Franz J. Wiedermann

Blunted erythropoietic response to anemia in multiply traumatized patients.

ObjectivesTo assess the relations between anemia, serum erythropoietin (EPO), iron status, and inflammatory mediators in multiply traumatized patients. DesignProspective observational study. SettingIntensive care unit. PatientsTwenty-three patients suffering from severe trauma (injury severity score ≥30). InterventionsNone. Measurements and Main Results Blood samples were collected within 12 hrs after the accident (day 1) and in the morning on days 2, 4, 6, and 9 to determine blood cell status, serum EPO, tumor necrosis factor-&agr; (TNF-&agr;), soluble tumor necrosis factor-receptor I (sTNF-rI), interleukin-1 receptor antagonist (IL1-ra), interleukin-6 (IL-6), neopterin, and iron status, respectively. Hemoglobin concentration was low at admission (mean, 10.0 g/dL; range, 6.8–12.9 g/dL) and did not increase during the observation time. Serum EPO concentration was 49.8 U/L (mean value) on day 1 and did not show significant increases thereafter. No correlation was found between EPO and hemoglobin concentrations. TNF-&agr; remained within the normal range. sTNF-rI was high at admission and increased further. IL1-ra was above the normal range. IL-6 was very high at admission and did not decrease thereafter. The initial neopterin concentration was normal, but increased until day 9. Serum iron was significantly decreased on day 2 posttrauma and remained low during the study. Serum ferritin increased steadily from day 2, reaching its maximum on day 9. In contrast, concentrations of transferrin were low from admission onward. ConclusionsMultiply traumatized patients exhibit an inadequate EPO response to low hemoglobin concentrations. Thus, anemia in severe trauma is the result of a complex network of bleeding, blunted EPO response to low hemoglobin concentrations, inflammatory mediators, and a hypoferremic state.

Migration of human monocytes in response to procalcitonin.

ObjectiveCirculating serum levels of procalcitonin rise significantly during bacterial infection. Because calcitonin is known to be a monocyte chemoattractant, we investigated whether procalcitonin, a prohormone of calcitonin, also affects leukocyte migration. DesignProspective, controlled in vitro study. SettingUniversity research laboratories. InterventionsForearm venous blood polymorphonuclear neutrophils and monocytes were isolated from healthy human donors. Cell migration was assessed in a blindwell chemotaxis chamber. The distance of migration into filter micropores was measured. To biochemically confirm functional data on cell migration, effects of procalcitonin on cellular levels of cyclic adenosine monophosphate were measured by high-performance liquid chromatography. Measurements and Main ResultsBoth procalcitonin and calcitonin elicited dose-dependent migration of monocytes at concentrations from the femtomolar to the micromolar range. Neutrophils did not migrate toward procalcitonin or calcitonin, nor was their oxygen free radical release affected as measured fluorimetrically. Checkerboard analysis of monocyte locomotion revealed procalcitonin-induced migration as true chemotaxis. Pretreatment of monocytes with procalcitonin or calcitonin rapidly deactivated their migratory response to formyl-Met-Leu-Phe, and both also induced homologous deactivation of migration. Procalcitonin elevated levels of cyclic adenosine monophosphate in monocytes. ConclusionsIn vitro procalcitonin is a monocyte chemoattractant that deactivates chemotaxis in the presence of additional inflammatory mediators. Procalcitonin stimulates cyclic adenosine monophosphate production in monocytes, suggesting that its action may be specific and comparable with calcitonin, which exerts similar functions.

Increase in immune activation, vascular endothelial growth factor and erythropoietin after an ultramarathon run at moderate altitude.

The present study was performed to investigate the effects of exhaustive long lasting exercise at moderate altitude on the time course of serum immunomodulatory peptides, vascular endothelial growth factor (VEGF) and serum erythropoietin (EPO). Thirteen well trained runners participated at the Swiss Alpine Marathon of Davos (distance 67 km, altitude difference 2300 m). Interleukin-6 was significantly elevated in the first 2h after the run. In contrast, tumor necrosis factor-alpha and both soluble tumor necrosis factor-a receptors I and II were increased after exercise termination and showed sustained serum concentrations the following days. Neopterin, a serum marker for the activation of the cellular immune system, was increased until day two after the run. Immediately after the run VEGF was significantly elevated and further increased 2.4-fold until day five post exercise (p = 0.005). EPO was also increased after exercise but reached its maximum 2 h after the run (2-fold increase; p = 0.004) and decreased thereafter. The main findings of our study are that prolonged strenuous exercise at moderate altitude induced a significant long lasting increase in serum VEGF and EPO which was accompanied by an activation of the immune system.

In vitro modulation of inducible nitric oxide synthase gene expression and nitric oxide synthesis by procalcitonin.

ObjectiveSerum procalcitonin (PCT) concentration was recently introduced as valuable diagnostic marker for systemic bacterial infection and sepsis. At present, the cellular sources and biological properties of PCT are unclear. During sepsis and septic shock, inducible nitric oxide synthase (iNOS) gene expression is stimulated followed by the release of large amounts of nitric oxide (NO). We investigated the possible association between PCT and iNOS gene expression in an in vitro cell culture model. DesignProspective, controlled in vitro cell culture study. SettingUniversity research laboratories. InterventionsConfluent rat vascular smooth muscle cells (VSMC) were incubated for 24 hrs and 48 hrs with PCT (1 ng/mL, 10 ng/mL, 100 ng/mL, 1000 ng/mL, 5000 ng/mL) alone or with the combination of tumor necrosis factor-alpha (TNF-&agr;, 500 U/mL) plus interferon-gamma (IFN-&ggr;, 100 U/mL). iNOS gene expression was measured by qualitative as well as quantitative polymerase chain reaction analysis, NO release was estimated by the modified Griess method. Measurements and Main Results PCT in increasing concentrations had no effect on iNOS gene expression and nitrite/nitrate release for 24 hrs and 48 hrs, respectively. However, PCT ameliorated TNF-&agr;/IFN-&ggr;–induced iNOS gene expression in a dose-dependent manner (maximal inhibition at PCT 100 ng/mL by −66% for 24 hrs and −80% for 48 hrs). This was accompanied by a significantly reduced release of nitrite/nitrate into the cell culture supernatant (maximal reduction at PCT 100 ng/mL by −56% and −45% for 24 hrs and 48 hrs, respectively). ConclusionsWe conclude that recombinant PCT inhibits the iNOS-inducing effects of the proinflammatory cytokines TNF-&agr;/IFN-&ggr; in a dose-dependent manner. This might be a counter-regulatory mechanism directed against the large production of NO and the concomitant systemic hypotension in severe sepsis and septic shock.

Association of endogenous G-CSF with anti-inflammatory mediators in patients with acute respiratory distress syndrome.

Upregulation of the anti-inflammatory mediators, soluble tumor necrosis factor-alpha receptors I and II (sTNFRI/RII) and interleukin-1 receptor antagonist (IL-1RA), by granulocyte colony-stimulating factor (G-CSF) may contribute to the pathophysiology of lung injury. We determined the relation of endogenous G-CSF to proinflammatory and anti-inflammatory mediators in bronchoalveolar lavage fluid (BALF) and serum of patients with acute respiratory distress syndrome (ARDS) and acute lung injury (ALI). Nineteen patients with ARDS and 10 with ALI were included in this prospective investigation. BAL was performed within 12 h and 24 h after onset of lung injury. Concentrations of G-CSF, TNF-alpha, IL-6, sTNFRI and sTNFRII, IL-1RA and IL-10 in BALF as well as in serum were determined by ELISA. G-CSF was associated with alveolar neutrophilia. Results in patients with ARDS and ALI exhibited significant positive correlations in BALF of G-CSF levels with that of IL-6, sTNFRII, and IL-1RA and of G-CSF levels in serum with that of serum IL-6, IL-1RA, and IL-10. Given the potential of G-CSF to directly induce anti-inflammatory cytokines in vitro, significant associations of endogenous G-CSF levels with these mediators early in the development of severe lung injury suggest an endogenous anti-inflammatory role of G-CSF in vivo.

Are Leukocytes in Salvaged Washed Autologous Blood Harmful for the Recipient? The Results of a Pilot Study

To explore whether polymorphonuclear leukocytes (PMNL) are activated to the priming threshold through intraoperative blood salvage, and are thus able to induce endothelial damage, we investigated chemotactic response (n = 20) and respiratory burst (RB;n = 20) of PMNL without (basal respiratory burst, bPMNL-RB) and after in vitro stimulation with formyl-Met-Leu-Phe (fMLP-RB) and phorbol myristate acetate (PMA-RB). Blood was processed with a continuous autotransfusion device (CATS). Heparin (Heparin group) and sodium citrate (Citrate group) were used alternately as an anticoagulant for each half of the chemotaxis and RB studies. Comparison of measurements from the processed autologous erythrocyte concentrates (paEC) to pre- and intraoperative arterial blood samples showed no statistically significant difference for any test of PMNL functional responses in an orthopedic patient population. Analysis of intraindividual changes demonstrated a significantly increased bPMNL-RB (both groups, P = 0.0032; Heparin group, P = 0.0098), fMLP-RB (both groups, P = 0.0484; Citrate group, P = 0.0371), and PMA-RB (Citrate group, P = 0.002) in the paEC compared with intraoperative arterial samples, whereas the chemotactic response did not change. Nevertheless, median values of all RB measurements in the paEC were within the range of pre- and intraoperative values, indicating that PMNLs contained in the paEC are neither impaired nor activated to the priming threshold. The results confirm the clinical experience that intraoperative blood salvage is safe to use during major orthopedic surgery and questions the beneficial effect of special leukocyte-removing filters.

Plasma levels of procalcitonin and interleukin-6 in acute myocardial infarction.

Estimation of cardiac morbidity in patients after major surgery is a difficult problem. In addition, infectious complications seriously decrease potential beneficial outcome after cardiovascular surgery. The present study assessed the use of a newer marker of the inflammatory response, procalcitonin, in the field of myocardial infarction, in conjunction with measurements of interleukin-6. Forty-four consecutive cases with acute myocardial infarction were included in the study 4 ± 1.3 h after the onset of symptoms. Plasma levels of procalcitonin and interleukin-6 were obtained at admission, and after 3, 6, 12, 18, 24 and 48 h, using commercially available test kits. The range of levels of interleukin-6 and procalcitonin was about normal at admission. Interleukin-6 levels increased significantly following myocardial infarction, whereas procalcitonin were essentially unchanged, i.e. remained close to the normal level threshold of 0.5 ng/ml; only minor variability occurred with a mean peak level of procalcitonin of 1 ± 0.4 ng/ml. Data demonstrate that, in contrast to the acute phase reactant interleukin-6, plasma levels procalcitonin are not significantly elevated during uncomplicated acute myocardial infarction. This observation may support the role of procalcitonin measurements in the differential diagnosis of infectious and cardiovascular complications after major surgery.

Acute respiratory failure associated with catastrophic antiphospholipid syndrome.

Abstract. Wiedermann FJ, Mayr A, Schobersberger W, Knotzer H, Sepp N, Rieger M, Hasibeder W, Mutz N (The Leopold‐Franzens‐University of Innsbruck, Innsbruck, Austria). Acute respiratory failure associated with catastrophic antiphospholipid syndrome (Case Report). J Intern Med 2000; 247: 723–730.

Low platelet count and elevated serum thrombopoietin after severe trauma.

Abstract: Platelet count is regularly low in patients after multiple trauma, mainly due to blood loss and dilution. Thrombopoietin (TPO) is the main regulator of the circulating platelet mass. Under several clinical conditions an inverse correlation between TPO and the circulating platelet mass was reported. Since platelets bind and internalize TPO, a platelet‐dependent regulation of TPO was suggested. Thus, acute blood loss should be accompanied by elevated TPO. We measured serum TPO, platelets, interleukin‐6 (IL‐6) and vascular endothelial growth factor (VEGF) in 17 multiple traumatized victims. Blood was collected within 12 h after trauma as well as in the morning of days 2, 4, 6 and 9 after admission at the intensive care unit. Platelet count was low at admission and remained low until day 4. Thereafter platelets increased until day 9. TPO nearly doubled within the first 2 d, reaching its maximum on day 6. IL‐6 was initially very high and steadily decreased until day 9. VEGF increased 3‐fold during the 9 d. Statistically significant correlations of TPO were found with platelets and IL‐6, but not with VEGF. In multiple traumatized patients low platelet count is followed by a rapid increase in serum TPO. This fits into the concept of a feedback regulation between circulating TPO and platelet mass.

Eculizumab and renal transplantation in a patient with catastrophic antiphospholipid syndrome: effect of heparin on complement activation.

Sir, Recently Lonze and co-workers reported on the successful use of eculizumab and renal transplantation in a patient with catastrophic antiphospholipid syndrome (CAPS), and promoted the therapy with the inhibitor of complement activation for other manifestations of the antiphospholipid syndrome (APS). It is important to note that the anticoagulation with heparin inhibits clot formation, lyses existing clots, inhibits the binding of antiphospholipid (aPL) antibodies in enzyme-linked immunosorbent assay (ELISA), and prevents aPL-induced complement activation in animal APS models. Furthermore, if the recommendation of the authors for the use of eculizumab in primary APS with renal evolvement is justified, this really needs further investigation. Pathophysiologically, acute renal failure in APS patients could be due to a thrombotic microangiopathy that does not show a complement activation as measured in the laboratory, e.g. by hypocomplementia, since this thrombotic microangiopathy is not associated with circulating immunocomplexes. Funding