Alternatives to RBC Transfusion: Erythropoietin and beyond · Alternatives to RBC Transfusion:...

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


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


Agenda





Basic Physiology

CO = SV x HR

CaO2 = ([Hgb] x SaO2 x Hgb O2 -binding capacity) + (PaO2 x plasma O2 solubility)

CaO2 = 1.39 ([Hgb]) (SaO2 ) + .003 (PaO2 )

global oxygen delivery = global blood flow x arterial oxygen content

DO2 = CO x CaO2


Physiology of Anemia

DO2 = 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



• Increase in CO– Decrease in viscosity– Increase in sympathetic tone



• 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



• Increase in sympathetic tone– Increase in heart rate– Increase in contractility– Mediated via stimulation of aortic chemoreceptors



• 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



• At some point a critical point is reached…

DO2 = CO x {(%Sat x 1.39 x [Hgb])} + (.003 x PaO2)}


DO2

VO2

SvO2

Lactate

Red CtOx

NADH

OER

DO2crit

Delivery independent VO2Delivery dependent VO2

DO2


Agenda





Controversies

InfectionInfection

RISKS BENEFITS


Guidelines

Crit Care Med 2009 Vol. 37, No. 12


Agenda





Conservation

• Decrease laboratory testing• Remove invasive lines• Decrease “waste” amount/return to

patient• Minimize amount drawn


Agenda





Erythropoietin

Stimulates bone marrow to produce red blood cellsElevated in anemiaBlunted levels in critically ill

Interleukin-1Tumor necrosis factor

“Anemia of critical illness”


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


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


Erythropoietin

Transfusion protocolNo RBC transfusion if Hgb > 90 g/L, unless clinically indicatedFor Hgb < 90 g/L, transfusion at the discretion of the physician


Erythropoietin

Baseline Hemoglobin

(g/dL)

Total number placebo

Total number rHuEPO

< 9 121 119

≥

9 531 529

Mean pretransfusion Hgb 8.5 g/dL


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


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


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)


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


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


Erythropoietin


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


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


Erythropoietin

Baseline characteristics same between study drug and placebo groups

HoweverSurgical 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%)


Erythropoietin


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 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


Erythropoietin

HoweverSignificant increase in thrombotic complications in the Epoetin Alfa group over the placebo group


Erythropoietin



Agenda





Hemoglobin-based Oxygen Carriers



RBC Hemoglobin

Hemoglobin-based Oxygen Carrier

Stroma Free Hemoglobin

PaO2 (mmHg)

Oxy

hem

oglo

bin

Sat

urat

ion

(%)

www.dcmsonline.org/jax-medicine/1998journals/december98/artificialblood.htm



Cross-linked Hb (intramolecular)Polymerized Hb (intermolecular)Conjugated Hb



• Cross-linked Hb

Napolitano Crit Care Clin 25 (2009) 279-301



• Polymerized Hb




• Conjugated Hb




• Renal Failure– Precipitation in tubules

• Systemic and Pulmonary Hypertension– NO scavenging



• Resolution of initial problems with second and third generation HBOC

• Some still with issues, others in phase II and phase III clinical trials


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



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



• Still requires Hb• Vasoactivity• Gastrointestinal side effects• Interference with laboratory results


Perfluorocarbon Emulsion


Oxygent™: Perfluorocarbon Emulsion

• Lecithin stabilization• Cleared very quickly by

reticuloendothelial system (<6H) and exhaled unchanged

• Perflubron (perfluoroocytl bromide)



PFC 2.4 g/dL

PFC 1.6 g/dL

Plasma Dissolved O2

PaO2 (mmHg)

O2

Con

tent

(m

L/10

0mL)

www.dcmsonline.org/jax-medicine/1998journals/december98/artificialblood.htm



• Requires high FIO2 to achieve higher oxygen content

• Increase in plasma cytokines (flu-like symptoms)

• Short half-life• Long shelf life• Easy to manufacture


Standl Infus Ther Transfus Med 2000;27:128-137

AOC: How they compare


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


Summary

• Hemoglobin-based oxygen carriers are still in testing and development, along with perfluorocarbons

• There are even still other ideas…

Alternatives to RBC Transfusion: Erythropoietin and beyond · Alternatives to RBC Transfusion:...

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