Moderate glucose supply reduces hemolysis during systemic inflammation

Johannes Jägers,1 Stephan Brauckmann,2 Michael Kirsch,1 Katharina Effenberger-Neidnicht1,3 1Institute of Physiological Chemistry, University Hospital Essen, Essen, Germany; 2Clinic for Anesthesiology and Intensive Care, University Hospital Essen, Essen, Germany; 3Institute of Physiological Chemistry, University Hospital Essen, Essen, Germany Background: Systemic inflammation alters energy metabolism. A sufficient glucose level, however, is most important for erythrocytes, since erythrocytes rely on glucose as sole source of energy. Damage to erythrocytes leads to hemolysis. Both disorders of glucose metabolism and hemolysis are associated with an increased risk of death. The objective of the study was to investigate the impact of intravenous glucose on hemolysis during systemic inflammation.Materials and methods: Systemic inflammation was accomplished in male Wistar rats by continuous lipopolysaccharide (LPS) infusion (1 mg LPS/kg and h, 300 min). Sham control group rats received Ringer’s solution. Glucose was supplied moderately (70 mg glucose/kg and h) or excessively (210 mg glucose/kg and h) during systemic inflammation. Vital parameters (eg, systemic blood pressure) as well as blood and plasma parameters (eg, concentrations of glucose, lactate and cell-free hemoglobin, and activity of lactate dehydrogenase) were measured hourly. Clot formation was analyzed by thromboelastometry.Results: Continuous infusion of LPS led to a so-called post-aggression syndrome with disturbed electrolyte homeostasis (hypocalcemia, hyperkalemia, and hypernatremia), changes in hemodynamics (tachycardia and hypertension), and a catabolic metabolism (early hyperglycemia, late hypoglycemia, and lactate formation). It induced severe tissue injury (significant increases in plasma concentrations of transaminases and lactate dehydrogenase), alterations in blood coagulation (disturbed clot formation), and massive hemolysis. Both moderate and excessive glucose supply reduced LPS-induced increase in systemic blood pressure. Excessive but not moderate glucose supply increased blood glucose level and enhanced tissue injury. Glucose supply did not reduce LPS-induced alterations in coagulation, but significantly reduced hemolysis induced by LPS.Conclusion: Intravenous glucose infusion can diminish LPS-related changes in hemodynamics, glucose metabolism, and, more interestingly, LPS-induced hemolysis. Since cell-free hemoglobin is known to be a predictor for patient’s survival, a reduction of hemolysis by 35% only by the addition of a small amount of glucose is another step to minimize mortality during systemic inflammation. Keywords: lipopolysaccharide, sepsis, erythrocytes, red blood cells, cell-free hemoglobin, glucose metabolis

Therapeutic effects of physostigmine during systemic inflammation

Katharina Effenberger-Neidnicht,1 Johannes Jägers,2 Rabea Verhaegh,1 Michael Kirsch1 1Institute of Physiological Chemistry, University Hospital Essen, Essen, Germany; 2Institute of Physiology, University Hospital Essen, Essen, Germany Introduction: Usually, physostigmine is used as antidote for anticholinergic poisons in order to improve hemodynamics and cardiac output. In addition, it causes beneficial effects during sepsis when added timely. Here, we studied whether physostigmine improves hemodynamics when treatment during systemic inflammation was delayed. Methods: Two series of randomized studies with overall 44 rats were conducted. Systemic inflammation was induced by lipopolysaccharide (LPS) infusion (0.5 mg LPS/kg×h). Physostigmine (PHY) was intravenously applied after an LPS infusion period of 90 minutes (50 µg PHY/kg within 10 minutes) with (series 1) and without (series 2) additional volume loading. Hemodynamic parameters, blood gases, and parameters for tissue damage were periodically determined for up to 180 minutes. Results: Even though volume was additionally administered (series 1), LPS caused a reduction of peripheral blood flow. Treatment with PHY improved hemodynamics in macrocirculation (mean arterial blood pressure) and microcirculation (peripheral blood flow). PHY neither affected alterations in blood gases, electrolyte homeostasis, and glucose metabolism nor prevented intestinal damage induced by LPS. In series 2, without any additional volume loading, PHY likewise resulted in an improvement of the LPS-induced alterations in macro- and microcirculation, but finally worsened the LPS-mediated effects on plasma parameters for tissue damage such as creatine kinase, probably due to the lack of volume and a further damage to the heart. Conclusion: The present results demonstrated that hemodynamic responses to PHY may not only be visible in patients with anticholinergic drug overdose but also be visible in septic patients, provided that fluid intake of these patients is adequate. Keywords: sepsis, septic shock, lipopolysaccharide, peripheral blood flow, mean arterial blood pressure, volume load, serine, ra

Microvascular stasis and hemolysis: coincidence or causality?

Katharina Effenberger-Neidnicht,1 Simon Bornmann,1 Johannes Jägers,2 Vivien Patyk,1 Michael Kirsch11Institute of Physiological Chemistry, University Hospital Essen, Essen, Germany; 2Institute of Physiology, University Hospital Essen, Essen, GermanyMicrovascular stasis in course of sepsis might be a consequence of hemolysisThere are various studies demonstrating that hemolysis or the presence of cell-free hemoglobin and heme causes microvascular stasis (Figure 1). Buurman and his team of researchers already showed that acute hemolysis (with plasma levels of cfHb ~20–30 μmol/L) – induced by infusion of water or pre-lysed red blood cells – was associated with an impaired renal, hepatic and intestinal microvasculature.2 They further showed that intraoperative hemolysis (with plasma levels of cfHb ~20 μmol/L) during major aortic surgery was associated with postoperative acute kidney injury.3 The offset times between occurring hemolysis and intestinal microvascular changes or renal microvascular changes were approximately 15–30 mins2 respective 120 mins3. Moreover, Vinchi and co-workers could reduce liver damage in a mouse model of heme overload in wild-type mice compared to hemopexin-null mice.4 They concluded that hemopexin prevents from hemolysis-induced hepatic microvascular stasis.4 Belcher et al compared different treatments to induce hemolysis and heme overload (eg, infusion of water, hemoglobin or heme) in transgenic sickle mice and found a relationship between microvascular stasis and total plasma heme concentrations (with plasma levels of heme ~25–80 μmol/L).5 They further proved that intravascular hemolysis during sickle cell disease elicits microvascular stasis via Toll-like receptor 4 signaling.5 Further studies of the researchers around Belcher and Vercellotti showed inhibition of hemoglobin-induced microvascular stasis in transgenic sickle mice by hemopexin and haptoglobin supplementation,6 overexpression of hemopexin7 or overexpression of ferritin heavy chain ferrioxidase.