Anemia'and'Red'Blood'Cell'Transfusion'in'the'ICU'

Karl%Thomas,%MD,%FCCP%%

Disclosure'and'Contact'Informa9on'

Disclosure:%UpToDate%%Contact:%Karl'W.'Thomas,'M.D.,'F.C.C.P.%Division'of'Pulmonary'and'Cri9cal'Care'Medicine%Department'of'Internal'Medicine%University'of'Iowa'Carver'College'of'Medicine%200'Hawkins'Drive,'CJ33JGH%Iowa'City,'Iowa''52242%'%Tel:'319J356J1620%Fax:'319J353J6406%eJmail:'karlJthomas@uiowa.edu%%

Objec9ves'

1)%Discuss%the%pathophysiology%and%causes%of%anemia%in%ICU%paAents.%%2)%Explain%the%indicaAons%and%appropriate%clinical%use%of%red%blood%cell%transfusion.%3)%DifferenAate%between%the%posiAve%and%negaAve%associaAons%of%red%blood%cell%transfusion%with%ICU%outcomes.%4)%List%the%specific%risks%associated%red%blood%cell%transfusion%including%disease%transmission.%5)%Discuss%the%components%of%blood%transfusion%management%and%surveillance%programs.%%%

Anemia'and'Transfusion'in'the'ICU'• Anemia%

• 1/3%of%admissions%to%ICU%have%baseline%hemoglobin%less%than%10%g/dL%• For%ICU%paAents%with%length%of%stay%>3%days,%90%%have%anemia%• Anemia%consistently%associated%with%worse%outcomes:%%

• ICU%length%of%stay%• VenAlator%days%• Mortality%• Cost%

ICU Hemoglobin Levels Day 1Through Day 30

Corwin et.al. The CRIT Study, 2004, Critical Care Medicine, 32:39-52. (figure 5, p. 44)

Causes'of'Anemia'in'the'Cri9cally'Ill'

• Extravascular%RBC%loss%• UnderproducAon%• Intravascular%hemolysis%

• CriAcally%ill%paAents%likely%to%have%more%than%one%contribuAng%factor%for%their%development%of%anemia.%• CoYexisAng%coagulopathy%as%a%contribuAng%factor%for%RBC%loss%(intravasc.%or%extravasc.)%must%also%be%considered.%

Common'causes'of'blood'loss'• “iatrogenic,”%predictable%

•  Phlebotomy%–%avg%40Y70%cc/day%•  Higher%rates%associated%with%central%venous%catheters%and%arterial%lines%

•  Surgery,%procedures%• Spontaneous,%possibly%preventable%

•  Trauma%•  GastrointesAnal%%•  Retroperitoneal,%thigh%and%intrabdominal%hemorrhage%

Decreased'RBC'Produc9on'• CriAcal%illness%results%in%state%of%diminished%producAon%

•  Suppressed%erythropoieAn%producAon%•  Blunted%erythropoieAn%response%by%bone%marrow%•  Abnormal%iron%metabolism,%iron%deficiency%•  Inflammatory%state%(TNF,%ILY6)%•  NutriAonal%deficiencies%•  Toxins,%drugs,%alcohol%

• CharacterisAc%features%•  Low%reAculocyte%count%•  Reduced%serum%iron%and%total%iron%binding%capacity%•  IndisAnguishable%from%anemia%of%chronic%disease%

Intravascular'Hemolysis'• %ImmuneYmediated%hemolysis%

•  Autoimmune%hemolyAc%anemia%•  DrugYinduced%hemolyAc%anemias%

• %Inherited%RBC%disorders%(hemoglobinopathies)%• %Enzyme%disorders%(gY6YPD%deficiency)%• %Microangiopathic%hemolyAc%anemia%

•  Disseminated%intravascular%coagulaAon%(DIC)%•  ThromboAc%thrombocytopenic%purpura%(TTP)%

• %InfecAon%(sepsis,%malaria)%%

Laboratory'Features'of'Anemia'• CBC%–%RBCs%only%or%general%bone%marrow%problem?%• CoagulaAon%Ames%%• Peripheral%blood%smear%

•  Schistocytes%–%intravascular%hemolysis%•  Spherocytes%–%autoimmune%hemolysis%•  Bite%cells%–%oxidant%damage%(eg.%GY6YPD%deficiency)%

• RBC%anAbody%and%complement%tests%•  Direct/Indirect%Coomb’s%test%

• LDH,%bilirubin,%haptoglobin%• RBC%volume%–%macroY,%microY,%normocyAc%anemia%

Tests'for'Iron'Deficiency'

• Serum%iron,%ferriAn,%transferrin%and%iron%binding%capacity%cannot%readily%disAnguish%iron%deficiency%anemia%from%anemia%of%chronic%disease%• Serum%transferrin%receptor%–%increased%in%iron%deficiency%(may%be%expressed%as%raAo%to%ferriAn%concentraAon)%• Zinc%protoporphyrin%–%zinc%is%incorporated%into%hemoglobin%in%condiAons%of%iron%deficiency%• Hepcidin%–%suppressed%in%condiAons%of%iron%deficiency,%increased%with%inflammaAon,%iron%overload%

Pathophysiology'of'Anemia'

• Reduced%oxygen%carrying%capacity%of%blood%and%the%cardiovascular%response%to%maintain%oxygen%delivery%• VO2%=%CO%x%(CaO2%Y%CVO2)%• VO2%=%HR%x%SV%x%1.39%x%[Hgb]%x%(SaO2YSvO2)%%• Predicted%clinical%response%to%anemia:%

•  Increased%HR,%increased%extracAon%(lower%SvO2)%•  Fluid%retenAon,%vasoconstricAon%(increased%SV)%•  Depends%on%underlying%organ%funcAon/paAent%status%

Pathophysiologic'response'to'anemia'

• Human'Cardiovascular'and'Metabolic'Response'to'Acute,'Severe'Isvolemic'Anemia'

– Weiskopf,%Viele%et%al%JAMA%1998,%279:217%• 11%healthy%conscious%paAents%prior%to%anesthesia%and%surgery,%21%healthy%volunteers%(avg%age%27)%• Isovolemic%phlebotomy%%

•  reduced%Hgb%from%13%g/dL%to%5%g/dL%• Observed%results%

•  Increased%HR,%SV,%CI%•  Decreased%oxygen%delivery,%systemic%vascular%resistance%

Laboratory'response'to'anemia'

Weiskopf, JAMA 1998; 279:217

VO2

Lactate

SvO2%

DO2

What'recommenda9on'would'expert'guidelines'make'for'transfusion'in'a'hemodyanmically'stable'but'cri9cally'ill'pa9ent'with'anemia'(except'pa9ents'with'acute'coronary'syndromes'or'unstable'angina)?'

a)  Transfuse%when%hemoglobin%falls%below%10%g/dL%b)  Transfuse%when%hemoglobin%falls%below%7%g/dL%c)  Transfuse%when%hemoglobin%falls%below%5%g/dL%d)  Transfusions%are%more%harmful%than%beneficial;%do%not%

transfuse%paAents%at%any%parAcular%hemoglobin%level%unless%the%paAent%has%severe,%ongoing%blood%loss%

e)  In%the%absence%of%hemorrhage,%transfuse%only%in%the%seqng%of%sepsis%with%venous%oxygen%saturaAon%<70%%and%hemoglobin%<%10%g/dL%

Transfusion'Requirements'in'Cri9cal'Care'Randomized'Clinical'Trial'(TRICC)'• Hebert,%Wells,%et%al.%Canadian%CriAcal%Care%Trials%Group,%New$Engl$J$Med,%1999%340:409Y417%• 838%mixed%medical,%surgical,%adult,%criAcal%care%paAents%• Randomized%

•  Liberal%(standard)%–%trigger%<%10%g/dL,%range%10%–%12%g/dL%•  RestricAve%–%trigger%<%7%g/dL,%range%7%to%9%g/dL%

• Results%•  No%significant%difference%in%30Yday%mortality%•  Age%<=55%and%APACHE%score%<20%%–%improved%mortality%with%restricAve%

transfusion%

Add'your'slides'here….%

Hebert P et al. N Engl J Med 1999;340:409-417

Kaplan-Meier Estimates of Survival in the 30 Days after Admission to the Intensive Care Unit in the Restrictive-Strategy and Liberal-Strategy Groups

Add'your'slides'here….%

Hebert P et al. N Engl J Med 1999;340:409-417

Kaplan-Meier Estimates of Survival in the 30 Days after Admission to the Intensive Care Unit in the Restrictive-Strategy and Liberal-Strategy Groups

Transfusion'in'Acute'Coronary'Syndromes'• Rao,%Jollis%et.al.%2004%JAMA%292:1555%• 24,112%paAents%enrolled%in%GUSTO%IIb,%PURSUIT,%and%PARAGON%B%trials%• 2401%paAents%had%at%least%1%transfusion%

–  Transfused%paAents%older,%more%comorbidiAes%–  Transfused%paAents%with%baseline%Hct%39%,%nadir%29%%

• Death:%8.0%%(transfusion)%vs.%3.1%%(no%Transfuse)%%• 30Yday%MI:%25%%vs.%8%%• 30%day%composite%Death/MI:%29%%vs%10%%

Mortality'and'Transfusion'in'ACS''

Rao, 2004 JAMA; 292:1555

TRANSFUSION

No transfusion

Transfusion'in'Cardiac'Pa9ents ''• 78,974%Medicare%paAents,%age%=>65,%with%acute%MI1%

•  Reduced%odds%mortality%only%for%paAents%with%baseline%hct%33%%or%lower%•  Increased%mortality%for%paAents%if%transfused%with%HCT%>36%%

• 2358%Acute%MI%paAents,%prospecAve%study2%•  Decreased%mortality%for%Hb%<%8,%increased%mort%Hb%>8%

• TRICC%subset%with%cardiovascular%diseases3%•  %no%difference%in%mortality,%but%there%was%a%nonYsignificant%trend%in%the%

subset%with%severe%ischemic%disease%for%lower%survival%in%restricAve%group%

1.  Wu, et al. 2001, New Engl J Med; 345:1230 2.  Aronson el al. 2008, Am J Cardiol; 102:115 3.  Hebert et al. 2001, Crit Care Med; 29: 227

RBC'Transfusion'and'Surgery'• Cardiac%Surgery%

•  TRACS%Randomized%Clinical%Trial:%502%paAents1%•  Transfuse%for%HCT%=>30%%vs.%>=24%%•  No%difference%in%mortality%•  Number%of%RBC%units%independently%correlated%with%risk%for%clinical%complicaAons%or%death%

• HIP%surgery%•  Randomized%trial%2016%paAents%age%50%or%older,%Hb%10%vs.%8%g/dL2%•  NO%benefit%in%60%day%mortality%or%60%day%walking%distance%for%liberal%

strategy%

1.  Hajjar, 2010, JAMA; 304:1559 2.  Carson, 2011, New Engl J Med; 365:2453

Mortality'by'units'transfused'aaer'cardiac'surgery'

Hajjar 2010, JAMA; 304:1559

RBC Units

> 6 u

5 – 6 u

1 – 2 u 3 – 4 u none

Transfusion,'ARDS'and'Mechanical'Ven9la9on'

• TRICC%subset%of%713%paAents%requiring%mech%vent1%•  No%difference%in%duraAon%of%vent,%vent%free%days,%or%extubaAon%

success%rates%

• In%paAents%receiving%mech%vent%>96%hrs,%transfusion%associated%with%increased%risk%of%hospital%death,%cost%and%LOS2%• Risk%of%ARDS%increased%in%paAents%receiving%transfusion;%in%paAents%with%established%lung%injury%transfusion%increased%risk%for%hospital%mortality3,4%

1.  Hebert, 2001, Chest; 119:1850 2.  Zilberberg, 2008, Crit Care, 12: R60 3.  Zilberberg, 2007, Crit Care; 11: R63 4.  Netzer, 2007, Chest; 132: 1116

Transfusion'and'Acute'Upper'GI'Bleed'• Villanueva,%2013,%NEJM;%368:11%• 460%Liberal%strategy:%transfuse%for%Hgb%<9,%target%9%–%11%• 461%RestricAve:%transfuse%for%Hgb%<%7,%target%7%–%9%• Inclusion%criteria:%adults,%hematemesis,%melena%with%clinical%suspicion%of%UGIB;%all%had%EGD%• Massive%transfusion,%ACS,%CVA%excluded%• PaAents%

•  PUD:%47%Y%51%;%esophageal%varices:%24%–%23%%

PRBC'Transfusion'in'UGIB'

Villanueva, 2013, NEJM; 368:11. Fig 1, p. 18

A%66%yo%woman%with%a%prior%history%of%diabetes%and%hypertension%presents%with%hematemesis.%%This%began%2%days%ago%and%she%esAmates%vomiAng%blood%“about%15%Ames.”%She%takes%aspirin.%%HR%104,%BP%114/66,%RR%18.%%Her%laboratory%tests%demonstrate%a%normal%platelet%count,%normal%coagulaAon%Ames%and%WBC.%%Serum%lactate%is%normal.%Hemoglobin%is%8.1%g/dl.%%While%waiAng%upper%endoscopy,%she%has%another%episode%of%hematemesis%of%a%small%amount%(20cc)%bloody%emesis.%%%Which%transfusion%approach%is%most%appropriate?%

%a)%IniAate%massive%transfusion%protocol%%b)%Transfuse%packed%RBC:Fresh%frozen%plasma%at%2:1%%c)%Transfuse%a%single%unit%of%PRBC%and%recheck%Hgb%%d)%Transfuse%6%u%pooled%platelets%alone%%e)%Do%not%transfuse%blood%products%at%this%Ame%

%

Clinical'Prac9ce'Guidelines'for'RBC'Transfusion'Napolitano,%Kurek%el%al,%2009;%Crit%Care%Med;%37:3124%

1.  Hemorrhagic%Shock:%early%empiric%RBC%transfusion%indicated%as%component%of%iniAal%resuscitaAon%

2.  Acute%hemorrhage%with%hemodynamic%instability%or%inadequate%oxygen%delivery:%RBC%transfusion%may%be%indicated%in%paAents%unresponsive%to%iniAal%resuscitaAon%with%crystalloid%infusion;%blood%lactate%may%be%used%to%monitor%physiologic%status%and%response%to%treatment%

Clinical'Prac9ce'Guidelines'for'RBC'Transfusion'Napolitano,%Kurek%el%al,%2009;%Crit%Care%Med;%37:3124%%3.%CriAcally%ill%paAents%with%hemodynamically%stable%anemia%except%paAents%with%acute%coronary%syndromes%or%unstable%angina:%A%restricAve%strategy%of%RBC%transfusion%to%be%administered%when%Hb%less%than%7%g/dL%%4.%Transfusion%trigger%based%on%hemoglobin%level%alone%should%not%be%used,%should%also%consider%volume%status,%shock,%duraAon%and%extent%of%anemia,%cardiovascular%and%pulmonary%status%%

Clinical'Prac9ce'Guidelines'for'RBC'Transfusion'Napolitano,%Kurek%el%al,%2009;%Crit%Care%Med;%37:3124%%5.%Number%of%Transfusions%to%Administer:%in%the%absence%of%hemorrhage%or%evidence%of%inadequate%Assue%oxygenaAon,%RBC%transfusion%should%be%administered%in%single%units.%%Need%for%mulAple%units%determined%by%assessment%of%clinical%response%%

Clinical'Prac9ce'Guidelines'for'RBC'Transfusion'• Napolitano,%Kurek%el%al,%2009;%Crit%Care%Med;%37:3124%• Consider%Transfusion%of%Hb%is%less%than%7%g/dl%

•  PaAents%requiring%mechanical%venAlaAon%•  Trauma%paAents%who%remain%criAcally%ill%beyond%iniAal%resuscitaAon%

•  Stable%Cardiac%Disease%• Acute%coronary%syndrome%

•  RBC%transfusion%my%be%beneficial%in%paAents%who%are%anemic%with%Hb%less%than%8g/dL%

Red'Blood'Cell'Products'• “Packed%RBC”%–%approx%300%cc%electrolyte/nutrient%soluAon,%plasma%and%platelets%removed,%usually%infused%over%1%to%4%hours;%most%common%

• Whole%blood%–%includes%plasma%and%platelets%–%rarely%used,%potenAal%uAlity%in%massive%/%baulefield%trauma%

• Specialized%RBC%–%rare%donor%phenotypes%–%stored%frozen%usually%at%regional%blood%centers,%delay%in%obtaining%

• Leukoreduced/leukofiltered%–%for%use%in%paAents%receiving%repeated%transfusions,%transplant%recipients,%may%reduce%febrile%transfusion%reacAon%

• Irradiated%–%used%to%prevent%grav%vs.%host%%

Clinical'Outcomes'in'Pa9ents'Receiving'RBC'Transfusion'%• 4%%of%all%RBC%transfusions%associated%with%some%form%of%complicaAon%%

•  Fever,%fluid%overload,%hypotension%• RBC%transfusion%consistently%associated%with%

•  Higher%LOS,%mortality,%illness%severity%scores,%costs%

Add'your'slides'here….%

Corwin, 2004, Crit Care Med; 32:39-52

Transfusion and Overall Mortality

transfused

nontransfused

A%58%year%old%man%with%small%bowel%arterioYvenous%malformaAons%is%admiued%with%hematochezia.%He%requires%transfusion%with%3%u%PRBC%on%his%iniAal%hospital%day.%%Aver%an%embolizaAon%procedure%his%bleeding%resolves%and%he%is%discharged%to%home%on%hospital%day%4.%%He%returns%5%days%aver%discharge%with%chills,%low%energy%and%jaundice.%%His%examinaAon%is%remarkable%for%no%tachycardia,%hypotension%or%fever,%but%he%does%have%symmetric%pedal%edema.%%Labs%show%total%bilirubin%7.8,%LDH%850;%Hemoglobin%8.2;%peripheral%blood%film%with%spherocytes.%%When%the%blood%bank%performs%type%and%anAbody%screening,%his%Coomb’s%test%returns%posiAve.%What%is%the%most%likely%diagnosis?%a)  Acute%hemolyAc%transfusion%reacAon%b)  NonhemolyAc%transfusion%reacAon%c)  TransfusionYassociated%circulatory%overload%d)  Viral%syndrome%resulAng%from%immune%modulaAon%e)  Delayed%hemolyAc%transfusion%reacAon%

Transfusion'and'Infec9on'Risk'•  RBC%transfusion%associated%with%increased%combined%risk%

of%nosocomial%sepsis,%bacteremia,%pneumonia,%urinary%tract,%peritoniAs%and%CNS%infecAons%infecAon,%%–  Taylor,%2006,%Crit%Care%Med;%34:2302%

Acute'Hemoly9c'Transfusion'Reac9on'

• IncompaAble%ABO,%RhD%or%(rarely)%other%RBC%surface%anAgen%results%in%hemolysis%of%the%donor%RBC’s%• Rate%1/12,000%–%1/100,000%with%1/600,000%fataliAes%• Usually%the%result%of%error%in%blood%specimen%processing,%crossmatching%or%bedside%administraAon%• Fever,%back%pain,%pain%at%infusion%site,%chest%pain,%anxiety,%nausea%• Tachypnea,%tachycardia,%shock%• Hypotension,%hemoglobinuria,%coagulopathy%resulAng%in%bleeding%from%venipuncture%and%surgical%sites%

Febrile'and'Anaphylac9c'Reac9ons'

• Febrile%(nonhemolyAc)%reacAon%%–  Most%common,%0.5%–%5.0%%all%transfusions%–  Donor%reacAon%to%recipient%leukocytes/cytokines%–  Management%with%anApyreAcs%

• UrAcarial%/%AnaphylacAc%–  Recipient%anAbody%against%nonYcellular%donor%protein%such%as%

immunoglobulins%–  IgA%deficient%paAents%at%parAcular%risk%–  Spectrum%from%fullYblown%anaphylaxis%to%simple%urAcaria,%occurs%

immediately%–  Washed%RBC%indicated%for%paAents%with%history%of%urAcaria,%IgA%

deficient%donor%products%for%paAents%with%IgA%deficiency%

Delayed'Reac9ons'

• PostYtransfusion%Purpura%–  InducAon%of%anAYplatelet%anAbodies%–  Specifically%platelet%anAgen%1a%–  Delayed%reacAon%3Y12%days%–  Thrombocytopenia%bleeding%which%may%be%severe%

• Delayed%hemolyAc%reacAon%–  3%–%14%days%post%transfusion%–  Fevers,%chills,%jaundice,%hemolyAc%anemia%posiAve%Coomb’s%test,%elevated%LDH,%decreased%haptoglobin%

TRALI'• Transfusion%Associated%Acute%Lung%Injury%• May%occur%with%any%RBC%or%plasmaYcontaining%blood%product,%but%probably%higher%with%plasma%• May%be%related%to%donor%anAYHLA%anAbodies,%or%anAYhuman%neutrophil%anAgen%anAbody%• Risks%include%female%donors,%sepsis,%mechanical%venAlaAon,%fluid%overload,%liver%surgery,%alcohol%use,%tobacco%use%

–  Incidence%decreased%if%FFP%produced%only%from%male%donors%• Clinical%definiAon:%abrupt%and%rapid%onset%of%ALI%within%6%hours%of%transfusion%in%paAent%without%prior%evidence%of%lung%injury%or%volume%overload%• Incidence:%1%/%1000%–%1/5000%RBC%units%transfused%

Infec9ous'Disease'Transmission'Risks'

• HIV%–%1/1,500,000%to%1/4,300,000%• Hep%C%–%1%/%1,935,000%• Hep%B%–%1%/%250,000%(anAgen%+%anAbody%tesAng)%• Hep%A%–%1%/%1,000,000%%

Blood'Management'Systems'

• Health%care%faciliAes%compelled%to%monitor%appropriate%used%of%RBC%and%other%blood%products%within%the%context%of%a%comprehensive%blood%management%program%• Required%by:%

•  Outcome%/%dataYdriven%systems%•  External%monitoring%and%accreditaAon%(Joint%Commission)%•  PaAent%demand%•  Expense%

Components'of'Blood'Management'Programs'• FoundaAon%includes%evidence%based%guidelines%and%locallyYadapted%standards%of%pracAce%• InsAtuAonal%goals%for%uAlizaAon%rates%and%quality%metrics%must%be%established%• Algorithms%for%evaluaAon%of%anemia%and%need%for%transfusion%• ComputerYorder%entry%for%blood%products,%barcode%scanning%• %CollaboraAve%across%departments%and%staff%• RouAne%feedback%and%reports%shared%with%prescribers,%nurses%and%technical%staff%• Process%for%reviewing%outliers%and%aberraAons%in%use%

The'Bocom'Line'•  Anemia%is%a%common%ICU%problem%that%is%evaluated%by%tests%

of%RBC%morphology,%CBC%and%selected%chemical%tests%•  The%iniAal%assessment%of%an%anemic%paAent%is%based%on%

understanding%causes%and%physiologic%response%•  Clinical%guidelines%for%transfusion%endorse%a%restricAve%

transfusion%strategy%for%most%paAent%subgroups%•  Transfusion%is%associated%with%many%known%complicaAons%

including%transfusion%reacAons,%increased%infecAon%risk%and%disease%transmission%

•  Transfusion%pracAce%should%be%monitored%within%an%systemaAc%blood%management%program%