Anemia in Critically Ill Patient1

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Anaemia in Critically ill Anaemia in Critically ill

patientpatient



IntroductionIntroduction

Mean Hb concentration of 11g/dl, with 63% &Mean Hb concentration of 11g/dl, with 63% &29% having a mean Hb of less than 12 and 1029% having a mean Hb of less than 12 and 10respectivelyrespectively

Prevalence of moderate to severe anaemiaPrevalence of moderate to severe anaemia

appears to be 40appears to be 40--50%50% over 90% of patients after 3d in ICU show Hbover 90% of patients after 3d in ICU show Hb

below normal value as compared to 24below normal value as compared to 24--40% in40% innonnon--ICU patientsICU patients

Among non Among non--bleeding ICU pts who did notbleeding ICU pts who did notreceive transfusion, Hb concentrationsreceive transfusion, Hb concentrations by a by amean 0.52g/dmean 0.52g/d



Figure 1. Course of Hemoglobin (Hb) Patterns by Admitting Hb Level Category Numbers donot total 3534 because of missing data (some forms incomplete).

Vincent, J. L. et al. JAMA 2002;288:1499-1507

Copyright restrictions may apply.



Classification of anaemiaClassification of anaemia

Decreased RBC productionDecreased RBC production

Lack of nutrients, such as iron, B12, or folate.Lack of nutrients, such as iron, B12, or folate.

Bone marrow disordersBone marrow disorders Bone marrow suppressionBone marrow suppression

Low levels of trophic hormonesLow levels of trophic hormones

The anaemia of chronic disease/inflammation,The anaemia of chronic disease/inflammation,

associated with infectious, inflammatory, or associated with infectious, inflammatory, or

malignant disorders,malignant disorders,



Increased RBC destructionIncreased RBC destruction ²² HaemolyticHaemolytic

anaemia will ensue when the bone marrow is unable toanaemia will ensue when the bone marrow is unable to

keep up with the need to replace more than about 5keep up with the need to replace more than about 5

percent of the RBC mass per day,percent of the RBC mass per day, Inherited haemolytic anaemiasInherited haemolytic anaemias

Acquired haemolytic anaemias (eg, Coombs' Acquired haemolytic anaemias (eg, Coombs'--

positive autoimmune haemolytic anaemia,positive autoimmune haemolytic anaemia,

thrombotic thrombocytopenic purpurathrombotic thrombocytopenic purpura--haemolytic uremic syndrome, malaria)haemolytic uremic syndrome, malaria)



Blood lossBlood loss ²² is the most common causeis the most common cause

of anaemia and may take any one of aof anaemia and may take any one of a

number of forms:number of forms: Obvious bleedingObvious bleeding

Occult bleedingOccult bleeding

Induced bleedingInduced bleeding



Causes of anaemia during criticalCauses of anaemia during critical

illnessillness PrePre--existing anaemiaexisting anaemia

Acquired anaemia Acquired anaemia1.1. HemodilutionHemodilution

2.2. Blood lossBlood loss3.3. Reduced red cell survivalReduced red cell survival

4.4. Reduced red cell productionReduced red cell production

5.5. Abnormal iron metabolism Abnormal iron metabolism

6.6. Nutritional deficienciesNutritional deficiencies7.7. Inappropriate erythropoietin productionInappropriate erythropoietin production

8.8. Abnormal red cell production Abnormal red cell production



The relation between red cell volume, plasma volume and haemoglobin concentration duringhaemorr hage, healthy euvolaemia, and fluid resuscitation with clear fluids.

Walsh T S , Saleh E Br. J. Anaesth. 2006;97:278-291

© The Board of Management and Trustees of the British Journal of Anaesthesia 2006. All rightsreserved. For Permissions, please e-mail: [email protected]



BLOOD LOSSBLOOD LOSS

i.i. Frequent blood samplingFrequent blood sampling

�� phlebotomy could account for up to 30% of totalphlebotomy could account for up to 30% of total

blood transfused in ICUblood transfused in ICU

�� ABC study +ve correlation between organ ABC study +ve correlation between organ

dysfunction and no of blood draws and totaldysfunction and no of blood draws and total

volume drawnvolume drawn



ii. Blood loss at the time of surgicalii. Blood loss at the time of surgical

procedures preceding admission to theprocedures preceding admission to theICUICU

iii. Blood loss due to trauma precedingiii. Blood loss due to trauma precedingadmission to the ICUadmission to the ICU



iv.iv. Clinically apparent and/or occult blood lossClinically apparent and/or occult blood loss(Stress Ulcer) from GIT(Stress Ulcer) from GIT

Clinically significant bleeding occurred in 1.5% of Clinically significant bleeding occurred in 1.5% of

ICU patientsICU patients

Incidence of overt GI bleeding ~1.5 to 8.5% amongIncidence of overt GI bleeding ~1.5 to 8.5% amongall ICU patients, but may be as high as 15% amongall ICU patients, but may be as high as 15% among

patients who do not receive stress ulcer prophylaxispatients who do not receive stress ulcer prophylaxis

Incidence significantly reduced due to SUIncidence significantly reduced due to SU

prophylaxis and early introduction of enteral feedingprophylaxis and early introduction of enteral feeding



Stress Ulcer Stress Ulcer

EarlyEarly-- begins in the proximal regions of thebegins in the proximal regions of thestomach within hoursstomach within hours

LateLate-- develop after the first several days of develop after the first several days of hospitalization tend to be deeper and morehospitalization tend to be deeper and moredistaldistal

Risk FactorsRisk Factors Mechanical ventilation for >48hrs (OR 15.6)Mechanical ventilation for >48hrs (OR 15.6)

Coagulopathy (OR 4.3)Coagulopathy (OR 4.3)



ProphylaxisProphylaxis

Coagulopathy, defined as a platelet countCoagulopathy, defined as a platelet count<50,000/m3, an INR >1.5, or PTT >2 times the<50,000/m3, an INR >1.5, or PTT >2 times thecontrol valuecontrol value

Mechanical ventilation for more than 48 hoursMechanical ventilation for more than 48 hours History of GI ulceration or bleeding with the pastHistory of GI ulceration or bleeding with the past

year year

Two or more of the following risk factorsTwo or more of the following risk factors ²²

sepsis, ICU admission lasting >1 week, occult GI sepsis, ICU admission lasting >1 week, occult GI bleeding lasting �6 days, and glucocorticoidbleeding lasting �6 days, and glucocorticoidtherapytherapy



What to give??What to give??

H2 blockers versus PPI H2 blockers versus PPI ²² A meta A meta--analysis of sevenanalysis of sevenrandomized trials found a less GI bleeding among thoserandomized trials found a less GI bleeding among thosewho received a PPIwho received a PPI

H2 blockers versus antacidsH2 blockers versus antacids ²² H2 blocker group had aH2 blocker group had asignificantly lower rate of overt GI bleedingsignificantly lower rate of overt GI bleeding

H2 blockers versus sucralfateH2 blockers versus sucralfate ²²H2 blocker decreasedH2 blocker decreasedovert GI bleeding compared to sucralfateovert GI bleeding compared to sucralfate

SucralfateSucralfate versus antacidsversus antacids ²²antacids group had a lower antacids group had a lower rate of clinically important GI bleeding, but the differencerate of clinically important GI bleeding, but the differencewas not statistically significantwas not statistically significant



Potential harmPotential harm

Studies suggest that agents that increase gastricStudies suggest that agents that increase gastric

pH maypH may the frequency of nosocomialthe frequency of nosocomial

pneumonia compared to agents that do not alter pneumonia compared to agents that do not alter

gastric pH (eg, sucralfate).gastric pH (eg, sucralfate). Randomly assigned 1200 mechanicallyRandomly assigned 1200 mechanically

ventilated patientsventilated patients-- received either an ivreceived either an iv

ranitidine or sucralfateranitidine or sucralfate-- found that VAP wasfound that VAP was

more frequent in the H2 blocker group, althoughmore frequent in the H2 blocker group, although

the difference was not statistically significantthe difference was not statistically significant



5.5. Reduced red cell survivalReduced red cell survival�� complement activationcomplement activation

�� changes in RBC deformability and membranechanges in RBC deformability and membrane

characteristicscharacteristics

�� Inflammatory mediators (ILInflammatory mediators (IL--1. TNF1. TNF ))

6.6. Reduced red cell productionReduced red cell production

blunting of the erythropoietic responseblunting of the erythropoietic response inhibit RBC production directly by inhibiting boneinhibit RBC production directly by inhibiting bone

marrowmarrow

inhibits differentiation of erythroid progenitor cellsinhibits differentiation of erythroid progenitor cells



7.7. Iron metabolismIron metabolism

�� acute inflammation decreases the iron available for acute inflammation decreases the iron available for

erythropoiesiserythropoiesis

�� Serum Fe & TIBC ( Serum Fe & TIBC (adequate stores of iron in theadequate stores of iron in thebone marrow which may not be effectively utilizedbone marrow which may not be effectively utilized

i.e. functional Fe def)i.e. functional Fe def)

�� Normal to high serum ferritin concentrationNormal to high serum ferritin concentration

�� no significant increase in circulating reticulocytesno significant increase in circulating reticulocytes�� reticulocyte hb concentration (CHR) and % of reticulocyte hb concentration (CHR) and % of

hypochromic red cells in peripheral bloodhypochromic red cells in peripheral blood



8.8. B12 and folate metabolismB12 and folate metabolism

�� Rodriguez et al. found evidence in only 2%Rodriguez et al. found evidence in only 2%

of ICU ptsof ICU pts

9.9. Inappropriately low circulatingInappropriately low circulating

erythropoietin levelerythropoietin level

�� from inhibition of the EPO gene byfrom inhibition of the EPO gene byinflammatory cytokinesinflammatory cytokines

10.10. Abnormal red cell maturation Abnormal red cell maturation

Inflammatory cytokines directly inhibit redInflammatory cytokines directly inhibit redcell formation and induce apoptosis of cell formation and induce apoptosis of

erythroid precursor cellserythroid precursor cells



Schematic diagram showing stages in red blood cell maturation from pluripotential stem cellsand the sites of action of potential inhibitors during critical illness.

Walsh T S , Saleh E Br. J. Anaesth. 2006;97:278-291

© The Board of Management and Trustees of the British Journal of Anaesthesia 2006. All rightsreserved. For Permissions, please e-mail: [email protected]



InvestigationsInvestigations

FBC/Peripheral blood filmFBC/Peripheral blood film

RBC indices and morphologyRBC indices and morphology

Reticulocyte countReticulocyte count Iron studyIron study

Red cell folate and Vitamin B12 levelRed cell folate and Vitamin B12 level

Bone marrow aspiration and biopsyBone marrow aspiration and biopsy



Bed side testBed side test-- for occult bloodfor occult blood -- NGNG

aspirate or faecesaspirate or faeces

Upper and lower GI

endoscopyUpper and lower GI

endoscopy Imaging studiesImaging studies





Management of anaemia inManagement of anaemia in

critically ill patientscritically ill patients



Iron Therapy Iron Therapy

Final decision will depend ultimately on theFinal decision will depend ultimately on theaetiology of anaemia in the critically illaetiology of anaemia in the critically illpatient.patient.

IDA is noted in a small subset of criticallyIDA is noted in a small subset of criticallyill patients and iron supplementation of ill patients and iron supplementation of such patients is appropriate.such patients is appropriate.

If anaemia is multifactorialIf anaemia is multifactorial -- may be usefulmay be useful

as an adjunct with erythropoietin.as an adjunct with erythropoietin. Specific populations of ICU patients maySpecific populations of ICU patients may

not benefit from iron therapynot benefit from iron therapy



Microbe require iron for growthMicrobe require iron for growth

High ferritinHigh ferritin-- binds to Fe making it lessbinds to Fe making it less

available for bacteriaavailable for bacteria Antibacterial effect of cytokines such as Antibacterial effect of cytokines such as

Interferon, TNF, IL is mediated byInterferon, TNF, IL is mediated by

intracellular depletion of ironintracellular depletion of iron



Oral formOral form

Ferrous sulphate/gluconate/fumarateFerrous sulphate/gluconate/fumarate

P arental formP arental form

Iron dextran/gluconate/sucroseIron dextran/gluconate/sucrose

Adverse effectAdverse effect

GI irritationGI irritation

Interferes with absorption of other drugs likeInterferes with absorption of other drugs like

phenytoin/tetracyclinephenytoin/tetracycline

Anaphylaxis with iron dextran Anaphylaxis with iron dextran



Blood transfusionBlood transfusion

At what plasma Hb do the risk of At what plasma Hb do the risk of

anaemia outweighs the potential risk of anaemia outweighs the potential risk of

transfusion in critically ill patients?????transfusion in critically ill patients?????



At 1982 At 1982-- Allen and colleagues suggested Allen and colleagues suggested

10/30 rule as a clinically useful transfusion10/30 rule as a clinically useful transfusion

trigger trigger-- Never been supported by RCTsNever been supported by RCTs

cost and availability of blood productscost and availability of blood products

along with risk a/w transfusionalong with risk a/w transfusion-- reasons toreasons to

reconsider the trigger for transfusionreconsider the trigger for transfusion



TRICC trialTRICC trial--

838 pts randomly assigned to liberal transfusion838 pts randomly assigned to liberal transfusiongroup or a restrictive groupgroup or a restrictive group

Restrictive transfusion strategy is at least as effectiveRestrictive transfusion strategy is at least as effective

as and possibly superior to liberal strategyas and possibly superior to liberal strategy

Among pts aged <55yrs, and admission APACHE II Among pts aged <55yrs, and admission APACHE II <20, statistically significantly better 30d mortality<20, statistically significantly better 30d mortality

among pts in restrictive groupamong pts in restrictive group

ABC trial ABC trial

Both ICU and overall mortality were significantlyBoth ICU and overall mortality were significantlyhigher in pts who had vs had not received ahigher in pts who had vs had not received a

transfusiontransfusion



Complications of blood transfusionComplications of blood transfusion

Immediate reactionsImmediate reactions Febrile nonFebrile non--haemolytic reactionshaemolytic reactions

Allergic reactions Allergic reactions-- mild urticaria to anaphylaxismild urticaria to anaphylaxis

Acute haemolytic reaction Acute haemolytic reaction

Volume overloadVolume overload-- FFP more prone because it isFFP more prone because it isinfusion volume and it being hyper infusion volume and it being hyper--oncoticoncotic

Bacterial contaminationBacterial contamination

HypothermiaHypothermia

CoagulopathyCoagulopathy Citrate toxicityCitrate toxicity-- metabolic alkalosismetabolic alkalosis

plasma calcium and magnesiumplasma calcium and magnesium



TRALITRALI

DefinitionDefinition-- hypoxia and pulmonary oedema occurringhypoxia and pulmonary oedema occurring

during or within 6 hours of a transfusion in the absenceduring or within 6 hours of a transfusion in the absence

of CCF or volume overloadof CCF or volume overload

diagnosis of TRALI

relies on the exclusion of cardiogenicdiagnosis of TRALI

relies on the exclusion of cardiogenicpulmonary oedema, volume overload and sepsispulmonary oedema, volume overload and sepsis

PathogenesisPathogenesis

controversialcontroversial

thought to occur secondary to lipids and cytokines in thethought to occur secondary to lipids and cytokines in the

transfused product or from interaction between patient white celltransfused product or from interaction between patient white cellantigens and donor antibodies (or vice versa).antigens and donor antibodies (or vice versa).



Risk factorsRisk factors

emergency cardiac surgeryemergency cardiac surgery hematologic malignancyhematologic malignancy

massive transfusionmassive transfusion

sepsissepsis

mechanical ventilation, andmechanical ventilation, and

high APACHE II scorehigh APACHE II score

9090--day survival of ICU patients developingday survival of ICU patients developingTRALI in this study was only 53 percent.TRALI in this study was only 53 percent.



TreatmentTreatment

supportive and ventilation is required insupportive and ventilation is required in

most patientsmost patients

most do well with an associated mortalitymost do well with an associated mortalityof 5of 5--10%10%

use of leucoreduced blood componentsuse of leucoreduced blood components

and fresher blood/blood components mayand fresher blood/blood components may

also have a benefitalso have a benefit



Delayed reactionsDelayed reactions

Delayed HaemolysisDelayed Haemolysis

AlloimmunisationAlloimmunisation

Transfusion associated Graft VersusTransfusion associated Graft Versus--Host Disease (TaHost Disease (Ta--GVHD)GVHD)

occurs when donor lymphocytes in cellular blood products engraft in aoccurs when donor lymphocytes in cellular blood products engraft in asusceptible transfusion recipient, which proliferate and damage target organssusceptible transfusion recipient, which proliferate and damage target organsespecially bone marrow, skin, liver and gastrointestinal tract.especially bone marrow, skin, liver and gastrointestinal tract.

Iron accumulationIron accumulation Predictable consequence of chronic RBCPredictable consequence of chronic RBC

Patients receiving chronic transfusion usually have their iron status monitoredPatients receiving chronic transfusion usually have their iron status monitoredand managed by their physician.and managed by their physician.

Infectious Disease transmissionInfectious Disease transmission Definitive evidence of transmission by transfusion requires demonstration of Definitive evidence of transmission by transfusion requires demonstration of

seroconversion or new infection in the recipient.seroconversion or new infection in the recipient.

Suspected transfusionSuspected transfusion--transmitted bacterial or parasitic infection (malaria) shouldtransmitted bacterial or parasitic infection (malaria) shouldbe reported urgently in order to recall other potentially infectious blood productsbe reported urgently in order to recall other potentially infectious blood productsfrom the same donation.from the same donation.



Transfusion relatedTransfusion related

Immunomodulation (TRIM)Immunomodulation (TRIM) first demonstrated in the renal transplant setting, when significantlyfirst demonstrated in the renal transplant setting, when significantly

improved renal allograft survival after transplant was seen inimproved renal allograft survival after transplant was seen in

patients who had received transfusion before transplantpatients who had received transfusion before transplant

PathogenesisPathogenesis transfused allogeneic WBCs are responsible for the majority of transfused allogeneic WBCs are responsible for the majority of

TRIM effects.TRIM effects.

impaired natural killer cell function, decreased macrophageimpaired natural killer cell function, decreased macrophage

phagocytic function, suppression of lymphocyte production andphagocytic function, suppression of lymphocyte production and

ineffective antigen presentation.ineffective antigen presentation.

Clinical effects of TRIMClinical effects of TRIM-- risk of cancer recurrence, postoperativerisk of cancer recurrence, postoperative

infection and shortinfection and short--term mortalityterm mortality



Other risks associated with bloodOther risks associated with blood

transfusiontransfusion

prolong storage may ability to improveprolong storage may ability to improve

oxygenationoxygenation

in animal models blood stored >28d didn¶tin animal models blood stored >28d didn¶t

improve O2 consumption as compared with thatimprove O2 consumption as compared with thatstored <3daysstored <3days

In a trauma registry of 16,824 pts, transfusion of In a trauma registry of 16,824 pts, transfusion of

old blood (storage>15d) was independentold blood (storage>15d) was independent

predictor of mortality, ICU admission/length of predictor of mortality, ICU admission/length of

stay and hospital length of staystay and hospital length of stay



what happens during prolongwhat happens during prolong

storage??storage??

RBC lose 2,3 DPG stores and ATPRBC lose 2,3 DPG stores and ATP

diminished cellular deformability,diminished cellular deformability,

cytoskeleton oxidation and impairedcytoskeleton oxidation and impaired

oxygen off oxygen off--loadingloading



Erythropoietin therapyErythropoietin therapy

RCT of 1302 pts from 65 ICUsRCT of 1302 pts from 65 ICUs

EpoetinEpoetin group when compared with placebogroup when compared with placebogroupgroup

had a greater mean increase in Hbhad a greater mean increase in Hb fewer median red blood cell units administered/ptfewer median red blood cell units administered/pt

a 19% reduction in total no of RBC unitsa 19% reduction in total no of RBC unitstransfusedtransfused

no statistical difference in secondary outcomesno statistical difference in secondary outcomes(ventilation free days, start of mechanical(ventilation free days, start of mechanicalventilation, ICU readmission, ICU length of stay or ventilation, ICU readmission, ICU length of stay or mortality)mortality)

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Anemia in Critically Ill Patient1