{"id":{"repo_id":"freiburg-diss","oai_identifier":"oai:freidok.uni-freiburg.de:2271"},"canonical_url":"https://search.dev.ndltd.org/etd/freiburg-diss/oai:freidok.uni-freiburg.de:2271","repository":{"repo_id":"freiburg-diss","name":"University of Freiburg","base_url":"https://freidok.uni-freiburg.de/oai/oai2.php"},"display":{"title":"Citrate kinetics during regional citrate anticoagulation in extracorporeal organ replacement therapy","abstract":"Regional citrate anticoagulation is an important alternative anticoagulation method for haemodialysis patients at high risk of bleeding. In order to better define the optimal dose of citrate and calcium infusion and to identify patients at risk for side effects, the kinetics of citrate and calcium were studied in vivo during and after 15 haemodialysis treatments and in vitro assessing the clearance of citrate-calcium complexes by F60S dialyzers. In addition, a mathematical model was developed to identify the parameters affecting calcium and citrate kinetics in order to predict citrate and calcium requirements in individual patients to avoid side effects. <br>Citrate and calcium doses for effective anticoagulation <br>Citrate dose should be adapted not only to blood flow (approx. 3 mmol per litre of blood) but also to hematocrit. Patients with low hematocrit need more citrate, because they have more plasma water per litre of blood. Sodium concentration in the dialysate of 138 mmol/l does not require any adaptation. Bicarbonate in the dialysate should be reduced by 4 mmol/l (e.g. from 32 to 28 mmol/l). Calcium supplementation should be at least as high as calcium removal by the dialyzer. Calcium removal is higher in patients with high initial total calcium, with use of effective high flux dialyzers, and with high blood flow. With use of high flux dialyzers previous recommendations of calcium supplementation in the literature may no longer be valid, because of the more efficient removal of calcium into the calcium free dialysate. Ionized calcium has to be monitored in the arterial line prior to citrate infusion for safety reasons, in order to detect any trend towards hypocalcemia. <br>Risk assessment <br>Citrate toxicity within the citrate concentration ranges that can be reached in intermittent haemodialysis is limited to the disturbances of ionized calcium concentration, mainly to the induction of hypocalcemia. Hypercalcemia rarely develops, probably due to calcium uptake e.g. by the bones. Hypocalcemia is potentially lethal and is the most important risk with use of citrate anticoagulation. During intermittent high-flux haemodialysis it is primarily due to calcium removal into the dialysate. Hypocalcemia develops rapidly (even within 15 minutes), if calcium substitution is interrupted and can reach life-threatening levels already after 1 hour in a small patient (45kg). All other possible causes for hypocalcemia are less important and less dangerous. <br>Special patient groups and continuous dialysis <br>Patients with liver failure have an increased risk to accumulate citrate, but removal by high-flux dialysis effectively limits accumulation. Slow continuous dialysis is more risky because of low citrate clearance. In this situation patients with liver failure may experience severe hypocalcemia. Patients with small body weight and thus smaller volume of distribution for citrate (e.g. children) can develop high citrate levels but can probably be managed safely with citrate anticoagulation if ionized calcium is closely monitored. The more precise estimation of the calcium requirements in these special patient groups needs further kinetic studies.","abstract_html":"Regional citrate anticoagulation is an important alternative anticoagulation method for haemodialysis patients at high risk of bleeding. In order to better define the optimal dose of citrate and calcium infusion and to identify patients at risk for side effects, the kinetics of citrate and calcium were studied in vivo during and after 15 haemodialysis treatments and in vitro assessing the clearance of citrate-calcium complexes by F60S dialyzers. In addition, a mathematical model was developed to identify the parameters affecting calcium and citrate kinetics in order to predict citrate and calcium requirements in individual patients to avoid side effects. &lt;br&gt;Citrate and calcium doses for effective anticoagulation &lt;br&gt;Citrate dose should be adapted not only to blood flow (approx. 3 mmol per litre of blood) but also to hematocrit. Patients with low hematocrit need more citrate, because they have more plasma water per litre of blood. Sodium concentration in the dialysate of 138 mmol/l does not require any adaptation. Bicarbonate in the dialysate should be reduced by 4 mmol/l (e.g. from 32 to 28 mmol/l). Calcium supplementation should be at least as high as calcium removal by the dialyzer. Calcium removal is higher in patients with high initial total calcium, with use of effective high flux dialyzers, and with high blood flow. With use of high flux dialyzers previous recommendations of calcium supplementation in the literature may no longer be valid, because of the more efficient removal of calcium into the calcium free dialysate. Ionized calcium has to be monitored in the arterial line prior to citrate infusion for safety reasons, in order to detect any trend towards hypocalcemia. &lt;br&gt;Risk assessment &lt;br&gt;Citrate toxicity within the citrate concentration ranges that can be reached in intermittent haemodialysis is limited to the disturbances of ionized calcium concentration, mainly to the induction of hypocalcemia. Hypercalcemia rarely develops, probably due to calcium uptake e.g. by the bones. Hypocalcemia is potentially lethal and is the most important risk with use of citrate anticoagulation. During intermittent high-flux haemodialysis it is primarily due to calcium removal into the dialysate. Hypocalcemia develops rapidly (even within 15 minutes), if calcium substitution is interrupted and can reach life-threatening levels already after 1 hour in a small patient (45kg). All other possible causes for hypocalcemia are less important and less dangerous. &lt;br&gt;Special patient groups and continuous dialysis &lt;br&gt;Patients with liver failure have an increased risk to accumulate citrate, but removal by high-flux dialysis effectively limits accumulation. Slow continuous dialysis is more risky because of low citrate clearance. In this situation patients with liver failure may experience severe hypocalcemia. Patients with small body weight and thus smaller volume of distribution for citrate (e.g. children) can develop high citrate levels but can probably be managed safely with citrate anticoagulation if ionized calcium is closely monitored. The more precise estimation of the calcium requirements in these special patient groups needs further kinetic studies.","abstract_has_math":false,"creators":["Kozik-Jaromin, Justyna"],"institution":null,"degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":["Böhler, Joachim"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":null,"date_issued":"","date_published":null,"updated_at":"2026-07-24T02:22:40Z","subjects":["Calciumsalze","Calciumkomplexe","Calciumhomöostase","Calcium","dialysis","citrate","anticoagulation","pharmacokinetics"],"languages":[],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://freidok.uni-freiburg.de/data/2271","outbound_label":"Repository record","outbound_source":"source_url"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Böhler, Joachim"]},{"key":"dc:creator","label":"Author","values":["Kozik-Jaromin, Justyna"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:type","label":"Dc Type","values":["DoctoralThesis"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Calciumsalze","Calciumkomplexe","Calciumhomöostase","Calcium","dialysis","citrate","anticoagulation","pharmacokinetics"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Regional citrate anticoagulation is an important alternative anticoagulation method for haemodialysis patients at high risk of bleeding. In order to better define the optimal dose of citrate and calcium infusion and to identify patients at risk for side effects, the kinetics of citrate and calcium were studied in vivo during and after 15 haemodialysis treatments and in vitro assessing the clearance of citrate-calcium complexes by F60S dialyzers. In addition, a mathematical model was developed to identify the parameters affecting calcium and citrate kinetics in order to predict citrate and calcium requirements in individual patients to avoid side effects. <br>Citrate and calcium doses for effective anticoagulation <br>Citrate dose should be adapted not only to blood flow (approx. 3 mmol per litre of blood) but also to hematocrit. Patients with low hematocrit need more citrate, because they have more plasma water per litre of blood. Sodium concentration in the dialysate of 138 mmol/l does not require any adaptation. Bicarbonate in the dialysate should be reduced by 4 mmol/l (e.g. from 32 to 28 mmol/l). Calcium supplementation should be at least as high as calcium removal by the dialyzer. Calcium removal is higher in patients with high initial total calcium, with use of effective high flux dialyzers, and with high blood flow. With use of high flux dialyzers previous recommendations of calcium supplementation in the literature may no longer be valid, because of the more efficient removal of calcium into the calcium free dialysate. Ionized calcium has to be monitored in the arterial line prior to citrate infusion for safety reasons, in order to detect any trend towards hypocalcemia. <br>Risk assessment <br>Citrate toxicity within the citrate concentration ranges that can be reached in intermittent haemodialysis is limited to the disturbances of ionized calcium concentration, mainly to the induction of hypocalcemia. Hypercalcemia rarely develops, probably due to calcium uptake e.g. by the bones. Hypocalcemia is potentially lethal and is the most important risk with use of citrate anticoagulation. During intermittent high-flux haemodialysis it is primarily due to calcium removal into the dialysate. Hypocalcemia develops rapidly (even within 15 minutes), if calcium substitution is interrupted and can reach life-threatening levels already after 1 hour in a small patient (45kg). All other possible causes for hypocalcemia are less important and less dangerous. <br>Special patient groups and continuous dialysis <br>Patients with liver failure have an increased risk to accumulate citrate, but removal by high-flux dialysis effectively limits accumulation. Slow continuous dialysis is more risky because of low citrate clearance. In this situation patients with liver failure may experience severe hypocalcemia. Patients with small body weight and thus smaller volume of distribution for citrate (e.g. children) can develop high citrate levels but can probably be managed safely with citrate anticoagulation if ionized calcium is closely monitored. The more precise estimation of the calcium requirements in these special patient groups needs further kinetic studies.","Die regionale Citrat-Antikoagulation ist eine wichtige Alternative für diejenigen Hämodialysepatienten, die ein hohes Blutungsrisiko haben. Um die Dosis von Citrat und Calcium besser definieren, und damit Komplikationen vermeiden zu können, wurde die Kinetik vom Citrat und Calcium sowohl in vivo während und nach 15 Dialysebehandlungen als auch in vitro durch die Clearancemessungen von Citrat-Calcium-Komplexen mit dem Dialysator F60S untersucht. Zusätzlich wurde ein mathematisches Modell der Citrat-Antikoagulation entwickelt. Mit diesem Model wurden die Faktoren, die die Kinetik beeinflussen, identifiziert, damit die verabreichten mengen von Citrat und Calcium zur Vermeidung von unerwünschten Wirkungen an die individuellen Bedürfnisse der Patienten angepasst werden können. <br>Citratdosis für die effektive Antikoagulation <br>Die Citratdosis sollte nicht nur an den Blutfluß (etwa 3 mmol/ pro Liter Blut), sondern auch an den Hämatokrit angepasst werden. Die Patienten mit niedrigem Hämatokrit benötigen mehr Citrat, weil sie mehr Plasma-Wasser pro Liter Blut haben. Eine übliche Natriumkonzentration im Dialysat von 138 mmol/l muss nicht geändert werden. Der Bikarbonatgehalt der Dialysatlösung sollte um 4 mmol/l reduziert werden (z. B. von 32 auf 28). Die Calciuminfusion sollte wenigstens den durch die Dialyse verursachten Calciumverlust ersetzen. Ein höherer Gesamtcalciumspiegel im Patientenkreislauf, die Verwendung eines high-flux Dialysators oder ein höherer Blutfluss sind mit einer grösseren Clearance und einem grösseren Verlust von Calcium verbunden. Die in der Literatur empfohlenen Calciumverabreichungen könnten nicht ausreichend sein, wenn ein high-flux Dialysator verwendet wird, weil mehr Calcium entfernt wird. Ionisiertes Calcium sollte durch die Messungen im arteriellen Schlauch überwacht werden um die Entwicklung einer Hypokalzämie frühzeitig erkennen zu können. <br>Riskoanalyse <br>Die Citratnebenwirkungen sind in der intermittierenden Dialyse auf Calciumstörungen, insbesondere auf Hypokalzämie beschränkt. Hyperkalzämie tritt sehr selten auf, vermutlich wegen der Calciumaufnahme z.B. in die Knochen. Hypokalzämie ist eine potentiell lebensgefährliche Komplikation, die in der Hämodialyse durch die Verwendung einer calciumfreien Dialysatlösung verursacht werden kann. Wenn bei der Hämodialyse mit Citrat-Antikoagulation die Calciuminfusion unterbrochen ist, tritt die Hypocalcemia sehr schnell auf (innerhalb von 15 Minuten) und kann bei kleinen Patienten (45 kg) schon innerhalb von 1 Stunde lebensbedrohliche Werte erreichen. Alle anderen möglichen Ursachen der Hypokalzämie sind weniger wichtig und weniger gefährlich. <br>Besondere Patientengruppen <br>Bei den Lebererkrankungen besteht ein besonderes Risiko der Citratakkumulation im Patientenkreislauf, wird jedoch durch die effektive Citratentfernung während der Hämodialyse begrenzt. Wegen der niedrigen Citratclearance ist die kontinuierliche Dialysetherapie riskanter. Bei diesem Verfahren kann Hypokalzämie bei Patienten mit Leberversagen auftreten. Eine geringe Körpergröße und das dadurch bedingte kleinere Citrat-Verteiligungsvolumen (z. B. bei Kindern) verstärkt das Risiko der Citratakkumulation. Trotzdem ist eine sichere Durchführung der Citrat-Antikoagulation unter Calciumüberwachung zu erwarten. Die genauere Schätzung des Calciumbedarfs in diesen Patientengruppen erfordert eine gezielte klinische Studie."]},{"key":"dc:format.medium","label":"Dc Format Medium","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["Citrate kinetics during regional citrate anticoagulation in extracorporeal organ replacement therapy","Zitratkinetik während regionaler Zitratantikoagulation bei extrakorporaler Organersatztherapie"]}]}],"canonical_facts":{"dc:contributor":["Böhler, Joachim"],"dc:creator":["Kozik-Jaromin, Justyna"],"dc:description.abstract":["Regional citrate anticoagulation is an important alternative anticoagulation method for haemodialysis patients at high risk of bleeding. In order to better define the optimal dose of citrate and calcium infusion and to identify patients at risk for side effects, the kinetics of citrate and calcium were studied in vivo during and after 15 haemodialysis treatments and in vitro assessing the clearance of citrate-calcium complexes by F60S dialyzers. In addition, a mathematical model was developed to identify the parameters affecting calcium and citrate kinetics in order to predict citrate and calcium requirements in individual patients to avoid side effects. <br>Citrate and calcium doses for effective anticoagulation <br>Citrate dose should be adapted not only to blood flow (approx. 3 mmol per litre of blood) but also to hematocrit. Patients with low hematocrit need more citrate, because they have more plasma water per litre of blood. Sodium concentration in the dialysate of 138 mmol/l does not require any adaptation. Bicarbonate in the dialysate should be reduced by 4 mmol/l (e.g. from 32 to 28 mmol/l). Calcium supplementation should be at least as high as calcium removal by the dialyzer. Calcium removal is higher in patients with high initial total calcium, with use of effective high flux dialyzers, and with high blood flow. With use of high flux dialyzers previous recommendations of calcium supplementation in the literature may no longer be valid, because of the more efficient removal of calcium into the calcium free dialysate. Ionized calcium has to be monitored in the arterial line prior to citrate infusion for safety reasons, in order to detect any trend towards hypocalcemia. <br>Risk assessment <br>Citrate toxicity within the citrate concentration ranges that can be reached in intermittent haemodialysis is limited to the disturbances of ionized calcium concentration, mainly to the induction of hypocalcemia. Hypercalcemia rarely develops, probably due to calcium uptake e.g. by the bones. Hypocalcemia is potentially lethal and is the most important risk with use of citrate anticoagulation. During intermittent high-flux haemodialysis it is primarily due to calcium removal into the dialysate. Hypocalcemia develops rapidly (even within 15 minutes), if calcium substitution is interrupted and can reach life-threatening levels already after 1 hour in a small patient (45kg). All other possible causes for hypocalcemia are less important and less dangerous. <br>Special patient groups and continuous dialysis <br>Patients with liver failure have an increased risk to accumulate citrate, but removal by high-flux dialysis effectively limits accumulation. Slow continuous dialysis is more risky because of low citrate clearance. In this situation patients with liver failure may experience severe hypocalcemia. Patients with small body weight and thus smaller volume of distribution for citrate (e.g. children) can develop high citrate levels but can probably be managed safely with citrate anticoagulation if ionized calcium is closely monitored. The more precise estimation of the calcium requirements in these special patient groups needs further kinetic studies.","Die regionale Citrat-Antikoagulation ist eine wichtige Alternative für diejenigen Hämodialysepatienten, die ein hohes Blutungsrisiko haben. Um die Dosis von Citrat und Calcium besser definieren, und damit Komplikationen vermeiden zu können, wurde die Kinetik vom Citrat und Calcium sowohl in vivo während und nach 15 Dialysebehandlungen als auch in vitro durch die Clearancemessungen von Citrat-Calcium-Komplexen mit dem Dialysator F60S untersucht. Zusätzlich wurde ein mathematisches Modell der Citrat-Antikoagulation entwickelt. Mit diesem Model wurden die Faktoren, die die Kinetik beeinflussen, identifiziert, damit die verabreichten mengen von Citrat und Calcium zur Vermeidung von unerwünschten Wirkungen an die individuellen Bedürfnisse der Patienten angepasst werden können. <br>Citratdosis für die effektive Antikoagulation <br>Die Citratdosis sollte nicht nur an den Blutfluß (etwa 3 mmol/ pro Liter Blut), sondern auch an den Hämatokrit angepasst werden. Die Patienten mit niedrigem Hämatokrit benötigen mehr Citrat, weil sie mehr Plasma-Wasser pro Liter Blut haben. Eine übliche Natriumkonzentration im Dialysat von 138 mmol/l muss nicht geändert werden. Der Bikarbonatgehalt der Dialysatlösung sollte um 4 mmol/l reduziert werden (z. B. von 32 auf 28). Die Calciuminfusion sollte wenigstens den durch die Dialyse verursachten Calciumverlust ersetzen. Ein höherer Gesamtcalciumspiegel im Patientenkreislauf, die Verwendung eines high-flux Dialysators oder ein höherer Blutfluss sind mit einer grösseren Clearance und einem grösseren Verlust von Calcium verbunden. Die in der Literatur empfohlenen Calciumverabreichungen könnten nicht ausreichend sein, wenn ein high-flux Dialysator verwendet wird, weil mehr Calcium entfernt wird. Ionisiertes Calcium sollte durch die Messungen im arteriellen Schlauch überwacht werden um die Entwicklung einer Hypokalzämie frühzeitig erkennen zu können. <br>Riskoanalyse <br>Die Citratnebenwirkungen sind in der intermittierenden Dialyse auf Calciumstörungen, insbesondere auf Hypokalzämie beschränkt. Hyperkalzämie tritt sehr selten auf, vermutlich wegen der Calciumaufnahme z.B. in die Knochen. Hypokalzämie ist eine potentiell lebensgefährliche Komplikation, die in der Hämodialyse durch die Verwendung einer calciumfreien Dialysatlösung verursacht werden kann. Wenn bei der Hämodialyse mit Citrat-Antikoagulation die Calciuminfusion unterbrochen ist, tritt die Hypocalcemia sehr schnell auf (innerhalb von 15 Minuten) und kann bei kleinen Patienten (45 kg) schon innerhalb von 1 Stunde lebensbedrohliche Werte erreichen. Alle anderen möglichen Ursachen der Hypokalzämie sind weniger wichtig und weniger gefährlich. <br>Besondere Patientengruppen <br>Bei den Lebererkrankungen besteht ein besonderes Risiko der Citratakkumulation im Patientenkreislauf, wird jedoch durch die effektive Citratentfernung während der Hämodialyse begrenzt. Wegen der niedrigen Citratclearance ist die kontinuierliche Dialysetherapie riskanter. Bei diesem Verfahren kann Hypokalzämie bei Patienten mit Leberversagen auftreten. Eine geringe Körpergröße und das dadurch bedingte kleinere Citrat-Verteiligungsvolumen (z. B. bei Kindern) verstärkt das Risiko der Citratakkumulation. Trotzdem ist eine sichere Durchführung der Citrat-Antikoagulation unter Calciumüberwachung zu erwarten. Die genauere Schätzung des Calciumbedarfs in diesen Patientengruppen erfordert eine gezielte klinische Studie."],"dc:format.medium":["application/pdf"],"dc:subject":["Calciumsalze","Calciumkomplexe","Calciumhomöostase","Calcium","dialysis","citrate","anticoagulation","pharmacokinetics"],"dc:title":["Citrate kinetics during regional citrate anticoagulation in extracorporeal organ replacement therapy","Zitratkinetik während regionaler Zitratantikoagulation bei extrakorporaler Organersatztherapie"],"dc:type":["DoctoralThesis"]},"updated_at":"2026-07-24T02:22:40Z"}