Massive blood transfusion

Author
Steven Kleinman, MD

Section Editor
Arthur J Silvergleid, MD

Deputy Editor
Stephen A Landaw, MD, PhD

Last literature review version 18.2: mayo 2010 | This topic last updated: enero 26, 2010

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 [1]. 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.
An overview of massive transfusion is presented here [2]. Other issues related to the use of
blood products are discussed separately. (See "Use of blood products in the critically
ill" and "Indications for red cell transfusion in the adult" and "Use of red blood cells for
transfusion" and "Management of shock in adult trauma".)
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 [3,4].
Each unit of packed cells with a volume of 300 mL 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. (See "Indications for red cell transfusion in the adult".)
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.
Oxygen release by transfused red cells is diminished compared with normal red cells.
Storage reduces 2,3-diphosphoglycerate (2,3-DPG) levels, leading to a leftward shift of the
oxyhemoglobin dissociation curve. This abnormality, however, has not been clinically
important; furthermore, the transfused red cells regenerate 2,3-DPG to normal levels within
six to 24 hours after transfusion.
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. (See "Management of shock in adult trauma", section on 'Transfusion
of red blood cells'.)

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 [5].
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 [2]. (See "Pathogenesis and etiology of
disseminated intravascular coagulation", section on 'Trauma and extensive surgery' and
"Clinical features, diagnosis, and treatment of disseminated intravascular coagulation in
adults", section on 'Acute DIC'.)
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 [6-8]. This occurs because
packed red cell transfusions are devoid of plasma and platelets, which are removed
immediately after collection.
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
[9,10].
Effects of acidosis and hypothermia Both acidosis and hypothermia interfere with the
normal functioning of the coagulation system. As examples [10-13]:

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.

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 30
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

(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 eight to 10 units of red cells in an adult.
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) [2]. (See "Clinical use of plasma components".)
Platelet count A similar dilutional effect on the platelet concentration can be seen with
massive transfusion [14]. 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 platelets should be given to an adult; each unit should increase
the platelet count by 5,000 to 10,000/microL.
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 (see below).
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 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 [9,15-17].

A retrospective study of 246 patients who presented to an Army combat

support hospital in Iraq has produced some data to evaluate the merits of this
regimen [9]. When patients who received massive transfusion were stratified by
transfusion therapy regimen, patients who received a high ratio of FFP to red cells
(median of 1:1.4) had a survival rate of 81 percent as compared with 66 percent for
those with an intermediate ratio (median 1:2.5) and 35 percent for those who
received a low ratio of FFP to red cells (median of 1:8).

In a retrospective study of 467 massively transfused trauma patients, 30-day

survival was increased in patients transfused at a high plasma:RBC ratio (ie, 1:2)
as well as in those transfused at a high platelet:RBC ratio (ie, 1:2) [15]. The
combination of high plasma and high platelet to RBC ratios was associated with

decreased truncal hemorrhage and increased 6-hour, 24-hour, and 30-day survivals,
with no change in deaths due to multiple organ failure.

In a retrospective study of 694 massively transfused trauma patients who did

not receive fresh whole blood, those receiving a high ratio of apheresis platelets
(equivalent to 6 units of pooled platelets) per stored red cell unit (ie, ratio 1:8) had
a higher 24-hour survival (95 percent) as compared with those receiving a medium
(ie, ratio 1:16 to 1:8, 87 percent) or a low ratio (ie, <1:16, 64 percent) [18]. On
multivariate analysis, higher plasma:red cell ratios and higher apheresis platelets:red
cell ratios were both independently associated with improved survival at both 24
hours and 30 days.
These observations have led these and other authors to recommend that patients who have
sustained severe traumatic injuries and/or who are likely to require massive transfusion
receive a 1:1:1 ratio of FFP to platelets to RBCs at the outset of their resuscitation and
transfusion therapy [10,15,19-21]. Since there are only a limited number of studies in
patients requiring massive transfusion [22,23], the value of this approach is still
controversial and remains to be proven. (See 'Summary and recommendations' below and
"Management of shock in adult trauma", section on 'Evaluation and management'.)
COMPLICATIONS OF CITRATE INFUSION Large amounts of citrate are given
with massive blood transfusion, since blood is anticoagulated with sodium citrate and citric
acid [24]. Metabolic alkalosis and a decline in the plasma free calcium concentration are the
two potential complications of citrate infusion and accumulation.
Metabolic alkalosis The pH of a unit of blood at the time of collection is 7.10 when
measured at 37C (7.6 at 1 to 6C) 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. Acidosis does not develop in a
massively bleeding patient even if "acidic" blood is infused as long as tissue perfusion is
restored and maintained. 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 [25]. (See "Potassium balance
in acid-base disorders".)
Free hypocalcemia Citrate binding of ionized calcium can lead to a clinically significant
fall in the plasma free calcium concentration. (See "Relation between total and ionized
plasma calcium concentration".) This change can lead to paresthesias and/or cardiac
arrhythmias in some patients [26].

Recommendations for citrate infusion By extrapolation from animal studies, it is

possible to calculate the maximum whole blood transfusion rate which would permit a
normal liver to metabolize the excess citrate, thereby avoiding hypocalcemia. 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). Thus:
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)
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). 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:

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.

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 [2]. 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 [27].
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-K-ATPase activity is inhibited at 1 to 6C. The potassium concentration
peaks at about 30 meq/L in whole blood and 90 meq/L in packed red cells [28].
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. This 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. However, 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 blood collected less than five days prior to transfusion.

Whole blood, if available, can be packed immediately before infusion and

the plasma removed before transfusion

Any unit of blood can be washed immediately before infusion to remove

extracellular potassium from the blood.

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. (See "Management of shock in adult
trauma", section on 'Evaluation and management'.)
Parameters to monitor As volume is replaced, attention must be paid to several
parameters to allow successful resuscitation:

The best approach to blood transfusion in trauma is unknown. Transfusions

are given based upon the patient's injuries and response to the initial transfusions,
with attention being paid to any underlying cardiopulmonary disease.

There is no clear threshold beyond which blood use is futile [29].

The coagulation system should be frequently monitored with measurements

of the PT, aPTT and platelet count, preferably after each five units of blood
replaced. If the PT and PTT exceed 1.5 times the control value, the patient should
be transfused with two units of fresh frozen plasma. If the platelet count falls below
50,000/microL, six units of platelets should be given.

A blood warmer should be used whenever more than three units are

transfused. Hypothermia should be either avoided or minimized.

Acidbase balance and the plasma ionized calcium and potassium levels

should be periodically monitored, particularly in patients with coexistent liver or

renal disease or in those with massive hemorrhage and low cardiac output [30].

Severe trauma and coagulopathy For the subset of patients who present with widespread
tissue trauma (as in combat injuries) and who present with coagulopathy, a different
approach to transfusion therapy has been advocated by the United States military. This
approach includes all of the following [10,19]:

Rapid identification of coagulopathic patients

Frequent use of recombinant human factor VIIa. (See "Therapeutic uses of

recombinant coagulation factor VIIa".)

Rapid treatment of acidosis and avoiding hypothermia

Prompt initiation of 1:1:1 resuscitation ratios with RBCs, prethawed

universal donor AB plasma, and apheresis platelets, with conversion to fresh whole
blood as soon as this can be obtained. This ratio has not been universally adopted by
civilian hospitals. (See 'FFP, platelets, and red cells in trauma patients' above.)

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