Massive blood transfusion Mohammad Faranoush MD Associate Professor

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

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 plasmapoor 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

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.

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 34 hours

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

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)

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

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/a. PTT spin time Tranexamic acid incorporated (CRASH-2 trial) No routine administration of cryoprecipitate Factor VIIa Termination? Evaluation?

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 m. L of red cells and, in an adult, will raise the hematocrit by roughly 3 to 4 percentage points unless there is continued bleeding.

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.

Cont’ • Oxygen release by transfused red cells is diminished compared with normal red cells. Storage reduces 2, 3 -bisphoglycerate (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.

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

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

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

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.

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

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

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 p. H of 7. 2, 7. 0, and 6. 8, respectively.

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.

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 (a. PTT). • In an adult, there will be an approximate 10 percent decrease in the concentration of clotting proteins for each 500 m. L 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.

Monitoring • Thus, the PT, a. PTT, 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, virusinactivated fibrinogen concentrate, may be used when fibrinogen levels are critically low (ie, <100 mg/d. L)

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/micro. L. • 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/micro. L.

Monitoring recommendations • In the massively transfused patient, assumptions about possible dilutional effects should be confirmed by measurement of the PT, a. PTT, 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

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

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.

Metabolic alkalosis • The p. H 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 p. H then falls 0. 1 p. H unit/week due to the production of lactic and pyruvic acids by the red cells.

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.

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

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

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/m. L).

Maximum citrate infusion rate • Maximum citrate infusion rate (mmol/kg per min) = (mmol citrate per m. L of blood x m. L of blood infused per min) ÷ wt (kg) • m. L of blood infused per min = (0. 02 ÷ 0. 015) x wt (kg) = 1. 33 x wt (kg)

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 m. L/min, which is equal to 8. 9 units of whole blood per hour (450 m. L per unit) and 33. 3 units of red cells per hour (approximately 120 m. L per unit).

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

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

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

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.

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-KATPase 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

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 m. L) 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.

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

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

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