 29% sepsis, 20% cardiovascular dysfunction, 40% septic shock, and 3% received vasopressors with lactate unmeasured. Hospital mortality was 13%, 20%, 39%, 51%, and 41%, respectively (p = 0.000). Independent predictors of outcome were lactate, Sequential Organ Failure Assessment score, comorbidities, prior duration of symptoms (hr), mechanical ventilation requirement, and infection by highly resistant microorganisms. Area under the receiver operating characteristic curves for mortality for systemic inflammatory response syndrome and Sequential Organ Failure Assessment were 0.53 (0.48-0.55) and 0.74 (0.69-0.77), respectively (p = 0.000). CONCLUSIONS: Increasing severity of Sepsis-3 categories adequately tracks mortality; cardiovascular dysfunction subgroup, not included in Sepsis-3, has distinct characteristics. Sequential Organ Failure Assessment score shows adequate prognosis accuracy-contrary to systemic inflammatory response syndrome. This study supports the predictive validity of Sepsis-3 definitions.

Sublingual microcirculatory alterations in cirrhotic patients.

OBJECTIVE: To assess sublingual microcirculation in cirrhotic patients and its relationship to spider angiomas, complications, and outcome. METHODS: Thirty-one cirrhotic patients were prospectively compared to 31 matched controls. Sublingual microcirculation was evaluated by videomicroscopy. We specifically looked for capillaries with increased RBCV, which was defined as a velocity higher than the percentile 100th of controls. RESULTS: Compared to controls, cirrhotic patients showed decreased total and PVD (14.4 ± 2.2 vs 16.0 ± 1.3 and 14.1 ± 2.3 vs 15.9 ± 1.6 mm/mm2 , respectively, P < .001 for both) and increased HFI (0.64 ± 0.39 vs 0.36 ± 0.21, P = .001). They also exhibited high RBCV in 2% of the microvessels (P < .0001). Patients with MELD score ≥10 had higher RBCV than patients with score <10 (1414 ± 290 vs 1206 ± 239 µm/s, P < .05). Patients with spider angiomas showed lower vascular densities. Microcirculation did not differ between survivors and nonsurvivors. CONCLUSIONS: Cirrhosis is associated with microcirculatory alterations that can be easily monitored in the sublingual mucosa. Alterations included decreased density and PPV and hyperdynamic microvessels. The most striking finding, however, was the microvascular heterogeneity. Patients with spider angiomas had more severe alterations. Larger studies should clarify the relationship between microcirculatory abnormalities and outcome.

Systemic and microcirculatory effects of blood transfusion in experimental hemorrhagic shock.

BACKGROUND: The microvascular reperfusion injury after retransfusion has not been completely characterized. Specifically, the question of heterogeneity among different microvascular beds needs to be addressed. In addition, the identification of anaerobic metabolism is elusive. The venoarterial PCO2 to arteriovenous oxygen content difference ratio (Pv-aCO2/Ca-vO2) might be a surrogate for respiratory quotient, but this has not been validated. Therefore, our goal was to characterize sublingual and intestinal (mucosal and serosal) microvascular injury after blood resuscitation in hemorrhagic shock and its relation with O2 and CO2 metabolism. METHODS: Anesthetized and mechanically ventilated sheep were assigned to stepwise bleeding and blood retransfusion (n = 10) and sham (n = 7) groups. We performed analysis of expired gases, arterial and mixed venous blood gases, and intestinal and sublingual videomicroscopy. RESULTS: In the bleeding group during the last step of hemorrhage, and compared to the sham group, there were decreases in oxygen consumption (3.7 [2.8-4.6] vs. 6.8 [5.8-8.0] mL min-1 kg-1, P < 0.001) and increases in respiratory quotient (0.96 [0.91-1.06] vs. 0.72 [0.69-0.77], P < 0.001). Retransfusion normalized these variables. The Pv-aCO2/Ca-vO2 increased in the last step of bleeding (2.4 [2.0-2.8] vs. 1.1 [1.0-1.3], P < 0.001) and remained elevated after retransfusion, compared to the sham group (1.8 [1.5-2.0] vs. 1.1 [0.9-1.3], P < 0.001). Pv-aCO2/Ca-vO2 had a weak correlation with respiratory quotient (Spearman R = 0.42, P < 0.001). All the intestinal and sublingual microcirculatory variables were affected during hemorrhage and improved after retransfusion. The recovery was only complete for intestinal red blood cell velocity and sublingual total and perfused vascular densities. CONCLUSIONS: Although there were some minor differences, intestinal and sublingual microcirculation behaved similarly. Therefore, sublingual mucosa might be an adequate window to track intestinal microvascular reperfusion injury. Additionally, Pv-aCO2/Ca-vO2 was poorly correlated with respiratory quotient, and its physiologic behavior was different. Thus, it might be a misleading surrogate for anaerobic metabolism.

Comparison of different methods for the calculation of the microvascular flow index.

The microvascular flow index (MFI) is commonly used to semiquantitatively characterize the velocity of microcirculatory perfusion as absent (0), intermittent (1), sluggish (2), or normal (3). There are three approaches to compute MFI: (1) the average of the predominant flow in each of the four quadrants (MFI(by quadrants)), (2) the direct assessment during the bedside video acquisition (MFI(point of care)), and (3) the mean value of the MFIs determined in each individual vessel (MFI(vessel by vessel)). We hypothesized that the agreement between the MFIs is poor and that the MFI(vessel by vessel) better reflects the microvascular perfusion. For this purpose, we analyzed 100 videos from septic patients. In 25 of them, red blood cell (RBC) velocity was also measured. There were wide 95% limits of agreement between MFI(by quadrants) and MFI(point of care) (1.46), between MFI(by quadrants) and MFI(vessel by vessel) (2.85), and between MFI(by point of care) and MFI(vessel by vessel) (2.56). The MFIs significantly correlated with the RBC velocity and with the fraction of perfused small vessels, but MFI(vessel by vessel) showed the best R(2). Although the different methods for the calculation of MFI reflect microvascular perfusion, they are not interchangeable and MFI(vessel by vessel) might be better.

Failure of nitroglycerin (glyceryl trinitrate) to improve villi hypoperfusion in endotoxaemic shock in sheep.

OBJECTIVE: To evaluate the effects of nitroglycerin (glyceryl trinitrate) on intestinal microcirculation during endotoxaemic shock. DESIGN: Controlled experimental study. SETTING: Research laboratory. SUBJECTS: 20 anaesthetised, mechanically ventilated sheep. INTERVENTIONS: Septic shock was induced by endotoxin infusion. After 60 minutes without resuscitation, sheep received fluid resuscitation and were randomised to control or nitroglycerin groups. Nitroglycerin was infused at a rate of 0.2 µg/kg/min for 90 minutes. MAIN OUTCOME MEASURE: Improved villi microcirculation. RESULTS: Endotoxin lowered arterial blood pressure, cardiac output and intestinal blood flow, which were improved by fluid resuscitation. Mean (SD) ileal intramucosal-arterial PCO2 gradient increased during shock and remained elevated after resuscitation in control and nitroglycerin groups (8 [8], 15 [9] and 17 [9], and 6 [6], 13 [11] and 14 [9]mmHg, respectively; P < 0.05, baseline v shock and resuscitation for both groups). Villi microvascular flow index was reduced during shock and remained lower than baseline after the resuscitation in both groups (3.0 [0.0], 2.5 [0.2] and 2.7 [0.2], and 3.0 [0.0], 2.3 [0.3] and 2.6 [0.3], respectively; P < 0.05, baseline v shock and resuscitation for both groups). The red blood cell velocity behaved similarly (859 [443], 553 [236] and 670 [276], and 886 [440], 447 [124] and 606 [235] µm/s, respectively; P < 0.05, baseline v shock and resuscitation for both groups). CONCLUSIONS: In endotoxaemic sheep, low doses of nitroglycerin failed to improve the subtle but persistent villi hypoperfusion that remains present after fluid resuscitation.

Comparison of 6% hydroxyethyl starch 130/0.4 and saline solution for resuscitation of the microcirculation during the early goal-directed therapy of septic patients.

PURPOSE: The aim of this study was to show that 6% hydroxyethyl starch (HES) 130/0.4 achieves a better resuscitation of the microcirculation than normal saline solution (SS), during early goal-directed therapy (EGDT) in septic patients. MATERIALS AND METHODS: Patients with severe sepsis were randomized for EGDT with 6% HES 130/0.4 (n = 9) or SS (n = 11). Sublingual microcirculation was evaluated by sidestream dark field imaging 24 hours after the beginning of EGDT. RESULTS: On admission, there were no differences in Sequential Organ Failure Assessment score, mean arterial pressure, lactate, or central venous oxygen saturation. After 24 hours, no difference arose in those parameters. Sublingual capillary density was similar in both groups (21 ± 8 versus 20 ± 3 vessels/mm(2)); but capillary microvascular flow index, percent of perfused capillaries, and perfused capillary density were higher in 6% HES 130/0.4 (2.5 ± 0.5 versus 1.6 ± 0.7, 84 ± 15 versus 53 ± 26%, and 19 ± 6 versus 11 ± 5 vessels/mm(2), respectively, P < .005). CONCLUSIONS: Fluid resuscitation with 6% HES 130/0.4 may have advantages over SS to improve sublingual microcirculation. A greater number of patients would be necessary to confirm these findings.

Increasing arterial blood pressure with norepinephrine does not improve microcirculatory blood flow: a prospective study.

INTRODUCTION: Our goal was to assess the effects of titration of a norepinephrine infusion to increasing levels of mean arterial pressure (MAP) on sublingual microcirculation. METHODS: Twenty septic shock patients were prospectively studied in two teaching intensive care units. The patients were mechanically ventilated and required norepinephrine to maintain a mean arterial pressure (MAP) of 65 mmHg. We measured systemic hemodynamics, oxygen transport and consumption (DO2 and VO2), lactate, albumin-corrected anion gap, and gastric intramucosal-arterial PCO2 difference (DeltaPCO2). Sublingual microcirculation was evaluated by sidestream darkfield (SDF) imaging. After basal measurements at a MAP of 65 mmHg, norepinephrine was titrated to reach a MAP of 75 mmHg, and then to 85 mmHg. Data were analyzed using repeated measurements ANOVA and Dunnett test. Linear trends between the different variables and increasing levels of MAP were calculated. RESULTS: Increasing doses of norepinephrine reached the target values of MAP. The cardiac index, pulmonary pressures, systemic vascular resistance, and left and right ventricular stroke work indexes increased as norepinephrine infusion was augmented. Heart rate, DO2 and VO2, lactate, albumin-corrected anion gap, and DeltaPCO2 remained unchanged. There were no changes in sublingual capillary microvascular flow index (2.1 +/- 0.7, 2.2 +/- 0.7, 2.0 +/- 0.8) and the percent of perfused capillaries (72 +/- 26, 71 +/- 27, 67 +/- 32%) for MAP values of 65, 75, and 85 mmHg, respectively. There was, however, a trend to decreased capillary perfused density (18 +/- 10,17 +/- 10,14 +/- 2 vessels/mm2, respectively, ANOVA P = 0.09, linear trend P = 0.045). In addition, the changes of perfused capillary density at increasing MAP were inversely correlated with the basal perfused capillary density (R2 = 0.95, P < 0.0001). CONCLUSIONS: Patients with septic shock showed severe sublingual microcirculatory alterations that failed to improve with the increases in MAP with norepinephrine. Nevertheless, there was a considerable interindividual variation. Our results suggest that the increase in MAP above 65 mmHg is not an adequate approach to improve microcirculatory perfusion and might be harmful in some patients.

Urinary bladder partial carbon dioxide tension during hemorrhagic shock and reperfusion: an observational study.

INTRODUCTION: Continuous monitoring of bladder partial carbon dioxide tension (PCO2) using fibreoptic sensor technology may represent a useful means by which tissue perfusion may be monitored. In addition, its changes might parallel tonometric gut PCO2. Our hypothesis was that bladder PCO2, measured using saline tonometry, will be similar to ileal PCO2 during ischaemia and reperfusion. METHOD: Six anaesthetized and mechanically ventilated sheep were bled to a mean arterial blood pressure of 40 mmHg for 30 min (ischaemia). Then, blood was reinfused and measurements were repeated at 30 and 60 min (reperfusion). We measured systemic and gut oxygen delivery and consumption, lactate and various PCO2 gradients (urinary bladder-arterial, ileal-arterial, mixed venous-arterial and mesenteric venous-arterial). Both bladder and ileal PCO2 were measured using saline tonometry. RESULTS: After bleeding systemic and intestinal oxygen supply dependency and lactic acidosis ensued, along with elevations in PCO2 gradients when compared with baseline values (all values in mmHg; bladder DeltaPCO2 3 +/- 3 versus 12 +/- 5, ileal DeltaPCO2 9 +/- 5 versus 29 +/- 16, mixed venous-arterial PCO2 5 +/- 1 versus 13 +/- 4, and mesenteric venous-arterial PCO2 4 +/- 2 versus 14 +/- 4; P < 0.05 versus basal for all). After blood reinfusion, PCO2 gradients returned to basal values except for bladder DeltaPCO2, which remained at ischaemic levels (13 +/- 7 mmHg). CONCLUSION: Tissue and venous hypercapnia are ubiquitous events during low flow states. Tonometric bladder PCO2 might be a useful indicator of tissue hypoperfusion. In addition, the observed persistence of bladder hypercapnia after blood reinfusion may identify a territory that is more susceptible to reperfusion injury. The greatest increase in PCO2 gradients occurred in gut mucosa. Moreover, the fact that ileal DeltaPCO2 was greater than the mesenteric venous-arterial PCO2 suggests that tonometrically measured PCO2 reflects mucosal rather than transmural PCO2. Ileal DeltaPCO2 appears to be the more sensitive marker of ischaemia.

Increased blood flow prevents intramucosal acidosis in sheep endotoxemia: a controlled study.

INTRODUCTION: Increased intramucosal-arterial carbon dioxide tension (PCO2) difference (DeltaPCO2) is common in experimental endotoxemia. However, its meaning remains controversial because it has been ascribed to hypoperfusion of intestinal villi or to cytopathic hypoxia. Our hypothesis was that increased blood flow could prevent the increase in DeltaPCO2. METHODS: In 19 anesthetized and mechanically ventilated sheep, we measured cardiac output, superior mesenteric blood flow, lactate, gases, hemoglobin and oxygen saturations in arterial, mixed venous and mesenteric venous blood, and ileal intramucosal PCO2 by saline tonometry. Intestinal oxygen transport and consumption were calculated. After basal measurements, sheep were assigned to the following groups, for 120 min: (1) sham (n = 6), (2) normal blood flow (n = 7) and (3) increased blood flow (n = 6). Escherichia coli lipopolysaccharide (5 microg/kg) was injected in the last two groups. Saline solution was used to maintain blood flood at basal levels in the sham and normal blood flow groups, or to increase it to about 50% of basal in the increased blood flow group. RESULTS: In the normal blood flow group, systemic and intestinal oxygen transport and consumption were preserved, but DeltaPCO2 increased (basal versus 120 min endotoxemia, 7 +/- 4 versus 19 +/- 4 mmHg; P < 0.001) and metabolic acidosis with a high anion gap ensued (arterial pH 7.39 versus 7.35; anion gap 15 +/- 3 versus 18 +/- 2 mmol/l; P < 0.001 for both). Increased blood flow prevented the elevation in DeltaPCO2 (5 +/- 7 versus 9 +/- 6 mmHg; P = not significant). However, anion-gap metabolic acidosis was deeper (7.42 versus 7.25; 16 +/- 3 versus 22 +/- 3 mmol/l; P < 0.001 for both). CONCLUSIONS: In this model of endotoxemia, intramucosal acidosis was corrected by increased blood flow and so might follow tissue hypoperfusion. In contrast, anion-gap metabolic acidosis was left uncorrected and even worsened with aggressive volume expansion. These results point to different mechanisms generating both alterations.

Intramucosal-arterial Pco2 gradient does not reflect intestinal dysoxia in anemic hypoxia.

BACKGROUND: An increase in intramucosal-arterial Pco2 gradient (DeltaPco2) might be caused by tissue hypoxia or by diminished blood flow. Our hypothesis was that DeltaPco2 should not be altered in anemic hypoxia with preserved blood flow. METHODS: In 18 anesthetized, mechanically ventilated sheep, oxygen transport was stepwise reduced by hemorrhage (hypovolemia, n = 9) or by hemorrhage and simultaneous dextran infusion (hemodilution, n = 9). RESULTS: Hypovolemia and hemodilution produced comparable decreases in systemic and intestinal oxygen transport and uptake. However, mixed venoarterial and mesenteric venoarterial Pco2 gradients and DeltaPco2 were significantly higher in hypovolemia than in hemodilution (25 +/- 5 vs. 10 +/- 2 mm Hg; 21 +/- 6 vs. 10 +/- 5 mm Hg; and 41 +/- 18 vs. 14 +/- 9 mm Hg, respectively; p < 0.01). CONCLUSION: DeltaPco2 did not reflect intestinal dysoxia during Vo2/Do2 dependency attributable to hemodilution. Blood flow seems to be the main determinant of DeltaPco2.