Alternatives to RBC Transfusion: Erythropoietin and beyond David Shimabukuro, MDCM Department of Anesthesia and Perioperative Care Medical Director, 13 ICU UC SF 1
Agenda Physiology of Oxygen Transport and Anemia Just a few words Controversies of RBC transfusion Risks versus the benefits Solutions/Alternatives to RBC transfusion Conservation Erythropoietin Artificial oxygen carriers UC SF 2
Agenda Physiology of Oxygen Transport and Anemia Just a few words Controversies of RBC transfusion Risks versus the benefits Solutions/Alternatives to RBC transfusion Conservation Erythropoietin Artificial oxygen carriers UC SF 3
Basic Physiology global oxygen delivery = global blood flow x arterial oxygen content DO 2 = CO x CaO 2 CO = SV x HR CaO 2 = ([Hgb] x SaO 2 x Hgb O 2 -binding capacity) + (PaO 2 x plasma O 2 solubility) CaO 2 = 1.39 ([Hgb]) (SaO 2 ) +.003 (PaO 2 ) UC SF 4
Physiology of Anemia DO 2 = CO x (%Sat x 1.39 x [Hgb]) To maintain oxygen delivery in euvolemia with a decrease in [Hgb] Increase in CO Right shift of hgb-oxygen saturation curve for optimal loading/unloading of oxygen UC SF 5
Physiology of Anemia Increase in CO Decrease in viscosity Increase in sympathetic tone UC SF 6
Physiology of Anemia Decrease in viscosity Increase in preload Non-Newtonian Fluid Viscosity is highest in post-capillary venules where flow is lowest Disproportionate decrease in blood viscosity, significant increase in venous return Decrease in afterload UC SF 7
Physiology of Anemia Increase in sympathetic tone Increase in heart rate Increase in contractility Mediated via stimulation of aortic chemoreceptors UC SF 8
UC SF 9
Physiology of Anemia For the most part, there is reserve in the system Oxygen extraction is about 20-30% at rest Tolerate rather low hemoglobin levels without sequelae UC SF 10
Physiology of Anemia At some point a critical point is reached DO 2 = CO x {(%Sat x 1.39 x [Hgb])} + (.003 x PaO2)} UC SF 11
DO2crit Delivery dependent VO2 Delivery independent VO2 VO2 SvO2 OER Lactate NADH Red CtOx DO2 DO2 UC SF 12
Agenda Physiology of Oxygen Transport and Anemia Just a few words Controversies of RBC transfusion Risks versus the benefits Solutions/Alternatives to RBC transfusion Conservation Erythropoietin Artificial oxygen carriers UC SF 13
Controversies Infection RISKS BENEFITS UC SF 14
Controversies Infection RISKS BENEFITS UC SF 15
Controversies Infection RISKS BENEFITS UC SF 16
Guidelines Crit Care Med 2009 Vol. 37, No. 12 UC SF 17
Agenda Physiology of Oxygen Transport and Anemia Just a few words Controversies of RBC transfusion Risks versus the benefits Solutions/Alternatives to RBC transfusion Conservation Erythropoietin Artificial oxygen carriers UC SF 18
Conservation Decrease laboratory testing Remove invasive lines Decrease waste amount/return to patient Minimize amount drawn UC SF 19
Agenda Physiology of Oxygen Transport and Anemia Just a few words Controversies of RBC transfusion Risks versus the benefits Solutions/Alternatives to RBC transfusion Conservation Erythropoietin Artificial oxygen carriers UC SF 20
Erythropoietin Stimulates bone marrow to produce red blood cells Elevated in anemia Blunted levels in critically ill Interleukin-1 Tumor necrosis factor Anemia of critical illness UC SF 21
Erythropoietin Corwin and colleagues Prospective, randomized, double-blind, placebo-controlled, multicenter trial Assess weekly dosing of recombinant human erythropoietin (rhuepo) of 40,000 units to decrease occurrence of RBC transfusion (transfusion independence) Corwin, et al. JAMA 288;22:2827-2835 UC SF 22
Erythropoietin 1302 patients 650 rhuepo and 652 placebo Received SQ injection on ICU day 3 Study days 1, 7, and 14 Held if HCT > 37% Exclusion Renal Failure on dialysis Acute ischemic heart disease Acute GI bleeding UC SF 23
Erythropoietin Transfusion protocol No RBC transfusion if Hgb > 90 g/l, unless clinically indicated For Hgb < 90 g/l, transfusion at the discretion of the physician UC SF 24
Erythropoietin Baseline Hemoglobin (g/dl) Total number placebo Total number rhuepo < 9 121 119 9 531 529 Mean pretransfusion Hgb 8.5 g/dl UC SF 25
Erythropoietin Placebo rhuepo Total number of units transfused Units transfused per patient: Mean Units transfused per patient: Median 1963 1590 3.0 2.4 2 1 UC SF 26
Erythropoietin Conclusion Weekly administration of rhuepo reduces allogeneic RBC transfusion and increases hemoglobin Addresses only RBC transfusion and not powered for mortality or significant adverse events Transfusion decided by individual physicians UC SF 27
Erythropoietin Corwin and colleagues (NEJM Sept 6 07) Efficacy and Safety of Epoetin Alfa in Critically Ill Patients Multicenter, prospective, randomized, placebo-controlled trial (2003-2006) UC SF 28
Erythropoietin Primary Endpoint: percentage of patients receiving RBC transfusion between study days 1 and 29 Secondary Endpoints: number of RBC units transfused between days 1 and 42, mortality at day 29 and 140 UC SF 29
Erythropoietin Inclusion Criteria Age > 18 Hgb < 12 g/dl At least 2 days in ICU Exclusion Critieria Acute ischemic heart disease during ICU stay History of DVT, PE, or ischemic stroke Dialysis Uncontrolled hypertension UC SF 30
Erythropoietin UC SF 31
Erythropoietin Epoetin Alfa 40,000 units or placebo was given SQ on study day 1 and weekly for a total of 3 doses (days 1, 8, and 15) Study drug withheld from patients with Hgb > 12 g/dl (for second and third doses) All patients received PO iron on day 1 or when able to take PO UC SF 32
Erythropoietin RBC transfusion determined by physician Target Hgb: 7-9 g/dl Transfusion not recommended if Hgb > 9 g/dl or Hct > 27 unless specific clinical indication (active bleeding or ischemia) No Hgb level of Hct concentration for which transfusion was mandated UC SF 33
Erythropoietin Baseline characteristics same between study drug and placebo groups However Surgical patients and medical patients were older than trauma patients (mean 64 vs 60 vs 41) Surgical patients and medical patients had more one or more coexisiting diseases (89% vs 89% vs 32%) UC SF 34
Erythropoietin UC SF 35
Erythropoietin UC SF 36
Erythropoietin UC SF 37
Erythropoietin UC SF 38
Erythropoietin Conclusions: No difference in percentage of patients receiving RBC transfusions between the Epoetin Alfa and placebo groups Decrease in 29-day and 140-day mortality for trauma patients who receive Epoetin Alfa versus placebo and may be beneficial Non-trauma surgical and medical patients should not receive Epoetin Alfa, unless there is an approved indication UC SF 39
Erythropoietin However Significant increase in thrombotic complications in the Epoetin Alfa group over the placebo group UC SF 40
Erythropoietin Crit Care Med 2009 Vol. 37, No. 12 UC SF 41
Erythropoietin Crit Care Med 2009 Vol. 37, No. 12 UC SF 42
Agenda Physiology of Oxygen Transport and Anemia Just a few words Controversies of RBC transfusion Risks versus the benefits Solutions/Alternatives to RBC transfusion Conservation Erythropoietin Artificial oxygen carriers UC SF 43
Hemoglobin-based Oxygen Carriers UC SF 44
Hemoglobin-based Oxygen Carriers Oxyhemoglobin Saturation (%) RBC Hemoglobin Hemoglobin-based Oxygen Carrier Stroma Free Hemoglobin PaO2 (mmhg) www.dcmsonline.org/jax-medicine/1998journals/december98/artificialblood.htm UC SF 45
Hemoglobin-based Oxygen Carriers Cross-linked Hb (intramolecular) Polymerized Hb (intermolecular) Conjugated Hb UC SF 46
Hemoglobin-based Oxygen Carriers Cross-linked Hb Napolitano Crit Care Clin 25 (2009) 279-301 UC SF 47
Hemoglobin-based Oxygen Carriers Polymerized Hb Napolitano Crit Care Clin 25 (2009) 279-301 UC SF 48
Hemoglobin-based Oxygen Carriers Conjugated Hb Napolitano Crit Care Clin 25 (2009) 279-301 UC SF 49
Hemoglobin-based Oxygen Carriers Renal Failure Precipitation in tubules Systemic and Pulmonary Hypertension NO scavenging UC SF 50
Hemoglobin-based Oxygen Carriers Resolution of initial problems with second and third generation HBOC Some still with issues, others in phase II and phase III clinical trials UC SF 51
Hemoglobin-based Oxygen Carriers Class Product Company Technology Status Cross-linked HemAssist (DCL) Baxter Cross-linked Discontinued US Army Cross-linked Discontinued rhb 1.1 Somatogen rhb Discontinued rhb 2.0 Baxter rhb Discontinued Polymerized PolyHeme Northfield Laboratories Gluteraldehyde, pyridoxal Hb HemoPure Biopure Glutaraldehyde bovine Hb Phase III Phase III HemoLink Hemosol Polymerized Discontinued Conjugated PHP Apex Bioscience PEG-human Hb Phase III PEG-Hb Enzon PEG-bovine Hb Discontinued MalPEG-Hb Sangart PEG-human Hb Phase III UC SF 52
Hemoglobin-based Oxygen Carriers Characteristic HemoPure PolyHeme MP4 RBC Volume (ml) 250 500 250 250 Hb concentration (g/dl) 13 10 4.3 23 P 50 (mmhg) 38 29 5 26 Oncotic pressure (mmhg) 25 23 50 25 Viscosity (cp) 1.3 2.1 2.5 5-10 (WB) Methemoglobin (%) <15 <8 <10 <1 Half-life 19 hours 24 hours 24 hours 30 days Shelf life at 4 C 3 years 1.5 years >1 year 42 days Refrigeration No No No Yes UC SF 53
Hemoglobin-based Oxygen Carriers Still requires Hb Vasoactivity Gastrointestinal side effects Interference with laboratory results UC SF 54
Perfluorocarbon Emulsion UC SF 56
Oxygent : Perfluorocarbon Emulsion Lecithin stabilization Cleared very quickly by reticuloendothelial system (<6H) and exhaled unchanged Perflubron (perfluoroocytl bromide) UC SF 57
Perfluorocarbon Emulsion O2 Content (ml/100ml) PFC 2.4 g/dl PFC 1.6 g/dl Plasma Dissolved O 2 PaO2 (mmhg) www.dcmsonline.org/jax-medicine/1998journals/december98/artificialblood.htm UC SF 58
Perfluorocarbon Emulsion Requires high FIO2 to achieve higher oxygen content Increase in plasma cytokines (flu-like symptoms) Short half-life Long shelf life Easy to manufacture UC SF 59
AOC: How they compare Standl Infus Ther Transfus Med 2000;27:128-137 UC SF 60
Summary Few alternatives available to PRBC transfusion to increase arterial oxygen content The use of erythropoietin is not clear for most situations of anemia of critical illness UC SF 61
Summary Hemoglobin-based oxygen carriers are still in testing and development, along with perfluorocarbons There are even still other ideas UC SF 62