Juliane K. Unger

Hepatitis B in chronic kidney disease: Moving toward effective prevention

Control of hepatitis B virus (HBV) infection has been a continuous challenge in the management of patients with advanced kidney disease. HBV infections are still difficult to treat, so the main objective is disease prevention by timely immunization with hepatitis B surface antigen vaccines. In the general population, a simple two- or three-standard-dose vaccination strategy has been proven to be highly successful. In contrast, an intensified and more tailored approach is evolving in patients with advanced renal failure.

Specific Removal of C-Reactive Protein by Apheresis in a Porcine Cardiac Infarction Model

Background: C-reactive protein (CRP) is a possible causative factor of the destructive processes observed during the weeks after myocardial infarction. Methods: We developed a clinically relevant animal model including the removal of CRP from blood plasma utilizing a specific CRP adsorber and the visualization of the infarct scar in the living animal by cardiovascular magnetic resonance imaging as a tool to investigate the impact of CRP after acute myocardial infarction. Results: We describe the facets of this model system and kinetics of clinical blood parameters like CRP and troponin. In addition, we demonstrate the potency of CRP apheresis reducing CRP levels by ∼70% in the established treatment system. Conclusion: We showed for the first time that it is possible to conduct apheresis at the following 2 days after acute myocardial infarction in a porcine infarction model and to analyze the infarct by cardiovascular magnetic resonance imaging at day 1 and 14.

Experimental high-volume hemofiltration with predilutional tris-hydroxymethylaminomethane for correction of low tidal volume ventilation-induced acidosis.

The most common method of controlling acidemia during lung-protective ventilation is CO₂ removal with an extracorporeal lung assist (ECLA) system. Another possibility to prevent acidemia is based on intravenous (i.v.) application of tris-hydroxymethyl-aminomethane (3 mol/L, THAM) buffer, which can bind hydrogen protons and which can be removed from the body via renal replacement therapy (RRT). We investigated whether RRT combined with predilutional (prefilter) THAM-application provides an alternative to ECLA for a rescue situation. For this, anesthetized pigs, 40 kg of body weight, six animals per group, underwent 5 h of acidemia (pH 7.19-7.24) induced by acid infusion and permissive hypercapnia (low tidal volume ventilation, PaCO₂ 80-90 mmHg). Isovolemic, high-volume hemofiltration (HVHF) was operated with predilutional THAM-infusion for treatment. To evaluate adverse effects of this approach, we set up further groups: HVHF with postdilutional (post-filter) THAM-application; i.v.-THAM without HVHF; normal pH homeostasis with HVHF. Acid-base parameters, hemodynamics, renal function, and lung morphology were investigated. HVHF with predilutional THAM-infusion of 8 mmol/kg/h allowed fast pH normalization, significant reduction in PaCO₂ to 56 mmHg and tolerable hemodynamics. HVHF alone or lower dose i.v. THAM (2 mmol/kg/h) failed to produce a comparable result. A postdilutional THAM infusion reduced hemodynamic tolerability and increased lung edema formation. HVHF in pigs with normal acid-base status resulted in a decreased base excess and urine acidification. In conclusion, predilutional THAM-application and HVHF corrected the acid-base disorder and improved pulmonary hemodynamics. Further studies are necessary to optimize the protocol including the dosage.

Selective apheresis of C-reactive protein: A new therapeutic option in myocardial infarction?

Background: There is substantial evidence that C‐reactive protein (CRP) mediates secondary damage of the myocardium after acute myocardial infarction (AMI). The aim of this animal trial in pigs was to specifically deplete CRP from porcine plasma after AMI and to study possible beneficial effects of the reduced CRP concentration on the infarcted area. Methods: Ten pigs received balloon catheter‐induced myocardial infarction. CRP was depleted from five animals utilizing a new specific CRP‐adsorber, five animals served as controls. The area of infarction was analyzed by cardiovascular magnetic resonance imaging on day 1 and day 14 after AMI. Porcine CRP levels were determined by ELISA. Results: CRP‐apheresis resulted in a mean reduction of the CRP levels up to 48.3%. The area of infarction was significantly reduced by 30 ± 6% (P = 0.003) within 14 days in the treatment group, whereas it increased by 19 ± 11% (P = 0.260) in the controls. Fourteen days after infarction, the infarcted area revealed compact, transmural scars in the controls, whereas animals receiving CRP‐apheresis showed spotted scar morphology. In the interventional group, a significantly higher left ventricular ejection fraction (LVEF) was observed after 14 days as compared to the controls (57.6 ± 2.4% vs. 46.4 ± 2.7%; P = 0.007). Conclusions: In a pig model for AMI, we observed that selective CRP‐apheresis significantly reduces CRP levels and the volume of the infarction zone after AMI. Additionally, it changes the morphology of the scars and preserves cardiac output (LVEF). J. Clin. Apheresis 30:15–21, 2015.

Total body Na+-depletion without hyponatraemia can trigger overtraining-like symptoms with sleeping disorders and increasing blood pressure: explorative case and literature study.

Exhausting physical exercise and insufficient nutritional intake impairing immunological and neuro-endocrine pathways are the most discussed issues in research on overtraining syndrome (OTS). Interestingly, depletion of the total body sodium (Na(+))-content which occurs in case of various diseases with completely different aetiologies is associated with a symptom pattern strikingly comparable to overreaching (OR) and/or OTS. The transient dilution based hyponatraemia gained attention due to its impact on reduced performance and the death of various endurance athletes. But the stepwise depletion of the total body (tissue) Na(+)-content is a completely different pathophysiology and is still relatively unknown. That is because depleted tissue Na(+)-content is hard to detect. The complex, dominant mechanisms for the maintenance of plasma homeostasis are concealing the Na(+)-depletion in the tissues quite successfully in a stage when symptoms already may be prominent. Furthermore, we are all programmed to think about sedentary people who are rather at risk to have a salt (Na(+)) intake which is far too high. But either, competitive top athletes and engaged recreational athletes have high losses of electrolytes with sweat and might be prone to a stepwise Na(+)-depletion. All the more because they also try to have a balanced, health sodium reduced diet. One person of our research group who is used to a rather low sodium-nutrition repeatedly experienced OR-(short term-OTS)-symptoms when training loads of recreational sport activities were increasing. Getting aware about identical symptoms between OR and total body Na(+)-depletion in another professional context the decision for a self experiment was settled. Under a given training protocol changing symptoms under low sodium-nutrition were recorded. When OR-like symptoms became prominent the training loads were maintained but stringent Na(+)-substitution was performed instead of the usually recommended resting period. As experienced before, typical symptoms such as sleeping disorders, harassed feeling, high diuresis, thirst and increasing blood pressure developed within 2 weeks with the increased training loads and the usual low Na(+)-nutrition. This was before plasma sodium decreased below the physiological range. High Na(+)-substitution instead of a resting period enabled the recovery from OR symptoms within some days. Out of various articles we choose and report some interesting further medical phenomenon where our hypothesis of Na(+)-depletion as a trigger mechanism might give new ideas for identifying pathophysiological mechanisms. The hypothesis: Tissue Na(+)-depletion triggers OR- and OTS- development via the renin-angiotensin-aldosterone system which initiate at first a stimulation and then exhaustion of the sympathetic system.

Feasibility study of an active wound dressing based on hollow fiber membranes in a porcine wound model

INVESTIGATION A novel active wound dressing (AWD) concept based on a microporous hollow fiber membrane network was investigated in an animal model. It provides a local solution-perfused environment for regenerative cell nutrition, wound irrigation, debris removal, electrolyte balancing, pH regulation, and topical antibiosis. The device is capable of supplying soluble factors, as tested experimentally for the recombinant human growth and differentiation factor-5 (rhGDF-5). METHODS Following in vitro studies for rhGDF-5 using primary human keratinocytes and dermal fibroblasts, we employed a porcine partial thickness wound model with five distinct wounds on each back of n=8 pigs. Four wound groups were perfused differently over 9 days and compared with a negative control wound without perfusion: (1) 1% trehalose solution, pH 5.5; (2) rhGDF-5 (150 ng/ml) in 1% trehalose solution, pH 5.5; (3) nutrition solution; and (4) rhGDF-5 (150 ng/ml) in nutrition solution with 1% trehalose, pH 5.5. RESULTS Promoted wound healing was observed within group 1 and more pronounced within group 2. Groups 3 and 4, with nutrition solution, showed significant adverse effects on wound healing (p<0.05). CONCLUSIONS The investigated AWD concept appears to be an interesting therapeutic tool to study further wound healing support. Additionally, topical application of rhGDF-5 could be promising.

Stable Mixed Acidemia in Anesthetized Pigs—A Model for Research on Biocompatibility of Hemofilters Under a Deteriorated Acid-Base Balance

In recent years, acidosis has been of growing interest in intensive care medicine. Most animal models only provide a short-term investigation of the effects of acidosis. They are not suitable for research on interactions with extracorporeal organ support (here continuous venovenous hemofiltration, CVVH). The rationale for this study was to establish a porcine model of prolonged mixed acidemia, which is suitable for research on the interactions of acidemia and CVVH. After the induction of anesthesia in pigs (40 kg), acidemia was induced and maintained in one group with a bolus of 0.4 mol/L lactic acid followed by continuous infusion and a reduced respiratory frequency (lactic acid-group, n = 4). In another group, mixed acidemia was induced with a 0.4 mol/L acid solution (lactic and hydrochloric acid) and low tidal volume ventilation (mixed acidemia-group, n = 8). To get first proof of the models suitability to operate over an extracorporeal circuit, CVVH was additionally performed in seven pigs (mixed acidemia/CVVH-group, n = 7). The target for the pH was 7.19-7.24. The targeted pH was constantly missed in the lactic acid group, whereas it was successfully maintained for 3.5 h in four out of eight pigs of the mixed acidemia group, and in five out of seven pigs of the mixed acidemia/CVVH group. The CVVH was performed successfully for 3 h in all pigs of the respective group. The mixed acidemia model was sufficient to maintain a low pH within a narrow range for some hours and enabled research on hemofilters in vivo.

Adverse Influence of Mixed Acidemia on the Biocompatibility of Continuous Veno‐Venous Hemofiltration With Respect to the Lungs

Experimental data indicate that hypercapnic adidosis has anti-inflammatory effects. These anti-inflammatory effects may even be a beneficial property in case of low tidal volume ventilation with consecutive hypercapnic acidosis. It is unclear whether these anti-inflammatory effects predominate in critically ill patients who suffer from multiple pro- and anti-inflammatory insults like extracorporeal organ support (pro-inflammatory), metabolic acidosis (pro- and anti-inflammatory), as well as hypoxia (pro-inflammatory). Eighteen pigs were randomized into three groups, mechanically ventilated and connected to a continuous veno-venous hemofiltration (CVVH) as pro-inflammatory insult. A reference group with normal acid-base state obtained normoventilation; a normoxemic acidemia group obtained normoxemic, mixed acidemia due to infusion of lactic and hyperchloremic acid and low tidal volume ventilation, and in a hypoxemic acidemia group the mixed acidemia was paralleled by hypoxemia. Lung histology including pulmonary leukocyte invasion, blood gases, blood cell counts, and hemodynamics were examined. The histological examination of the lungs of acidemic pigs showed a suppressed invasion of leukocytes and thinner alveolar walls compared with normoventilated and with hypoxemic pigs. Enhanced congestion and alveolar red blood cells (RBCs) combined with an increase of the pulmonary artery pressure were observed in acidemic pigs in comparison with the reference group. Normoxemic acidemia reduced the pro-inflammatory reaction to the CVVH and mechanical ventilation in the ventilated lung areas in the form of pulmonary leukocyte invasion. However, this did not result in reduced scores for lung injury. Instead, an increased score for criteria which represent lung injury (congestion and alveolar RBCs) was observed in acidemic pigs.

Influence of acidaemia and hypoxaemia on CVVH haemocompatibility in a porcine model

BACKGROUND Reduced haemocompatibility and early filter failure during continuous venovenous haemofiltration (CVVH) can be attributed to various aspects from filter engineering to rheological problems. Still, little is known about the impact of acidaemia and hypoxaemia on the haemocompatibility of a CVVH. In a porcine model, we investigated blood and coagulation parameters, filter performance and blockage of filter capillaries to assess the impact of acidaemia and hypoxaemia on haemocompatibility. METHODS Pigs were assigned to three groups (n = 6). One group received mixed acidaemia (pH 7.2) by acid infusion (0.2 M of lactic acid and 0.2 M HCl diluted in normal saline) and low tidal volume ventilation (6-8 mL/kg(-)(1)), one group underwent an additional hypoxaemia (pH 7.2; PaO(2) < 70 mmHg) and another was treated with normal saline and normoventilation (control group; pH 7.4). To accelerate biocompatibility reactions, CVVH was operated with reinfusion of the filtrate to the venous line for 3 h based on standardized heparinization. RESULTS Acidaemia led to a contradictory pattern with respect to prothrombin time (prolongation), activated partial thrombin time and activated clotting time (acceleration). In comparison to normal pH homeostasis, acidaemia led to increasing activation markers such as terminal complement complex marker sC5b-9, thrombin-anti-thrombin complexes (TAT) and D-dimers. Additional hypoxaemia intensified activation with regard to TAT and complement complex marker sC5b-9. Platelet counts suffered from acidaemia and a tendency for higher rates of blocked hollow fibres was found. CONCLUSION Acidaemia led to deteriorated haemocompatibility reactions to a CVVH circuit. The coagulation pattern developed towards complications for the coagulatory state.

Six percent hydroxyethyl starch 130/0.4 impacts differently on blood glucose than 4% gelatine in a swine model of mixed acidaemia.

Background Tris-hydroxymethyl aminomethane can be used as a buffer in case of restricted ventilation, but hypoglycaemia is one adverse effect. The influence of a starch-based colloid [6% hydroxyethyl starch 130 kDa/0.4 (HES130)] vs. a gelatine-based colloid (4% polysuccinated gelatine) on blood glucose was investigated in a swine model of mixed acidaemia. Methods Continuous colloid infusion was done in anaesthetized pigs with exogenously induced mixed acidaemia, which was maintained for 3 h. Pigs (∼40 kg, n = 6 in each group) were randomized to HES130 or 4% gelatine infusion (4 ml kg−1 h−1). Infusion of an acid solution and low tidal volume ventilation induced mixed acidaemia. Treatment of mixed acidaemia with tris-hydroxymethyl aminomethane buffer, which is known to induce hypoglycaemia, prolonged anaesthesia, and volume support challenged the control of blood glucose. Hypoglycaemia was treated by individually dosed infusion of 5% glucose in sterile water. Results Bolus infusion of HES130 led to a moderate peak in blood glucose in four pigs. Four pigs in the 4% gelatine group and three in the HES130 group needed glucose infusion to prevent a drop in blood glucose levels below the set threshold (4 mmol l−1). The total amount of the glucose infusion was significantly lower in the HES130 group compared with the 4% gelatine group (100 vs. 295 ml per pig, median, P < 0.05). Generally, the HES130 pigs required glucose at later time points during anaesthesia. The first HES130 pig needed 5% glucose 2 h later than the first 4% gelatine pig to prevent a drop of blood glucose below 4 mmol l−1. Conclusion Volume support impacted specifically on blood glucose in this porcine model. Thus, an additional control of blood glucose seems recommendable whenever a change in the volume support occurs.