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University of California,San Francisco 1UCSF
Alternatives to RBC Transfusion: Erythropoietin and
beyond
David Shimabukuro, MDCMDepartment of Anesthesia and Perioperative Care
Medical Director, 13 ICU
University of California,San Francisco 2UCSF
Agenda
• Background
• Erythropoietin• Hemoglobin-based oxygen carrier
(HBOC)• Perfluorocarbon emulsion
University of California,San Francisco 3UCSF
Background
InfectionInfection
RISKS BENEFITS
University of California,San Francisco 4UCSF
Background
InfectionInfection
RISKS BENEFITS
University of California,San Francisco 5UCSF
Background
InfectionInfection
RISKS BENEFITS
University of California,San Francisco 6UCSF
Agenda
• Background
• Erythropoietin• Hemoglobin-based oxygen carrier
(HBOC)• Perfluorocarbon emulsion
University of California,San Francisco 7UCSF
Erythropoietin
Stimulates bone marrow to produce red blood cellsElevated in anemiaBlunted levels in critically ill
Interleukin-1Tumor necrosis factor
“Anemia of critical illness”
University of California,San Francisco 8UCSF
Erythropoietin
Corwin and colleaguesProspective, randomized, double-blind, placebo-controlled, multicenter trialAssess 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
University of California,San Francisco 9UCSF
Erythropoietin
1302 patients650 rHuEPO and 652 placeboReceived SQ injection on ICU day 3
Study days 1, 7, and 14Held if HCT > 37%
ExclusionRenal Failure on dialysisAcute ischemic heart diseaseAcute GI bleeding
University of California,San Francisco 10UCSF
Erythropoietin
Transfusion protocolNo RBC transfusion if Hgb > 90 g/L, unless clinically indicatedFor Hgb < 90 g/L, transfusion at the discretion of the physician
University of California,San Francisco 11UCSF
Erythropoietin
Baseline Hemoglobin
(g/dL)
Total number placebo
Total number rHuEPO
< 9 121 119
≥ 9 531 529
Mean pretransfusion Hgb 8.5 g/dL
University of California,San Francisco 12UCSF
Erythropoietin
Placebo rHuEPO
Total number of units transfused 1963 1590
Units transfused per patient: Mean 3.0 2.4
Units transfused per patient: Median 2 1
University of California,San Francisco 13UCSF
Erythropoietin
ConclusionWeekly administration of rHuEPO reduces allogeneic RBC transfusion and increases hemoglobinAddresses only RBC transfusion and not powered for mortality or significant adverse eventsTransfusion decided by individual physicians
University of California,San Francisco 14UCSF
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)
University of California,San Francisco 15UCSF
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
University of California,San Francisco 16UCSF
Erythropoietin
Inclusion CriteriaAge > 18Hgb < 12 g/dLAt least 2 days in ICU
Exclusion CritieriaAcute ischemic heart disease during ICU stayHistory of DVT, PE, or ischemic strokeDialysisUncontrolled hypertension
University of California,San Francisco 17UCSF
Erythropoietin
University of California,San Francisco 18UCSF
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
University of California,San Francisco 19UCSF
Erythropoietin
RBC transfusion determined by physician
Target Hgb: 7 - 9 g/dLTransfusion 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
University of California,San Francisco 20UCSF
Erythropoietin
Baseline characteristics same between study drug and placebo groups
HoweverSurgical patients and medical patients were older than trauma patients (mean 64 vs 60 vs41)Surgical patients and medical patients had more one or more coexisiting diseases (89% vs 89% vs 32%)
University of California,San Francisco 21UCSF
Erythropoietin
University of California,San Francisco 22UCSF
Erythropoietin
University of California,San Francisco 23UCSF
Erythropoietin
University of California,San Francisco 24UCSF
Erythropoietin
University of California,San Francisco 25UCSF
Erythropoietin
Conclusions:No difference in percentage of patients receiving RBC transfusions between the Epoetin Alfa and placebo groupsDecrease in 29-day and 140-day mortality for trauma patients who receive EpoetinAlfa versus placebo and may be beneficial Non-trauma surgical and medical patients should not receive Epoetin Alfa, unless there is an approved indication
University of California,San Francisco 26UCSF
Erythropoietin
HoweverSignificant increase in thrombotic complications in the Epoetin Alfa group over the placebo group
University of California,San Francisco 27UCSF
Hemoglobin-based Oxygen Carriers
University of California,San Francisco 28UCSF
Hemoglobin-based Oxygen Carriers
RBC Hemoglobin
Hemoglobin-based Oxygen Carrier
Stroma Free Hemoglobin
PaO2 (mmHg)
Oxy
hem
oglo
bin
Sat
urat
ion
(%)
University of California,San Francisco 29UCSF
Hemoglobin-based Oxygen Carriers
Cross-linked Hb (intramolecular)Polymerized Hb (intermolecular)Conjugated Hb
University of California,San Francisco 30UCSF
Hemoglobin-based Oxygen Carriers
• Cross-linked Hb
Napolitano Crit Care Clin 25 (2009) 279-301
University of California,San Francisco 31UCSF
Hemoglobin-based Oxygen Carriers
• Polymerized Hb
Napolitano Crit Care Clin 25 (2009) 279-301
University of California,San Francisco 32UCSF
Hemoglobin-based Oxygen Carriers
• Conjugated Hb
Napolitano Crit Care Clin 25 (2009) 279-301
University of California,San Francisco 33UCSF
Hemoglobin-based Oxygen Carriers
• Renal Failure– Precipitation in tubules
• Systemic and Pulmonary Hypertension– NO scavenging
University of California,San Francisco 34UCSF
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
University of California,San Francisco 35UCSF
Hemoglobin-based Oxygen CarriersClass Product Company Technology StatusCross-linked HemAssist (DCL) Baxter Cross-linked Discontinued
US Army Cross-linked DiscontinuedrHb 1.1 Somatogen rHb DiscontinuedrHb 2.0 Baxter rHb Discontinued
Polymerized PolyHeme Northfield Laboratories
Gluteraldehyde, pyridoxal Hb
Phase III
HemoPure Biopure Glutaraldehyde bovine Hb
Phase III
HemoLink Hemosol Polymerized DiscontinuedConjugated PHP Apex
Bioscience PEG-human Hb Phase III
PEG-Hb Enzon PEG-bovine Hb DiscontinuedMalPEG-Hb Sangart PEG-human Hb Phase III
University of California,San Francisco 36UCSF
Hemoglobin-based Oxygen Carriers
Characteristic HemoPure PolyHeme MP4 RBCVolume (mL) 250 500 250 250Hb concentration (g/dL) 13 10 4.3 23P50 (mmHg) 38 29 5 26Oncotic pressure (mmHg) 25 23 50 25Viscosity (cp) 1.3 2.1 2.5 5-10 (WB)Methemoglobin (%) <15 <8 <10 <1Half-life 19 hours 24 hours 24 hours 30 daysShelf life at 4 C 3 years 1.5 years >1 year 42 daysRefrigeration No No No Yes
University of California,San Francisco 37UCSF
Hemoglobin-based Oxygen Carriers
• Still requires Hb• Vasoactivity• Gastrointestinal side effects• Interference with laboratory results
University of California,San Francisco 38UCSF
University of California,San Francisco 39UCSF
Perfluorocarbon Emulsion
University of California,San Francisco 40UCSF
Oxygent™: Perfluorocarbon Emulsion
• Lecithin stabilization• Cleared very quickly by
reticuloendothelial system (<6H) and exhaled unchanged
• Perflubron (perfluoroocytl bromide)
University of California,San Francisco 41UCSF
Perfluorocarbon Emulsion
PFC 2.4 g/dL
PFC 1.6 g/dL
Plasma Dissolved O2
PaO2 (mmHg)
O2
Con
tent
(m
L/10
0mL)
University of California,San Francisco 42UCSF
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
University of California,San Francisco 43UCSF
Standl Infus Ther Transfus Med 2000;27:128-137
University of California,San Francisco 44UCSF
Summary
• Few alternatives available to PRBC transfusion to increase arterial oxygen content
• Erythropoietin is not recommended for most situations of anemia of critical illness
University of California,San Francisco 45UCSF
Summary
• Hemoglobin-based oxygen carriers are still in testing and development, along with perfluorocarbons
• There are even still other ideas…
