Jacques Creteur

Persistent microcirculatory alterations are associated with organ failure and death in patients with septic shock

Objective:To characterize the time course of microcirculatory alterations and their relation to outcome in patients with septic shock. Design:Prospective, observational study. Setting:Thirty-one-bed, medico-surgical intensive care unit in a university hospital. Patients:Forty-nine patients with septic shock. Interventions:The sublingual microcirculation was investigated with an orthogonal polarization spectral imaging device on the day of onset of septic shock (baseline) and each day until resolution of shock. Measurements and Main Results:Five sequences of 20 secs each were recorded and analyzed off-line by a semiquantitative method. Data were analyzed with nonparametric tests and presented as median (25th–75th percentiles). Three patients died after the resolution of shock from unrelated causes and were excluded. Of the other 46 patients, 26 survived and 20 died: 13 due to unresolving shock and seven due to persistent multiple organ failure after resolution of shock. At the onset of shock, survivors and nonsurvivors had similar vascular density (5.6 [4.7–7.0] vs. 6.2 [5.4–7.0]/mL; p = nonsignificant) and percentage of perfused small vessels (65.0 [53.1–68.9] vs. 58.4 [47.5–69.1]%; p = nonsignificant). Small vessel perfusion improved over time in survivors (analysis of variance, p < .05 between survivors and nonsurvivors) but not in nonsurvivors. Despite similar hemodynamic and oxygenation profiles and use of vasopressors at the end of shock, patients dying after the resolution of shock in multiple organ failure had a lower percentage of perfused small vessels than survivors (57.4 [46.6–64.9] vs. 79.3 [67.2–83.2]%; p = .02). Conclusions:Microcirculatory alterations improve rapidly in septic shock survivors but not in patients dying with multiple organ failure, regardless of whether shock has resolved.

The effects of dobutamine on microcirculatory alterations in patients with septic shock are independent of its systemic effects.

Objective:To evaluate the effects of dobutamine on microcirculatory blood flow alterations in patients with septic shock. Design:Prospective, open-label study. Setting:A 31-bed, medico-surgical intensive care unit of a university hospital. Patients:Twenty-two patients with septic shock. Interventions:Intravenous administration of dobutamine (5 &mgr;g/kg·min) for 2 hrs (n = 22) followed by the addition of 10−2 M acetylcholine (topically applied, n = 10). Measurements and Main Results:Complete hemodynamic measurements were obtained before and after dobutamine administration. In addition, the sublingual microcirculation was investigated with an orthogonal polarization spectral imaging technique before and after dobutamine administration and after topical application of acetylcholine. Dobutamine significantly improved capillary perfusion (from 48 ± 15 to 67 ± 11%, p = .001), but with large individual variation, whereas capillary density remained stable. The addition of topical acetylcholine completely restored capillary perfusion (98 ± 1%, p = .001) and capillary density. The changes in capillary perfusion during dobutamine administration were not related to changes in cardiac index (p = .45) or arterial pressure (p = .29). Interestingly, the decrease in lactate levels was proportional to the improvement in capillary perfusion (y = 0.07 − 0.02x, r2 = .46, p = .005) but not to changes in cardiac index (p = .55). Conclusions:The administration of 5 &mgr;g/kg·min dobutamine can improve but not restore capillary perfusion in patients with septic shock. These changes are independent of changes in systemic hemodynamic variables.

Effects of dopamine, norepinephrine, and epinephrine on the splanchnic circulation in septic shock: which is best?

OBJECTIVE To assess the effects of different doses of dopamine, norepinephrine, and epinephrine on the splanchnic circulation in patients with septic shock. DESIGN Prospective, randomized, open-label study. SETTING A 31-bed, medicosurgical intensive care unit of a university hospital. PATIENTS Convenience sample of 20 patients with septic shock, separated into two groups according to whether (moderate shock group, n = 10) or not (severe shock, n = 10) dopamine alone was able maintain mean arterial pressure >65 mm Hg. INTERVENTIONS Dopamine was progressively withdrawn and replaced successively by norepinephrine and then epinephrine (the order of the two agents was randomly determined) to maintain mean arterial pressure constant (moderate shock) or to increase mean arterial pressure above 65 mm Hg (severe shock). MEASUREMENTS AND MAIN RESULTS Systemic circulation (pulmonary artery catheter) and splanchnic circulation (indocyanine green dilution and hepatic vein catheter) and gastric mucosal Pco(2) (gas tonometry) were measured during dopamine (moderate shock only), norepinephrine, and epinephrine administration (both groups). Data were analyzed with nonparametric tests and are presented as median [percentiles 25-75]. In moderate shock, cardiac index was similar to dopamine and norepinephrine (3.1 [2.7-3.8] vs. 2.9 [2.7-4.1] L/min.m2, p = nonsignificant) but greater with epinephrine (4.1 [3.5-4.4] p <.01 vs. dopamine and norepinephrine). Splanchnic blood flow was similar with the three agents (732 [413-1483] vs. 746 [470-1401] vs. 653 [476-1832] mL/min.m, p = nonsignificant). The gradient between mixed-venous and hepatic venous oxygen saturations was lower with dopamine than with norepinephrine and epinephrine, but the Pco(2) gap was similar with the three agents. In severe shock, cardiac index was higher, but splanchnic blood flow was lower, with epinephrine than with norepinephrine (4.6 [3.7-5.3] vs. 3.4 [3.0-4.1] L/min.m2, p <.01 and 860 [684-1334] vs. 977 [806-1802] mL/min.m2, p <.05, respectively). Epinephrine increased the mixed-venous and hepatic venous oxygen saturation gradient but did not alter Pco(2) gap. CONCLUSIONS Dopamine and norepinephrine have similar hemodynamic effects, but epinephrine can impair splanchnic circulation in severe septic shock.

Monitoring the microcirculation in the critically ill patient: current methods and future approaches

PurposeTo discuss the techniques currently available to evaluate the microcirculation in critically ill patients. In addition, the most clinically relevant microcirculatory alterations will be discussed.MethodsReview of the literature on methods used to evaluate the microcirculation in humans and on microcirculatory alterations in critically ill patients.ResultsIn experimental conditions, shock states have been shown to be associated with a decrease in perfused capillary density and an increase in the heterogeneity of microcirculatory perfusion, with non-perfused capillaries in close vicinity to perfused capillaries. Techniques used to evaluate the microcirculation in humans should take into account the heterogeneity of microvascular perfusion. Microvideoscopic techniques, such as orthogonal polarization spectral (OPS) and sidestream dark field (SDF) imaging, directly evaluate microvascular networks covered by a thin epithelium, such as the sublingual microcirculation. Laser Doppler and tissue O2 measurements satisfactorily detect global decreases in tissue perfusion but not heterogeneity of microvascular perfusion. These techniques, and in particular laser Doppler and near-infrared spectroscopy, may help to evaluate the dynamic response of the microcirculation to a stress test. In patients with severe sepsis and septic shock, the microcirculation is characterized by a decrease in capillary density and in the proportion of perfused capillaries, together with a blunted response to a vascular occlusion test.ConclusionsThe microcirculation in humans can be evaluated directly by videomicroscopy (OPS/SDF) or indirectly by vascular occlusion tests. Of note, direct videomicroscopic visualization evaluates the actual state of the microcirculation, whereas the vascular occlusion test evaluates microvascular reserve.

Effects of levosimendan on systemic and regional hemodynamics in septic myocardial depression

We read with interest the contribution by Morelli et al. [1]. However, we find that the manuscript makes a number of omissions and is sometimes quite confusing. We would like to raise the following questions: First, one would like to know when and where the study was conducted. Indeed, this raises the issue of selection criteria. Clearly the patients were not enrolled consecutively, and we suppose that there was some convenience factor in the enrollment. Indeed, the patient population was very homogeneous: their cardiac output values were very close to 4.1 l min–1 m–2 at baseline (with a standard deviation of only 0.2 l min–1 m–2); likewise the standard deviation for mean arterial pressure was less than 3 mmHg, and that for PCO2 gap 1 mmHg (less than the measurement error). There should also be some information about the degree of organ dysfunction in these patients. At least the number of patients treated with extracorporeal renal support should be provided. Second, it is difficult to appreciate whether the baseline measurements were performed on or off dobutamine. The text only mentions in the protocol section that “the dobutamine infusion was stopped for a short time necessary to start the syringe-pumps containing either dobutamine or levosimendan.” If the patients were off dobutamine at baseline, the total lack of effect of dobutamine at 24 h is quite surprising. If the baseline measurements were obtained on dobutamine, the measurements obtained at 24 h on levosimendan would be a comparison of levosimendan (at 24 h) vs. dobutamine (at baseline). If the aim was to study the hemodynamic effects of levosimendan, why was the study not performed over a shorter period of time? It is quite unusual that the patients remained so stable during a 24-h period without any change in lactate level in patients treated with dobutamine. Even patients who do not improve experience a decrease in blood lactate levels over time: we therefore presume that some patients deteriorated substantially. Third, there should be more information about the source of sepsis. It is also surprising that all patients had either a Gram-positive or a Gramnegative culture (Table 1) but never a mixed flora, other micro-organisms than bacteria or negative cultures. Fourth, the statistical analysis is suboptimal: As two groups are compared over time, an analysis of variance should be applied. We would thank the authors for adding this important information to their interesting study. References

Microvascular response to red blood cell transfusion in patients with severe sepsis.

Objectives:Microvascular alterations may play a role in the development of multiple organ failure in severe sepsis. The effects of red blood cell transfusions on microvascular perfusion are not well defined. We investigated the effects of red blood cell transfusion on sublingual microvascular perfusion in patients with sepsis. Design:Prospective, observational study. Setting:A 31-bed, medical-surgical intensive care unit of a university hospital. Patients:Thirty-five patients with severe sepsis requiring red blood cell transfusions. Interventions:Transfusion of one to two units of leukocyte-reduced red blood cells. Measurements and Main Results:The sublingual microcirculation was assessed with an Orthogonal Polarization Spectral device before and 1 hr after red blood cell transfusion. Red blood cell transfusions increased hemoglobin concentration from 7.1 (25th–75th percentile, 6.7–7.6) to 8.1 (7.5–8.6) g/dL (p < .01), mean arterial pressure from 75 (69–89) to 82 (75–90) mm Hg (p < .01), and oxygen delivery from 349 (278–392) to 391 (273–473) mL/min·M2 (p < .001). Microvascular perfusion was not significantly altered by transfusion, but there was considerable interindividual variation. The change in capillary perfusion after transfusion correlated with baseline capillary perfusion (Spearman-rho = −.49; p = .003). Capillary perfusion was significantly lower at baseline in patients who increased their capillary perfusion by >8% compared with those who did not (57 [52–64] vs. 75 [70–79]; p < .01), while hemodynamic and global oxygen transport variables were similar in the two groups. Red blood cell storage time had no influence on the microvascular response to red blood cell transfusion. Conclusions:The sublingual microcirculation is globally unaltered by red blood cell transfusion in septic patients; however, it can improve in patients with altered capillary perfusion at baseline.

Albumin administration improves organ function in critically ill hypoalbuminemic patients: A prospective, randomized, controlled, pilot study*

Objective:To test the hypothesis that administration of albumin to correct hypoalbuminemia might have beneficial effects on organ function in a mixed population of critically ill patients. Design:Prospective, controlled, randomized study. Setting:Thirty-one-bed, mixed medicosurgical department of intensive care. Patients:All adult patients with a serum albumin concentration ≤30 g/L were assessed for eligibility. Principal exclusion criteria were expected length of stay <72 hrs, life expectancy <3 months or a do-not-resuscitate order, albumin administration in the preceding 24 hrs, or evidence of fluid overload. Interventions:The 100 patients were randomized to receive 300 mL of 20% albumin solution on the first day, then 200 mL/day provided their serum albumin concentration was <31 g/dL (albumin group), or to receive no albumin (control group). Measurements and Main Results:The primary outcome was the effect of albumin administration on organ function as assessed by a delta Sequential Organ Failure Assessment score from day 1 to day 7 (or the day of intensive care discharge or death, whichever came first). The two groups of 50 patients were comparable at baseline for age, gender, albumin concentration, and Acute Physiology and Chronic Health Evaluation II score. Albumin concentration did not change over time in the control group but increased consistently in the albumin group (p < .001). Organ function improved more in the albumin than in the control group (p = .026), mainly due to a difference in respiratory, cardiovascular, and central nervous system components of the Sequential Organ Failure Assessment score. Diuretic use was identical in both groups, but mean fluid gain was almost three times higher in the control group (1679 ± 1156 vs. 658 ± 1101 mL, p = .04). Median daily calorie intake was higher in the albumin than in the control group (1122 [935–1158] vs. 760 [571–1077] kcal, p = .05). Conclusions:Albumin administration may improve organ function in hypoalbuminemic critically ill patients. It results in a less positive fluid balance and a better tolerance to enteral feeding.

Sublingual capnometry tracks microcirculatory changes in septic patients.

ObjectiveTo test the hypothesis that microcirculatory blood flow is the main determinant of sublingual carbon dioxide pressure in patients with septic shock.DesignProspective, open-label studySettingA 31-bed medico-surgical department of intensive care.PatientsEighteen consecutive mechanically ventilated patients with septic shock.InterventionsA 5 μg/kg · min dobutamine infusion was used to increase blood flow.MethodsSublingual carbon dioxide pressure was monitored using a microelectrode sensor, and sublingual microcirculation was assessed using orthogonal polarization spectral imaging. The sublingual carbon dioxide pressure gap was calculated as the difference between sublingual and arterial carbon dioxide pressures. In each patient, a nasogastric tonometry catheter was inserted for gastric mucosal carbon dioxide pressure measurement. The gastric carbon dioxide pressure gap was calculated as the difference between gastric mucosal and arterial carbon dioxide pressures. Measurements and resultsDobutamine infusion was associated with increases cardiac index and mixed venous blood oxygen saturation. Dobutamine infusion resulted in decreases in sublingual carbon dioxide pressure gap from 40 ± 15 to 17 ± 8 mmHg (p < 0.01). There was a significant correlation between sublingual and gastric mucosal carbon dioxide pressures (r2 = 0.61, p < 0.05). At baseline, sublingual carbon dioxide pressure gap correlated with the proportion of well-perfused capillaries (r2 = 0.80). The decrease in sublingual carbon dioxide pressure gap paralleled the increase in the proportion of well-perfused capillaries in each patient.ConclusionsRegional microcirculatory blood flow is the main determinant of sublingual carbon dioxide pressure. Sublingual capnometry could represent a simple, non-invasive method to monitor these microcirculatory alterations in septic patients.

Monitoring Gastric Mucosal Carbon Dioxide Pressure Using Gas Tonometry: In Vitro and in Vivo Validation Studies

Background Saline gastric tonometry of carbon dioxide has been proposed as a means to assess the adequacy of splanchnic perfusion. However, this technique has several disadvantages, including the long time interval needed for gases to reach equilibrium in saline milieu. Thus the authors evaluated a system that uses a gas-filled instead of a saline-filled gastric balloon. Methods In vitro, we simultaneously placed two tonometry catheters in an equilibration water bath maintained at a predetermined and constant pressure of carbon dioxide (PCO2). The first catheters balloon was filled with air and the second with saline. The performance of gas tonometry was tested by comparing the PCO2 measurements of the bath obtained via gas tonometry (PgCO2) to the PCO2 measurements of direct bath samples (PbathCO2). These results were also compared with the PCO2 measurements obtained simultaneously by saline tonometry (PsCO2). The response time of gas versus saline tonometry was also studied. In vivo, the performance of gas tonometry was tested comparing the measurements of gastric intramucosal PCO2 obtained by gas tonometry (PgCO2) at different equilibration times with those obtained by saline tonometry (PsCO2) using an equilibration time of 30 min. Two nasogastric tonometry catheters were placed simultaneously in seven stable patients in the intensive care unit. The first balloon was filled with air and the second with saline. Results In vitro, there was a close correlation between PgCO sub 2 and PbathCO2, for each level of PbathCO2, and for each different gas equilibration time. For an equilibration time of 10 min at a PbathCO2 level of approximately 40 mmHg, the bias of the gas device defined as the mean of the differences between Pbath sub CO2 and PgCO2, and its precision defined as the standard deviation of the bias, were -0.3 mmHg and 0.7 mmHg, respectively. Using the same definitions, the bias and precision of saline tonometry were 11.2 mmHg and 1.4 mmHg, respectively. If the equilibration time-dependent correction factor provided by the catheter manufacturer for saline tonometry was applied, the bias and precision were -6.9 mmHg and 2.9 mmHg, respectively. In vivo, using an equilibration time of 10 min for gas and 30 min for saline tonometry, there was a close correlation between the two techniques (r2 = 0.986). A Bland and Altman analysis revealed a bias (+/- 2 SD) of 0.1 +/- 6.8 mmHg. The correlation between the two methods was not improved if we prolonged the equilibration time of the gas tonometer. Conclusions Gas tonometry is comparable to saline tonometry for measuring gastric intramucosal PCO2. Because gas tonometry is easier to automate, it may offer advantages over saline tonometry.

Near-infrared spectroscopy technique to evaluate the effects of red blood cell transfusion on tissue oxygenation

IntroductionThe aim of this study was to evaluate the effects of red blood cell (RBC) transfusions on muscle tissue oxygenation, oxygen metabolism and microvascular reactivity in critically ill patients using near-infrared spectroscopy (NIRS) technology.MethodsThis prospective, observational study included 44 consecutive patients hospitalized in the 31-bed, medical-surgical intensive care unit of a university hospital with anemia requiring red blood cell transfusion. Thenar tissue oxygen saturation (StO2) and muscle tissue hemoglobin index (THI) were measured using a tissue spectrometer (InSpectra™ Model 325; Hutchinson Technology Inc., Hutchinson, MN, USA). A vaso-occlusive test was performed before and 1 hour after RBC transfusion by rapid inflation of a pneumatic cuff around the upper arm. The following variables were recorded: THI, the StO2 desaturation slope during the occlusion (%/minute) and the StO2 upslope of the reperfusion phase following the ischemic period (%/second). Muscle oxygen consumption (NIR VO2; arbitrary units) was calculated as the product of the inverse StO2 desaturation slope and the mean THI over the first minute of arterial occlusion.ResultsBlood transfusion resulted in increases in hemoglobin (from 7.1 (6.7 to 7.7) to 8.4 (7.1 to 9) g/dl; P < 0.01) and in oxygen delivery (from 306 (259 to 337) to 356 (332 to 422) ml/minute/m2; P < 0.001). However, systemic VO2 was unchanged. RBC transfusion did not globally affect NIRS-derived variables, but there was considerable interindividual variation. Changes in the StO2 upslope of the reperfusion phase after transfusion were negatively correlated with baseline StO2 upslope of the reperfusion phase (r2 = 0.42; P < 0.0001). Changes in NIR VO2 after transfusion were also negatively correlated with baseline NIR VO2 (r2 = 0.48; P = 0.0015). There were no correlations between RBC storage time and changes in StO2 slope or NIR VO2.ConclusionsMuscle tissue oxygenation, oxygen consumption and microvascular reactivity are globally unaltered by RBC transfusion in critically ill patients. However, muscle oxygen consumption and microvascular reactivity can improve following transfusion in patients with alterations of these variables at baseline.