Lothar Engelmann

Selenium in Intensive Care (SIC): results of a prospective randomized, placebo-controlled, multiple-center study in patients with severe systemic inflammatory response syndrome, sepsis, and septic shock.

Objective: Sepsis is associated with an increase in reactive oxygen species and low endogenous antioxidative capacity. We postulated that high‐dose supplementation of sodium‐selenite would improve the outcome of patients with severe sepsis and septic shock. Design: Prospective randomized, placebo‐controlled, multiple‐center trial. Setting: Eleven intensive care units in Germany. Patients: Patients were 249 patients with severe systemic inflammatory response syndrome, sepsis, and septic shock and an Acute Physiology and Chronic Health Evaluation (APACHE) III score >70. Interventions: Patients received 1000 &mgr;g of sodium‐selenite as a 30‐min bolus injection, followed by 14 daily continuous infusions of 1000 &mgr;g intravenously, or placebo. Measurements and Main Results: The primary end point was 28‐day mortality; secondary end points were survival time and clinical course of APACHE III and logistic organ dysfunction system scores. In addition, selenium levels in serum, whole blood, and urine as well as serum gluthation‐peroxidase‐3 activity were measured. From 249 patients included, 11 patients had to be excluded. The intention‐to‐treat analysis of the remaining 238 patients revealed a mortality rate of 50.0% in the placebo group and 39.7% in the selenium‐treated group (p = .109; odds ratio, 0.66; confidence interval, 0.39–1.1). A further 49 patients had to be excluded before the final analysis because of severe violations of the study protocol. In the remaining 92 patients of the study group, the 28‐day mortality rate was significantly reduced to 42.4% compared with 56.7% in 97 patients of the placebo group (p = .049, odds ratio, 0.56; confidence interval, 0.32–1.00). In predefined subgroup analyses, the mortality rate was significantly reduced in patients with septic shock with disseminated intravascular coagulation (n = 82, p = .018) as well as in the most critically ill patients with an APACHE III score ≥102 (>75% quartile, n = 54, p = .040) or in patients with more than three organ dysfunctions (n = 83, p = .039). Whole blood selenium concentrations and glutathione peroxidase‐3 activity were within the upper normal range during selenium treatment, whereas they remained significantly low in the placebo group. There were no side effects observed due to high‐dose sodium‐selenite treatment. Conclusions: The adjuvant treatment of patients with high‐dose sodium‐selenite reduces mortality rate in patients with severe sepsis or septic shock.

Exhaled breath condensate acidification in acute lung injury

Lung injury in ventilated lungs may occur due to local or systemic disease and is usually caused by or accompanied by inflammatory processes. Recently, acidification of exhaled breath condensate pH (EBC-pH) has been suggested as marker of inflammation in airway disease. We investigated pH, ammonia, Lactate, pCO2, HCO3-, IL-6 and IL-8 in EBC of 35 ventilated patients (AECC-classification: ARDS: 15, ALI: 12, no lung injury: 8). EBC-pH was decreased in ventilated patients compared to volunteers (5.85 +/- 0.32 vs. 7.46 +/- 0.48; P < 0.0001). NH4+, lactate, HCO3-, pCO2, IL-6 and IL-8 were analyzed in EBC and correlated with EBC-pH. We observed correlations of EBC-pH with markers of local (EBC IL-6: r = -0.71, P < 0.0001, EBC IL-8: r = -0.68, P < 0.0001) but not of systemic inflammation (serum IL-6, serum IL-8) and with indices of severity of lung injury (Murrays Lung Injury Severity Score; r = -0.73, P < 0.0001, paO2/FiO2; r = 0.54, P < 0.001). Among factors potentially contributing to pH of EBC, EBC-lactate and EBC-NH4+ were found to correlate with EBC-pH. Inflammation-induced disturbances of regulatory mechanisms, such as glutaminase systems may result in EBC acidification. EBC-pH is suggested to represent a marker of acute lung injury caused by or accompanied by pulmonary inflammation.

Thrombin generation in severe haemophilia A and B: the endogenous thrombin potential in platelet-rich plasma

Thrombin generation was investigated in platelet-rich plasma (PRP) from 11 healthy controls, 17 patients with severe haemophilia A and 7 patients with severe haemophilia B. Mean endogenous thrombin potential (ETP) in arbitrary fluorescence units (FU) was 226.9 +/- 44.6, 186.4 +/- 22.5, 154.2 +/- 41.3 in controls, haemophilia A and B, respectively, all at a platelet count of 200 x 10(9)/l (p = 0.004 for controls vs. haemophilia A, p = 0.003 for controls vs. haemophilia B, no significant difference between haemophilia A and B). The contribution of FVIII to thrombin generation in haemophilia A was 1.31 +/- 0.16 FU/% of FVIII:C activity, while for FIX in haemophilia B this was 0.80 +/- 0.21 FU/% of FIX activity. There was an almost linear relationship between increasing platelet count and thrombin generation up to a mean platelet count of 100 x 10(9)/l. Further increase in platelet count has only a marginal influence on thrombin generation. Platelets increase ETP in haemophilia A by 0.184 +/- 0.022 FU/10(9) platelets/l and in haemophilia B by 0.319 +/- 0.085 FU/10(9) platelets/l, and this was significantly different between the two groups (p = 0.0002). This influence of plate-lets diminishes with increasing concentration of either FVIII or FIX. In conclusion, there is a difference in thrombin generation between haemophilia A and B, and this may be attributed to the role of platelets in the assembly of the tenase complex on their surface.

Adrenocortical hormones in survivors and nonsurvivors of severe sepsis: diverse time course of dehydroepiandrosterone, dehydroepiandrosterone-sulfate, and cortisol.

ObjectiveActivation and suppression of immune responses are crucial events during sepsis. Based on substantial new data, a complex picture of differential immune-enhancing and immunosuppressive actions of adrenocortical steroids is emerging. The adrenal androgen dehydroepiandrosterone and its precursor, dehydroepiandrosterone-sulfate, show a considerable decrease with increasing age and serve as functional antagonists to endogenous glucocorticoids. Therefore, we examined time-dependent changes in dehydroepiandrosterone, dehydroepiandrosterone-sulfate, cortisol, adrenocorticotropin, and inflammatory variables in surviving and nonsurviving patients with severe sepsis. DesignProspective observational study in consecutive patients. SettingMedical and interdisciplinary intensive care units in two university hospitals and one city hospital. PatientsThirty nonsurgical patients (25 men and 5 women) with severe sepsis (American College of Chest Physicians/Society of Critical Care Medicine criteria); 15 survivors (mean age, 54 ± 14 yrs; Acute Physiology and Chronic Health Evaluation III score, 59 ± 35) and 15 nonsurvivors (mean age, 63 ± 15 yrs; Acute Physiology and Chronic Health Evaluation III score, 67 ± 24) were included. Hormones were compared individually and between survivors/nonsurvivors by sequential blood drawings from early sepsis till time of recovery/death. InterventionsNone. Measurements and Main ResultsDuring early sepsis, cortisol (nmol/L) was not significantly higher in survivors than nonsurvivors (750 ± 121 vs. 454 ± 92, p < .08) and decreased in survivors (p < .01) during late sepsis. During early sepsis, dehydroepiandrosterone-sulfate (percentage of age-matched normal levels) was higher in survivors than nonsurvivors (85 ± 19 vs. 22 ± 7, p < .01). Dehydroepiandrosterone-sulfate decreased in survivors (p = .0001) but remained low in nonsurvivors during late sepsis. Dehydroepiandrosterone (percentage of age-matched normal levels) was not significantly elevated in survivors compared to nonsurvivors during early sepsis (282 ± 42 vs. 214 ± 63, p < .08). Dehydroepiandrosterone decreased in survivors (p < .01) but not in nonsurvivors during late sepsis. Linear regression for dehydroepiandrosterone levels showed a reconstitution of age dependence only in survivors during recovery. Adrenocorticotropin levels did not change. The dehydroepiandrosterone-sulfate/cortisol ratio decreased significantly in both survivors and nonsurvivors, whereas dehydroepiandrosterone/cortisol ratio only decreased in survivors during course of sepsis. ConclusionsDuring sepsis, adrenal androgens and glucocorticoids show a diverse time-dependent course in survivors and nonsurvivors.

The endogenous thrombin potential and high levels of coagulation factor VIII, factor IX and factor XI

High plasma concentrations of factor VIII, factor IX and factor XI have been reported as thrombosis risk factors. Using the thrombin generation test in platelet-poor plasma, it was aimed to describe the mechanism for this increased thrombosis risk. Endogenous thrombin potential was measured in platelet-poor plasma in 180 patients with a history of thromboembolism, and results were compared with those of 180 age-matched and sex-matched controls. Subjects with major hereditary and acquired thrombophilia were excluded. Plasma concentrations of the clotting factor VIII, factor IX and factor XI were significantly elevated in patients compared with controls. The mean endogenous thrombin potential was significantly higher in patients than in controls: 191.3 ± 3.1 (95% confidence interval, 185.3–197.4) arbitrary units versus 180.8 ± 2.6 (95% confidence interval, 175.7–185.9) arbitrary units (P = 0.009). The endogenous thrombin potential was significantly higher in patients with elevated factor IX and factor XI, but elevated factor VIII was not associated with a significant increase in endogenous thrombin potential. In conclusion, the increased thrombosis risk associated with high plasma concentrations of factor IX and factor XI may be explained by the increase in endogenous thrombin potential. However, this did not help explain the association between elevated factor VIII and thrombosis risk.

The effect of different anticoagulants on thrombin generation.

Decrease in thrombin generation is the key effect in anticoagulation. The aim of the present study was to investigate the effect of anticoagulants on thrombin generation and the relation to platelet count. Plasma samples from 10 healthy volunteers (mean age 43.0 ± 9 years) were incubated at preset platelet counts with different doses of the anticoagulants lepirudin, fondaparinux and low molecular weight heparins. Thrombin generation was measured in a tissue factor-mediated assay using a fluorometer and a slow-reacting fluorogenic substrate. The endogenous thrombin potential, the lag phase, the maximum reaction velocity (Vmax) and the concentration of a given anticoagulant required for 50% inhibition of thrombin generation (IC50) are presented. All three anticoagulants decreased endogenous thrombin potential and prolonged the lag phase in a dose-dependent manner. Fondaparinux and low molecular weight heparins, but not hirudin, decreased Vmax in a concentration-dependent manner. With increasing platelet count, the IC50 increased but the extent of this increase was not uniform for the three anticoagulants and the three variables investigated. The influence of anticoagulants on thrombin generation is variable, depending on their basic mechanism of action. In defining and comparing their effects, the endogenous thrombin potential, the lag phase and the maximum reaction velocity should be considered together. Platelets have a considerable influence on the magnitude of thrombin generation.

Human experience with transvenous biventricular defibrillation using an electrode in a left ventricular vein.

BUTTER, C., et al.: Human Experience with Transvenous Biventricular Defibrillation Using an Elec‐trode in a Left Ventricular Vein. This study investigated the safety and feasibility of transvenous biventricular defibrillation in ICD patients. Some patients may have high DFTs due to weak shock field intensity on the LV. Animal studies showed a LV shocking electrode dramatically lowered DFTs. This approach might benefit heart failure patients already receiving a LV lead or conventional ICD patients with high DFTs. A modified guidewire was used as a temporary left venous access defibrillation electrode (LVA lead). In 24 patients receiving an ICD, the LVA lead was advanced through a guide catheter in the coronary sinus (CS) and into a randomized LV vein (anterior or posterior) using a venogram for guidance. Paired DFT testing compared a standard right ventricular defibrillation system to a biventricular defibrillation system. There were no complications or adverse events. As randomized, LVA lead insertion success was 87% and 71% for anterior and posterior veins, respectively, and 100% after crossover. Total insertion process time included venogram time (32.5 ± 26.9 minutes, range 5–115, mode 15 minutes) and LVA lead insertion time (15 ± 14 minutes, range 1–51, mode 7 minutes). An apical LVA lead position was achieved in 11 (45%) of 24 patients and 7 (64 %) of these 11 displayed a DFT reduction; however, mean DFTs were not statistically different. Transvenous biventricular defibrillation is feasible and was safe under the conditions tested. Additional clinical studies are justified to determine if optimized LV lead designs, lead placement, and shock configurations can yield the same large DFT reductions as observed in animals.

Serum Procalcitonin and Proinflammatory Cytokines in a Patient with Acute Severe Leptospirosis

Leptospirosis is a zoonosis, with clinical manifestations ranging from the imperceptible to severe, potentially fatal renal and liver failure accompanied by haemorrhage and jaundice. In this case report of a patient with severe leptospirosis, serum levels of procalcitonin decreased ahead of any obvious clinical improvement, and thus may be useful as a prognostic marker. Levels of soluble IL-2 receptor were very high and correlated well with the clinical course.Leptospirosis is a zoonosis, with clinical manifestations ranging from the imperceptible to severe, potentially fatal renal and liver failure accompanied by haemorrhage and jaundice. In this case report of a patient with severe leptospirosis, serum levels of procalcitonin decreased ahead of any obvious clinical improvement, and thus may be useful as a prognostic marker. Levels of soluble IL-2 receptor were very high and correlated well with the clinical course.

Das Open-lung-Konzept

Zum ThemaDas Konzept der “offenen Lunge” ist Teil der gegenwärtigen Therapiestrategie bei akuter Lungenschädigung (“acute lung injury”, ALI) und dem akuten Atemnotsyndrom des Erwachsenen (“adult respiratory distress syndrome”, ARDS). Formal besteht das Beatmungskonzept aus den Komponenten Wiedereröffnung (Rekrutierung, “recruitment”, “open up the lung”) nicht-ventilierter Alveolen und dem Offenhalten (“keep the lung open”) noch ventilierter bzw. rekrutierter Alveolen sowie der vorgeschalteten Atemwege, die inhaltlich jedoch ineinander übergehen. Kein Therapieansatz hat so viel Bewegung in die Behandlung von ALI und ARDS gebracht wie das Open-lung-Konzept, was sich in umfangreicher intensivmedizinischer, auch publikatorischer Aktivität widerspiegelt. Das Konzept ist eingebettet in eine Behandlungsstrategie aus kausalen und medikamentösen Maßnahmen, Volumenrestriktion, 4-Seiten-Lagerung, NO-Inhalation und extrakorporaler Oxygenierung sowie additiver, derzeit in der Phase der Überführung in die klinische Praxis befindlicher Ansätze wie Surfactantinstillation, Prostazyklininhalation und partielle Flüssigkeitsbeatmung (“partial liquid ventilation”).

Applying logic to pulmonary artery catheter use

Mansour and colleagues recommend not routinely using the pulmonary artery catheter to guide hemodynamic management in the intensive care unit, because the perceived benefits are largely intangible [1]. Pulmonary artery catheter monitoring of the right ventricular ejection fraction (RVef) and of the right ventricular end-diastolic volume (EDV), however, reflects powerful yet underutilized relationships that assess right ventricular performance. Since the cardiac output equals the product of the RVef, the EDV and the heart rate, one can assess the RVef to EDV relations as direct measures of right ventricular performance. A series of RVef, EDV and heart rate combinations can give the same cardiac output (Figure ​(Figure1);1); monitoring or targeting cardiac output alone ignores this reality. For example, in hypovolemia the EDV is low and the RVef is increased, whereas in right ventricular failure the opposite is true. Furthermore, resuscitation from hypovolemia will increase the EDV and decrease the RVef [2], while reversal of cor pulmonale will decrease the EDV and increase the RVef. Figure 1 Right ventricular ejection fraction, right ventricular end-diastolic volume and heart rate relationship with cardiac output. CO, cardiac output; EDV, right ventricular end-diastolic volume; HR, heart rate; RVef, right ventricular ejection fraction. No monitoring device other than the pulmonary artery catheter can continually assess these variables. These concepts are often used in the cardiac surgery suite, but are rarely codified for diagnosis and management. Monitoring devices can improve outcome only if they are coupled to treatments that improve outcome. Applying the above logic to previously proposed treatment protocols, such as using the mixed venous oxygen saturation [3], may therefore be the first step toward defining pulmonary artery catheter utility [4].