für die IAKH interessant ? Das NATA Konzept des Blutmanagements- für die IAKH interessant ? A B C Prä- Intra- Post- operativ Prof. Dr. med. Thomas Frietsch, MBA Gesundheitsökonomie(EBS) IAKH e.V. Präsentiert am 6.4.2011 im BwZK Koblenz mit freundl. Genehmigung bei einigen Anteilen von A. Hofmann

NATA Leitlinie Hb-Bestimmung 28 Tage vor elektivem Eingriff- Grad 1C Präop. Ziel Hb- Niveau oberhalb WHO-Grenzen- Grad 2C Labordiagnose der Anämie- Grad 1C Behandlung von nutritiven Ursachen Grad 1C Epo-Therapie, wenn nicht nutritiv oder korrigiert Grad 2A Grad 1- empfohlen Grad 2- vorgeschlagen A-B-C Evidenzlevel von hoch bis niedrig

Evidenz

NATA Algorithmus

WHO Definition of Anemia vs Hb Distribution in the General Population Anemia in Men: Hb <13 g/dL Hb distribution in women: 13.3  0.9 g/dL 3000 Hb distribution in men: 15.2  0.9 g/dL 2500 Anemia in Women: Hb <12 g/dL 2000 N=40,000 (NHANES III, 1988-1994) Frequency 1500 1000 Superimposing the World Health Organization (WHO) anemia definition over graphs of the distribution of Hb levels by gender is revealing: anemia under this definition comprises Hb levels that are significantly lower than mean Hb levels in the population. Although there is no definitive agreement on the definition of anemia, one of the most commonly used definitions is the one used by the WHO. The WHO defines anemia as Hb <13 g/dL in men and <12 g/dL in premenopausal, nonpregnant women. 500 10 10.5 11 11.5 12 12.5 13 13.5 14 14.5 15 15.5 16 16.5 17 17.5 18 Hb Level (g/dL) World Health Organization. Geneva, Switzerland; 2001. Dallman PR, et al. In: Iron Nutrition in Health and Disease. London, UK: John Libbey & Co; 1996:65-74.

Anemia: A Potent Multiplier of Mortality No HF, No CKD, No Anemia 1 Anemia Only 1.9 CKD Only 2.05 HF Only 2.86 CKD, Anemia 3.37 HF, Anemia 3.78 HF, CKD 4.86 HF, CKD, Anemia The top bar depicts patients without heart failure, chronic kidney disease, or anemia; they have a relative risk of 2-year mortality of 1. However, when you start adding each one of the diseases independently, the risk of mortality increases to 2 to 3 times that of normal. And when you add anemia to any one of the other 2 diseases, the risk of mortality increases even higher. When all 3 are present—heart failure, chronic kidney disease and anemia—the risk of mortality increases to 6 times the normal level. Therefore, it appears that anemia is a potential multiplier of mortality. However, it is still not clear whether anemia is in itself a potent additive to mortality or whether anemia is merely a signal of the 2 other diseases being more severe. 6.07 1 2 3 4 5 6 7 Relative Risk of 2-Year Mortality N = 1.1 million (5% Medicare sample, 1996-1997) Herzog CA, et al. Presented at: 6th Annual Scientific Meeting of the Heart Failure Society of America; September 22-25, 2002; Boca Raton, Florida. Abstract 226.

NATA Algorithmus

Eisenverteilung im Gewebe Duodenum (average, 1-2 mg per day) Utilization Utilization Plasma transferrin (3 mg) Bone marrow (300 mg) Muscle (myoglobin) (300 mg) Circulating erythrocytes (hemoglobin) (1800 mg) Storage iron Absorption of iron is about 1 to 2 mg per day, and the iron loss is equivalent to that. Most of the iron is stored in the liver―about 1 gram is stored in the liver and about .3 grams is stored in muscle. The plasma transferrin, which is a protein that transfers iron from the different locations is very important because it contains the majority of the iron in the body in liquid form. Bone marrow contains about .3 grams and about 1.8 grams of iron is contained in the red cells. If you add bone marrow production and the endothelial cells, you end up with approximately 1.5 grams of iron. In addition to the 1 to 2 mg of iron that is replenished a day, the same amount is also absorbed from dietary intake. Sloughed mucosal cells Desquamation Menstruation Other blood loss (average, 1-2 mg per day) Iron loss Liver parenchyma (1000 mg) Reticulo- endothelial macrophages (600 mg) Adapted with permission from Andrews NC. N Engl J Med. 1999;341:1986-1995.

Eisenmangelanämie Ferritin- Depot, Speicher in Leber und KM Kinder: 7-142 ng/ml Frauen: -50J 22-112 ng/ml, > 50J 13-651 ng/ml Männer: -50J 34-310 ng/ml, > 50J 4-665 ng/ml Ferritinwert zu niedrig - EIsenmangel Ferritinwert zu hoch –Tumor, Infekt, Hämochromatose, Thalassämie Transferrin- Transport, Aufnahme Blood management can be broken down into 3 pillars, which consist of optimizing hemoglobin levels, understanding anemia and harnessing the physiology of it, and having a consistent approach. Transferrin norm: 200-400mg/dl Sättigung normal: 25-30% Transferrin zu niedrig - Tumor, Infekt, Hämochromatose, Thalassämie Transferrin zu hoch –Eisenmangel

Differentialdiagnostik Anämie

Präoperative Anämie : Ursache & Prävalenz J.Tomeczkowski, C. von Heymann 2011 unpublished Präoperative Anämie : Ursache & Prävalenz Ursache der Anämie Referenz n Kollektiv Alter Def. Prä valenz Eisen- ACD andere [Mean] [Hb in g/dl] mangel (EPO-M.) Guralnik et al.[1] 2 069 ohne 75 M13,0;F12,0 11% 20% 32% 34% Ezekowitz et al.[2] 12 065 Herzinsuff 77 k.A. 17% 21% 58% Saleh et al.[3] 1 142 THA/TKA 68 M13,0;F11,5 23%1 64%2 13% Bisbe et al.[4] 715 M+F 13,0 19% 30%3 44% 26% Myers et al.[5] 225 THA 64 M12,5;F11,5 15% 60%4 4% Basora et al.[6] 218 71 39% 30% k.A.7 Theusinger et al.[7] 93 21%8 Goodnough et al.[8] 290 60 57 21%9 33%10 70%11

NATA Algorithmus

Current Status of Intravenous Iron Therapy Beneficial No Benefit Investigational Anemia of renal failure, with or without erythropoietin therapy Autologous blood donation in patients with or without iron deficiency Blood loss, iron deficiency, and erythropoietin therapy Patients with ongoing blood loss Anemia of chronic disease and erythropoietin therapy Jehovah’s Witness patients with iron deficiency and/or blood loss Perisurgical anemia, with or without erythropoietin therapy This slide shows instances for which intravenous iron is beneficial, offers no benefit, and instances for which the benefit remains unclear. Absolute iron deficiency is defined as ferritin <200 μg/L and/or iron saturation <20%, or relative iron deficiency (ferritin <400 μg/L in dialysis patients receiving erythropoietin therapy, or the presence of >10% hypochromic erythrocytes and/or reticulocytes).

Dosierung iv Eisen Eisencarboxymaltose (Ferinject®) Eisendextran (Dexferrum®, INFeD®) Natriumeisenglukonatkomplex in Sucrose (Ferrlecit®) 10 mL (125 mg of elemental iron) verdünnt in 100 mL 0.9% NaCl langsam über 1 h oder langsam unverdünnt i.v. (Rate max. 12.5 mg/min) Eisensucrose (Venofer®) HDD-CKD: 100 mg unverdünnt langsam i.v. über 2-5 min oder als Infusion in 100 mL 0.9% NaCl über 15 min (Gesamtdosis 1000 mg) NDD-CKD: Gesamtdosis von 1000 mg über 14 d als eine 200 mg IV Injektion über 2-5 min Eisencarboxymaltose (Ferinject®) 500-1000mg in 100-250 ml über 20 min Keine Hypotonien und allergischen Reaktionen durch höhere Komplexstabilität This slide includes the dosing regimens for available intravenous iron agents.

Preoperative Iron Supplementation in Colorectal Cancer Patients Kohorte von 569 Patienten 32 Pat. Hb ≤10 g/dL -2 Wochen präoperative Eisentherapie (200 mg) 84 Pat. Hb ≤10 g/dL ohne Eisentherapie Results: Anstieg Hb um 2 g/dL Transfusionsrate: 9% der Verumgruppe vs 27% Okuyama et al conducted a study to investigate whether giving an iron preparation to anemic patients before colorectal cancer surgery improves their anemia and reduces the need for intraoperative blood transfusion. Among 569 patients who underwent colorectal cancer surgery, they studied 32 anemic patients who received iron supplementation for at least 2 weeks preoperatively and 84 anemic patients who did not. Anemia was defined as a hemoglobin (Hb) level at first presentation of ≤10.0 g/dL. Hemoglobin and hematocrit (Ht) levels were measured at first presentation, then immediately before and after surgery. They also calculated intraoperative blood loss and compared intraoperative transfusion rates. Hb and Ht values were similar in both groups at first presentation, but significantly different immediately before surgery (P<.0001). There were no significant differences in intraoperative blood loss between the groups, but significantly fewer patients in the iron supplementation group needed an intraoperative blood transfusion (9.4% vs 27.4%; P<.05). Okuyama M, et al. Surg Today. 2005;35:36-40.

NATA Algorithmus

Substitution Folsäure und Vit B 12 Folsäure 5mg/d iv oder oral Hydroxocobalamin iv 1000µg/Woche Ferinject 500 mg iv. Blood management can be broken down into 3 pillars, which consist of optimizing hemoglobin levels, understanding anemia and harnessing the physiology of it, and having a consistent approach. 17

NATA Algorithmus

Erythropoietin Regulates Red Blood Cell Production Renal interstitial peritubular cells detect low blood oxygen levels EPO stimulates the proliferation and differentiation of erythroid progenitors into reticulocytes and prevents apoptosis Erythropoietin (EPO) secreted into the blood EPO More reticulocytes enter circulating blood Increased oxygen delivery to tissues This slide illustrates the life cycle of erythropoietin in response to a reduced oxygen level or even hypoxia, which is detected by the interstitial peritubular cells in the kidney. A signal is sent out and erythropoietin, which is produced in the kidney in adults, and then stimulates the bone marrow. The bone marrow, in response to erythropoietin, proliferates and differentiates the erythroid progenitors into reticulocytes and prevents apoptosis. More reticulocytes enter the circulating blood, and the reticulocytes differentiate into erythrocytes, increasing the erythron size, resulting in increased oxygen delivery to the tissues. Reticulocytes differentiate into erythrocytes, increasing the erythron size Dessypris E. In: Lee G, et al, eds. Wintrobe’s Clinical Hematology. Vol 1. Baltimore, Md: Lippincott, Williams & Wilkins; 1998:169-192. Bunn H. In: Isselbacher K, et al, eds. Harrison’s Principles and Practice of Internal Medicine. 13th ed. New York, NY: McGraw-Hill; 1994:1717-1721.

Erythropoietin: Dosierung Chronisches Nierenversagen: SC 3x / Woche 100U/kg * Zidovudine-beh. HIV: IV or SC 3x / Woche 100U/kg Tumoranämie/Chemotherapie: SC 3x / Woche 100U/kg Präoperativ: 300 U/kg/d SC for 10 days before surgery, on the day of surgery, and for 4 days after surgery; or 600 U/kg SC once weekly (21, 14, and 7 days before surgery) plus a fourth dose on the day of surgery Immer zusammen mit Eisengabe This slide reviews the appropriate dosing regimens for epoetin alfa and darbepoetin alfa. *IV route is recommended for patients on dialysis. .

EPO nicht indiziert bei (gemäß CMS*) Tumoranämie bedingt durch Folsäuremangel, Eisenmangel, Hämolyse, chron. Blutverlust , Vit. B12 Mangel, KM-Fibrose Anämie bei akuter und chronischer myeloischer Leukämie (CML, AML), or erythroipetischen Tumoren Tumoranämie nicht auf Chemotherapie zurückzuführen Bestrahlungsinduzierte Chemotherapie Prophylaktische Therapie Epo-Resistenz durch AK-Bildung Kombination von Tumoranämie und schlecht eingestellten HTN Individuelle Modulationsmöglichkeit durch Berücksichtigung CMS proposed that ESA treatment is not reasonable and necessary for the following conditions: Any anemia in cancer or cancer treatment patients due to folate deficiency, B12 deficiency, iron deficiency, hemolysis, bleeding, or bone marrow fibrosis Anemia of myelodysplasia Anemia of myeloid cancers Anemia associated with the treatment of myeloid cancers or erythroid cancers Anemia of cancer not related to cancer treatment Anemia associated with radiotherapy Prophylactic use to prevent chemotherapy-induced anemia Prophylactic use to reduce tumor hypoxia Patients with erythropoietin-type resistance due to neutralizing antibodies Patients with treatment regimens including anti-angiogenic drugs such as bevacizumab Patients with treatment regimens including monoclonal/polyclonal antibodies directed against the epidermal growth factor receptor Anemia due to cancer treatment in patients with uncontrolled hypertension Patients with thrombotic episodes related to malignancy *Centers for Medicare & Medicaid Services (CMS). Decision Memo for Erythropoiesis Stimulating Agents (ESAs) for non-renal disease indications (CAG-00383N). Available at: https://www.cms.hhs.gov/mcd/viewdecisionmemo.asp?id=203. Accessed September 20, 2007.

Standard in Studien (Ferritin > 100 μg/l und/oder TSAT > 20%) -4 Monate -3 Monate -2 Monate -1 Monat OP ERYPO 40.000 IE s.c. EPO s.c. EPO s.c. EPO s.c. EPO s.c. 200 mg Fe-II-Substitution pro Tag Eisen per os +Fe p.o./i.v. Standard bei Eisenmangel (Ferritin < 100 μg/l und/oder TSAT < 20%) -4 Monate -3 Monate -2 Monate -1 Monat OP ERYPO 40.000 IE s.c. EPO s.c. EPO s.c. EPO s.c. EPO s.c. i.v. entsprechend Eisenmangel p.o. 200 mg Fe-II-Substitution pro Tag +Fe i.v. +Fe i.v. +Fe i.v. +Fe i.v. oder Eisen per os +Fe p.o./i.v.

präoperativer Hb-Wert <10 g/dl Ziel 13g/dl Stratifiziert nach Hb-Wert und dosisadaptiert (Ferritin > 100 μg/l und/oder TSAT > 20%) präoperativer Hb-Wert <10 g/dl Ziel 13g/dl OP -4 Monate -3 Monate -2 Monate -1 Monat ERYPO Nach Fach- Information 600 I.E./kg KG zum Bsp.: 68kg KG = 40 000 I.E. (40K) 85kg KG= 40K + 10K 102kg KG= 40K + 20K 119kg KG= 40K + 30K 136kg KG= 40K + 40K EPO s.c. EPO s.c. EPO s.c. EPO s.c. Eisen per os +Fe p.o./i.v. präoperativer Hb-Wert 10-11 g/dl Ziel 13g/dl -4 Monate -3 Monate -2 Monate -1 Monat OP EPO s.c. EPO s.c. EPO s.c. Eisen per os +Fe p.o./i.v. FERRITIN i.v. entsprechend Eisenmangel p.o. 200 mg Fe-II-Substitution pro Tag präoperativer Hb-Wert 11-12 g/dl Ziel 13g/dl -4 Monate -3 Monate -2 Monate -1 Monat OP EPO s.c. EPO s.c. Eisen per os +Fe p.o./i.v.

Modifikation 14 ♂ „Hüft Tep-Wechsel“ ♀„Hüft Tep“ präop. Ziel HB 14 OP Stratifiziert nach Hb-Wert und dosisadaptiert (Ferritin > 100 μg/l und/oder TSAT > 20%) präop. Hb-Wert 10-12 g/dl Ziel 14g/dl OP -4 Monate -3 Monate -1 Monat ERYPO Nach Fach- Information 600 I.E./kg KG zum Bsp.: 68kg KG = 40 000 I.E. (40K) 85kg KG= 40K + 10K 102kg KG= 40K + 20K 119kg KG= 40K + 30K 136kg KG= 40K + 40K -2 Monate Modifikation 14 ♀„Hüft Tep“ Blutverlust > 1000 ml auch Knie-TEP Wechsel ♂ „Hüft Tep-Wechsel“ Blutverlust > 1500 ml präop. Ziel HB 14 EPO s.c. EPO s.c. EPO s.c. Eisen per os +Fe p.o./i.v. präop. Hb-Wert 12-13 g/dl Ziel 14g/dl -4 Monate -3 Monate -1 Monat OP -2 Monate EPO s.c. EPO s.c. Eisen per os +Fe p.o./i.v. FERRITIN i.v. entsprechend Eisenmangel p.o. 200 mg Fe-II-Substitution pro Tag präop. Hb-Wert 13 g/dl Ziel 14g/dl -4 Monate -3 Monate -1 Monat OP -2 Monate EPO s.c. Eisen per os +Fe p.o./i.v.

Modifikation 15 ♀ „Hüft Tep Wechsel“ präop. Ziel HB 15 Kollektiv: OP Stratifiziert nach Hb-Wert und dosisadaptiert (Ferritin > 100 μg/l und/oder TSAT > 20%) präop. Hb-Wert 10-12 g/dl Ziel 15g/dl OP -4 Monate -3 Monate -1 Monat ERYPO Nach Fach- Information 600 I.E./kg KG zum Bsp.: 68kg KG = 40 000 I.E. (40K) 85kg KG= 40K + 10K 102kg KG= 40K + 20K 119kg KG= 40K + 30K 136kg KG= 40K + 40K -2 Monate Modifikation 15 ♀ „Hüft Tep Wechsel“ Blutverlust > 1500 ml auch Spondylodesen > 3 Ebenen Knie/Hüft-TEP mit Blutungsneigung . präop. Ziel HB 15 Kollektiv: weiblich normal bis untergewichtig EPO s.c. EPO s.c. EPO s.c. EPO s.c. Eisen per os +Fe p.o./i.v. präop. Hb-Wert 12-13 g/dl Ziel 15g/dl -4 Monate -3 Monate -1 Monat OP -2 Monate EPO s.c. EPO s.c. EPO s.c. Eisen per os +Fe p.o./i.v. FERRITIN i.v. entsprechend Eisenmangel p.o. 200 mg Fe-II-Substitution pro Tag präop. Hb-Wert 13 g/dl Ziel 15g/dl -4 Monate -3 Monate -1 Monat OP -2 Monate EPO s.c. EPO s.c. Eisen per os +Fe p.o./i.v.

Säule A: Präoperative Strategien Optimierung der Erythrozytenmasse in der perioperativen Medizin bei zu erwartendem Transfusionsbedarf Adäquate Bedarfsplanung (Bereitsstellung und Berechnung des Patientenblutvolumens) Anämievermeidung, -diagnostik und -therapie Autologe Blutspende Aufdeckung von Blutungsneigungen und hämorrgaischen Diathesen Algorithmen und Patientenpfade zur Diagnostik und Therapie Allianzen- und Netzwerkbildung zu Niedergelassenen, Akutkrankenhaus und Rehabilitationszentrum unter Einbezug der Kostenträger A

ITM- A 1: Prähospitale Optimierung der Erythrozytenmasse: Adäquate Bedarfsplanung 1.1 Schätzung / Berechnung der Erythrozytenmasse EM: EM = [Hb](g/l) x Blutvolumen BV (l) BV = KG (kg) x 0,07 (Männer) oder 0,065 (Frauen) 1.2 Statistischer Blutverlust des geplanten Eingriffs in Krankenhaus x- Abteilung y von Team z 1.3 Real zu planender Blutbedarf unter Berücksichtigung der individuellen Risiken

ITM- A 2: Vermeidung einer prähospitalen Anämie Inzidenz bei 25-30% → Transfusionsbedarf ↑ Diagnose- (Labor : Hb, MCV/MCH, Fe, Ferritin) Therapie: Kausal Fe EPO und Fe

NATA-Konzept der Anämie: für die IAKH ok aber zu modifizieren! Einbindung nach Modifikation in das IAKH-Konzept Eines von vielen Stellgliedern Spezifischer: Angabe von Dosen iund Applikationsrouten Individuelle Modulationsmöglichkeit durch Berücksichtigung von Eingriff, Blutverlust und Körpergewicht