DR IMRAN GAFOORDR DINESH RAWATFELLOW.DEPT. OF CCEMSGRH,NEW DELHIBLOOD & BLOOD PRODUCTS
INCIDENCE :: Anemia has an incidence of 29-37% in critically ill.: Recent cross-sectoinal analysis showed that,29%had Hb < normal & 37% required RBCtransfusions.[vincent et al;JAMA-02]:MOST SIGNIFICANT RISK assoc with anemia isthe harm resulting from decrease in Oxy carryingcapacity & plasma volume.
NATURAL HISTORY OFUNCORRECTED ANEMIA: Leung et al found ECG changes that may beindicative of myocardial ischemia in subjects ofisovol hemodilution to a conc. Of Hb 5gm/dl.[leung et al-anaesthesi. 2000]:Descriptive studies in pt refusing RBC transfusionhave demonstrated that pt can survive surgicalinterventions with Hb as low as 4.5gm/dl.[spencer et al-Am j surg 1990]
: Development of consequences of anemiadepends on pt’s ability to compensate.: less tolerating group of pt’s are –a) olderb)severly illc) coronary,cerebrovas,resp co-morbidities
:Researches have revealed that increasing degrees ofanemia were associated with a disproportionateincrease in mortality rates in cardiac patients.[Hebert et al-Am j resp criti care 1997]:Anemia increases risk of death in patients of significantcardiac disease.
: CURRENT RECOMMENDATIONS –- except in circumstances of ACS pt can betransfused for Hb<7gm/dl with a goal of main-taining levels between 7-9 gm/dl .- in ACS,increased survival has been demon-strated with transfusion for Hb<10 gm/dl.
[Hebert et al NEJM-1999]: enrolled 838 patients: it’s only trial powered adequately to evaluate theimpact of different transfusion strategies on mor-tality/morbidity of recepients.: concluded – 30 days mortality rates were signif-icantly lower with restrictive transfusion strategy(≤7 gm/dl),who were less acutely ill(APACHE<20) & among patients < 55 yrs of age.
SUBGROUPS OF TRICC TRIALEffects of transfusion in pt with cardiovascular d/e :pt when equally divided in restrictive transfusion &liberal transfusion groups, study, revealed thatrestrictive group required lesser diuretic usage but nodifference in mortality was noted between two groups.
SUBGROUPS OF TRICC TRIALEffects of transfusion on weaning :- 82% of pt in restrictive transfusion group weresuccessfully weaned & extubated compared with78% in liberal group.- In pt’s who required > 7 days of ventilation,nodifference in time of successful ventilation b/n twogroups.- Each additional transfusion was associated with inc-reased duration of ventilation.
QUESTIONS UNANSWERED IN TRICCTRIAL? Why liberal strategy group failed to improvemortality & rates of organ failure in criticallyill ??Possible explanations :a) greater no. of allogenic RBC units depressedhost immune responses.[Hermans j et al circulation 1998]b) altered microcirculatory flow as consequenceof prolonged storage times.
. Pulmonary edema & ARDS were increased in libe-ral strategy group. Thus further concluding –“ restrictive RBC transfusion strategy didn’tadversely affect outcomes related to mechanicalventilation .[Hebert pc et al – chest 2001]
- Goal directed transfusion triggers :If fall in Scvo2 < 70% is used as a transfusiontrigger , for increasing Hct > 30%, Rivers et alconcluded that it only led to increased no. of tran-sfusions with no added survival benefit.[Rivers et al NEJM 2001]
ALTERNATIVES TO TRANSFUSION- Two most useful approaches in ICU :1) decrease phlebotomies ,2) use of erythropoietin .- Other strategies :: decreased use of NSAIDS ,: blood conservation in form of pediatrictest tubes,arterial catheter reinfusionsetups.: use of tranexamic acid .
ERYTHROPOIETIN* Critical illness is characterized by blunted erythro-poietin production & response.[Rodriguez et al –j critical care 2001]• Anemia in critically ill is result of erythro. gene in-hibition by inflammatory mediators.[Jelkmannw et al-j inter cytoki 1998]• Inflammatory cytokines directly inhibit RBC productionby bone marrow & may produce Femetabolism abnormalities.[Krantz sb et al-Am j med sci 1994]
: 300 units / Kg daily for 5 days f/b everyother day till ICU discharge.• Studies demonstrate that recom. erythro. therapyin critically ill can decrease RBC transfusion & in-crease Hb levels.thus consistent with hypothesisthat anemia in critically ill is similar to anemia inchronic disease pt & characterised by RELATIVEERYTHROPOIETIN DEFICIENCY.
sHOWEVER due to highcosts,lack of clinical benefit,& delayed effects(weeks to act),,its use is not reco-mmended as a blood conservation strategy.RECOMMENDATIONS (FINK Textbook cri care)-1) Adopt a transfusion threshold of 7 gm/dl in vol-resuscitated critically ill adult,child & post oppatients including pt with h/o CAD;septic shockafter initial resuscitation.2) Aim to maintain Hb between 7-9 gm/dl.
3) Transfuse one unit at a time & measure afterevery transfusion.4) Insufficient evidence regarding transfusiontrigger in ACS & early septic shock(<10gm/dlmight be beneficial)5) Erythropoietin is not routinely recommendedexcept in chronic renal failure.
NAPOLITAM LM et al (critical care clinic)2004* RBC transfusion doesn’t improve tissue oxygenation consistently in critically ill & may sometimeresult in worsening.Lack of efficacy related to changes during storage :- storage time- increased endothelial adherence of st-ored RBC- NO binding of free Hb in stored blood- donor leucocytes- host inflammatory response- decrease RBC deformabilitySUGGESTION : conservative RBC transfusion strategy in cr-itically ill.
DOSING & ADMINISTRATION- Each unit of packed cell~300 ml,given over 2-3hrs- Each unit increases Hb by 1g/dl or Hct by 3% inhealthy individuals without ongoing blood lossor destruction,however,it takes 24 hrs for intra-vascular volume to equlibrate for full effect.- In emergency O neg RBC can be given.
TYPES OF RBC PRODUCTSWHOLE BLOOD : RBC+platelets+plasma proteins- indicated in hemorrhage & anemia- autologous donation prior to surgeryPACKED RBC’S : 200ml of RBC’S + preservatives- each bag has Hct of 60% & approx200 mg elemental iron.GAMMA IRRADIATED : destruction of donor T-lym.for GVHD prevention in immunocom.,stem cell recepient.
- CMV antibody neg : used in transplant & pregna-ncy(high risk of CMV complications)- Leukocyte depleted : in febrile reactions,to avo-id leucocyte immunization in hema-tological malignancy.- Washed RBC’S : washed with NS to removedonor serum,-used in IgA def & those at highrisk for anaphylaxis,- in PNH pt ( to deplete complement)
RISKS OF TRANSFUSION :- UNIFACTORIAL : (transfusion is the cause)- compatibility/technical errors,- HIV / hepatitis,- endotoxemia,- GVHD.- OLIGIFACTORIAL: (transfusion + other factors)- fever- anaphylactoid reaction- TRALI- CMV- allergies
- MULTIFACTORIAL (transfusion as a risk factor):- ARDS- MODS- TRIM(transfusion related immuno-modulation)- thrombosis.
TRANSFUSION RELATEDCOMPLICATIONSA) Acute Hemolytic Transfusion Reactions(AHTR):- most severe & life threatening,- IgM against donor major RBC antigen,- manifes. : fever,dyspnea,tachycardia,back pain,hypotension,chills,chest painpain at infusion sites,lumbosacral pain- hemoglobinuria may be first sign in se-dated patient,- centrifuged blood & reddish plasma co-nfirms diagnosis.
b)Delayed Hemolytic Transfusion Reaction(DHTR):, -occurs by 1-2 days,can be seen by 10 days- recipients antibodies against minor donorRBC antigens produced by anamanesticresponse,d/t previous sensitization- manifesn. : dec Hb,inc indirect bilirubin,positive direct coombs test-T/t : compatible PC transfusion.
c) Nonhemolytic febrile reactions :- minimum 1 dec rise in temp,not explained bypt’s clinical condition(usually within 1Hr)- most common with platelet transfusion- maybe due to recepients Ab’s against donorWBC antigens,D/d with bacterial contamination(high fever/se-psis in infection)- T/t : antipyretics & tramadol for shivering.
d) ALLERGIC REACTIONS :- d/t transfused allergens in donor products,- may reach anaphylactic proportion in IgA def.- presents as urticaria,bronchospasm,- T/t : antihistaminicse) IRON OVERLOAD :- each ml of PC contains ~ 1mg elemental iron- seen in sickle cell d/e,thalassemia,myelodys-plastic syndromes.- iron deposited in myocardium,liver,bone-marrow
f) Transfusion related acute lung injury(TRALI) :- due to diffuse neutrophilic activation & ca-pillary leakage,- both immune & non immune mechanismsinvolved,- manif. : dyspnea,tachypnea,fever,hypoxia,B/L pulmonary infiltrates- picture resembling ARDS (vol overload,heart failure excluded)- T/t is supportive as most cases self limiting.
g) Bacterial infections :- commonly yersinia through blood & staph/strepto/gram neg through platelets/cryopt.- incidence decreased d/t plastic blood bags,- hypotension,fever,chills within 3 hrs f/b se-ptic shock & DIC,- both pt’s & blood bag’s blood should be cu-ltured
h) Viral infections :- Hep C,B,A HIV(I,II) HTLV(I,II) CMVprions,parvovirus B19- CMV infection in immunocom. Is asympto-matic but in immunocompromised can leadto end organ d/e.i) Others :malaria ,syphilis,tryp. Cruzi(chagas d/e)
j) Transfusion assoc. cardiovascular overload :-resembles TRALI clinically but respondsto diuretics.k) GVHD(Graft versus host disease) :- d/t donor lymphocytes that engraft & thenproliferate in response to stimuln. by fore-ign antigens,- seen post transfusion 2-50 days,- rash,diarrhea,hepatitis,pancytopenia.- seen in HSCT,neonates,lymphoprol. d/e- prevention by gamma-irradiation of blood
l) Hyperbilirubinemia :~30% of aged RBC’s don’t survive,- bilirubin from destroyed RBC’s can lead to un-conj. Hyperbil. & impaired excretion into bilia-ry canaliculus leads to conjugated hyperbil.m) Post transfusion purpura :-potentially life threatening- platelet specific alloantibodies develop 5-10days after transfusion & can cause severethrombocytopenia,-paradoxically recip. Platelets are destroyed
- Platelet transfusion is ineffective rather IVIG 2g/kg over 2-5 days is recommended.n) Imunomodulation :- transfusion induced immunosupp. has beenimplicated in post op infections,cancer recu,non-hodgkins lymphoma,- but clinically proven only in AML pt undergoi-ng chemo[slichter et al hemato basic princip]- leukoreduction decreases immunomodulation
PLATELETS- Spontaneous bleeding doesn’t occur unless pltcount falls below 5000-10,000/µl.- For majority of invasive procedures plt count of30-50K/µl will be adequate.- For high risk procedures (neurological/opthalmo-logical) ASA & amer coll of pathologists recomm-end count of 1L/µl.- In massively hemorrhaging patient factors deficitcorrection along with platelets is required if<50k/µ/L & if there is microvascular bleed <1L/µL
Thrombocytopathy(dysfunctional platelets) :seen in- liver/kidney d/e- sepsis,malignancy- trauma,obs. complications- extra corporeal circulation,some medications.requires higher platelet count to achievehemostasis-
- Treating cause abates thrombocytopenia;therap-ies which might be helpful :- dialysis & desmopressin in renal failure- rewarming in hypothermic trauma pt- correction of acidosis.- Platelet transfusion not needed in :- 1) ITP- 2) post transfusion purpura- Instead IVIG needed
- Relatively contraindicated in TTP/HUS.- Amount : 3-4 units of pooled random donor platel-ts is adequate.- Survival : ~3 – 5 days in room temp.- Plt units have to be stored in room temp. as pltsloose shape & release their granular contents ifrefrigerated.APHERESIS :contains equivalent of 4-8 units ofwhole blood platelets.
- Also has 200-400 ml plasma,- For pts who have become refractory to randomdonor platelets d/t alloimmunization.- PLATELET & HEMATOCRIT :platelet function &interaction with subendothelial tissue declines atlower hematocrits.In thrombocytoenic & thrombo-cytopathic pt’s;transfusion to higher Hct is better.[Valeri c r et al –transfusion 2001]
GRANULOCYTES- Used in profound & prolonged neutropeniasecondary to marrow suppression.- Collected by : 1) filtration leukapheresis- 2) continuous flow centrifugation- Usefulness is doubted d/t :1) inability to collect sufficient cells2) early development of allo-immuniz.
FRESH FROZEN PLASMA (FFP)- 1 unit of FFP is plasma taken from one unit ofwhole blood,- approx. 200-250 ml in volume,- No leukocytes ,so,no risk of CMV/GVHD,- Indicated in hemorrhaging pt as well as coagula-tion factor defeciencies condn.(massive transf-usion,DIC,liver d/e,cardiac bypass surgery)- Never used for volume expansion or isolatedfactor deficiencies(VIII/IX)
- Usually there is an increase of 1.6 times normalPT/aPTT before clinically imp factor def. exists(which is ~20% reduction in normal factor conc.)- THUS- FFP is indicated when PT/aPTT ratio(re-ference midrange normal ÷ actual) > 1.5 times.- Dose : 10-15 ml/Kg recommended- In a 70 kg adult male :1 unit FFP increases most factors ~ 2.5%4 “ “ “ “ “ ~ 10%
CRYOPRECIPITATEcontains fibrinogen,v-Wfactor,VIII,XIII,fibronectin,- conc. of fibrinogen in cryo > 10 times of FFPIndications : 1) DIC, along with FFP2) isolated hypofibrinogenemia(<100-mg/dl)3) platelet dysfunction not respondingto DDAVP/dialysis.Dose : ~ one bag / 10 kg body weight
FIBRINOGEN CONCENTRATE RiaSTAP : heat treated,lyophilized fibrinogenpowder.- made from pooled human plasma.RECOMBINANT FACTOR VIIa :- popularized as ‘panhemostatic agent’- but evidence outside hemophilia setting islacking,- no decrease in mortality + increased riskof thromboembolism
CONCENTRATED ALBUMIN :severe hypoalbuminemic states with compli-cating hypovolemia:.ANTI-THROMBIN CONCENTRATES :- used in anti-thrombin deficiency thrombophiliaGAMMA-GLOBULINS :- in hypogammaglobulinemia,- in high doses in autoimmune diseases
- SPECIFIC IMMUNOGLOBULINS :- for prophylaxis in rhesus,tetanus,zoster,Hep B.
TRANSFUSION IN MASSIVEACUTE HEMORRHAGE- Pathophysiology of coagulopathy in actively blee-ding should be viewed in context of primary/initi-ating event(which may be d/t trauma,hypoxia,hemorrhage,hypothermia),followed by,second-ary insult in resuscitated patient(d/t stored bloodtransfusion,hemodilution,continuing hypoxia)- Recent focus in managing a bleeding patient isavoiding massive transfusion coagulopthy whichleads to triad of death i.e. coagulopathy,acidosis& hypothermia.
- Lab parameters co-relate poorly with clinicalevidence of hemostatic failure.- Rather global tests of hemostatic plug formation& stability, such as, thromboelastography(TEG),thrombin generation tests,clot waveform analysisare more clinically relevant.
CRASH-2 TRIAL : EFFECT OF TRANEXAMIC ACIDON DEATH,VASC. OCCLUSIVE EVENTS & BLOODTRANSFUSION IN TRAUMA PATIENTS.- Early administration of tranexamic acid,an antifibrinolyticagent,to trauma patients,with or at risk of significant bleedingreduces the risk of death from hemorrhage with no apparentincrease in fatal or non-fatal vascular occlusive events.(with nostastically significant difference in transfusion requirements)- DOSAGE : 1gm loading dose in 10 mins f/b infusionof 1gm over 8hrs.[lancet- 2010]
BLOOD STORAGE LESIONS & POTENTIALCLINICAL CONSEQUENCES- The storage lesions progressively increase until the time ofexpiry & extent of these changes depend on specific bloodcomponents,preservative medium,container,storagetime,storage condns.- Quantative deficiencies may result in reduced RBCsurvival & thus excessive donor exposures.- Qualitative deficiencies leads to decrease membraneflexibility which impairs microcirculation hemodynamics.-
- Decreased 2,3-DPG decreases Hb’s oxygen affinity thusimpairing oxygen unloading.- transfusion leads to increased unconjugatedhyperbilirubinimia ,neutrophilia,saturation of serum Fe.- Biologically active lipids in stored blood leads to ALI.- Blood transfusion is risk factor for post injury multi-organfailure & ARDS.- Many of these changes can be minimised by pre-storageleukoreduction
HAZARDS OF RAPID BLOODTRANSFUSION- CITRATE TOXICITY :- pt responds to citrate by removal of citrate &mobilization of ionized calcium.- toxicity seen when > 500 ml transfused in 5 min- citrate metabolism impaired by hypotension,hypovolemia,hypothermia,liver d/e- toxicity potentiated by alkalosis,hyperkalemia,hypothermia,cardiac d/e
- But,a well perfused warm,adult pt with normalliver tests can tolerate without Ca replacement.ACID-BASE/ELECTROLYTE CHANGES :- acidity of stored blood is d/t citric acid of anticoagulant+ lactic acid of storage- Citrate is metabolised to bicarbonate & thusleads to metabolic alkalosis after transfusion.- acid base status of recepients is predominantlydetermined by tissue perfusion.
- High potassium levels in stored blood is harmlessexpect in acute renal failure.In contrast after 24hrhypokalemia can ensue.(transfused cells attaini-ng electrolyte balance in donor plasma)- high sodium content in FFP/whole bloodmandates caution in patients having disorderedsalt water handling.