Kinetic Analysis of Lidocaine Elimination by Pig Liver Cells Cultured in 3D Multi-Compartment Hollow Fiber Membrane Network Perfusion Bioreactors.

Liver cells cultured in 3D bioreactors is an interesting option for temporary extracorporeal liver support in the treatment of acute liver failure and for animal models for preclinical drug screening. Bioreactor capacity to eliminate drugs is generally used for assessing cell metabolic competence in different bioreactors or to scale-up bioreactor design and performance for clinical or preclinical applications. However, drug adsorption and physical transport often disguise the intrinsic drug biotransformation kinetics and cell metabolic state. In this study, we characterized the intrinsic kinetics of lidocaine elimination and adsorption by porcine liver cells cultured in 3D four-compartment hollow fiber membrane network perfusion bioreactors. Models of lidocaine transport and biotransformation were used to extract intrinsic kinetic information from response to lidocaine bolus of bioreactor versus adhesion cultures. Different from 2D adhesion cultures, cells in the bioreactors are organized in liver-like aggregates. Adsorption on bioreactor constituents significantly affected lidocaine elimination and was effectively accounted for in kinetic analysis. Lidocaine elimination and cellular monoethylglicinexylidide biotransformation featured first-order kinetics with near-to-in vivo cell-specific capacity that was retained for times suitable for clinical assist and drug screening. Different from 2D cultures, cells in the 3D bioreactors challenged with lidocaine were exposed to close-to-physiological lidocaine and monoethylglicinexylidide concentration profiles. Kinetic analysis suggests bioreactor technology feasibility for preclinical drug screening and patient assist and that drug adsorption should be accounted for to assess cell state in different cultures and when laboratory bioreactor design and performance is scaled-up to clinical use or toxicological drug screening.

Preclinical assessment of a modified Occlutech left atrial appendage closure device in a porcine model.

Left atrial appendage (LAA) closure is being developed as an alternative for stroke prevention in patients with atrial fibrillation that cannot tolerate long-term oral anticoagulation. To assess the feasibility, safety, and performance of a novel modified Occlutech LAA closure device in a preclinical porcine model, the modified Occlutech modified Occlutech Plus LAA closure device was implanted in 12 female pigs (25-39 kg body weight) under fluoroscopic and transesophageal echocardiography (TEE) guidance. Procedural and technical success, as well as safety of LAA closure, were evaluated peri-procedurally and after 4, 8, and 12 weeks. Moreover, after 4, 8 and, 12 weeks animals were sacrificed for pathological analysis (e.g., thrombus formation, device ingrowth, endothelialization, and inflammation). All LAA closure devices were successfully implanted. On follow-up, no serious adverse events such as device-associated thrombus or translocalization/embolization were observed. A clinically non-significant pericarditis was observed in 4 animals at the time of autopsy. Endothelialization of the device was visible after 4 weeks, advanced after 8 weeks and completed after 12 weeks. Immunohistochemistry showed low amounts of inflammatory infiltration on the edges of the device. The results of this study indicate that implantation of a modified Occlutech LAA closure device is feasible with rapid endothelialization and low inflammatory infiltration in a porcine model. Human data are needed to further characterize safety and efficacy.

C-Reactive Protein Causes Blood Pressure Drop in Rabbits and Induces Intracellular Calcium Signaling.

Systemic diseases characterized by elevated levels of C-reactive protein (CRP), such as sepsis or systemic inflammatory response syndrome, are usually associated with hardly controllable haemodynamic instability. We therefore investigated whether CRP itself influences blood pressure and heart rate. Immediately after intravenous injection of purified human CRP (3.5 mg CRP/kg body weight) into anesthetized rabbits, blood pressure dropped critically in all animals, while control animals injected with bovine serum albumin showed no response. Heart rate did not change in either group. Approaching this impact on a cellular level, we investigated the effect of CRP in cell lines expressing adrenoceptors (CHO-α1A and DU-145). CRP caused a Ca2+ signaling being dependent on the CRP dose. After complete activation of the adrenoceptors by agonists, CRP caused additional intracellular Ca2+ mobilization. We assume that CRP interacts with hitherto unknown structures on the surface of vital cells and thus interferes with the desensitization of adrenoceptors.

Increased compensatory kidney workload results in cellular damage in a short time porcine model of mixed acidemia - Is acidemia a 'first hit' in acute kidney injury?

Acute kidney injury (AKI) corrupts the outcome of about 50% of all critically ill patients. We investigated the possible contribution of the pathology acidemia on the development of AKI. Pigs were exposed to acidemia, acidemia plus hypoxemia or a normal acid-base balance in an experimental setup, which included mechanical ventilation and renal replacement therapy to facilitate biotrauma caused by extracorporeal therapies. Interestingly, extensive histomorphological changes like a tubular loss of cell barriers occurred in the kidneys after just 5 hours exposure to acidemia. The additional exposure to hypoxemia aggravated these findings. These 'early' microscopic pathologies opposed intra vitam data of kidney function. They did not mirror cellular or systemic patterns of proinflammatory molecules (like TNF-α or IL 18) nor were they detectable by new, sensitive markers of AKI like Neutrophil gelatinase-associated lipocalin. Instead, the data suggest that the increased renal proton excretion during acidemia could be an 'early' first hit in the multifactorial pathogenesis of AKI.

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.

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).

Impact of different types of resuscitation fluids on coagulation and continuous venovenous hemofiltration hemocompatibility in a porcine model.

Intensive therapy demanding diseases (organ failure or sepsis) are assumed to be the etiology behind a decreased biocompatibility of extracorporeal systems for renal replacement therapy (RRT). There are also potential interactions between different components of the overall therapy. Volume substitutes are known to influence hemorheology and coagulation. To define a potential net effect of volume substitutes on the hemocompatibility of an RRT, we chose an animal model without interfering pathophysiologies. According to the problem of early filter failure and coagulation disorders in critically ill patients, we focused on the hypothesized interaction between RRT and different volume substitutes with respect to blood cell counts, coagulation parameters and required heparin dose. Forty-eight pigs were assigned to four groups of fluid therapy with either normal saline (NaCl), 6%HES130kD/0.4 (HES130), 6%HES200kD/0.5 (HES200) or 4%gelatin (GEL). Six pigs of each fluid group underwent continuous venovenous hemofiltration (CVVH), the remaining six served as the control group. Anticoagulation was performed with continuous heparin infusion. CVVH was run in a recirculation-mode for 4.5 h to force hemocompatibility reactions, thereafter in a standard-mode for 2 h. During the CVVH-treatment GEL reduced platelet counts and fibrinogen concentration and additionally lowered ATIII levels. Heparin requirements did not differ between different volume substitutes or CVVH and control groups. Severe pathophysiologies are not the only reason for a reduced hemocompatibility of CVVH treatment. Interaction of a particular volume substitute with CVVH should be considered when interpreting study results and evolving new strategies.

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.

Evaluation of a new large animal model for controlled intracranial pressure changes induced by capnoperitoneum.

BACKGROUND: A standardized large animal model for controlled ICP manipulation within a relevant range and repetitive ICP measurements is missing. We sought to develop such a model on the base of controlled IPP changes induced by capnoperitoneum. METHODS: We utilized six female pigs (mean body weight 59.5 ± 18.4 kg) for experiments. A ventricular catheter connected with a burr hole reservoir was implanted. ICP was measured directly as cm H2O within a riser tube after percutaneous cannulation of the reservoir. A noninvasive intraperitoneal pressure (IPP) measurement was established (intravesical). Animals were placed in lateral position and a capnoperitoneum was induced. Measurements of ICP, IPP, MAP and respiratory parameters were performed at baseline IPP and after CO2 insufflation to IPP levels of 20 and 30 mmHg. RESULTS: Baseline IPP in lateral position referenced to median line was 9.8 (±2) mm Hg, while corresponding ICP was 10 (±2.2) mm Hg. After IPP elevation to 20 mmHg, ICP increased to 18.8 (±1.9) mm Hg. At 30 mmHg IPP, ICP increased to 22.8 (±2.8) mm Hg. Except peak airway pressure, all other parameters were kept constantly. Mean ICP variation in the individual subject was 13.4 (±2.5) mm Hg, while a ICP range from minimum 9 to maximum 31 mmHg was documented. CONCLUSIONS: We report a large animal model that allows (1) repeated measurement of the ICP and (2) manipulation of the ICP within a large pressure range by controlled IPP changes due to capnoperitoneum.

First level prevention instead of third level intervention-review of research to improve biocompatibility and performance of capillary membrane apheresis in critically ill patients.

In intensive care medicine, convection-based apheresis is of growing interest. Applying extracorporeal systems in the critically ill patient can cause severe complications like nosocomial infections and bleeding, which can be worsened or even initialized by the anticoagulation protocol used. Furthermore, the filter modules (hemo- and plasmafilters) often tend to a fast blockage. A decrease in sieving performance due to membrane fouling may be tolerable for some time, but the complete blockage of high percentages of hollow fibers, which is named "clotting," often requires the immediate exchange of the filter. Extracorporeal detoxification and high clearance renal replacement regimes both require high blood flow and filtration rates. As a consequence, filter clotting and anticoagulation-associated bleeding are the most sensitive aspects in these applications. We were interested in the paradox phenomenon of the parallel occurrence of intra vitam bleeding and filter clotting in critically ill patients. Through stepwise investigations based on in vitro and animal experiments, we identified a stasis of blood flow followed by blood cell sedimentation and aggregation ("clogging") as the main factor of hollow fiber blockage in hemo- and plasma filters. As a result, various aspects which increase the risk of stasis inside the hollow fibers were investigated, for example, patient's hemorheology, configuration of an extracorporeal treatment system including interaction of catheter features with the filtration procedure, and basic therapeutic approaches such as colloidal volume substitutes and tolerated acidosis. Finally, an etiological triad for the blockage of hollow fibers due to filter clogging and consecutive filter failure was formed.

In a porcine model of mixed acidemia HES 130/0.4 may support more stable hemodynamics during CVVH when compared to gelatine.

PURPOSE: Continuous veno-venous hemofiltration (CVVH) and mixed acidemia often occur simultaneously in critically ill patients. In a previous study in non-acidemic pigs we found that colloids and CVVH interact specifically with respect to hemodynamic stability, with favorable effects for 6% HES 130/0.4 versus 4% gelatine (GEL) infusion. In a porcine model, we investigated whether these colloid-type associated differences are still dominant under acidemic conditions. METHODS: We utilized 5 groups, a non-acidemic reference group receiving HES130 and CVVH; two acidemic groups receiving HES130 infusion (one with and one without CVVH); and two acidemic groups receiving GEL infusion (one with and one without CVVH). Mixed acidemia (pH ~7.20) was established by low tidal volume ventilation and acid infusion. Stable acidemia/CVVH application was maintained for 3 hours. Hemodynamics and blood gases were recorded. RESULTS: Mixed acidemia led to a significant decrease in MAP and increase in MPAP in all groups. CVVH led to a further decrease in MAP but improved MPAP. During CVVH, HES130 ensured significantly higher MAP, Hb, and DO2 values than GEL infusion. In the groups without CVVH these differences between HES 130/0.4 and GEL were not observed. CONCLUSIONS: As in a previous study in non-acidemic pigs, we found a colloid-specific influence of HES130 versus GEL on hemodynamics during CVVH under acidemia. Again, HES130 infusion may lead to favorable effects. In contrast, acidemia without CVVH application was dominant over the impact of a respective colloid. The application of a CVVH seems to be an important trigger for the overall circulatory response to a particular colloid.

Safety and efficacy of new integrated bipolar and ultrasonic scissors compared to conventional laparoscopic 5-mm sealing and cutting instruments.

BACKGROUND: Hemostasis is a central issue in laparoscopic surgery. Ultrasonic scissors and bipolar clamps are commonly used, with known advantages with each technique. METHODS: The prototype of new surgical scissors, delivering ultrasonically generated frictional heat energy and bipolar heat energy simultaneously (THUNDERBEAT(®) [TB]), was compared to ultrasonic scissors (Harmonic ACE(®) [HA]) and an advanced bipolar device (LigaSure(®) [LS]) using a pig model. As safety parameters, temperature profiles after single activation and after a defined cut were determined. As efficacy parameters, seal failures and the maximum burst pressure (BP) were measured after in vivo sealing of vessels of various types and diameters (categories 2-4 and 5-7 mm). Moreover, the vertical width of the tissue seal was measured on serial histological slices of selected arteries. The cutting speed was measured during division of isolated arteries and during dissection of a defined length of compound tissue (10 cm of mesentery). Burst-pressure measurement and histological analysis were performed by investigators blinded to the used sealing device. RESULTS: Using the TB, the burst pressure in larger arteries was significantly higher (734 ± 64 mmHg) than that of the HA (453 ± 50 mmHg). No differences in the rate of seal failures were observed. The cutting speed of the TB was significantly higher than that of all other devices. Safety evaluation revealed temperatures below 100 °C in the bipolar device. The maximum temperature of the HA and the TB was significantly higher. No relevant differences were observed between the HA and the TB. CONCLUSIONS: The ultrasonic and bipolar technique of the TB has the potential to surpass the dissection speed of ultrasonic devices with the sealing efficacy of bipolar clamps. However, heat production that is comparable to conventional ultrasonic scissors should be minded for clinical use.

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.

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 model's 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.

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.

Prolonged hypoxemia and acidemia in anesthetized pigs: a model for research on extracorporeal organ support in an intensive care setting.

PURPOSE: Hypoxemia and acidemia (hypoxemia/acidemia) are serious complications in the critically ill and often occur in unstable patients exposed to extracorporeal organ support. Still, little is known about the biocompatibility interactions of hypoxemia/acidemia with extracorporeal circuits (ECC). Existing animal models often include the release of mediator cascades (sepsis-, lung injury models) or are based on small laboratory animals. We established a porcine model of hypoxemia/acidemia without an underlying disease and further challenged the situation with an extracorporeal circuit (ECC). METHODS: Hypoxemia/acidemia were induced (3.5 h) and maintained (3 h) in anesthetized pigs (40 kg) by a stepwise reduction in oxygenation, infusion of 0.4 mol.l⁻¹ lactic and hydrochloric acid and by low tidal volume ventilation, targeting an PaO2 < 70 mmHg, SvO2 < 65%, pH ~ 7.2. Venovenous hemofiltration (CVVH) operated in recirculation mode without volume exchange was chosen to prove the suitability of the model for studies on ECCs under clinical conditions (ECC group, n=6). Another 6 animals underwent the same protocol except for the CVVH (reference group, n=6). RESULTS: The median PaO2 during hypoxemia/acidemia was 62 mmHg, the median SvO2 was 38%, and the median pH was 7.22. Hypoxemia/acidemia was successfully induced and maintained for 6.5 h in all pigs. CVVH could be performed for 3 h with blood flow rates up to 300 ml.min⁻¹ and filtrate rates up to 60 ml.min⁻¹. CONCLUSIONS: Our model provides hypoxemia/acidemia with blood gas values comparable to critically ill adult patients for several hours, during which it is possible to perform CVVH. Thus, it enables research on the biocompatibility reactions of extracorporeal circuits under intensive care conditions.

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 (approximately 40 kg, n = 6 in each group) were randomized to HES130 or 4% gelatine infusion (4 ml kg 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.