E. Christiaan Boerma

Quantifying bedside-derived imaging of microcirculatory abnormalities in septic patients: a prospective validation study

IntroductionThe introduction of orthogonal polarization spectral (OPS) imaging in clinical research has elucidated new perspectives on the role of microcirculatory flow abnormalities in the pathogenesis of sepsis. Essential to the process of understanding and reproducing these abnormalities is the method of quantification of flow scores.MethodsIn a consensus meeting with collaboraters from six research centres in different fields of experience with microcirculatory OPS imaging, premeditated qualifications for a simple, translucent and reproducible way of flow scoring were defined. Consecutively, a single-centre prospective observational validation study was performed in a group of 12 patients with an abdominal sepsis and a new stoma. Flow images of the microcirculation in vascular beds of the sublingual and stoma region were obtained, processed and analysed in a standardised way. We validated intra-observer and inter-observer reproducibility with kappa cross-tables for both types of microvascular beds.ResultsAgreement and kappa coefficients were >85% and >0.75, respectively, for interrater and intrarater variability in quantification of flow abnormalities during sepsis, in different subsets of microvascular architecture.ConclusionSemi-quantitative analysis of microcirculatory flow, as described, provides a reproducible and transparent tool in clinical research to monitor and evaluate the microcirculation during sepsis.

Relationship between sublingual and intestinal microcirculatory perfusion in patients with abdominal sepsis

Objective:To evaluate the relation between sublingual and intestinal microcirculatory alterations in patients with abdominal sepsis. Design:Prospective observational study. Setting:A 23-bed mixed intensive care unit of a tertiary teaching hospital. Patients:Twenty-three patients with abdominal sepsis and a newly constructed intestinal stoma were included in the study group. Nineteen outpatient healthy individuals with an intestinal stoma and ten nonsepsis patients with a <24-hr-old intestinal stoma were included as controls. Interventions:None. Measurements and Main Results:Orthogonal polarization spectral imaging of the sublingual and intestinal microcirculation was performed on days 1 and 3. In addition, variables of systemic hemodynamics, such as cardiac index, heart rate, blood pressure, central venous pressure, and dosages of vasopressor and inotropic agents, were obtained. On day 1 there was no correlation of the microvascular flow index between the sublingual and intestinal microcirculatory beds (Spearmans rho [rs] = .12; 95% confidence interval, −.51 to .31; p = .59). Furthermore, there was no significant correlation between microcirculatory alterations and variables of systemic circulation (rs ≤ .25). On day 3, however, a correlation between sublingual and intestinal microcirculatory flow appeared to be restored (rs = .74; 95% confidence interval, .28–.92; p = .006), mainly due to a normalization of flow in both regions. Conclusions:On day 1 of abdominal sepsis there is a complete dispersion of flow, not only between hemodynamic compartments of a different order but also between the sublingual and intestinal microcirculation. Over time, both sublingual and intestinal microvascular flow indexes trended to normal values.

Effects of nitroglycerin on sublingual microcirculatory blood flow in patients with severe sepsis/septic shock after a strict resuscitation protocol: a double-blind randomized placebo controlled trial.

Objectives:Microcirculatory alterations have been associated with morbidity and mortality in human sepsis. Such alterations occur despite pressure-guided resuscitation. Earlier data suggested that impaired microcirculatory blood flow could be corrected with intravenous nitroglycerin in these patients. We tested this concept after fulfillment of preset systemic hemodynamic resuscitation end points in the early phase of sepsis. Design:Prospective, single center, randomized, placebo-controlled, double-blind clinical trial. Setting:Closed-format 22-bed mixed intensive care unit in a tertiary teaching hospital. Patients:Patients ≥18 yrs with sepsis, according to international criteria, and at least one early sign of organ dysfunction, as the principal reason for intensive care unit admission, were eligible for enrollment. Interventions:Patients were randomly assigned to receive nitroglycerin (n = 35) or placebo (n = 35) after fulfillment of protocol-driven resuscitation end points. This trial is registered with ClinicalTrials.gov as NCT00493415. Measurements and Main Results:Primary outcome was sublingual microcirculatory blood flow of small vessels, as assessed by side-stream dark field imaging. After protocolized resuscitation, we observed recruitment of sublingual microcirculation in both groups, as indicated by a significant improvement in the microcirculatory flow index after 24 hrs, in comparison to baseline. However, no difference in the sublingual microvascular flow index was observed between groups. The median microvascular flow index in sublingual small-sized vessels was 2.71 (1.85-3) in the nitroglycerin group and 2.71 (1.27-3), p = .80, in the placebo group. In medium-sized vessels, the respective values were 3 (2.75-3) vs. 2.86 (2.19-3), p = .21, and in large-sized vessels, 3 (3-3) vs. 3 (2.89-3), p = .06. In-hospital mortality, as a secondary outcome, was 34.3% in the nitroglycerin group and 14.2% in the placebo group, p = .09. Conclusions:In the context of a strict resuscitation protocol, based upon fulfillment of systemic hemodynamic end points in patients with early-phase severe sepsis or septic shock, we conclude that intravenous nitroglycerin does not promote sublingual microcirculatory blood flow.

Furosemide does not improve renal recovery after hemofiltration for acute renal failure in critically ill patients: a double blind randomized controlled trial.

Objective:To study the potential beneficial role of furosemide in resolving renal failure after hemofiltration in mechanically ventilated critically ill patients. Design:Single-center randomized, double blind, placebo-controlled study. Setting:A 13-bed mixed intensive care unit (ICU) in a teaching hospital. Patients:Patients who had been treated with continuous venovenous hemofiltration were included. Interventions:After the end of continuous venovenous hemofiltration, the urine of the first 4 hours was collected for measuring creatinine clearance. Patients were subsequently randomized for furosemide (0.5 mg/kg/hr) or placebo by continuous infusion. To prevent hypovolemia, the rate of fluid infusion was adapted every hour and was set as the urinary production of the previous hour. Measurements and Main Results:End points were renal recovery (creatinine clearance more than 30 mL/min or stable serum creatinine without renal replacement therapy) in the ICU and in the hospital. Seventy-two patients were included and 71 were eligible for the analysis. The 36 furosemide-treated patients had a significantly increased urinary volume compared with the 35 placebo-treated patients (median 247 mL/hr (interquartile range [IQR] 774 mL/hr) vs. 117 mL/hr (IQR 158 mL/hr), p = 0.003) and greater sodium excretion (median 73 mmol/L (IQR 48) vs. 37 (IQR 48) mmol/L, p = 0.001). In the furosemide group 25 patients and in the placebo group 27 patients showed recovery of renal function at ICU discharge (p = 0.46). Two patients of the furosemide group needed long-term dialysis dependency (p = 0.23). Conclusion:Furosemide by continuous infusion in the recovery phase of hemofiltration-dependent acute kidney failure did increase urinary volume and sodium excretion but did not lead to a shorter duration of renal failure or more frequent renal recovery.

International study on microcirculatory shock occurrence in acutely ill patients

Objectives:Microcirculatory alterations are associated with adverse outcome in subsets of critically ill patients. The prevalence and significance of microcirculatory alterations in the general ICU population are unknown. We studied the prevalence of microcirculatory alterations in a heterogeneous ICU population and its predictive value in an integrative model of macro- and microcirculatory variables. Design:Multicenter observational point prevalence study. Setting:The Microcirculatory Shock Occurrence in Acutely ill Patients study was conducted in 36 ICUs worldwide. Patients:A heterogeneous ICU population consisting of 501 patients. Interventions:None. Measurements and Main Results:Demographic, hemodynamic, and laboratory data were collected in all ICU patients who were 18 years old or older. Sublingual Sidestream Dark Field imaging was performed to determine the prevalence of an abnormal capillary microvascular flow index (< 2.6) and its additional value in predicting hospital mortality. In 501 patients with a median Acute Physiology and Chronic Health Evaluation II score of 15 (10–21), a Sequential Organ Failure Assessment score of 5 (2–8), and a hospital mortality of 28.4%, 17% exhibited an abnormal capillary microvascular flow index. Tachycardia (heart rate > 90 beats/min) (odds ratio, 2.71; 95% CI, 1.67–4.39; p < 0.001), mean arterial pressure (odds ratio, 0.979; 95% CI, 0.963–0.996; p = 0.013), vasopressor use (odds ratio, 1.84; 95% CI, 1.11–3.07; p = 0.019), and lactate level more than 1.5 mEq/L (odds ratio, 2.15; 95% CI, 1.28–3.62; p = 0.004) were independent risk factors for hospital mortality, but not abnormal microvascular flow index. In reference to microvascular flow index, a significant interaction was observed with tachycardia. In patients with tachycardia, the presence of an abnormal microvascular flow index was an independent, additive predictor for in-hospital mortality (odds ratio, 3.24; 95% CI, 1.30–8.06; p = 0.011). This was not true for nontachycardic patients nor for the total group of patients. Conclusions:In a heterogeneous ICU population, an abnormal microvascular flow index was present in 17% of patients. This was not associated with mortality. However, in patients with tachycardia, an abnormal microvascular flow index was independently associated with an increased risk of hospital death.

Intravenous glucose intake independently related to intensive care unit and hospital mortality: an argument for glucose toxicity in critically ill patients.

Objective It is assumed that the toxic effects of glucose play a role in the outcome of critically ill patients. We studied the impact of the amount of infused glucose as a determinant of mortality.

Detection of citrate overdose in critically ill patients on citrate-anticoagulated venovenous haemofiltration: use of ionised and total/ionised calcium

Abstract Background: The objective of this study was to elucidate the most practical and effective laboratory measurement for monitoring citrate in critically ill patients undergoing citrate-anticoagulated continuous venovenous haemofiltration (CVVH). Methods: This observational study was performed at the mixed medical and surgical intensive care unit of a regional teaching hospital. The study population comprised ten consecutive critically ill patients with acute renal failure and indication for haemofiltration with the use of regional anticoagulation with citrate. Serum samples for the measurement of citrate and total and ionised calcium were taken from the pre- and post-filter compartments and from the arterial circulation of patients during citrate-anticoagulated CVVH. Results: Receiver operating characteristic (ROC) curve analysis showed that for detecting citrate overdose (defined as a citrate concentration >1.0mmol/L) the best cut-off limits for total/ionised calcium and ionised calcium were 2.1 and 0.8mmol/L, respectively. Sensitivity and specificity for the cut-off limit of 2.1 for total/ionised calcium were 89% and 100%, and 84% and 100%, respectively, for the cut-off limit of 0.8mmol/L for ionised calcium. Conclusions: In patients without liver insufficiency, total/ionised calcium performed slightly better than ionised calcium in detecting elevated citrate concentrations. However, because of the simplicity of its measurement, ionised calcium is preferred. Measurement of citrate is not necessary. Clin Chem Lab Med 2006;44:962–6.

HDL-cholesterol level and cortisol response to synacthen in critically ill patients

ObjectiveTo explore the relationship between cholesterol levels and the adrenal cortisol response to synacthen in critically ill patients.DesignProspective observational study.PatientsCritically ill patients with multiple organ dysfunction syndrome (MODS) with possible adrenal dysfunction defined as unexplained hypotension, ongoing inotropic support, unexplained fever, unexplained hyponatraemia or a combination of these symptoms.MeasurementsHDL-cholesterol levels (HDL), total cholesterol levels (TC), and triglycerides (TG) before administration of synacthen. LDL-cholesterol was calculated using the Friedewald formula. Basal cortisol and response to 250 μg synacthen intravenously was measured. A cortisol rise of 0.25 μmol/l in a 30-min or 60-min blood sample after synacthen infusion was defined as a proper adrenal response.ResultsPatients with a proper response to synacthen showed higher HDL-cholesterol levels than patients without that response (P=0.02). Severity of disease as measured by APACHE II or SOFA was not a confounder. LDL-cholesterol levels were extremely low in both responders and non-responders and were not associated with the absolute rise in cortisol. In linear and logistic regression analysis HDL-cholesterol was the sole predictor of cortisol response.ConclusionsAdrenal cortisol response to a “classic” 250-μg synacthen test relates in critically ill patients to HDL-cholesterol levels. LDL and TC levels did not show such a relation. These findings are in concordance with known biochemical pathways of cortisol production.

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.

No agreement of mixed venous and central venous saturation in sepsis, independent of sepsis origin

IntroductionControversy remains regarding the relationship between central venous saturation (ScvO2) and mixed venous saturation (SvO2) and their use and interchangeability in patients with sepsis or septic shock. We tested the hypothesis that ScvO2 does not reliably predict SvO2 in sepsis. Additionally we looked at the influence of the source (splanchnic or non-splanchnic) of sepsis on this relationship.MethodsIn this prospective observational two-center study we concurrently determined ScvO2 and SvO2 in a group of 53 patients with severe sepsis during the first 24 hours after admission to the intensive care units in 2 Dutch hospitals. We assessed correlation and agreement of ScvO2 and SvO2, including the difference, i.e. the gradient, between ScvO2 and SvO2 (ScvO2 - SvO2). Additionally, we compared the mean differences between ScvO2 and SvO2 of both splanchnic and non-splanchnic group.ResultsA total of 265 paired blood samples were obtained. ScvO2 overestimated SvO2 by less than 5% with wide limits of agreement. For changes in ScvO2 and SvO2 results were similar. The distribution of the (ScvO2 - SvO2) (< 0 or ≥ 0) was similar in survivors and nonsurvivors. The mean (ScvO2 - SvO2) in the splanchnic group was similar to the mean (ScvO2 - SvO2) in the non-splanchnic group (0.8 ± 3.9% vs. 2.5 ± 6.2%; P = 0.30). O2ER (P = 0.23) and its predictive value for outcome (P = 0.20) were similar in both groups.ConclusionsScvO2 does not reliably predict SvO2 in patients with severe sepsis. The trend of ScvO2 is not superior to the absolute value in this context. A positive difference (ScvO2 - SvO2) is not associated with improved outcome.