2. Massive blood transfusion
Mohammad Faranoush ,MD
Associate Professor
Rasool Akram Medical Center

3. All bleeding eventually stops Epidemiology of Massive Transfusion
Massive transfusion accounts for 3-5% of civilian and 8-10% of military trauma, but has a 30-60% mortality
Uncontrolled hemorrhage = most common cause of preventable early death
Resuscitation with crystalloids/colloids or plasma-poor red cell concentrates causes dilutional coagulopathy
Conducting a massive transfusion is a COMPLEX medical procedure
Health care professionals and hospitals remain ill-prepared for such an event

4. INTRODUCTION 
Massive transfusion, defined as the replacement by transfusion of more than 50 percent of a patient's blood volume in 12 to 24 hours, may be associated with a number of hemostatic and metabolic complications
Massive transfusion involves the selection of the appropriate amounts and types of blood components to be administered, and requires consideration of a number of issues including volume status, tissue oxygenation, management of bleeding and coagulation abnormalities, as well as changes in ionized calcium, potassium, and acid-base balance.

5. What is a “Massive Transfusion”
Replacement of one blood mass, or 10 units of RBCs in a 24 hour period
Dynamic Definitions
Transfusion of ≥4 PRBC units with 1 hour when ongoing need is foreseeable
Replacement of 50% of the total blood volume within 3-4 hours

6. Challenges inherent to the management of severe bleeding
Complex medical scenarios
High mortality
Consistently identified weaknesses
Poor planning
Poor communication
Infrequent laboratory monitoring
Significant delay in ordering/administering plasma
Failure to prevent hypothermia & low use of fluid warmers
Early reliance on cryoprecipitate and rescue medications

7. Massive Transfusion Protocols
Purpose of an MTP:
To improve relevant clinical outcomes
Formalization of an institutional plan or SOP
Facilitate/protocolize communication
Ensure frequent laboratory monitoring
Reduce delay in ordering and administering blood products
Deliver a reasonable ratio of plasma to red blood cells (FP:RBC)

8. Are Massive Transfusion Protocols Evidence-informed?
Riskinet al, 2009
Mortality rate -45% before MTP implemented-19% post-implementation
Improved communication
Better systems flow and optimize blood product availability

10. Protocol Code Omega Physician order sheet Hourly blood work
1:1:1 ratio of RBC:FP:PLT
Dedicated porters for blood and coag testing
2 minute INR/aPTT spin time
Tranexamic acid incorporated (CRASH-2 trial)
No routine administration of cryoprecipitate
Factor VIIa
Termination?
Evaluation?

12. RED CELL AND VOLUME REPLACEMENT
Correction of the deficit in blood volume with crystalloid volume expanders will generally maintain hemodynamic stability, while transfusion of red cells is used to improve and maintain tissue oxygenation
Each unit of packed cells contains approximately 200 mL of red cells and, in an adult, will raise the hematocrit by roughly 3 to 4 percentage points unless there is continued bleeding.

13. Cont’
At rest, oxygen delivery is normally four times oxygen consumption, indicating the presence of an enormous reserve.
Thus, if intravascular volume is maintained during bleeding and cardiovascular status is not impaired, oxygen delivery will theoretically be adequate until the hematocrit (packed cell volume) falls below 10 percent.
This is because adequate cardiac output plus increased oxygen extraction can compensate for the decrease in arterial oxygen content.

14. Cont’
Oxygen release by transfused red cells is diminished compared with normal red cells. Storage reduces 2,3-bisphosphoglycerate (2,3-BPG) levels, leading to a leftward shift of the oxyhemoglobin dissociation curve.
This abnormality, however, has not been shown to be clinically important as the transfused red cells regenerate 2,3-BPG to normal levels within six to 24 hours after transfusion.

15. Cont’
These above considerations, however, represent the optimal clinical response to massive blood loss.
An approach to the use of crystalloid and red cell transfusions in adult patients suffering from shock due to loss of circulating blood volume secondary to hemorrhage is presented separately

16. ALTERATIONS IN THE COAGULATION SYSTEM
A patient being massively transfused may present with preexisting coagulopathy because of activation of coagulation secondary to tissue trauma, prolonged hypoxia, hypothermia, massive head injury, or muscle damage

17. DIC
Such coagulopathy (eg, disseminated intravascular coagulation) may be suspected in these patients when there is microvascular oozing, prolongation of the PT and aPTT in excess of that expected by dilution, together with significant thrombocytopenia, low fibrinogen levels, and increased levels of D-dimer

18. Transfusion
Even if coagulopathy does not exist and coagulation parameters are normal before blood is replaced, coagulation abnormalities may be induced by the dilutional effects of blood replacement on coagulation proteins and the platelet count
This occurs because packed red cell transfusions are devoid of plasma and platelets, which are removed immediately after collection.

19. Coagulopathy
Some patients who suffer massive trauma may present upon arrival at a trauma center with a coagulopathy of trauma which is not due to DIC or dilutional coagulopathy.
This coagulopathy is caused by widespread tissue injury/trauma and associated physiologic changes (ie, acidosis, hypothermia, consumption of coagulant proteins, and fibrinolysis) combined with extensive blood loss and dilutional effects of fluid replacement therapy

20. Effects of acidosis and hypothermia
Both acidosis and hypothermia interfere with the normal functioning of the coagulation system

21. Acidosis
Acidosis (ie, excess protons) specifically interferes with the assembly of coagulation factor complexes involving calcium and negatively-charged phospholipids. As an example, the activity of the factor Xa/Va/prothrombinase complex is reduced by 50, 70, and 90 percent at a pH of 7.2, 7.0, and 6.8, respectively.

22. Hypothermia
Hypothermia reduces the enzymatic activity of plasma coagulation proteins, but has a greater effect by preventing the activation of platelets via traction on the glycoprotein Ib/IX/V complex by von Willebrand factor. In tests of shear-dependent platelet activation, this pathway stops functioning in 50 percent of individuals at 30º C, and is markedly diminished in most of the rest.

23. Coagulation proteins 
The replacement of blood loss with red cells and a crystalloid volume expander will result in gradual dilution of plasma clotting proteins, leading to prolongation of the prothrombin time (PT) and the activated partial thromboplastin time (aPTT).
In an adult, there will be an approximate 10 percent decrease in the concentration of clotting proteins for each 500 mL of blood loss that is replaced.
Additional bleeding based solely on dilution can occur when the level of coagulation proteins falls to 25 percent of normal.
This usually requires 8 to 10 units of red cells in an adult.

24. Monitoring
Thus, the PT, aPTT, and fibrinogen should be monitored in patients receiving massive blood transfusions of this magnitude.
Two units of fresh frozen plasma (FFP) should be given if the values exceed 1.5 times control.
Each unit (in an adult) will increase the clotting protein levels by 10 percent.
Cryoprecipitate or, when available, virus-inactivated fibrinogen concentrate, may be used when fibrinogen levels are critically low (ie, <100 mg/dL)

25. Platelet count 
A similar dilutional effect on the platelet concentration can be seen with massive transfusion
In an adult, each 10 to 12 units of transfused red cells can produce a 50 percent fall in the platelet count; thus, significant thrombocytopenia can be seen after 10 to 20 units of blood, with platelet counts below 50,000/microL.
For replacement therapy in this setting, six units of whole blood derived platelets or one apheresis concentrate should be given to an adult; each unit should increase the platelet count by 5000 to 10,000/microL.

26. Monitoring recommendations
In the massively transfused patient, assumptions about possible dilutional effects should be confirmed by measurement of the PT, aPTT, and platelet count after the administration of every five to seven units of red cells.
Replacement therapy should not be based upon any formula (eg, one unit of fresh frozen plasma (FFP) for every four units of red cells), except perhaps in patients with severe trauma

27. FFP, platelets, and red cells in trauma patients
While replacement therapy with plasma, platelets, and red cells should not generally be based upon any set formula, results from a number of observational studies suggest that patients with severe trauma, massive blood replacement, and coagulopathy have improved survival when the ratio of transfused FFP (units) to transfused platelets (units) to red cells (units) approaches 1:1:1

28. COMPLICATIONS OF CITRATE INFUSION
Large amounts of citrate are given with massive blood transfusion, since blood is anticoagulated with sodium citrate and citric acid
Metabolic alkalosis and a decline in the plasma free calcium concentration are the two potential complications of citrate infusion and accumulation.

29. Metabolic alkalosis
The pH of a unit of blood at the time of collection is 7.10 when measured at 37ºC (7.6 at 1 to 6ºC) due to citric acid present in the anticoagulant/preservative in the collection bag.
The pH then falls 0.1 pH unit/week due to the production of lactic and pyruvic acids by the red cells.

30. Acidosis
Acidosis does not develop in a massively bleeding patient even if "acidic" blood is infused as long as tissue perfusion is restored and maintained.

31. Metabolic alkalosis
In this setting, the metabolism of each mmol of citrate generates three meq of bicarbonate (for a total of 23 meq of bicarbonate in each unit of blood).
As a result, metabolic alkalosis can occur if the renal ischemia or underlying renal disease prevents the excess bicarbonate from being excreted in the urine. This may be accompanied by hypokalemia as potassium moves into cells in exchange for hydrogen ions that move out of the cells to minimize the degree of extracellular alkalosis

32. Free hypocalcemia
Citrate binding of ionized calcium can lead to a clinically significant fall in the plasma free calcium concentration.
This change can lead to paresthesias and/or cardiac arrhythmias in some patients

33. Recommendations for citrate infusion
The maximum citrate infusion rate should be 0.02 mmol/kg per minute (since this represents the maximum rate of citrate metabolism) and the citrate concentration in whole blood is 15 mmol/L (0.015 mmol/mL).

34. Maximum citrate infusion rate
Maximum citrate infusion rate (mmol/kg per min)   =   (mmol citrate per mL of blood   x   mL of blood infused per min)   ÷   wt (kg)
  mL of blood infused per min   =   (0.02  ÷  0.015)  x  wt (kg)   =   1.33  x  wt (kg)

35. Maximum citrate infusion rate
For a 50 kg recipient with normal hepatic function and perfusion, the maximum rate of blood transfusion to avoid citrate toxicity is 66.5 mL/min, which is equal to 8.9 units of whole blood per hour (450 mL per unit) and 33.3 units of red cells per hour (approximately 120 mL per unit).

36. Hypocalcemia
Thus, significant hypocalcemia should not develop in this setting except under extreme circumstances.
However, the risk is substantially greater in a patient with either preexisting liver disease or ischemia-induced hepatic dysfunction.
In such patients, the plasma ionized calcium concentration should be monitored and calcium replaced with either calcium chloride or calcium gluconate if ionized hypocalcemia develops

37. Calcium Gluconate
If 10 percent calcium gluconate is used, 10 to 20 mL should be given intravenously (into another vein) for each 500 mL of blood infused.
If 10 percent calcium chloride is used, only two to five mL per 500 mL of blood should be given.

38. Cont’
Calcium chloride may be preferable to calcium gluconate in the presence of abnormal liver function, since citrate metabolism is decreased, resulting in slower release of ionized calcium
Care must be taken to avoid administering too much calcium and inducing hypercalcemia, ideally by monitoring the ionized calcium concentration

39. PREVENTION OF HYPOTHERMIA
Rapid transfusion of multiple units of chilled blood may reduce the core temperature abruptly and can lead to cardiac arrhythmias
Thus, during massive transfusion, a commercial blood warmer should be used to warm blood toward body temperature during infusion.

40. PREVENTION OF HYPERKALEMIA
Plasma potassium levels in stored blood increase by approximately one meq/L per day due to passive leakage of potassium out of red cells.
This potassium is not actively transported back into the red cells because membrane Na-K-ATPase activity is inhibited at 1 to 6ºC.
The potassium concentration peaks at about 30 meq/L in whole blood and 90 meq/L in packed red cells

41. potassium concentration
The effect of blood transfusion on the plasma potassium concentration can be appreciated from a few simple calculations. Loss of one unit (500 mL) of blood through bleeding results in the loss of 1.5 meq of potassium (five meq/L x 0.3 L of plasma); transfusion of one unit of whole blood or red cells should provide approximately 10 meq of potassium, leading to a net gain of 8.5 meq.

42. Excess potassium
Does not usually lead to a significant rise in the plasma potassium concentration due to movement into the cells, urinary excretion, and dilution
Infants and patients with renal impairment may develop hyperkalemia. In these patients, the following steps can be used to minimize the risk of hyperkalemia:
Select only red cells collected less than five days prior to transfusion.
Any unit of red cells can be washed immediately before infusion to remove extracellular potassium

43. SUMMARY AND RECOMMENDATIONS
 The management of the patient who is being massively transfused requires careful and ongoing consideration of a number of complex physiological relationships.
The primary concern is correction of ischemia which can be accomplished at the outset by aggressive volume expansion to maintain perfusion pressure as blood is being readied for infusion

45. Thank You