Massive Transfusion: Where are We Now?

Review Article

INTRODUCTION

Major hemorrhage is a leading cause of mortality worldover. Traditionally, massive transfusion has been definedas the replacement of the patient’s total blood volume inless than 24 hours or replacement of more than 50% of thepatient’s blood volume within 3-4 hours. However, most ofthe studies done on this subject have consideredtransfusion of 10 or more PRBC (Packed Red Blood Cells)units in 24 hours as a defining criterion for massivetransfusion.

PATHOPHYSIOLOGY

Massive blood loss commonly occurs in traumapatients, patients undergoing extensive surgeries e.g. solidorgan transplantation, aneurysm repairs as well as incertain obstetrical and medical conditions. This leads to aseries of compensatory physiological changes namelytachycardia, vasoconstriction and the activation ofcytokines and hormones, as well as the clotting cascade totry to preserve the ongoing intravascular volume loss [1].The resulting tissue hypoperfusion (shock) leads tometabolic acidosis which further leads to hypothermia.The clotting factors and platelet function become derangedat a drop of core temperature to 35ºC [1-3]. Theresuscitation of patients with both crystalloid, or non-blood colloid solutions leads to haemodilution associatedwith clotting factor dilution, further exacerbating thepotential for excessive bleeding and eventualcoagulopathy. [3, 4] All these factors combine to createwhat is known as the lethal triad of acidosis, hypothermiaand ongoing coagulopathy (‘the vicious cycle’). [1]

53 Apollo Medicine, Vol. 8, No. 1, March 2011

MASSIVE TRANSFUSION: WHERE ARE WE NOW?

R N Makroo*, Rimpreet Walia**, Aakanksha Bhatia*** and Richa Gupta***Director & Senior Consultant, **DNB Trainee,***Registrar,Department of Transfusion medicine,

Indraprastha Apollo Hospitals, Sarita Vihar, New Delhi 110076, India.Correspondence to: Dr RN Makroo, Director & Senior Consultant, Department of Transfusion Medicine,

Indraprastha Apollo Hospitals, Sarita Vihar, New Delhi 110076, India.e-mail:raj_makroo@hotmail.com

Major hemorrhage is a leading cause of mortality world over. Counteracting severe blood loss usually requirestransfusion of a large number of blood units, qualifying as massive transfusion more often than not. Conceptsin massive transfusion have undergone substantial changes in the past years not just with acquisition of newknowledge on this subject but with technical advances in component preparation. We aim at providing anoverview of the changing trends and concepts in management of massive blood loss.

Key words: Major Hemorrhage, Massive Transfusion, Component preparation.

MANAGEMENT

Although, the concepts of damage control surgery andresuscitation have now evolved as aggressive treatmentregimens to avoid the development of this triad [5], theconcept of massive transfusion, itself, came into recog-nition predominantly during the World Wars. The benefitsof whole blood transfusion for traumatic hemorrhagicshock became apparent during World War II [6]. Sincethen, management of massive bleeding has been one ofthe most talked about controversies. The major issues ofdebate have been the use of fresh blood versus storedblood, whole blood versus components and last but notthe least the ratio of various blood components to begiven.

It was the knowledge of various storage lesions thatled to the debate whether to use fresh blood or storedblood for the purpose of massive transfusion. The term“storage lesion” is used to describe the progressivedegradation of red cell structure and function that occursduring storage. The most important ones of these beingshape change of erythrocytes leading to decreasedsurvival, decreased oxygen delivery due to decreased 2,3– diphosphoglyceric acid (2,3-DPG), decreased ATP andaccumulation of bioactive substances like cytokines,histamines, lipids and enzymes that lead to febriletransfusion reactions and immunological activation orsuppression [7].

The consensus has gradually shifted from usage offresh blood to stored blood for the purpose of massivetransfusions. This was a result of several challenges that

Apollo Medicine, Vol. 8, No. 1, March 2011 54

Review Article

were faced by the concept of using fresh blood like theavailability of a ready volunteer donor pool, priorinfectious marker testing, and cross match compatibilityand also increased transmission of transfusion transmittedinfections (TTIs). Microchimerism and TA-GVHD(Transfusion Associated Graft Versus Host Disease) werealso reported with the use of fresh blood. Finally therewere studies that disproved any relation between the useof stored RBCs and morbidity [8, 9].

The next point of controversy was to choose betweenwhole blood and blood components. Initially thetransfusion of whole blood was recommended and a studyby Ronald D. Miller [10], concluded that FFP (FreshFrozen Plasma) was ineffective and should not be part of amassive transfusion paradigm for treating coagulopathies.Yet, Leslie and Toy [11] found the prothrombin and partialthromboplastin times sufficiently prolonged to necessitateFFP therapy after administration of 12 units of blood.

Further, the crossing of blood group barrier and use ofalternative blood groups due to minimal plasma content inpacked red cells came up as a major boon to emergencyblood demands with the advancements in componenttherapy.

Appropriate proportions of various blood componentsthat should be used to compensate for the losses were thenext to be worked out. The Berne concept of componenttherapy was introduced in 1992 (Table 1).

Latest reports based on retrospective observationsindicate that red cells, plasma and platelets in a 1: 1: 1 ratioi.e. equal parts of PRBCs, FFP and Platelet Concentrates(PC) should be provided to massively bleeding patients,which simulates the composition of whole blood [12].Many studies have demonstrated that patients transfusedwith higher FFP: PRBC ratio have a better outcome [14-18]. These strategies have been said to improve patientsurvival, reduce hospital / intensive care unit (ICU) length

of stay, decrease ventilator days, and reduce patient carecosts [19].

Borgman, et al demonstrated that early and aggressivereplacement of coagulation factors is associated withimproved survival in trauma patients requiring massivetransfusion. The mortality was 65% for an FFP: RBC (Redblood cells) ratio of 1 : 8, 34% for a ratio of 1 : 2·5, and19% for 1 : 1·4 [20].

In addition, various laboratory parameters likehaemoglobin, platelet count, Prothrombin Time (PT),Partial Thromboplastin Time (PTT), fibrinogen levels andalong with relevant clinical considerations should be usedto guide effective management and blood componentreplacement.

COMPLICATIONS

Although, transfusion of blood components isimperative to prevent mortality in patients with massiveblood loss, their use is not free from complications andadverse events. However, these can be effectivelyminimized with a planned and vigilant transfusionstrategy. Various adverse effects associated with massivetransfusion and ways to ovecome these are summarizedbelow.

Increased oxygen affinity of RBCs

Storage impairs the ability of the red blood cells torelease oxygen. The levels of 2,3-diphosphoglyceric aciddecrease in stored blood which shifts the blood’s oxygendissociation curve to the left. Blood merely acts as avolume expander in the initial few hours of transfusion. Arapid rise in the 2, 3 - diphosphoglyceric acid levelsthereafter, restores normal oxygen affinity.

Hypothermia

Hypothermia is caused by the administration of bloodproducts and other resuscitation fluids without priorwarming.The adverse effects of hypothermia in traumapatients include major coagulation derangements,peripheral vasoconstriction, metabolic acidosis,compensatory increased oxygen requirements duringrewarming, and impaired immune response. This can beminimized by using fluid warming devices such as in lineblood warmers. In addition convective warming can beused to maintain appropriate room temperature.

Citrate Intoxication, Hyperkalemia

Blood is stored in citrate phosphate dextrose with orwithout additive solutions at 40ºC. Citrate, being acalcium chelator, an excessive dose during massive

Table 1. Berne concept of component therapy [13]

Blood loss Component therapy

20% Plasma substitutes (Crystalloids,Colloids)

20-50% 3-4 PRBC units with plasma substitutes>50% PRBC:FFP; 3:1>150% PRBC, FFP, PC

(PRBC- Packed Red Blood Cells, FFP- Fresh FrozenPlasma, PC-Platelet Concentrates)

Review Article

55 Apollo Medicine, Vol. 8, No. 1, March 2011

the transfusion trigger may aid in minimising such adverseevents. Further, red cell salvage and use of oxygen-carrying red blood cell substitutes can be helpful in thisregard.

Dilutional coagulopathy

Patients undergoing massive transfusion may sufferfrom coagulopathy after replacement of approximately 1blood volume due to dilution of various coagulationfactors especially Factor V, VIII and fibrinogen. This mayresult in microvascular bleeding and clinical evidence ofcoagulopathy [23-25] which may be corrected with earlytransfusion of an appropriate dosage of fresh frozenplasma. An INR within the range of 1–1.5 X the normalshould ideally be targeted [26].

Similarly, dilutional thrombocytopenia is anothercause of hemorrhagic diathesis in these patients, whichcan be taken care of by transfusion of platelets. Plateletsshould be maintained over 50000/mm3 [26].

Transfusion-induced immunosuppression

Blood transfusion therapy is also associated withallosensitization, immunosuppression, and an increasedincidence of postoperative infections. These effects maybe mediated by reduced lymphocyte function, downregulation of macrophage function, and altered cytokineproduction and activity. This can similarly be avoided bylowering the transfusion trigger, Red cell salvage and useof oxygen-carrying red blood cell substitutes. The use ofthird-generation leukocyte filters reduces the chances ofimmunosuppression. Prestorage leucoreduction furtherenhances blood safety.

Emerging technologies for reducing blood use

Since, blood transfusion is not completely devoid ofcomplications and adverse effects, continuous effortstoward developing newer technologies to arrest bleedingand minimise the use of blood and blood components arebeing made. Some of these newer initiatives areThromboelastography (TEG) that provides better endpoints to guide transfusions, fibrin sealants, antifibrino-lytics, Recombinant factor VIIa and Artificial hemo-globin-based oxygen carriers.

The Apollo experience

In our experience at Indraprastha Apollo Hospitals, wehave observed that owing to a ready availability of allblood components, strengthened by the fact that they arethoroughly tested and to a large extent leucoreduced,component therapy has been well accepted by our clinicalcolleagues. We have observed an approximate 28%

transfusion may result in decreased serum levels ofionized calcium. This can be corrected by infusingappropriate dosage of calcium gluconate/calciumchloride.

The potassium level in stored blood rises with lengthof storage. Note for signs of hyperkalemia by monitoringthe ECG. Treatment of hyperkalemia with calciumchloride, bicarbonate, glucose and insulin may benecessary at times.

Hemolytic transfusion reactions

Although extremely rare, acute hemolytic reactionsmay occur from errors involving ABO incompatibility.This highlights the importance of verifying andidentifying each and every donor unit for recipientcompatibility both at the source and the user end. In caseof a hemolytic transfusion reaction, stop transfusionimmediately and maintain systemic perfusion and renalblood flow. The suspected unit should be sent back to theblood bank along with requisite samples for evaluation.

Non hemolytic transfusion reactions are relativelymore frequent especially with components containingplasma such as FFP and platelets. These are in mostinstances, a result of an allergic response to plasmaproteins. Febrile non hemolytic transfusion reactions canto a large extent be minimized by using prestorageleucoreduced blood.

Infection

Inspite of extensive screening protocols for infectiousmarkers, transfusion centres across the globe are stillstruggling to achieve “zero risk blood”. Among thevarious transfusion transmissible infections, hepatitis B isstill the most clinically significant, with a per unit risk of 1:82,000 [19]. The risk of contracting HIV, on the otherhand is to the tune of 1:4.7 million and that for HCV isapproximately 1:3.1 million per unit of transfused blood[21].The chances of contracting viral infection especiallyHBV and HCV is much more in the developing countriesincluding India [22]. However, the introduction of latesttechnologies for screening of transfusion transmittedinfections, like fourth generation ELISA tests and NucleicAcid Amplification Testing (NAT) have contributedsignificantly to improve the safety of blood and bloodcomponents.

Incidence of bacterial infection through bloodcomponents especially platelets is a hot topic these days.Since platelets are stored at room temperature makingthem liable for bacterial contamination.

Avoidance of unnecessary transfusions by lowering

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Review Article

mortality rate among the massively transfused. A definiteshift in the trend towards the use of FFP and PCs in a near1:1 ratio with PRBCs has been observed over a period oftime, resulting in not just a decrease in overall mortalitybut also a reduction in the average length of stay amongthe massively transfused patients. The rate of nonhemolytic transfusion reactions at our institute wasapproximately 0.04 % in 2010. A hemolytic transfusionreaction among the massively transfused patients has notbeen reported till date.

CONCLUSION

The main priorities in the management of massiveblood loss are controlling hemorrhage and restoringadequate oxygen delivery to tissues. Resuscitation withcrystalloids and blood components in accordance with thelatest guidelines, clinical situation and laboratoryparameters are imperative to reduce the number of suchpotentially preventable deaths.

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