Microcirculatory dysfunction and dead-space ventilation in early ARDS: a hypothesis-generating observational study.

BACKGROUND: Ventilation/perfusion inequalities impair gas exchange in acute respiratory distress syndrome (ARDS). Although increased dead-space ventilation (VD/VT) has been described in ARDS, its mechanism is not clearly understood. We sought to evaluate the relationships between dynamic variations in VD/VT and extra-pulmonary microcirculatory blood flow detected at sublingual mucosa hypothesizing that an altered microcirculation, which is a generalized phenomenon during severe inflammatory conditions, could influence ventilation/perfusion mismatching manifested by increases in VD/VT fraction during early stages of ARDS. METHODS: Forty-two consecutive patients with early moderate and severe ARDS were included. PEEP was set targeting the best respiratory-system compliance after a PEEP-decremental recruitment maneuver. After 60 min of stabilization, hemodynamics and respiratory mechanics were recorded and blood gases collected. VD/VT was calculated from the CO2 production ([Formula: see text]) and CO2 exhaled fraction ([Formula: see text]) measurements by volumetric capnography. Sublingual microcirculatory images were simultaneously acquired using a sidestream dark-field device for an ulterior blinded semi-quantitative analysis. All measurements were repeated 24 h after. RESULTS: Percentage of small vessels perfused (PPV) and microcirculatory flow index (MFI) were inverse and significantly related to VD/VT at baseline (Spearman's rho = - 0.76 and - 0.63, p < 0.001; R2 = 0.63, and 0.48, p < 0.001, respectively) and 24 h after (Spearman's rho = - 0.71, and - 0.65; p < 0.001; R2 = 0.66 and 0.60, p < 0.001, respectively). Other respiratory, macro-hemodynamic and oxygenation parameters did not correlate with VD/VT. Variations in PPV between baseline and 24 h were inverse and significantly related to simultaneous changes in VD/VT (Spearman's rho = - 0.66, p < 0.001; R2 = 0.67, p < 0.001). CONCLUSION: Increased heterogeneity of microcirculatory blood flow evaluated at sublingual mucosa seems to be related to increases in VD/VT, while respiratory mechanics and oxygenation parameters do not. Whether there is a cause-effect relationship between microcirculatory dysfunction and dead-space ventilation in ARDS should be addressed in future research.

Microcirculatory blood flow derangements during severe preeclampsia and HELLP syndrome.

OBJECTIVE: To evaluate the microcirculatory blood flow in severe preeclampsia and compare it with healthy pregnant and non-pregnant women controls, using a portable intravital-microscopy technique. METHODS: Using a side-stream dark field (SDF) device, we prospectively evaluated the sublingual microcirculatory blood flow before placental delivery in 40 women with severe preeclampsia (PE-group) complicated (n=8) or not (n=32) with HELLP syndrome, 40 healthy pregnant women (HP-group) matched by gestational and chronological age, and 20 healthy non-pregnant women (NP-group). Microvessels were classified as large or small using a cutoff value of 20µm and those with continuous flow were considered as normal while sluggish, intermittent and stopped flows were considered as abnormal. We computed the proportion of well-perfused small vessels (PPV), and total and functional capillary densities (TCD and FCD) were calculated according to the total number and quantity of well-perfused small vessels per area unit, respectively. RESULTS: Total capillary densities were significantly higher in all pregnant women when compared to non-pregnant controls. The PE-group exhibited, however, significantly lower TCD compared with the HP-group. Meanwhile, significant decreases in PPV and FCD were observed in the PE-group, with deeper alterations in those with coexisting HELLP syndrome. These altered PPVs were significant although incompletely reversed after placental delivery in pregnancies complicated by HELLP syndrome, while capillary densities remained unaltered at least during very early post-delivery period. CONCLUSIONS: Substantial distributive microcirculatory blood flow alterations and restricted capillary densities are observed in preeclampsia, suggesting a key role for microvascular dysfunction in the pathophysiology of this condition.

Effects of dobutamine on intestinal microvascular blood flow heterogeneity and O2 extraction during septic shock.

Derangements of microvascular blood flow distribution might contribute to disturbing O2 extraction by peripheral tissues. We evaluated the dynamic relationships between the mesenteric O2 extraction ratio ([Formula: see text]) and the heterogeneity of microvascular blood flow at the gut and sublingual mucosa during the development and resuscitation of septic shock in a swine model of fecal peritonitis. Jejunal-villi and sublingual microcirculation were evaluated using a portable intravital-microscopy technique. Simultaneously, we obtained arterial, mixed-venous, and mesenteric blood gases, and jejunal-tonometric measurements. During resuscitation, pigs were randomly allocated to a fixed dose of dobutamine (5 µg·kg-1·min-1) or placebo while three sham models with identical monitoring served as controls. At the time of shock, we observed a significant decreased proportion of perfused intestinal-villi (villi-PPV) and sublingual percentage of perfused small vessels (SL-PPV), paralleling an increase in [Formula: see text] in both dobutamine and placebo groups. After starting resuscitation, villi-PPV and SL-PPV significantly increased in the dobutamine group with subsequent improvement of functional capillary density, whereas [Formula: see text] exhibited a corresponding significant decrease (repeated-measures ANOVA, P = 0.02 and P = 0.04 for time × group interactions and intergroup differences for villi-PPV and [Formula: see text], respectively). Variations in villi-PPV were paralleled by variations in [Formula: see text] (R2 = 0.88, P < 0.001) and these, in turn, by mesenteric lactate changes (R2 = 0.86, P < 0.001). There were no significant differences in cardiac output and systemic O2 delivery throughout the experiment. In conclusion, dynamic changes in microvascular blood flow heterogeneity at jejunal mucosa are closely related to the mesenteric O2 extraction ratio, suggesting a crucial role for microvascular blood flow distribution on O2 uptake during development and resuscitation from septic shock.NEW & NOTEWORTHY Our observations suggest that dynamic changes in the heterogeneity of microvascular blood flow at the gut mucosa are closely related to mesenteric O2 extraction, thus supporting the role of decreasing functional capillary density and increased intercapillary distances on alterations of O2 uptake during development and resuscitation from septic shock. Addition of a low-fixed dose of dobutamine might reverse such flow heterogeneity, improving microcirculatory flow distribution and tissue O2 consumption.

Can venous-to-arterial carbon dioxide differences reflect microcirculatory alterations in patients with septic shock?

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.

Combination of arterial lactate levels and venous-arterial CO2 to arterial-venous O 2 content difference ratio as markers of resuscitation in patients with septic shock.

PURPOSE: To evaluate the prognostic value of the Cv-aCO2/Da-vO2 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-aCO2/Da-vO2 ratio at 6 h of resuscitation (T6): group 1, lactate ≥2.0 mmol/L and Cv-aCO2/Da-vO2 >1.0; group 2, lactate ≥2.0 mmol/L and Cv-aCO2/Da-vO2 ≤1.0; group 3, lactate <2.0 mmol/L and Cv-aCO2/Da-vO2 >1.0; and group 4, lactate <2.0 mmol/L and Cv-aCO2/Da-vO2 ≤1.0. RESULTS: Combination of hyperlactatemia and high Cv-aCO2/Da-vO2 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-aCO2/Da-vO2 ratio and lactate <2.0 mmol/L had similar outcomes to hyperlactatemic patients with low Cv-aCO2/Da-vO2 ratio. The multivariate analysis revealed that Cv-aCO2/Da-vO2 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-aCO2/Da-vO2 ratio during early stages of resuscitation of septic shock can better identify patients at high risk of adverse outcomes. The Cv-aCO2/Da-vO2 ratio may become a potential resuscitation goal in patients with septic shock.

Persistently high venous-to-arterial carbon dioxide differences during early resuscitation are associated with poor outcomes in septic shock.

INTRODUCTION: Venous-to-arterial carbon dioxide difference (Pv-aCO2) may reflect the adequacy of blood flow during shock states. We sought to test whether the development of Pv-aCO2 during the very early phases of resuscitation is related to multi-organ dysfunction and outcomes in a population of septic shock patients resuscitated targeting the usual oxygen-derived and hemodynamic parameters. METHODS: We conducted a prospective observational study in a 60-bed mixed ICU in a University affiliated Hospital. 85 patients with a new septic shock episode were included. A Pv-aCO2 value ≥ 6 mmHg was considered to be high. Patients were classified in four predefined groups according to the Pv-aCO2 evolution during the first 6 hours of resuscitation: (1) persistently high Pv-aCO2 (high at T0 and T6); (2) increasing Pv-aCO2 (normal at T0, high at T6); (3) decreasing Pv-aCO2 (high at T0, normal at T6); and (4) persistently normal Pv-aCO2 (normal at T0 and T6). Multiorgan dysfunction at day-3 was compared for predefined groups and a Kaplan Meier curve was constructed to show the survival probabilities at day-28 using a log-rank test to evaluate differences between groups. A Spearman-Rho was used to test the agreement between cardiac output and Pv-aCO2. Finally, we calculated the mortality risk ratios at day-28 among patients attaining normal oxygen parameters but with a concomitantly increased Pv-aCO2. RESULTS: Patients with persistently high and increasing Pv-aCO2 at T6 had significant higher SOFA scores at day-3 (p < 0.001) and higher mortality rates at day-28 (log rank test: 19.21, p < 0.001) compared with patients who evolved with normal Pv-aCO2 at T6. Interestingly, a poor agreement between cardiac output and Pv-aCO2 was observed (r2 = 0.025, p < 0.01) at different points of resuscitation. Patients who reached a central venous saturation (ScvO)2 ≥ 70% or mixed venous oxygen saturation (SvO2) ≥ 65% but with concomitantly high Pv-aCO2 at different developmental points (i.e., T0, T6 and T12) had a significant mortality risk ratio at day-28. CONCLUSION: The persistence of high Pv-aCO2 during the early resuscitation of septic shock was associated with more severe multi-organ dysfunction and worse outcomes at day-28. Although mechanisms conducting to increase Pv-aCO2 during septic shock are insufficiently understood, Pv-aCO2 could identify a high risk of death in apparently resuscitated patients.