Massive Blood Transfusion

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Dr Susheela J. Innah Joint Director Blood Safety KSACS 1

Definition
Loss of one blood volume within a 24h period (normal blood volume being approximately 7% of ideal body weight in adults and 89% in children) 50% blood volume loss within 3h A rate of loss of 150ml/min

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Acidosis

Lethal Triad Hypothermia Coagulopathy

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Priorities for treatment

Restoration of blood volume to maintain tissue perfusion and oxygenation Achieving haemostasis by treating any surgical source of bleeding Correcting coagulopathy by the judicious use of blood component therapy

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Complications of Massive Transfusion

Blood Volume Replacement Thrombocytopenia Coagulation Factor Depletion Hypocalcaemia Hyperkalemia Acid/Base Disturbances Hypothermia Acute Respiratory Distress Syndrome (ARDS)

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Blood Volume Replacement

Transfusion requirements should be based on the patient's physiologic needs - defined by their oxygen demand (consumption).

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Thrombocytopenia
Dilutional thrombocytopenia is inevitable following massive transfusion as platelet function declines to zero after only a few days of storage. (At least 1.5 times blood volume must be replaced for this to become a clinical problem) Thrombocytopenia can occur following smaller transfusions if disseminated intravascular coagulation (DIC) occurs or there is pre-existing thrombocytopenia
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Coagulation Factor Depletion

Stored blood contains all coagulation factors except V and VIII. Production of these factors is increased by the stress response to trauma. Therefore only mild changes in coagulation are due to the transfusion per se, DIC is more likely to be responsible for disordered haemostasis. DIC is a consequence of delayed or inadequate resuscitation
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Hypothermia = prolonged PT/aPTT and bleeding time Release of thromboplastins = DIC and consumption of factors Infusion of large volumes of fluid = dilutional coagulopathy Current coagulation monitoring ineffective

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Decision to Transfuse
Restore oxygen delivery and tissue perfusion Fluid resuscitation not effective Hgb level may be meaningless Achieve hemostasis Coagulation tests may not be timely POCT for PT/INR - thromboelastograph (TEG) Reverse thrombocytopenia Early transfusion indicated for penetrating injuries, pelvic fraction, and severe abdominal injuries

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Decision to Transfuse
Use fairly fresh red cell transfusions (<1 week old). Use of fresh (<24 hours) blood is not indicated (2,3 DPG levels rise rapidly following transfusion and normal oxygen affinity is usually restored in a few hours)

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Hypocalcaemia
Each unit of blood contains approximately 3g citrate, which binds ionized calcium. The healthy adult liver will metabolise 3g citrate every 5 minutes. Transfusion at rates higher than one unit every five minutes or impaired liver function may thus lead to citrate toxicity and hypocalcaemia. Hypocalcaemia does not have a clinically apparent effect on coagulation, but patients may exhibit transient tetany and hypotension. Calcium should only be given if there is biochemical, clinical or electrocardiographic evidence of hypocalcaemia
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Hyperkalemia
Plasma potassium concentration of stored blood increases during storage and may be over 30mmol/l Hyperkalemia is generally not a problem unless very large amounts of blood are given quickly Hypokalemia is more common as red cells begin active metabolism and intracellular uptake of potassium restarts

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Acid/Base Disturbances
Lactic acid levels in the blood bag gives stored blood an acid load of up to 30-40mmol/l. Lactic acid + citric acid is usually metabolised rapidly Citrate is metabolised to bicarbonate, and may lead to profound metabolic alkalosis The acid-base status of the recipient is more important final acid/base status being dependent on tissue perfusion, rate of administration and citrate metabolism
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Hypothermia
Hypothermia leads to:reduction in citrate and lactate metabolism (leading to hypocalcaemia and metabolic acidosis), increase in affinity of haemoglobin for oxygen, impairment of red cell deformability platelet dysfunction an increased tendency to cardiac dysrhythmias
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 Patient in shock
Diminished heat production Cannot spontaneously rewarm
Degree Degree Prognosis

Affects coag factor and platelet function Temperature management

External rewarming devices Airway rewarming Peritoneal lavage Warm IV fluids/blood products
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37 35 32

98.6 95 89.6

Alive Bad Death

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Acute Respiratory Distress Syndrome (ARDS)

The aetiology of ARDS is as yet not fully understood Risk factors have been identified. Both under- and over-transfusion are associated with an increased risk of ARDS, Microaggregate filters should be used during massive transfusion except when giving fresh whole blood or platelets
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Monitoring
During massive transfusion regular monitoring of:haemoglobin platelet count prothrombin time (PT) partial thromboplastin time?(PTT) fibrinogen levels The results should be used as a to guide component replacement
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Components
Component replacement should occur only in the presence of active bleeding or if interventional procedures are to be undertaken. Platelet concentrates (1 pack/10kg) are given if platelet count falls below 50. Each platelet concentrate also provides around 50ml of fresh plasma. Fresh frozen plasma (12ml/kg)is administered if PT or PTT are running higher than 1.5 times control levels. Cryoprecipitate (1-1.5 packs/10kg) is given for Fibrinogen levels < 0.8g/l.

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For massive uncontrolled traumatic haemorrhage, maintenance of full haemostatic ability is usually unrealistic. The priority is for definitive surgical arrest of haemorrhage from major vessels. Combinations of stored whole blood, packed cells, colloids & crystalloids are given to maintain blood volume or pressure at adequate levels and haemoglobin at around 7g/dl or haematocrit at 0.25. Conserve limited supplies of fresh blood, plasma or platelets until the bleeding is controlled. When blood loss has lessened (0.5L/hour) and major vessels have been controlled, it becomes worthwhile correcting haemostasis
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Red Cell
In an extreme situation it may be necessary to use group O un-crossmatched red cells if the blood group is unknown. In premenopausal females whose blood group is unknown should be given ORh(D) negative red cells in order to avoid sensitization and the risk of haemolytic disease of the newborn in subsequent pregnancy. It is acceptable to give ORh(D) positive cells to males and postmenopausal females of unknown blood group. Group-specific red cells should be given at the earliest possible opportunity
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Areas of Controversy
Blood Bankers versus the Trauma Team Can massive transfusion be orderly? Can less blood be used? Dealing with blood shortages

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Investigation and Management of DIC

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What Is DIC? Death Is Coming

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DIC: Definition
An acquired syndrome characterized by the intravascular activation of coagulation with loss of localization arising from different causes. It can originate from and cause damage to the microvasculature, which if sufficiently severe, can produce organ dysfunction

Taylor, FB, www.similima.com et al. Thromb Haemost 2001;86:1327 25

Pathogenesis of DIC
Release of thromboplastic material into circulation

Consumption of coagulation factors;

Coagulation
Fibrinogen
Thrombin

Fibrinolysis

Plasmin

aPTT PT TT Fibrinogen Presence of plasmin FDP

Fibrin Monomers

Fibrin(ogen) Degradation Products

Fibrin Clot (intravascular) Plasmin www.similima.com

Intravascular clot Platelets Schistocytes

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SUMMARY

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COAGULATION INHIBITORS
Tissue Factor Pathway Inhibitor (TFPI) Lipoprotein Associated Coagulation Inhibitor (LACI) Extrinsic Pathway Inhibitor (EPI) Complexes with Factors VIIa/TF/Xa; inactivates Xa Antithrombin III/Heparin Cofactor II/Heparin Binds and Inactivates Enzymes Protein C/Protein S/Thrombomodulin Cleaves & Inactivates Cofactors (Va & VIIIa) Plasminogen - 3 hemostasis Cleaves Fibrin

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Action of Protein C

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Massive tissue destruction

Sepsis Release of tissue factor

Endothelial injury

Activation of plasmin

Widespread microvascular thrombosis Vascular occlusion

Platelet aggregation

Microangiopathic hemolytic anemia Consumption of clotting factors & platelets

Fibrinolysis Proteolysis of Fibrin split products Clotting factors Ischemic tissue damage

Bleeding
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Inhibition of thrombin,platelet aggregation & fibrin polymerisation

DIC result from pathologic activation of 1. Coagulation pathway 2. Impairment of clot inhibiting influences

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Causes
Infection/septicemia
Any microorganism bacterial, viral, parasitic, rickettsial, mycotic Triggered by membrane components of microorganism, i.e. endotoxin, exotoxin, LPS

Trauma & Burns

Soft tissue injury, fat embolism, head injury Combination of triggers: fat, phospholipids, hemolysis, endothelial injury, activation of cytokines

Malignancy
Solid tumors, especially metastatic tumors and hematologic Tissue factor involved in mechanism

Obstetrical complications
Abruptio placentae, amniotic fluid embolism, retained deceased fetus, 2nd trimester abortion Due to leakage of thromboplastin-like material Degree of placental separation correlates with severity of DIC Usually short-lived and self-limited
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Mechanisms of Bleeding in DIC

1. Hyper-acute process leading to uncompensated rapid consumption of clotting factors and platelets (e.g. Obstetric causes) 2. Hyper-fibrinolytic bleeding due to ectopic production of plasminogen activators

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DIC: Phases
Overt DIC Decompensated form Non-overt DIC More subtle hemostatic dysfunction

Taylor, FB, www.similima.com et al. Thromb Haemost 2001;86:1327 34

The Ideal Algorithm for the Diagnosis of DIC

Flexible Diagnosis of DIC (whether overt or non-overt) non-overt should be coupled with diagnosis and staging of the underlying disorder based on clinical signs and symptoms (e.g. SIRS) Reliable The paradigm (particularly when used with available molecular marker data) authenticates appropriate and timely therapeutic intervention

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Overt DIC Scoring System

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36 Taylor, FB, et al. Thromb Haemost 2001;86:1327

Diagnostic Work-up
Clinical manifestations of bleeding, thrombosis and/ or organ failure Fibrin degradation products (D-dimer) Fibrinogen* nl/ Protein C Antithrombin Coagulation factors

Laboratory findings
PT aPTT Platelets Initial level <100,000 or rapid decline

Frachini, Massimo. Thrombosis Journal Recent www.similima.com the pathophysiology, diagnosis and treatment 37 acquisitions in of disseminated intravascular coagulation Feb 2006, 4:4.

Pathological Changes
Thrombi are found in:Brain -bizarre neurologic symptoms Heart Lung -pulmonary oedema,H membrane Kidneym-micro infracts,cortical necrosis Adrenals massive hemorrhage Spleen &liver

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Ratio RBC/FFP, FFP/platelets,

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Disseminated Intravascular Coagulation Treatment approaches

Treatment of underlying disorder Anticoagulation with heparin Platelet transfusion Fresh frozen plasma Coagulation inhibitor concentrate (ATIII) rFVIIa

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Role of Blood Products in DIC

No randomized trials; not even true consensus guidelines Do not use routine blood product as prophylaxis, but. Consider blood products for those who are actively bleeding or about to undergo an invasive procedure. Goals: platelets >50,000 fibrinogen > 1g/L PT and aPTT as close to normal as possible
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Treatment
Restore anticoagulation pathway Antithrombin III Might be of benefit in sepsis with improvement of DIC and organ function Recombinant tissue plasminogen activator (rTPA) Activated protein C (APC) Also has anti-inflammatory and anti-apoptotic properties Only anti-coagulant shown to be efficacious in trials with sepsis-triggered DIC Given as 96 hr infusion Must use with caution in thrombocytopenia increased risk of intracerebral hemorrhage

Frachini, Massimo. Thrombosis Journal Recent acquisitions in the pathophysiology, diagnosis and treatment of disseminated intravascular coagulation Feb 2006, 4:4. www.similima.com 42 Davis-Jackson, Rachel. Thrombosis Journal Antithrombin III and R-TPA used singly and in combination vs. supportive care for treatment of endotoxin-induce DIC in the neonatal pig May 18, 2006, 4:7.

RBC, FFP, Platelets

Early administration of FFP on a 2:3 or 1:1 ratio with units of RBC seems advisable in the massively bleeding patients. A standard 6 unit platelet transfusion for each 7-8 units of RBC may be associated with improved survival. The combination of circumstances leading to life-threatening bleeding makes that a ratio applying to each possible situation is impossible Ketchum et al. J Trauma 2006;60:S51
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Recombinant FVIIa
It is reasonable to consider rFVIIa in situations where there is blood loss of > 300 ml/h, with no evidence of heparin or warfarin effect, where surgical control is not possible and there has been adequate replacement of coagulation factors, platelets and correction of acidosis. There should be a local protocol in place and the decision should be made at consultant level

Stainsby et al (BSH). BJH 2006;131:634 www.similima.com

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Timing for rFVIIa in life-threatening bleeding?

???

rFVIIa

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