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Patient Blood Management-

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1 Patient Blood Management-
das moderne perioperative Transfusionskonzept A B C Prä- Intra- Post- operativ Prof. Dr. med. Thomas Frietsch, MBA Gesundheitsökonomie(EBS) IAKH e.V. Präsentiert am im BwZK Koblenz mit freundl. Genehmigung bei einigen Anteilen von A. Hofmann

2 Conflict of interests CLS Behring Essex Pharma Janssen Cilag
Novo Nordisk Interdisziplinäre Arbeitsgemeinschaft für Klinische Hämotherapie IAKH Arbeitskreis Bluttransfusion der DGAI und BDA Sektion Hämotherapie und Hämostaseologie der DIVI 2

3 Learning Objectives: Was sind die Risiken & Gefahren der Bluttransfusion ? Welches sind die Bestandteile des ITM /PBM ? Kenntnis der Anämieprävalenz in der inneren Medizin und der Chirurgie Anämietherapie mit Epo und Eisen Kenntnis der realen Kosten der Fremdbluttransfusion Kenntnis der potenziellen klinischen und ökonomischen Vorteile von ITM /PBM Homework: Entwickeln Sie klinische Patientenpfade für das Blutmanagement in Ihrer Klinik 3

4 Risiken & Komplikationen
Transfusion-related immunomodulation (TRIM) Systemic inflammatory response syndrome (SIRS) Transfusion-related acute lung injury (TRALI) Übertragung von Erregern (viral u. bakteriell) Nosokomiale Infektionsrate ↑ Mortalität ↑ Administrationsfehler Akute und verzögerte Transfusionsreaktionen Lagerungsschaden: “The Cold Storage Lesion” Freies Hämoglobin High on the list of complications today is transfusion-related immune modulation (TRIM). Blood is a foreign object and when it is transfused to the recipient, not only are the cells active but the plasma itself contains a large number of proteins, which may be foreign to the recipient. Data from trauma patients shows that patients who receive allogeneic blood after trauma have an increase in the systemic inflammatory response syndrome (SIRS), and those patients are at high risk of developing complications secondary to SIRS. Patients who receive transfusions can also developed what is called transfusion-related lung injury (TRALI), which is also immune mediated. It is thought to be due to the HLA type 1 and 2 antigens, as well as from lipid-based particles from the blood of the donor. These complications are associated with increased risk for morbidity and mortality, and are now considered greater risks than administrative errors, which were once considered the greatest risk of mortality after transfusion. The risk of viral and bacterial infection exists but is extremely low. However, nosocomial infection is a very common complication, probably second to that of TRIM. Administrative error—the wrong unit of blood to the wrong patient—occurs between 1 and 12,000 to 1 in 14,000 units in the US and about 1 in 28,000 units in the UK. Why there is a difference between the US and the UK is unclear. Administrative error results in mortality in about 1 in 600,000 units. The so-called “cold storage lesion” is another complication. Blood is stored at 4 °C up to 42 days. During that time, 23DPG is completely removed from the red cells as well as ATP, which is lost. This does not allow the red cells that are stored to have the same configuration as the native red cells. The transfused cells are spherocytes and rigid, and cannot get through the microcirculation, which may actually block the entry of native cells into the microcirculation. The cold storage also increases the senescence of these cells so that they die quicker than native cells do, releasing free hemoglobin. Free hemoglobin can cause vasoconstriction compounding the problem of oxygen delivery.

5 Serious Hazards of Transfusion (SHOT)
DTR (28) 4.6% TRALI (23) 3.8% TTI (3) 0.5% PTP (2) 0.3% ATR (68) 11.2% IBCT (485) 79.6% The SHOT study is being conducted in the UK and Ireland. Because those countries handle blood in the same fashion as is handled in the US, the data can be extrapolated for use in the US. Incorrect blood component transfused comprises almost 80% of all the reported severe complications associated with transfusions. This is therefore a major concern. However, as already mentioned, the immune modulatory events are currently probably more of a concern in terms of mortality. N=609 ATR = acute transfusion reaction; DTR = delayed transfusion reaction; IBCT = incorrect blood component transfused; PTP = posttransfusion purpura; TRALI = transfusion related acute lung injury; TTI = transfusion transmitted infection. Serious Hazards of Transfusion Annual Report Available at:: Accessed April 24, 2007.

6 IAKH Fehlerregister 2010 = 53 % 16% 37% 6% 2% 4% 6% 22% (16) 9%
Fehlerregister in der Hämotherapie IAKH Fehlerregister 2010 Summe aller Verwechslungen 16% 37% = 53 % 6% 2% 4% 6% Indikationsstellung 22% (16) 9% Blutproben- verwechslung 15% (8) Verabreichungs- fehler Blutprodukt verwechselt, -entdeckt, Teilschritt 3 -entdeckt, Teilschritt 5 -unentdeckt. Verfallenes Blut transfund.. 26% (8) 11% (20) n.a. : n=3

7 Verwechslungen “Fehltransfusion” geschätzt
1:14,000 RBC units in the US1 1:28,000 RBC units in the UK2 ~ 10% – Ettikettierfehler (1:1 000 Proben) ~ 25% – Laborfehler Rest – Klinik Letalität übersteigt HIV-assoz. Transmissionsrisiko um das 4- to 8-fold This slide again shows that mistransfusion occurs in approximately 1 in 14,000 units transfused in the US and in approximately 1 in 28,000 units transfused in the UK. Approximately 10% of these are due to labeling errors and about 25% are due to laboratory errors. The lion’s share of the complications and errors are associated with the clinical setting—that is on the floor with physicians and nurses. Fatality from administrative errors exceeds fatality from HIV by about 4- to 8-fold. So again, this is much more of a concern than the risk of viral transmission, but less of a concern than that of transfusion-related immune modulation. Williamson LM, et al. BMJ. 1999;319:16-19. Sazama K. Transfusion. 1990;30:

8 Transfusion-related Acute Lung Injury (TRALI)
Incidence estimates vary1 Difficulty in ruling out left atrial hypertension (eg, transfusion-associated circulatory overload [TACO], congestive heart failure) as cause Characteristics of acute lung injury indistinguishable from TRALI Lack of agreement on case definition Lack of awareness, underreporting/underdiagnosis of TRALI Leading cause of transfusion-related mortality1 (1:200,000 cases2) Proposed mechanisms Passively transfused donor HLA class I/II or neutrophil antigens3 Mixture of predisposition and infusion of blood-related lipid-derived mediators4,5 Incidence estimates for TRALI vary for a number of reasons, as shown on the slide. TRALI is now considered the leading cause of transfusion-related mortality, as reflected by transfusion-related fatality data reported to the FDA. Assuming that there are 3.2 million transfusion recipients annually and that there is not underreporting of TRALI fatalities to the FDA, this leads to an estimate that TRALI contributes to mortality in 1:200,000 transfusion recipients. Several mechanisms for TRALI have been proposed. One mechanism cites the interaction between passively transfused donor HLA class I/II or neutrophil antibodies and reciprocal recipient antigens. An alternative mechanism is the infusion of biologically active lipids that accumulate in blood components during storage. Kleinman S. Transfusion. 2006;46: Holness L. Available at: Accessed May 22, 2007. Popovsky MA, Moore SB. Transfusion. 1985;25: Silliman CC, et al. Vox Sang. 1992;63: Silliman CC, et al. Transfusion. 1997;37:

9 Blood Components Associated With TRALI
Significant # reported Whole blood RBC FFP Apheresis platelets Whole-blood–derived platelet Isolated # WBC IVIG Cryoprecipitate Stem cells Blood components associated with TRALI are listed in this slide. FFP = fresh frozen plasma; IVIG = IV immune globulin; RBC = red blood cells; WBC = white blood cells. Shander A, Popvsky MA. Chest. 2005;128:

10 Übertragung Infektionen
Simian foamy virus (SFV) HHV-8 West Nile virus Chagas nCJD Malaria SARS Influenza The simian population is hunted, butchered, and sold on the open market as animal protein in sub-Sahara Africa. All of these animals are infected with simian foamy virus. In addition, the meat handlers and their family members are also infected with the virus. Just as was initially the case with HIV, simian foamy virus does not at this point cause disease in these animals or in the meat handlers; however, there is concern that at some point, just as was the case with HIV, the virus is going to mutate or change in behavior. Human herpes virus 8 and West Nile virus have also been demonstrated to be transmitted by blood. One of the current concerns of the FDA is the appearance of trypanosoma cruzi, which is responsible for Chagas disease, in the blood supply in the United States. It used to only be endemic in Central and South America. We now know that trypanosoma cruzi is in the blood supply in the United States, and there is now a test to help identify donors who have trypanosoma cruzi, and to eliminate them from the donor pool. Chagas disease causes blindness and attacks the heart. To date, there is no cure for Chagas disease. nCJD, malaria, SARS, in addition to other infections that are not listed, can all be transmitted through transfusion. The potential risk of an epidemic exists any time a new organism enters the blood pool, dependent on the type and behavior of the organism.

11 Bakterielle Infektionen
Risiko der bakteriellen Sepsis FFP 1: TE EK 1:25,000 TE Thrombos 1:3000 TE Bacterial detection performed early will miss late infection (platelets) Pathogen inactivation, is that the answer? Blajchman MA, et. al. Transfus Med Rev. 2005;19:

12 of Transfused Blood Component Risk of Transmission per Unit
Decline in Risks of Transfusion-Transmitted HIV, HBV, HCV, and Bacterial Infections Dashed lines represent estimates. 10-2 10-3 10-4 10-5 10-6 10-7 1984 1987 1990 1993 1996 1999 2002 2005 of Transfused Blood Component Risk of Transmission per Unit Bacteria in platelets HBV HCV HIV This graph shows the decline in the risks associated with both HIV and hepatitis C viruses, which is due to the judicious work of the blood industry in both detecting and eliminating donors who can potentially effect the population. We have been somewhat successful with hepatitis B, but not to the extent that we have been with hepatitis C and HIV, partially due to the testing that is done but also due to the behavior of the virus. Of the patients who do contract hepatitis B from transfusion, 95% of them have no sequelae thereafter. Revised HIV Non-A, non-B HCV p24 HCV and HIV West Nile Bacterial donor antibody hepatitis antibody antigen nucleic acid virus nucleic screening deferral screening surrogate screening testing testing acid testing of platelets criteria testing Adapted with permission from Blajchman MA, Vamvakas EC. N Engl J Med. 2006;355: and Busch MP, et al. JAMA. 2003;289:

13 Acute Transfusion Reactions
Anaphylaxis 1:10,000–1: transfusions (platelets) IgA-mediated, IgA-deficient recipient Fatal – up to 5% Transfusion-associated circulatory overload (TACO) – 1:3000 for all products Other immune- and antibody-mediated reactions Acute transfusion reactions are listed here.

14 Spender-Leukozyten Persistenz bei Unfallpatienten bis zu 1.5 J nach Fremdbluttransfusion 2 x 109 WBCs in einem undepletierten EK 1 x 108 WBCs – spezielles Zentrifugenprogramm, buffy- coat scharf abgetrennt 1-5 x 106 WBCs – Leukozytenfilter, depletiert The amount of white cells that accompany the red cells in the bag of red cell concentrate—about 109 white cells. Those white cells carry DNA in them, and they may persist as a lineage within the recipient for years. One case report on a patient who received a single unit of blood after postpartum hemorrhage found that white donor cells were detected 10 years later. This persistence of donor white cells in the recipient circulation is called microchimerism. To reduce the exposure of the recipient to white cells, the blood can be either buffy coated or centrifuged, removing about 10-fold of the white cells. With the new leukocyte filters, white blood cells can now be reduced to 1-5 x 105. Although this reduces the amount of white blood cells substantially, it does not eliminate them, and therefore does not eliminate the risk of donor leukocytes. Lee TH, et al. Blood. 1999;93:

15 The Cold Storage Lesion
Storage Effects Consequences Reduced to absent 2,3-diphosphoglycerate Increased oxygen affinity and decreased oxygen unloading by hemoglobin Reduced to absent ATP Erythrocyte shape changes Increased osmotic fragility Decreased deformability Microvesiculation and loss of lipid membrane Decreased erythrocyte viability Lipid peroxidation Cellular injury and early cell death – free Hb Loss of NO Vasoconstriction and poor unloading Due to the cold storage lesion effect there is reduced benefit in allogeneic blood due to the fact that the blood is stored at 4 °C for up to 42 days. During that time, there is reduced to absent 2,3-diphosphoglycerate (2,3-DPG), which is responsible for the unloading of oxygen in the periphery. Under those circumstances, this blood, which is devoid of 2,3-DPG, can carry oxygen very well, so it becomes like a sponge and may actually compete with the tissues for oxygen until it replenishes the 2,3-DPG, which may take hours to a full day. The reduction of ATP can change the shape of the erythrocytes, making them more fragile, as well as decreasing their ability to deform. Microvesiculation and lipid peroxidation can also contribute to this. The loss of nitric oxide, because of the free hemoglobin binding of nitric oxide, causes vasoconstriction. When the cells are devoid of ATP, they become fragile. They die quicker and free large amounts of free hemoglobin into the circulation. Free hemoglobin has an 8,000 times greater affinity for nitric oxide than it does for oxygen. So favorably, it attaches itself to nitric oxide. Nitric oxide being the most potent vasodilator produced by the endothelial cells, causes vasoconstriction when it is being completely absorbed by hemoglobin. So, for those cells that are poorly deformed, if vasoconstriction occurs, they cannot get to the periphery to unload oxygen. Offner PJ, et al. Arch Surg. 2002;137: Brown M, Whalen PK. Crit Care Nurse. 2000;20(suppl):1-14. Zallen G, et al. Shock. 2000;13:29-33.

16 Transfusion-related Immunomodulation (TRIM)
Allogeneic blood transfusion Infuses recipient with potentially immunomodulatory substances: foreign cells, cell-associated + soluble antigens, biological response modifiers Human studies (controversial and hotly debated) suggest ABT (vs no transfusion/autologous transfusion): ‘Positive’ effects: ↑ renal allograft survival; ↓ risk of recurrent abortion; ↓ recurrence of Crohn’s disease Negative effects: ↑ recurrence rate of resected malignancies; ↑ post-op bacterial infections; ↑ mortality TRIM effect thought to be due to leukocytes Animal data Strong signal in human data Human studies, which are controversial, suggest that allogeneic blood transfusion versus no transfusion or autologous transfusion improved renal allograft survival. This is old data. It also has been shown to reduce the risk of recurrent abortion and reduced the risk of Crohn’s disease—all due to the reduction of the receipient’s immune modulation. Today there drugs are available to do that and they are much better than the use of blood. Studies have also shown that patients undergoing colon resection or any type of cancer resection who receive allogeneic blood have a higher incidence of recurrence of malignancy compared with patients who do not receive blood. In addition, there is an increased incidence of bacterial and nosocomial infection and mortality in patients who are transfused versus those that are not. Evidence suggests that the transfusion-related immunomodulation (TRIM) effect is believed to be due to leukocytes. Limited human data suggest that lipid depletion reduces febrile effects of transfusion and may actually improve mortality and morbidity.

17 Effect of Blood Transfusion on Long-term Survival After Cardiac Surgery
1.00 No XFN n=546 0.95 Patients at Risk 1-y 2-y 3-y 4-y 5-y Tx: 528 518 502 349 188 No Tx: 539 519 408 254 Survival 0.90 XFN n=546 0.85 Engoren et al conducted a retrospective study that included 1915 patients who underwent first-time isolated coronary artery bypass operations. Patients with transfusions were compared with those who had not been transfused. Long-term survival data were obtained from the United States Social Security Death Index. Transfused patients were older, smaller, and more likely to be female, and had more comorbidity. Transfused patients also had twice the 5-year mortality (15% vs 7%) of nontransfused patients. After correction for comorbidities and other factors, transfusion was still associated with a 70% increase in mortality. 12 24 36 48 60 Months after CABG Kaplan-Meier estimates of survival based on equal propensity scores of any transfusion (XFN) versus no transfusion (No XFN). CABG = coronary artery bypass grafting. Figure reproduced with permission from Engoren MC, et al. Ann Thorac Surg. 2002;74:

18 Nosocomial Infections in the ICU
Overall 18 P<.005 Transfused patients 15.4 Nontransfused patients 16 12 Percentage of Patients 8 5.9 2.9 4 To determine whether critically ill patients who receive allogeneic packed red blood cell transfusions are at increased risk of developing nosocomial infections during hospitalization, Taylor et al conducted a retrospective database study utilizing Project IMPACT. Nosocomial infection rates were compared among 3 groups: the entire cohort (N=1717), the transfusion group (n=416), and the nontransfusion group (n=1301). The average number of units transfused per patient was 4.0. The nosocomial infection rate for the entire cohort was 5.9%. The nosocomial infection rates for the transfusion group and the nontransfusion group was 15.4% and 2.9%, respectively (P<.005). Transfusion of packed red blood cells was related to the occurrence of nosocomial infection, and there was a dose-response pattern (the more units of packed red blood cells transfused, the greater the chance of nosocomial infection; P<.0001). The transfusion group was 6 times more likely to develop nosocomial infection compared with the nontransfusion group. N=1717 n=416 n=1301 Reproduced with permission from Taylor RW, et al. Crit Care Med. 2002;30:

19 Transfusions Correlate With Infections in a Dose-Dependent Manner
1.2 0-15 Units of PRBC 1.0 Y = e0.1187x R2 = 0.8 Incidence of Infection 0.6 0.4 0.2 The tradition has been that if you are going to transfuse a patient, you should give 2 units versus 1 unit. However, these data and many other data show that each transfused unit of blood carries its own additive risk. Therefore, nonexsanguinating patients should be transfused 1 unit at a time, and should be re-evaluated between each unit. As you can see, even with the first unit, the incidence of infection does not start out at zero. And then every time you add a unit, the incidence of infection becomes additive. So, the data dispel that dictum that 2 units should be given when 1 is being considered. 0.0 2 4 6 8 10 12 14 16 Transfusions Reproduced with permission from Claridge JA, et al. Am Surg. 2002;68:

20 Association Between Allogeneic Blood Transfusion and Mortality
Odds ratio: d mortality in OHS studies (all European)2-4 0.1 1 10 100 Meta-analysis, RCTs: WBC-containing transfusions and mortality1 No association detected across clinical settings Association may exist in open heart surgery (OHS)2-4 van de Watering et al Bilgin et al Wallis et al A meta-analysis of randomized controlled trials investigating WBC-containing transfusions and mortality detected no association across clinical settings. However, an association may exist in open heart surgery (OHS). Netherlands, N=914: CABG +/- valves and valves; infections, LOS: no significant difference Netherlands, N=496: valves +/- CABG; infections: significant  with S-RBCs Britain, N=509: CABG +/- valve and valves; infections: with S-RBCs  in hospital but  postdischarge: no difference Summary OR Figure adapted with permission from Vamvakas EC.1 Vamvakas EC. Transfusion. 2003;43: Van de Watering LM, et al. Circulation. 1998;97: Bilgin YM, et al. Circulation. 2004;109: Wallis JP, et al. Transfusion. 2002;42:

21 Die 3 Elemente des Patient Blood Management
Optimierung des Hämoglobinspiegels durch Diagnose und Therapie in allen klinischen Situationen Individuelles perioperatives Anämiemanagement Alternative Transfusionsmethoden 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. Medical Society for Blood Management Society of Advancement in Blood Management

22 Patient Blood Management
Patienten- zentrierte Optimierung der Erythrozyten masse Angemessene Transfusions- Strategien Blutsparende Maßnahmen According to a conservative estimate, 30% of blood and blood products in the United States are given to patients that actually do not need them and have no impact in terms of improving patient outcomes, and that may actually be detrimental. Blood management encompasses the full spectrum of techniques designed to avoid allogeneic blood transfusion—appropriate transfusion medicine (allogeneic blood transfusion is periodically necessary); blood conservation, which should be recognized as a valued and valid approach for all patients, medical or surgical; and the approach must be patient-centered—that is, it should result in improved patient outcomes, and that the needs of different patients with different requirements be addressed in a rational way and in a manner that will lead to positive outcomes.

23 Die 3 Säulen des IAKH – ITM Interdisziplinäres Transfusionsmanagement
A: Präoperative Strategien: Anämie, Algorithmen, Allianzen B: Individuelles intraoperatives Anämiemanagement im Akutkrankenhaus C: Postoperatives Transfusionsmanagement 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. 23

24 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

25 Säule B: Intrahospitale Strategien
Berücksichtigung und konsequente Einhaltung von evidenzbasierten, restriktiven Transfusionstriggern Blutarme Chirurgische Technik Chirurgische Technik mit sorgfältiger Blutstillung Minimal invasive und endoskopische Techniken Ultraschall/Laser/Elektrokautertechnik Saugdisziplin/Wiegen der Tücher Bedarfsgerechte Hämotherapie Maschineller Autotransfusion Homologen Transfusionskonzepten Prophylaktischer Einsatz von Antifibrinolytika Point of Care-Gerinnungsmonitoring Minimierung des Blutverlusts durch Schnelle Diagnostik zielgerechte Komponententherapie B 25

26 3 Säulen-Strategie in der Chirurgie
Präoperativ Gesenkter Transfusionstrigger Gesteigerte Erythrozytenmasse Intraoperativ Sorgfältige Blutstillung Spezielle Operationstechnik ANH MAT Postoperative Reduzierte Laborkontrollen Strategies to reduce surgical patients’ exposure to allogeneic blood can be broken down into those that are appropriate during the preoperative, intraoperative, and postoperative periods. Adapted from Goodnough LT, et al. Transfusion. 2003;43:

27 Säule C: Postoperative Strategien
Toleranz der chirurgisch bedingten Anämie Berücksichtigung und konsequente Einhaltung von evidenzbasierten, restriktiven Transfusionstriggern Vermeidung unnötiger Blutverluste Einsatz von Mikrolaborgefäßen, restriktive Diagnostik Einsatz von POCT-Gerinnungsdiagnostik Rechtzeitige Revisionschirurgie bei anhaltenden Drainagenverlusten MAT-Einsatz, wo möglich Frühmobilisation und enge Kooperation von Akutkrankenhaus und Rehabilitationszentrum C 27

28 Potenzieller Nutzen des Interdisziplinären Transfusionsmanagements
Beseitigt die Symptome und Effekte der Anämie Reduziert die Fremdblutexposition Verbessert das Patienten-”Outcome” Reduziert Versorgungsengpässe mit Blut durch verringerten Verbrauch Reduziert die Trägerkosten für Blutprodukte Bereitet die Klinik für den Wettbewerb (Blutverbrauchvergleiche der Krankenkassen) There are many potential benefits of blood management, which are listed here. Interdisziplinarität involviert alle Beteiligten → Akzeptanz ↑ Größerer Methodenreichtum → Effekt ↑ + +

29 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

30 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

31 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, ) 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.

32 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

33 Prevalence of Anemia in Critically Ill Patients
Hb <10 g/dL Vincent et al, 2002 (N=3534) Hb <12 g/dL Vincent et al, 2002 Hb 11 g/dL von Ahsen et al, 1999 (N=96) 20 40 60 80 100 29% 63% 77% These data, which are from intensive care units in Europe, show the prevalence of anemia in the critical care population. Approximately 30% of patients have a hemoglobin level <10 g/dL. When the hemoglobin level used is ≤11 g/dL, the prevalence reaches 77%. Therefore, the prevalence of anemia varies widely, partly because of the issue of definition, and partly because studies vary in regard to which hemoglobin levels are used—initial, nadir, or discharge values. Percentage of Critically Ill Patients With Anemia Vincent JL, et al. JAMA. 2002;288: von Ahsen N, et al. Crit Care Med. 1999;27:

34 Prevalence of Anemia at Admission Among Various Patient Groups
Patient type Prevalence (%) Reference Rheumatoid arthritis 33-60 Wilson, 20041 Surgery 5-75.8 Shander, 20042 Cancer 30-90 Knight, 20043 HIV 1.3-95 Belperio, 20044 Again, the data show tremendous variability for the prevalence of anemia among various patient groups. Wilson A, et al. Am J Med. 2004;116(suppl 7A):50S-57S. Shander A, et al. Am J Med. 2004;116(suppl 7A):58S-69S. Knight K, et al. Am J Med. 2004;116(suppl 7A):11S-26S. Belperio PS, et al. Am J Med. 2004;116(suppl 7A):27S-43S.

35 Preoperative evaluation
Alter und Anämie 30 25 20 15 10 5 65,788 patients ( ) Preoperative evaluation WHO anemia definition Men Women % Using the WHO definition for anemia, Kulier et al conducted a large study that included patients over a 20-year period; they evaluated the incidence of preoperative anemia. This graph clearly shows an increase in the incidence of anemia with advanced age, which may reflect underlying disease. 20-30 31-40 41-50 51-60 61-70 71-80 81-90 >90 Years Reproduced with permission from Kulier A, Gombotz H. Anaesthesist. 2001;50:73-86.

36 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, ) 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.

37 NATA Leitlinie Hb-Bestimmung 28 Tage vor elektivem Eingriff- Grad 1C
Präop. Ziel Hb- Niveau oberhalb WHO-Grenzen- Grad 2C Labordiagnose der Anämie- Grad 1A 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

38 NATA Algorithmus

39 Effects of Anemia Treatment
Partial correction of anemia to Hb g/dL in patients with CKD may: Reduce morbidity, hospitalization, and mortality1-3 Improve QOL,6,7 exercise capacity,8 cognitive function,2 and sexual function3 Improve LV structure and function4,5 The evidence suggests that the partial correction of anemia (Hb g/dL) can reduce morbidity, hospitalization, and mortality in patients with chronic renal disease. Data also suggest that LV structure and function is improved, and that quality of life and exercise capacity is also improved. The data, however, are less robust for improved cognitive and sexual function. 1. Xia H, et al. J Am Soc Nephrol. 1999;10: 2. Bedani PL, et al. Nephron. 2001;89: 3. Wu SC, et al. Scand J Urol Nephrol. 2001;35: 4. Hayashi T, et al. Am J Kidney DIs. 2000;35: 5. Portoles J, et al. Am J Kidney Dis. 1997;29: 6. Revicki DA, et al. Am J Kidney Dis. 1995;25: 7. Furuland H, et al. Nephrol Dial Transplant. 2003;18: 8. Clyne N, et al. Nephron. 1992;60:

40 Chronic Anemia: Lower the Transfusion Trigger Point?
Hb 7.0 g/dL-9.0 g/dL sufficient in critically ill patients Hébert PC, et al. N Engl J Med. 1999;340: Much lower Hb tolerated (>5.0 g/dL) in nonstressed normal patients Weiskopf RB, et al. Anesthesiology. 2000;92: Patients with CAD may require Hb levels in slightly higher ranges (8.0 g/dL-9.0 g/dL) and avoid tachycardia -blockers Euvolemia Minimum, safe (optimal) Hb/Hct unknown Trigger can be lowered to avoid transfusions One frequently asked question is “What is the lowest possible tolerated hemoglobin level?” Hébert et al conducted a randomized, controlled trial that included over 800 critically ill patients with euvolemia after initial treatment who had hemoglobin concentrations of <9.0 g/dL within 72 hours after admission to the ICU. They were randomly assigned to a restrictive strategy of transfusion, in which red cells were transfused if the hemoglobin concentration dropped below 7.0 g/dL and hemoglobin concentrations were maintained at 7.0 to 9.0 g/dL, and to a liberal strategy, in which transfusions were given when the hemoglobin cencentration fell below 10.0 g/dL and hemoglobin concentrations were maintained at 10.0 to 12.0 g/dL. Overall, 30-day mortality was similar in the 2 groups. However, the rates were significantly lower with the restrictive transfusion strategy among patients who were less acutely ill and among patients who were <55 years of age, but not among patients with clinically significant cardiac disease. Weiskopf et al showed that nonstressed normal volunteers were able to tolerate hemoglobin levels between 5.0 to 6.0 g/dL; however they did experience subtle, reversible increases in reaction time and impaired immediate and delayed memory. Without any definitive data, there is a prevailing belief that patients who have active coronary artery disease may require higher hemoglobin concentrations compared to the other groups. However, anemia is well tolerated, even in the patients with coronary artery disease, provided that they are euvolemic and nontachycardic. Because patients vary in the way they react to low hemoglobin levels, a single recommended concentration value is not appropriate. However, the optimal hemoglobin range versus the minimal hemoglobin level is still unknown. But we do know that the reserve is significant and that the trigger for transfusion of allogeneic blood can be lowered.

41 Compensatory Mechanisms of Anemia
Hb = g/dL tolerable (blood loss controlled + good cardiac function)  Cardiac output  Coronary flow  Blood viscosity  O2 consumption  O2 extraction This slide shows the compensatory mechanisms associated with anemia. When the hemoglobin concentration falls to 6.0 to 7.0 g/dL (or to 7.0 to 8.0 g/dL in some people) cardiac output increases to compensate for the reduction of oxygen delivery, and coronary flow improves. The lowering of blood viscosity probably has the greatest impact—a patient needs to be euvolemic to gain the benefit of reduced hemoglobin and improved flow. Oxygen consumption is reduced because the tolerance to exercise is reduced and total body oxygen extraction is actually increased. Corwin HL, Hébert PC. Physiology of anemia and red blood cell transfusion. In: Spiess BD, Spence RK, Shander A, eds. Perioperative Transfusion Medicine. 2nd ed. Philadelphia: Lippincott Williams & Wilkins; 2006:chap 6.

42 Funktionaler Eisenmangel
Ungleichgewicht zwischen Angebot ans KM und Verbrauch Retikulozytenzahl und HCC (Hypochromie) reduziert Niedriges Transferrin When patients receive erythropoietin, they also need to receive the substrate. If they do not receive the substrate, iron is depleted very quickly. The iron stores in the bone marrow and other tissues are very tightly regulated and there is no stimulation to release of the iron store. To overcome this, the patient needs to receive a supplement with small amounts of iron, either orally or intravenously, so that the red cells that are being produced have enough iron to be incorporated, producing normal functioning and normal sized red cells. Scigalla P, et al. Contrib Nephrol. 1990;82: Mcdougall IC, et al. Br Med J. 1989;29: Thomas C, Thomas L. Clin Chem. 2002;48: Mittman N, et al. Am J Kidney Dis. 1997;30:

43 Andere nutritiv bedingte Anämien
Eisen Folsäure Vitamin B12 Erythropoetintherapie When treating patients with epoetin, it is important to provide simultaneous treatment with iron, folic acid, and vitamin B12. Epoetin increases the production of red cells, but does not increase the release of iron or the availability of folic acid or vitamin B12.

44 Distribution of Iron in Tissue
Dietary iron 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:

45 Gründe für den Eisenmangel
Inadequate iron absorption Increased blood loss Gastrointestinal blood loss (eg, epistaxis, varices, gastritis, ulcer, tumor, IBD) Genitourinary blood loss (menorrhagia, cancer, chronic infection) Pulmonary blood loss (pulmonary hemosiderosis, infection) Other blood loss (trauma, excessive phlebotomy, large vascular malformations) This slide lists the causes of iron deficiency. Andrews NC. N Engl J Med. 1999;341:

46 Efficacy of IV Iron Therapy
Quickly replenishes depleted iron stores Raises serum ferritin Corrects iron-deficient erythropoiesis Raises transferrin saturation (TSAT) and Hb reticulocyte content (CHr) Increases Hb, or decreases epoetin dose for same Hb Maintains iron-sufficient erythropoiesis Replenishing iron stores assures adequate iron supply in patients prone to blood loss (eg, hemodialysis-related) Intravenous iron quickly replenishes depleted iron stores and raises the amount of iron in serum ferritin and corrects iron-deficient erythropoiesis, measured by the serum iron over the total iron binding capacity, which is transferrin saturation (TSAT). It also increases hemoglobin and may actually attenuate the amount of epoetin that is required, especially in the presence of iron deficiency anemia or slight iron deficiency. Again, replenishing iron stores ensures adequate iron supply in patients prone to blood loss, such as those patients on hemodialysis where iron is constantly being repleted through the blood system. As was mentioned already, the RBCs and the reticuloendothelial macrophages contain a significant amount of iron. If those are lost in the dialysis machine, these patients lose large amounts of iron.

47 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).

48 FDA-Approved Indications for IV Iron Therapy
Iron dextran injection, USP1,2 Patients with documented iron deficiency in whom oral administration is unsatisfactory or impossible Black box warning regarding risk of fatal anaphylactic-type reactions Sodium ferric gluconate complex in sucrose injection3 Iron deficiency anemia in patients undergoing chronic hemodialysis who are receiving supplemental epoetin therapy Iron sucrose injection, USP4 Iron deficiency anemia in: Nondialysis dependent-chronic kidney disease (NDD-CKD) patients receiving or not receiving an erythropoietin Hemodialysis dependent-chronic kidney disease (HDD-CKD) patients receiving an erythropoietin Pentoneal dialysis dependent-chronic kidney disease (PDD-CKD) patients receiving an erythropoietin The FDA-approved indications for IV iron therapy are listed on this slide. Dexferrum® (iron dextran injection, USP) full prescribing information. Shirley, NY: American Regent Laboratories, Inc. INFeD® (iron dextran injection, USP) full prescribing information. Morristown, NJ: Watson Pharma, Inc. Ferrelecit® (sodium ferric gluconate complex in sucrose injection) full prescribing information. Corona, Calif: Watson Pharma, Inc. Venofer® (iron sucrose injection, USP) full prescribing information. Shirley, NY: American Regent Laboratories, Inc.

49 Dosierung des intravenösen Eisens
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 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 This slide includes the dosing regimens for available intravenous iron agents. Dexferrum® (iron dextran injection, USP) full prescribing information. Shirley, NY: American Regent Laboratories, Inc. INFeD® (iron dextran injection, USP) full prescribing information. Morristown, NJ: Watson Pharma, Inc. Ferrelecit® (sodium ferric gluconate complex in sucrose injection) full prescribing information. Corona, Calif: Watson Pharma, Inc. Venofer® (iron sucrose injection, USP) full prescribing information. Shirley, NY: American Regent Laboratories, Inc.

50 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.

51 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: Bunn H. In: Isselbacher K, et al, eds. Harrison’s Principles and Practice of Internal Medicine. 13th ed. New York, NY: McGraw-Hill; 1994:

52 Erythropoietic Agents: Exogenous Erythropoietin
Formulations Epoetin alfa (global) Epoetin beta, epoetin delta, epoetin omega (non-US, international) Darbepoetin alfa (novel erythropoiesis-stimulating protein with longer terminal half-life than epoetin alfa) Hematologic effects identical to endogenous erythropoietin Apoptotic agents – neuro-/cardioprotection The FDA-approved formulations of erythropoietin available in the United States are epoetin-alpha and darbepoetin-alpha; epoetin beta, epoetin delta, and epoetin omega are not currently available in the United States. The hematologic effects of these exogenous formulations are identical to endogenous erythropoietin. These agents also provide neuro- and cardiac protection.

53 Erythropoietin: Dosierung
Chronisches Nierenversagen: IV or SC injection 3 x weekly* Zidovudine-treated HIV-infected patients: IV or SC injection 3 x weekly Cancer patients on chemotherapy: SC 3 x weekly or weekly Surgery patients: 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 All patients should receive adequate iron supplementation This slide reviews the appropriate dosing regimens for epoetin alfa and darbepoetin alfa. *IV route is recommended for patients on dialysis. .

54 Standard in Studien (Ferritin > 100 μg/l und/oder TSAT > 20%)
-4 Monate -3 Monate -2 Monate -1 Monat OP ERYPO 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 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.

55 präoperativer Hb-Wert 10-12 g/dl Ziel 15g/dl
Stratifiziert nach Hb-Wert und dosisadaptiert (Ferritin > 100 μg/l und/oder TSAT > 20%) präoperativer Hb-Wert g/dl Ziel 15g/dl OP -4 Monate -3 Monate -2 Monate -1 Monat ERYPO Nach Fach- Information 600 I.E./kg KG zum Bsp.: 68kg KG = 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 g/dl Ziel 15g/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 13 g/dl Ziel 15g/dl -4 Monate -3 Monate -2 Monate -1 Monat OP EPO s.c. EPO s.c. Eisen per os +Fe p.o./i.v.

56 New Safety Information
Black Box Warnung der FDA: risk for death and serious cardiovascular events when administered to achieve a target Hb >12 g/dL in cancer, renal failure, and surgical patients1-4 Venöse Thromboembolien und Tumorprogress Revised product labeling for Aranesp, Epogen, and Procrit includes a new boxed warning about using the lowest dose possible to avoid the need for blood transfusion because of the increased risk for death and serious cardiovascular events when administered to achieve a target hemoglobin (Hb) >12 g/dL in cancer, renal failure, and surgical patients. It had been previously thought that achieving a target Hb >12 g/dL improves patient quality of life, but the recent data does not show that to be the case. US Food and Drug Administration Center for Drug Evaluation and Research. Information for Healthcare Professionals. Erythropoiesis stimulating agents (ESA) [Aranesp (darbepoetin), Epogen (epoetin alfa), and Procrit (epoetin alfa). FDA alert 11/16/2006, updated 2/16/2007 and 3/09/2007. Available at: Accessed April 30, 2007. Aranesp® (darbepoetin alfa) prescribing information. Thousand Oaks, Calif: Amgen Inc.; 3/2007. Epogen® (epoetin alfa) prescribing information. Thousand Oaks, Calif: Amgen Inc.; 3/2007. Procrit® (epoetin alfa) prescribing information. Raritan, NJ: Ortho Biotech Products, LP; March 2007.

57 New Safety Information (cont.)
In patients receiving ESAs preoperatively for reduction of allogeneic RBC transfusions, a higher incidence of DVT was documented in patients not receiving prophylactic anticoagulation Antithrombotic prophylaxis should be strongly considered for such patients The remainder of the black box warning is detailed on this slide. US Food and Drug Administration Center for Drug Evaluation and Research. Information for Healthcare Professionals. Erythropoiesis stimulating agents (ESA) [Aranesp (darbepoetin), Epogen (epoetin alfa), and Procrit (epoetin alfa). FDA alert 11/16/2006, updated 2/16/2007 and 3/09/2007. Available at: Accessed April 30, 2007. Aranesp® (darbepoetin alfa) prescribing information. Thousand Oaks, Calif: Amgen Inc.; 3/2007. Epogen® (epoetin alfa) prescribing information. Thousand Oaks, Calif: Amgen Inc.; 3/2007. Procrit® (epoetin alfa) prescribing information. Raritan, NJ: Ortho Biotech Products, LP; March 2007.

58 Strategies for Primary and Secondary Prevention of Venous Thromboembolism
Pharmacologic1,2 LMWH (eg, enoxaparin, dalteparin) Unfractionated heparin (UFH) Oral anticoagulants (eg, warfarin) Antiplatelet (eg, aspirin) Pentasaccharide (eg, fondaparinux) Direct thrombin inhibitors (eg, bivalirudin, argatroban) Mechanical1 Intermittent pneumatic compression Graduated compression elastic stockings Strategies to prevent DVT and PE should include both nonpharmacologic approaches, such as the use of intermittent pneumatic compression and graduated compression elastic stockings, and pharmacologic approaches. For prevention and treatment of VTE, low-molecular-weight heparin (LMWH) is presently the standard of care. Current recommendations for thromboprophylaxis in general surgery, orthopedic surgery, trauma, abdominal surgery, spinal cord surgery, and medical conditions include a combination of LMWH (or, in some cases, unfractionated heparin) and warfarin, used in combination with nonpharmacologic approaches. However, limitations to these approaches include a narrow therapeutic window, lack of oral bioavailability, and variable dose response. This has led to the development of newer agents. One of the new anticoagulants, fondaparinux, has been found more effective than enoxaparin in the prevention of VTE in hip fracture surgery. The direct thrombin inhibitors hirudin, bivalirudin, argatroban, and the investigational agent ximelagatran are not approved for use in VTE prophylaxis or treatment; however, they are being studied in this capacity and may prove effective. 1. Geerts WH, et al. Chest. 2004:126(3 suppl):338S-400S. 2. Nutescu E, Racine E. Am J Health-Syst Pharm. 2002;59:S7-S14.

59 Conditions for Which CMS Proposed ESA Treatment “Not Reasonable and Necessary”
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 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, B 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.

60 CMS’s EPO- Therapie-Richtlinien
bei Malignompatienten Anämie <10 g/dL (or HCT <30%) Start Dosis: 150/U/kg 3 x wk Hb-Kontrolle alle 14 Tage Dosisverringerung um 25% wenn Anstieg Hb >1 g/dL (HCT >3%) in 2 wk Dosiserhöhung um 25% wenn nach 4 Wochen immer noch <10 g/dL (or HCT <30%) Und gleichzeitigen Anstieg Hb 1 g/dL (HCT 3%) 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,

61 Efficacy of Erythropoietin in Treating Patients Undergoing Major Elective Orthopedic Surgery
60 N=200 rHuEPO 300 U/kg SC 50 N=208 N=316 Placebo 40 Transfusions, % 30 20 10 In 3 trials that evaluated the efficacy of erythropoietin in patients undergoing major elective orthopedic surgery, erythropoietin significantly reduced the number of patients who underwent transfusions. COPES1* Faris et al2 de Andrade et al3 * Primary outcome event = any transfusion or Hb concentration <8 g/dL. Canadian Orthopedic Perioperative Erythropoietin Study Group. Lancet. 1993;341: Faris PM, et al. J Bone Joint Surg Am. 1996;78A(suppl):62-72. de Andrade JR, et al. Am J Orthop. 1996;25:

62 Efficacy of Erythropoietin in Treating Critically Ill Patients
RHuEPO (n=80) Placebo (n=80) Total units transfused* 166 305 % Transfused or died days 8-42 45 55 Hct change (baseline to final)† 4.8 (95% CI, 3.8, 5.9) 1.4 (95% CI, 0.3, 2.8) Final Hct‡ 35.1 ± 5.6 31.6 ± 4.1 Reticulocyte % change (baseline to final)† 2.5 (95% CI, 1.9, 3.0) 0.8 (95% CI, 0.3, 1.3) In a study by Corwin et al, critically ill ICU patients were randomized to receive rHuEPO 300 units/kg (n=80) or placebo (n=80). rHuEPO was given for a minimum of 2 weeks or until ICU discharge up to a total of 6 weeks postrandomization. The cumulative number of units of RBCs transfused was significantly less in the rHuEPO group than in the placebo group. The rHuEPO was transfused with a total of 166 units of RBCs versus 305 units of RBCs tranfused in the placebo group. The final hematocrit concentration of the rHuEPO patients was significantly greater than the final hematocrit concentration of placebo patients. A total of 45% of patients in the rHuEPO group received a blood transfusion between days 8 and 42 or died before study day 42 compared with 55% of patients in the placebo group. There were no significant differences between the 2 groups either in mortality or in the frequency of adverse events. The administration of rHuEPO to critically ill patients is effective in raising their hematocrit concentrations and in reducing the total number of units of RBCs they require. *P<.002; †P<.001; ‡P<.01. Adapted with permission from Corwin HL, et al. Crit Care Med. 1999;27:

63 Strategies for Reducing Blood Loss During Surgery
Careful surgical dissection and hemostasis Use of controlled hypotensive anesthesia1 Maintenance of normothermia1 Blood cell salvage1 Tolerance of normovolemic anemia1 Elevating the surgical site2 The strategies for reducing blood loss during surgery are outlined in this slide. Gil O, et al. Ann Thorac Surg. 1995;60: Park CK. Anesth Analg. 2000;91:

64 Kosteneffekte PBM/ITM
KH-Perspektive Vorstationäre EPO-Kosten (Präparat und Verabreichung) Präparatekosten Epo und Eisen Perioperative Kosten Blut- management  Entnahme Eigenblut Aufbewahrung Eigenblut MAT: Material und Personal letzte 1-2 EPO-u. Fe-Injektionen Transfusionen: Präparate Transfusionen: Vorbereitung, Verabreichung, Logistik (in KH) Effekte Infektionen und Revisionen Höhere Fallkosten bei gleicher DRG durch Antibiose (ca € bei 3-6%) Ungeplante Revision Effekte Verweildauer  erhöhte Pflegekosten

65 Anwender-Kosten der Fremdbluttransfusion
Fixkosten und variable Kosten Basha et al. Transfusions And Their Costs: Managing Patients Needs And Hospitals Economics. Int J Emer Int Care Med 2009

66 Fremdbluttransfusion Reale Kosten
1 jährlichesTransfusionsvolumen in den USA D (gemäß PEI) €: 29 Mio TE (14.2 Mio EK, 5.5 Mio FFP (2005-6)) 4,8 Mio TE (2009) 2,5 Mrd Komplikationen / Risiko/ verursachte Kosten > 125 Todesfälle durch Transfusion ? (1/6 USA = 21) > 64 TRALI 1: : (2006/7) 9 AB0 Inkompatibilität 1: (FDA) < 1: (IAKH) 1Solheim BG. Indications for use and cost-effectiveness of pathogen reduced AB0-universal plasma. Curr Opin Hematol 2008; 15:612-7 2Chaiwat O, et al. Early Packed Red Blood Cell Transfusion and ARDS after Trauma. Anesthesiology 2009; 110:

67 Fremdbluttransfusion
Komplikationsrisiko und -kosten USA D € Letale Sepsis 1: : (UK Erlangen) 1000/Tag 2ARDS  0,6 Mrd US$/14 Tage ? 700/Tag 2Intensivmedizin/beatmete Pat.: Kosten  Verweildauer 6.3 Tage (CI ) ? 6 300  Mortalität 21% (OR 1.21, CI 1.00 – 1.48) ?  Infektionen US$/Infektion  Kosten US $ (CI ) 2Zilberberg MD et al. Transfusion-attributable Acute Respiratory Distress Syndrome, Hospital: Materials and Methods Transfusionsmedizin Transfusionsmedizin Alter Med 2008, 10/1 3Zilberberg MD et al. Anemia, transfusions and hospital outcomes among critically ill. CritiCare 2008; 12: R60 ( n=4400, retrospekiv, Beatmung > 96h)

68 Korrekte Berechnung der kompletten Kosten der Fremdbluttransfusion
Kosten autologer Techniken hängen in erster Linie von Infektionsrisiko ab Mittleres Infektionsrisiko von 3,7% Mittlere Kosten einer Infektion US$ RR > 2.4autolog dominant ( RR 3.7, $/QUALY) 2,4 > RR > 1.1  autolog noch dom < $/QALY 1,1 > RR > 0 cost effectiveness up to 3,400,000 $/QALY

69 Wahrscheinlichkeit des Auftretens bestimmt Mehrkosten
Linzer Transfusionsgespräche Workshop STrategie/Ökonomie

70 Angebot von Kleingruppenarbeit
Überdenken Sie die kritischen Elemente des Transfusionsmanagements in ihrer Klinik und denken Sie über Modifikationen nach (10 min) Wo erwarten Sie Widerstand bei der Umsetzung in Ihrer Klinik (10 min) Entwickeln Sie einen Plan zur Umsetzung (10 min)

71 Wiesbaden Transfusionsgespräche der IAKH e.V. 18/19.Nov. 2011
18./19. März 2011 Wiesbaden Transfusionsgespräche der IAKH e.V. 18/19.Nov. 2011 Arbeitskreis der DIVI Hämotherapie in Zusammenarbeit mit der Interdisziplinären Arbeitsgemeinschaft für Klinische Hämotherapie (IAKH) Sektion Klinische Hämotherapie der DIVI Fehlerregister der IAKH Fehlermelden unter

72 Vielen Dank für Ihre Aufmerksamkeit

73 Welche Kosten müssen Sie wissen?
Fixkosten: Geräte/Investitionskosten (Abschreibungs- und altersabh.) Blutgruppenautomat Gefrier- und Kühlschränke Räume, Strom, Licht etc. (verzichtbar) Personal Laborpersonal für Blutgruppe und Verträglichkeitsprobe Arzt für BedSide und Administration Hol und Bringe Dienst Variable Kosten: Erwerbskosten aller Blutprodukte von Blutbank, aller Gerinnungspräparate von Apotheke Laborkosten- Verträglichkeitsproben, Blutgruppenautomat

74 Welche Kosten müssen Sie wissen?
2. Variable Kosten: Eingriffs- und Patientenbezogener Blutverbrauch Risikogruppe 1 Arthroskopien 0 Fuß/Sprunggelenk- Ops 0 Hand-OPs 0 Kreuzbandersatz 0 Kypho/Vertebroplastie 0 Nucleo-/Laminotomie 0 Osteotomie Hüfte 0 Osteotomie Knie 0 Schulter-OPs 0 Spondylodese HWS 0 Spondylodese LWS dorsal 0 Spondylodese LWS ventral 2 Knie-TEP, Primär 0 Wechsel Knie-TEP Nur Plateau 0 Komponenten 0 Hüft-TEP, primär 0 Wechsel Hüft-TEP Nur Steckkopf 0 Nur Pfanne 0 Mit Schaft 2 Risikogruppe 2 Arthroskopien 0 Fuß/Sprunggelenk-Ops 0 Hand-OPs 0 Kreuzbandersatz 0 Kypho/Vertebroplastie 0 Nucleo-/Laminotomie 0 Osteotomie Hüfte 0 Osteotomie Knie 0 Schulter-OP´s 0 Spondylodese HWS 0 Spondylodese LWS dorsal 0 Spondylodese LWS ventral 2 Knie-TEP, primär 0 Wechsel Knie-TEP Nur Plateau 0 Komponenten 1 Hüft-TEP, primär 0 Wechsel Hüft-TEP Nur Steckkopf 0 Nur Pfanne 0 Mit Schaft 2 Risikogruppe 3 Arthroskopien 0 Fuß/Sprunggelenk-Ops 0 Hand-OPs 0 Kreuzbandersatz 0 Kypho/Vertebroplastie 0 Nucleo-/Laminotomie 1 Osteotomie Hüfte 1 Osteotomie Knie 1 Schulter-OPs 0 Spondylodese HWS 0 Spondylodese LWS dorsal 1 SpondylodeseLWS ventral 2 Knie-TEP, primär 1 Wechsel Knie-TEP Nur Plateau 0 Komponenten 2 Hüft-TEP, primär 2 Wechsel Hüft-TEP Nur Steckkopf 1 Nur Pfanne 1 Mit Schaft 4

75 Fremdblut- Erwerbskosten
UNIT acquisition cost PRBC, non leuko-depleted $154 >€ 300 / US$ 400 = hospital costs for the unit (€ 150), storage, cross match, labelling, processing etc.  administration € and production (donor testing €35, donor fee €5-80, transport, cooling, centrifugation, baging and storage until delivery of blood products), if possible detrimental outcomes are accounted US$1600 to $2400 fresh frozen plasma (FFP) $ 51 € 80 / US$ 100 platelets (pooled or apheresis) $ 461 € 450 / US$ 600 Prothrombin complex / Cryoprecipitate € 800 / US $ 750 2,4 mg FVIIa (Eptacog alfa) € 2600 / US$ 2500 600 IU/ kg rhEpo (30 000IU) € 570 / US$ 420 Custer B & Hoch JS. Cost-Effectiveness Analysis: What it really means for transfusion medicine decision making. Transfus Med Rev 2009; 23: 1-12

76 Einkaufspreise der Blutprodukte
Produkt (1 TE-Transfusionseinheit) Aquisition / EB Produktion EK FFP TK Vollblut, leukozytendepletiert Vollblut, nativ **) Doppelspende (Apheresis) MAT (320 ml) **) Leukocyte depletion does not improve outcome: Frietsch T, Karger R, Schöler M, Huber D, Bruckner T, Kretschmer V, Schmidt S, Leidinger W, Weiler-Lorentz A: Leukodepletion of autologous whole blood has no impact on perioperative infection rate and length of hospital stay. Transfusion 2008 Oct;48(10): 76

77 Eigenblutspende MAT Wie berechne ich eigene Produkte?
Welche Kombination autologer Verfahren? Eigenblutspende MAT

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