Mario Omar Pozo

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

IntroductionOur goal was to assess the effects of titration of a norepinephrine infusion to increasing levels of mean arterial pressure (MAP) on sublingual microcirculation.MethodsTwenty 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 (ΔPCO2). 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.ResultsIncreasing 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 ΔPCO2 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).ConclusionsPatients 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.

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.

Persistent villi hypoperfusion explains intramucosal acidosis in sheep endotoxemia.

Objective: To test the hypothesis that persistent villi hypoperfusion explains intramucosal acidosis after endotoxemic shock resuscitation. Design: Controlled experimental study. Setting: University-based research laboratory. Subjects: A total of 14 anesthetized, mechanically ventilated sheep. Interventions: Sheep were randomly assigned to endotoxin (n = 7) or control groups (n = 7). The endotoxin group received 5 &mgr;g/kg endotoxin, followed by 4 &mgr;g·kg−1·hr−1 for 150 mins. After 60 mins of shock, hydroxyethylstarch resuscitation was given to normalize oxygen transport for an additional 90 mins. Measurements and Main Results: Endotoxin infusion decreased mean arterial blood pressure, cardiac output, and superior mesenteric artery blood flow (96 ± 10 vs. 51 ± 20 mm Hg, 145 ± 30 vs. 90 ± 30 mL·min−1·kg−1, and 643 ± 203 vs. 317 ± 93 mL·min−1·kg−1, respectively; p < .05 vs. basal), whereas it increased intramucosal–arterial Pco2 (&Dgr;Pco2) and arterial lactate (3 ± 3 vs. 14 ± 8 mm Hg, and 1.5 ± 0.5 vs. 3.7 ± 1.3 mmol/L; p < .05). Sublingual, and serosal and mucosal intestinal microvascular flow indexes, and the percentage of perfused ileal villi were reduced (3.0 ± 0.1 vs. 2.3 ± 0.4, 3.2 ± 0.2 vs. 2.4 ± 0.6, 3.0 ± 0.0 vs. 2.0 ± 0.2, and 98% ± 3% vs. 76% ± 10%; p < .05). Resuscitation normalized mean arterial blood pressure (92 ± 13 mm Hg), cardiac output (165 ± 32 mL·min−1·kg−1), superior mesenteric artery blood flow (683 ± 192 mL·min−1·kg−1), and sublingual and serosal intestinal microvascular flow indexes (2.8 ± 0.5 and 3.5 ± 0.7). Nevertheless, &Dgr;Pco2, lactate, mucosal intestinal microvascular flow indexes, and percentage of perfused ileal villi remained altered (10 ± 6 mm Hg, 3.7 ± 0.9 mmol/L, 2.3 ± 0.4, and 78% ± 11%; p < .05). Conclusions: In this model of endotoxemia, fluid resuscitation corrected both serosal intestinal and sublingual microcirculation but was unable to restore intestinal mucosal perfusion. Intramucosal acidosis might be due to persistent villi hypoperfusion.

Effects of levosimendan and dobutamine in experimental acute endotoxemia: a preliminary controlled study

ObjectiveTo test the hypothesis that levosimendan increases systemic and intestinal oxygen delivery (DO2) and prevents intramucosal acidosis in septic shock.DesignProspective, controlled experimental study.SettingUniversity-based research laboratory.SubjectsNineteen anesthetized, mechanically ventilated sheep.InterventionsEndotoxin-treated sheep were randomly assigned to three groups: control (n = 7), dobutamine (10 μg/kg/min, n = 6) and levosimendan (100 μg/kg over 10 min followed by 100 μg/kg/h, n = 6) and treated for 120 min.Measurements and main resultsAfter endotoxin administration, systemic and intestinal DO2 decreased (24.6 ± 5.2 vs 15.3 ± 3.4 ml/kg/min and 105.0 ± 28.1 vs 55.8 ± 25.9 ml/kg/min, respectively; p < 0.05 for both). Arterial lactate and the intramucosal–arterial PCO2 difference (ΔPCO2) increased (1.4 ± 0.3 vs 3.1 ± 1.5 mmHg and 9 ± 6 vs 23 ± 6 mmHg mmol/l, respectively; p < 0.05). Systemic DO2 was preserved in the dobutamine-treated group (22.3 ± 4.7 vs 26.8 ± 7.0 ml/min/kg, p = NS) but intestinal DO2 decreased (98.9 ± 0.2 vs 68.0 ± 22.9 ml/min/kg, p < 0.05) and ΔPCO2 increased (12 ± 5 vs 25 ± 11 mmHg, p < 0.05). The administration of levosimendan prevented declines in systemic and intestinal DO2 (25.1 ± 3.0 vs 24.0 ± 6.3 ml/min/kg and 111.1 ± 18.0 vs 98.2 ± 23.1 ml/min/kg, p = NS for both) or increases in ΔPCO2 (7 ± 7 vs 10 ± 8, p = NS). Arterial lactate increased in both the dobutamine and levosimendan groups (1.6 ± 0.3 vs 2.5 ± 0.7 and 1.4 ± 0.4 vs. 2.9 ± 1.1 mmol/l, p = NS between groups).ConclusionsCompared with dobutamine, levosimendan increased intestinal blood flow and diminished intramucosal acidosis in this experimental model of sepsis.

Intramucosal–arterial PCO2 gap fails to reflect intestinal dysoxia in hypoxic hypoxia

IntroductionAn elevation in intramucosal–arterial PCO2 gradient (ΔPCO2) could be determined either by tissue hypoxia or by reduced blood flow. Our hypothesis was that in hypoxic hypoxia with preserved blood flow, ΔPCO2 should not be altered.MethodsIn 17 anesthetized and mechanically ventilated sheep, oxygen delivery was reduced by decreasing flow (ischemic hypoxia, IH) or arterial oxygen saturation (hypoxic hypoxia, HH), or no intervention was made (sham). In the IH group (n = 6), blood flow was lowered by stepwise hemorrhage; in the HH group (n = 6), hydrochloric acid was instilled intratracheally. We measured cardiac output, superior mesenteric blood flow, gases, hemoglobin, and oxygen saturations in arterial blood, mixed venous blood, and mesenteric venous blood, and ileal intramucosal PCO2 by tonometry. Systemic and intestinal oxygen transport and consumption were calculated, as was ΔPCO2. After basal measurements, measurements were repeated at 30, 60, and 90 minutes.ResultsBoth progressive bleeding and hydrochloric acid aspiration provoked critical reductions in systemic and intestinal oxygen delivery and consumption. No changes occurred in the sham group. ΔPCO2 increased in the IH group (12 ± 10 [mean ± SD] versus 40 ± 13 mmHg; P < 0.001), but remained unchanged in HH and in the sham group (13 ± 6 versus 10 ± 13 mmHg and 8 ± 5 versus 9 ± 6 mmHg; not significant).DiscussionIn this experimental model of hypoxic hypoxia with preserved blood flow, ΔPCO2 was not modified during dependence of oxygen uptake on oxygen transport. These results suggest that ΔPCO2 might be determined primarily by blood flow.

Severe abnormalities in microvascular perfused vessel density are associated to organ dysfunctions and mortality and can be predicted by hyperlactatemia and norepinephrine requirements in septic shock patients

PURPOSE The aims of this study are to determine the general relationship of perfused vessel density (PVD) to mortality and organ dysfunctions and to explore if patients in the lowest quartile of distribution for this parameter present a higher risk of bad outcome and to identify systemic hemodynamic and perfusion variables that enhances the probability of finding a severe underlying microvascular dysfunction. MATERIALS AND METHODS This is a retrospective multicenter study including 122 septic shock patients participating in 7 prospective clinical trials on which at least 1 sublingual microcirculatory assessment was performed during early resuscitation. RESULTS Perfused vessel density was significantly related to organ dysfunctions and mortality, but this effect was largely explained by patients in the lowest quartile of distribution for PVD (P = .037 [odds ratio {OR}, 8.7; 95% confidence interval {CI}, 1.14-66.78] for mortality). Hyperlactatemia (P < .026 [OR, 1.23; 95% CI, 1.03-1.47]) and high norepinephrine requirements (P < .019 [OR, 7.04; 95% CI, 1.38-35.89]) increased the odds of finding a severe microvascular dysfunction. CONCLUSIONS Perfused vessel density is significantly related to organ dysfunctions and mortality in septic shock patients, particularly in patients exhibiting more severe abnormalities as represented by the lowest quartile of distribution for this parameter. The presence of hyperlactatemia and high norepinephrine requirements increases the odds of finding a severe underlying microvascular dysfunction during a sublingual microcirculatory assessment.

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

IntroductionIncreased intramucosal–arterial carbon dioxide tension (PCO2) difference (ΔPCO2) 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 ΔPCO2.MethodsIn 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 μg/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.ResultsIn the normal blood flow group, systemic and intestinal oxygen transport and consumption were preserved, but ΔPCO2 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 ΔPCO2 (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).ConclusionsIn 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.

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 (MFIby quadrants), (2) the direct assessment during the bedside video acquisition (MFIpoint of care), and (3) the mean value of the MFIs determined in each individual vessel (MFIvessel by vessel). We hypothesized that the agreement between the MFIs is poor and that the MFIvessel 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 MFIby quadrants and MFIpoint of care (1.46), between MFIby quadrants and MFIvessel by vessel (2.85), and between MFIby point of care and MFIvessel by vessel (2.56). The MFIs significantly correlated with the RBC velocity and with the fraction of perfused small vessels, but MFIvessel by vessel showed the best R 2. Although the different methods for the calculation of MFI reflect microvascular perfusion, they are not interchangeable and MFIvessel by vessel might be better.

Intestinal and sublingual microcirculation are more severely compromised in hemodilution than in hemorrhage

The alterations in O2 extraction in hemodilution have been linked to fast red blood cell (RBC) velocity, which might affect the complete release of O2 from Hb. Fast RBC velocity might also explain the normal mucosal-arterial Pco2 (ΔPco2). Yet sublingual and intestinal microcirculation have not been completely characterized in extreme hemodilution. Our hypothesis was that the unchanged ΔPco2 in hemodilution depends on the preservation of villi microcirculation. For this purpose, pentobarbital-anesthetized and mechanically ventilated sheep were submitted to stepwise hemodilution (n = 8), hemorrhage (n = 8), or no intervention (sham, n = 8). In both hypoxic groups, equivalent reductions in O2 consumption (V̇o2) were targeted. Microcirculation was assessed by videomicroscopy, intestinal ΔPco2 by air tonometry, and V̇o2 by expired gases analysis. Although cardiac output and superior mesenteric flow increased in hemodilution, from the very first step (Hb = 5.0 g/dl), villi functional vascular density and RBC velocity decreased (21.7 ± 0.9 vs. 15.9 ± 1.0 mm/mm(2) and 1,033 ± 75 vs. 850 ± 79 μm/s, P < 0.01). In the last stage (Hb = 1.2 g/dl), these variables were lower in hemodiution than in hemorrhage (11.1 ± 0.5 vs. 15.4 ± 0.9 mm/mm(2) and 544 ± 26 vs. 686 ± 70 μm/s, P < 0.01), and were associated with lower intestinal fractional O2 extraction (0.61 ± 0.04 vs. 0.79 ± 0.02, P < 0.01) but preserved ΔPco2 (5 ± 2 vs. 25 ± 4 mmHg, P < 0.01). Therefore, alterations in O2 extraction in hemodilution seemed related to microvascular shunting, not to fast RBC velocity. The severe microvascular abnormalities suggest that normal ΔPco2 was not dependent on CO2 washout by the villi microcirculation. Increased perfusion in deeper intestinal layers might be an alternative explanation.

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

IntroductionContinuous 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.MethodSix 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.ResultsAfter 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 ΔPCO2 3 ± 3 versus 12 ± 5, ileal ΔPCO2 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 ΔPCO2, which remained at ischaemic levels (13 ± 7 mmHg).ConclusionTissue 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 ΔPCO2 was greater than the mesenteric venous–arterial PCO2 suggests that tonometrically measured PCO2 reflects mucosal rather than transmural PCO2. Ileal ΔPCO2 appears to be the more sensitive marker of ischaemia.