Massive transfusion

It describes indications protocol and complications in detail

1. Massive Transfusion Dr P K Maharana, Department of Anesthesiology, KIMS, BHUBANESWAR.

2. Introduction Severe traumatic injury continues to present challenges to healthcare systems around the world. Post-traumatic bleeding remains a leading cause of potentially preventable death among injured patients. Worldwide 5 million patients die due to trauma or trauma-related complications each year. Deaths by exsanguination in trauma are preventable with hemorrhage control and resuscitation with allogeneic blood products (ABPs).

3. Definitions Various definitions of massive blood transfusion (MBT) have been published in the medical literature such as: Replacement of one entire blood volume within 24 hours , or Replacement of 50% of total blood volume (TBV) within 3 hours , or Transfusion of > 4 units of PRBCs in 1 h when on-going need is foreseeable, or Transfusion of >10 units of packed red blood cells (PRBCs) in 24 h. Data regarding MBT in the paediatric population is scarce. Definitions of MBT suggested for use in children are : transfusion of >50% TBV in 4 h, transfusion >100% TBV in 24 h or transfusion support to replace on-going blood loss of >10% TBV/min . (Blood Volume 70ml/kg in adult, 80ml/kg for about 1 month old).

4. Common Clinical conditions requiring massive transfusion Massive transfusion occurs in settings, such as- Severe trauma , Ruptured aortic aneurysm , Surgery and Obstetrics complications .

5. Changing concepts in the management of hemorrhagic shock. With better understanding of the pathophysiology of haemorrhagic shock, resuscitation of patients with massive haemorrhage has advanced from reactive to supportive treatment with fluid C rystalloid , PRBC, and laboratory report based use of coagulation factors, & use of proactive standardized protocols called MTPs . 

6. Present Concept in the Resuscitation in hemorrhagic shock A . The present concept is Permissive hypotension and minimal volume resuscitation ,( where systolic blood pressure is kept between 80–100 mmHg, well tolerated while bleeding is controlled and have shown survival benefit in several studies). It is widely practiced for ruptured abdominal aortic aneurysm; but contraindicated in patients with traumatic brain and spinal injuries. B . Aggressive fluid resuscitation with crystalloids  ( Previously recommended to achieve and maintain normal blood pressure associated with : pulmonary oedema and acute lung injury; exacerbation of anaemia, thrombocytopenia & coagulopathy due to haemodilution; and exacerbation of bleeding due to possible clot disruption). .

7. Ideal Crystalloids for volume resuscitation L-isomer of LR causes less inflammation, immune dysfunction , and mortality in critically ill patients and is recommended fluid of choice in hemorrhagic shock patients.  In children, isotonic and balanced crystalloid (20 mL/kg) is recommended for initial resuscitation. Clear fluid volume should be < 40 mL/kg to prevent dilutional coagulopathy and edema . NS or RL ; NS (pH 5.0) NS produces Hyperchlorimic Acidosis , RL ( pH 6.5), Alkalosis due to conversion of Lactate to Bicarbonate.

8. Whole Blood Earlier practice was to transfuse whole blood , but the modern practice is to transfuse only components of the blood; such as red blood cells, white blood cells, plasma, clotting factors, and platelets as needed. Major limitation to the use of WB are; Requirement for type-specific blood , Patient blood Group is unknown frequently .( particularly during the early phase of resuscitation).

9. Low titer group O whole blood (LTOWB) It is O group blood with low antibody titer. Low antibody titer is defined as whole blood with IgM anti-A and anti-B titer < 250. LTOWB is unseparated blood, collected from a donor with “low” IgM and/or IgG anti-A and anti-B and can either be stored or given fresh (within 8-24 hours). The presence or absence of the Rhesus (Rh) (D) antigen is much less relevant during hemorrhagic shock resuscitation; therefore, LTOWB is not defined by its Rh factor status. Rh negative patients do not develop sensitivity to Rh positive blood until weeks after exposure. Therefore, in the acute trauma setting, Rh positive blood can be administered to Rh negative patients without significant risk of transfusion reaction The cold-stored LTOWB product is an FDA licensed product, with an IgM anti-A and anti-B titer of < 150.

10. Whole Blood or Component therapy Whole blood is better than component therapy. But availability in large quantity is a problem in emergencies. Adding preservative to whole blood dilutes it by about 12%. And there are concerns that cooling it may have effects on platelet function.  ( Recent data suggests that platelet function in cooled whole blood is preserved, but platelet longevity is decreased.) It contains a full complement of white blood cells, and this may be related to reports of venous thrombosis, respiratory distress, and even graft vs host disease. Unfortunately, removing the white cells (leukoreduction) also tends to remove the platelets, and there is little literature detailing the safety of this practice.

11. Red cell transfusion The decision to administer red cell transfusion during resuscitation should include: assessment of the patient's intravascular volume status , cardiopulmonary parameters, and the extent of, or potential for, ongoing haemorrhage . Red cell transfusion is likely to be required when 30–40% blood volume is lost (approximately 2000 mL in an adult); Pre-transfusion compatibility testing should be done early. It is best practice to transfuse red cells of the same ABO and Rh group as the patient ; however if there are insufficient supplies of the patient's ABO group available locally, red cells of another ABO compatible group may be released by the transfusion provider In an emergency situation uncrossmatched Group O, Rh negative red cells (especially for females of childbearing age) may be appropriate.

12. PRBC Each unit of packed red blood cells (RBCs) contains approximately 200 mL of red cells and, in an adult, will raise the hematocrit by roughly 3 percentage points unless there is continued bleeding.  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 .

13. Uncrossmatched Blood Due to the emergent need for blood products, routine pre-transfusion testing is bypassed and uncrossmatched ,(Group O RhD negative) RBCs are often given. (This removal of safety assurances received from the antibody screen and product cross-matching leaves alloimmunized patients at increased risk for acute or delayed hemolysis ). In addition, residual plasma within Group O RBC units can accumulate  when large quantities of Group O RBC units are transfused .  Thus, for A, B, or AB patients, it is safest to repeat the blood type , with particular consideration of the reverse type, before resuming transfusion of RBCs of the patient’s own blood group.

14. Plasma Circulating coagulation factors have variable half-lives and are homeostatically maintained . During massive hemorrhage, the acute nature of significant blood volume loss could lead to uncompensated coagulopathy . Therefore, early transfusion of plasma-containing physiologic coagulation factors intuitively should reverse this condition.    Until recently, universal Group AB plasma has been the standard product used during MT when the patient’s blood group is initially unknown. ( Since Group AB donors comprise only approximately 4% of all eligible blood donors, and the availability of Group AB plasma donors has been further reduced by the transfusion-related acute lung injury (TRALI) mitigation strategies, Group AB plasma and platelet products remain scarce resources ).  Use of Group A plasma with low titer anti-B agglutinin has been considered as a practical alternative to Group AB plasma.( Group A US donors are approximately ten times more abundant than AB donors). FFP takes 30-45 minutes for thawing and after thawing can be stored at 1-6°C for 24 hours.

15. FFP There is insufficient evidence to support or refute a specific RBC:FFP:PLT ratio.      transfusion should be based on clinical criteria & frequent monitoring of laboratory values.  Institutions should develop their own  MTP (Massive Transfusion Protocol)  with locally agreed ratios of blood component therapy. Give FFP to maintain PT & APTT ≤ 1.5x mean control Usual dose is 15 ml/kg If the patient's blood group is unknown, give group AB FFP. Allow 1/2 hour thawing time.

16. Platelets Thrombocytopenia <50 x 10 9  /L can be anticipated after two blood volume replacement due to dilution and increased consumption. Aim  is to keep the platelet count >50 x 10 9  /L (or >100 x 10 9 /L in situations such as CNS injury or diffuse microvascular bleeding) The usual dose in an adult is 1 unit SDP/ 6units of RDP. The Protocol says transfuse blood products ( PRBC:FFP:RDP) 1:1:1 when you are following massive transfusion..

17. Storage of Platelets After collection from blood donors, platelets are typically stored between 20°C and 24°C with constant agitation for up to 5 days. ( While refrigeration (1°C–6°C) is associated with ↓decreased platelet viability and post-infusion increments, cold platelets have been shown to more readily aggregate in vitro and to have a better metabolic profile) .   During emergency resuscitation, the clinical emphasis often weighs more in favor of achieving rapid hemostasis rather than a durable increase in platelet count. Therefore, it has been suggested that refrigerated platelets dedicated for emergency transfusion may have clinical benefits .

18. Dilutional coagulopathy in haemorrhagic shock .During haemorrhagic shock, there is fluid shift from the interstitial to the intravascular compartment that leads to dilution of the coagulation factors. .This is further accentuated when the lost blood is replaced with coagulation factor deficient fluids. . Low colloid oncotic pressure giving rise to interstitial edema .

19. Cryoprecipitate FFP may supply enough fibrinogen to correct any deficiency but if fibrinogen < 1 g/L  cryoprecipitate may be indicated Usual dose is 3–4 g of fibrinogen . ( Worldwide, cryoprecipitate remains the most common blood product used to replace fibrinogen and contains approximately 200–250 mg of fibrinogen per unit, your local transfusion provider can advise on the number of units to provide ). In obstetrics haemorrhage, early DIC is often present so consider cryoprecipitate early in this situation. Allow 1/2 hour thawing time Cryoprecipitate products are usually pooled units of five. It is plasma-derived blood component enriched in fibrinogen, factor VIII, factor XIII and von Willebrand factor; generated by thawing fresh frozen plasma (FFP) at 1-6 degrees C (33.8-42.8 degrees F) and collecting precipitates by centrifugation.

20. Fibrinogen concentrate Fibrinogen is a coagulation factor with a large molecular weight and a long half-life. Worldwide, cryoprecipitate remains the most common blood product used to replace fibrinogen and contains approximately 200–250 mg of fibrinogen per unit. A retrospective study correlating the fibrinogen level with mortality in critically injured patients revealed that fibrinogen levels less than 180 mg dL −1  were significantly associated with higher in-hospital death. In addition to the time delay from thawing the cryoprecipitate, the thawed product expires within 6 hours in most countries.  European guidelines recommend the initiation of fibrinogen replacement by fibrinogen concentrate when the plasma fibrinogen level falls below 1.5 g L. fibrinogen concentrate is used in most European countries to treat acquired disorders of fibrinogen Worldwide to treat congenital fibrinogen deficiency or dysfibrinogenemia. Fibrinogen concentrate :  Concentrated fibrinogen derived from pooled human plasma and available as pasteurized and lyophilized powder .

21. FIBRINOGEN CONTENT IN VARIOUS BLOOD PRODUCTS Products Fibrinogen Content 1-10 unit of Cryoprecipitate 2500 mg / 150 ml 1 Unit of FFP 400 mg / 250 ml 1 Unit of PRBC < 100 mg 1 six pack of platelets 480 mg 1 unit of apheresis platelets 300 mg 1 unit of whole blood 1000 mg

22. Hemostatic therapies The use of lyophilized factor concentrates and pharmacologic agents during MT has gained popularity as they can be stored and administered at the bedside to avoid time delays due to product processing and issuing. In addition, this allows the use of target-specific treatment rather than the broad and non-specific use of plasma to attempt to correct all coagulopathies. Three factor concentrates have been used in MT: prothrombin complex concentrates (PCCs), recombinant-activated factor VII , and fibrinogen concentrate.

23. Tranexamic acid Antifibrinolytics: {( such as aminocaproic acid or tranexamic acid (TXA)},  inhibit the formation of plasmin. ( plasmin breaks down the fibrin-based clot). Therefore, they are used to improve the durability and firmness of the clot in order to enhance clinical hemostasis.  Dose: 1gm 6 hourly in PPH proved effective. In Trauma: Loading dose of 1gm over 10 minutes repeated 8 hourly.  The largest prospective RCT utilizing antifibrinolytics is the Clinical Randomization of an Antifibrinolytic in Significant Hemorrhage (CRASH-2) trial , a multicenter study that evaluated more than 10,000 trauma patients. The data analyses revealed that timely administration of TXA (within 3 hours of injury) was associated with a modest but highly significant reduction in both overall and bleeding-related mortalities, but not in MOF or head injury.

24. Recombinant-activated factor VII (rFVIIa) and PCCs. With rapid activation of thrombin in the presence of adequate fibrinogen and platelets, the early use of rFVIIa was associated with less blood product usage and lower mortality in military patients requiring MT. The use of 3- or 4-factor PCCs ( Prothrombin complex concentrates) in a MT setting is observed due to its rapid availability and potent/rapid restoration of key vitamin K-dependent clotting factors in a concentrated, low volume dose.  PCCs may carry potential enhanced risk of  thrombosis in subsets of MT patients due to patients’ increased circulating tissue factor and decreased plasma or endothelial anticoagulant activity With the lack of safety evidence, European guidelines do not endorse the use of PCC in a MT setting. Routine use of rFVIIa is not recommended due to lack of effect on mortality. It is not licensed for the prevention or management of haemorrhage in critically bleeding patients. The MTP should include considerations for rFVIIa use.

25. Patients on Warfarin For life-threatening clinically significant bleeds : the consensus is to use the maximum dose of Prothrombinex-VF . Prothrombinex (PTX-VF): 50 IU/kg When Prothrombinex(PTX –VF) is unavailable  Vitamin K1 and FFP. Vitamin K 1 : 5–10 mg IV Fresh Frozen Plasma : 150–300 mL or 15 mL/kg. 

26. Goals of Massive Transfusion Protocol Early recognition of blood loss. Maintenance of tissue perfusion and oxygenation by restoration of blood volume and haemoglobin (Hb). Arrest of bleeding in combination with use of early surgical or radiological intervention, and Judicious use of blood component therapy to correct coagulopathy.

27. Targets of resuscitation in massive blood loss A. Mean arterial pressure (MAP) around 60 mmHg, systolic arterial pressure 80-100 mmHg (in hypertensive patients one may need to target higher MAP) B. Hb 7-9 g/dl ( This should not be used alone as transfusion trigger; and, should be interpreted in context with haemodynamic status, organ & tissue perfusion ). C. INR <1.5; activated PTT < 42 s ( > 1.5 of normal value ) D. Fibrinogen > 1g/L E. Platelets >50 × 10 9 /L, (>100 x 10^9 if head injury/ intracranial haemorrhage) F. pH > 7.2, Base Excess < -6, Lactate < 4 G. Core temperature > 35.0°C Ionized Calcium > 1.1 mmol/L

28. Massive Transfusion Protocol 1.Massive transfusion protocols are activated ( by a clinician in response to massive bleeding ). 2 . Generally this is activated after transfusion of 4-10 units. 3 . MTPs have a predefined ratio of RBCs, FFP/cryoprecipitate and platelets units ( random donor platelets ) in each pack (e.g. 1:1:1 or 2:1:1 ratio) for transfusion . 4. Once the patient is in the protocol, the blood bank ensures rapid and timely delivery of all blood components together to facilitate resuscitation.   MTPs are designed to interrupt the lethal triad of : A cidosis , H ypothermia and C oagulopathy that develops with massive transfusion thereby improving outcome . By developing locally agreed and specific guidelines that include clinical, laboratory, blood bank and logistic responses, clinicians can ensure effective management of massive blood loss and improve outcome.

29. Lab values to be monitored include : PT/INR PTT Fibrinogen Platelet count Hct / Hgb ABG Electrolytes 

30. Common Transfusion Pitfalls For females ( of childbearing age whose blood type is not known )  O negative red cells should be reserved. Male traumas of unknown ABORh  may receive O positive RBC. All patients should be switched to type-specific blood as soon as their native type is discovered in blood bank. O negative RBC can be readily transfused if available, the non RBC products like; FFP, PPH(SDP) & Cryoprecipitate may take time to prepare.

31. Complications of Massive Transfusions Acidosis Hyperkalemia Hypothermia Citrate Toxicity Hypocalcaemia Hypomagnesaemia Usual Transfusion reaction problems. Late Complications.

32. Lethal Triad of Massive Haemorrhage Acidosis Hypothermia Coagulopathy.

33. Pathogenesis of Coagulopathy in Trauma

34. Acidosis: After 2 weeks of storage ; PRBCs have a pH below 7.0 , and each unit has an acid load of approximately 6 mEq. One of these mEq of acid comes from the fact that PRBCs are made from venous blood with a starting pH of 7.35, a second mEq is acquired in buffering the citric acid in the anticoagulant , and 4 mEqs. are generated by glycolysis during PRBC storage . A pH decrease from 7.4 to 7.0 reduces the activity of FVIIa and FVIIa/TF by over 90% and 60% respectively . Acidosis directly reduces activity of both extrinsic and intrinsic coagulation pathways.

35. Genesis of hypothermia. Factors contributing to hypothermia include: infusion of cold fluids and blood and blood products , opening of coelomic cavities and decreased heat production. Coagulopathy due to hypothermia is not reflected in laboratory tests as the samples are warmed during processing .

36. Hypothermia and its adverse effects. Hypothermia is a frequent pathophysiologic consequence of severe injury and subsequent resuscitation . It is estimated that as many as 66% of trauma patients arrive in the emergency department with hypothermia. Body temperatures less than 33°C produce a coagulopathy that is functionally equivalent to factor deficiency states seen when coagulation factor concentrations are less than 50%. Thrombin generation on platelets is reduced by 25% at 33°C. The average size of aggregates formed by thrombin-activated platelets was decreased by 40% at 33°C and Platelet adhesion was reduced by 33% . Adverse clinical effects such as cardiac dysrhythmias, reduction in cardiac output, increase in systemic vascular resistance, and a left shift in the oxy-hemoglobin saturation curve have been described.

37. Hyperkalaemia: Potassium concentrations in PRBCs can range from 7 to 77 mEq / L depending on age of stored blood. At transfusion rates exceeding 100-150 ml/min, transient hyperkalaemia is frequently seen. Development of hyperkalaemia will depend on the underlying renal function, severity of tissue injury, and rate of transfusion. Also , acidosis secondary to hypoperfusion may worsen hyperkalaemia. Cardiac effects of hyperkalaemia are accentuated by hypocalcaemia.

38. Citrate toxicity 1. 80 ml of citrate phosphate dextrose adenine solution present in each blood bag contains approximately 3 g citrate . 2. Unmetabolised citrate can then lead to hypocalcaemia, hypomagnesemia and worsen the acidosis. 3. Hypocalcaemia can lead to myocardial depression that manifests earlier than hypocalcaemic coagulopathy . 4. Calcium supplementation is thus required in most cases of MBT . A healthy adult can metabolize this load in 5 min. However, hypoperfusion or hypothermia associated with massive blood loss can decrease this rate of metabolism leading to citrate toxicity. Hypotension not responding to fluids should alert the physician to this complication .

39. Hypomagnesemia: Citrate also binds to magnesium and can lead to hypomagnesaemia which can further accentuate effects of hypocalcaemia.  Infusion of large amounts of magnesium poor fluid can also contribute to hypomagnesemia.

40. Late complications of massive transfusion 1. Transfusion related acute lung injury (TRALI): The risk of TRALI increases with the number of allogenic blood and blood products transfused . The exact pathologic mechanisms of TRALI have not been clearly understood and both immunologic and nonimmunologic mechanisms have been suggested 2.SIRS. 3.Sepsis. 4.Thrombotic complications.

41. Guidelines Guidelines are designed to provide evidence-based, well-balanced information regarding the benefits and limitations of therapeutic interventions. Two major guidelines are available for MT: a). European guidelines by the Task Force for Advanced Bleeding Care in Trauma (updated in 2013) and the b). Trauma Quality Improvement Program (TQIP) recommendations from the American College of Surgeons.

42. European guidelines by the Task Force for Advanced Bleeding Care in Trauma (updated in 2013) The pan-European, multidisciplinary Task Force for Advanced Bleeding Care in Trauma was founded in 2004 and included representatives of six relevant European professional societies. Recommendations were formulated to reflect current clinical concerns and areas in which new research data have been generated. This guideline represents the fourth edition of a document first published in 2007 and updated in 2010 and 2013. The guideline now recommends that patients be transferred directly to an appropriate trauma treatment centre and encourages use of a restricted volume replacement strategy during initial resuscitation. Best-practice use of blood products during further resuscitation continues to evolve and should be guided by a goal-directed strategy. The identification and management of patients pre-treated with anticoagulant agents continues to pose a real challenge, despite accumulating experience and awareness. 

43. National Blood Authority, Australia Guidelines on MTP

44. Preparation for Massive transfusion . Essentials of massive Transfusion: 1. Wide bore cannula . 2. Warming devices : In-line fluid warmers and surface warmers. 3. Continuous core temperature monitoring . 4. Invasive arterial pressure monitoring. 5. Adequate amount of colloid (gelatins), crystalloid, infusion sets and IV calcium preparations . 6 . Communication with blood bank about emerging massive blood loss situation. 7. Adequate manpower for sending samples for investigations and getting blood and blood products. 8. Point-of-care testing is highly desirable : Arterial blood gas (ABG) and thromboelastograph (TEG). ABG with haemoglobin (Hb), electrolyte and lactate levels, repeated hourly, are useful in directing therapy.

45. Inadequate resuscitation: Hypo perfusion leads to  lactic acidosis , systemic inflammatory response syndrome (SIRS), disseminated intravascular coagulation and multi organ dysfunction.  It also increases the expression of thrombomodulin on endothelium , which then complexes with  thrombin , which in turn leads to  a reduced amount of thrombin available to produce fibrin and increases the circulating concentrations of anticoagulant activated protein C, which worsens the coagulopathy.

46. Clinical Monitoring A. Essential to monitor : Electrocardiogram, capnometry , pulse oximetry, arterial blood pressure , core temperature, and urine output. B . Invasive arterial pressure measurement .allows beat-to-beat pressure measurement and has greater accurate, the arterial catheter allows frequent arterial blood sampling, modern haemodynamic monitors calculate pulse pressure variation which is a more specific indicator of volume responsiveness. C . Central venous catheters are useful for assessment of the haemodynamic status( preload), administration of vasoactive agents and blood sampling.

47. Lab Monitoring Laboratory monitoring: Laboratory values should be obtained frequently . The time lag between collection of samples and obtaining the reports is a serious limitation in their utility during rapid on-going blood loss . Recommended lab tests include: Hb%, platelet count , prothrombin time, partial thromboplastin time (PTT), fibrinogen, potassium, ionized calcium , ABG, Lactate , SVO2. (ABG for acid base status and central venous oxygen saturation/lactate as an indicator of tissue hypoperfusion).

48. Thromboelastography (TEG) Thromboelastography (TEG) is test of the visco elastic properties of blood that examines the entire haemostatic system including platelet function and fibrinolytic system and is particularly useful in complicated coagulopathies. Its rapid availability of results helps in timely intervention.

49. Management of loss of blood components Mild to moderate blood loss can be managed with crystalloid or colloid infusions alone.  Coagulopathy during cardio pulmonary bypass (CPB): Heparin given before CPB and hypothermia lead to platelet dysfunction that has been shown to be a major cause for bleeding in patients on CPB . Postpartum haemorrhage: Recent studies suggest that acquired fibrinogen deficiency may be the major coagulation abnormality associated with obstetric bleeding[ which may be compounded by dilutional coagulopathy and hyperfibrinolysis.

50. Summery Understanding the complex pathophysiology of massive blood loss and its replacement is crucial to a successful outcome. Recent evidence supports early use of coagulation factors to improve outcome .  Indian hospitals should formulate MTPs suited to their need and resources to improve survival in massive blood loss.

51. Conclusion While these recommendations provide guidance for the diagnosis and treatment of major bleeding and coagulopathy, emerging evidence supports the author group’s belief that the greatest outcome improvement can be achieved through education and the establishment of and adherence to local clinical management algorithms.

52. References National Blood Authority.  Patient Blood Management Guidelines: Module 1 – Critical Bleeding/Massive Transfusion.  [cited 2011 Jun 30]. Available from:  http://www.nba.gov.au . American College of Surgeons (ACS) Committee on Trauma. Advanced trauma life support for doctors: ATLS student course manual ACS, Chicago 2008. Tran HA, Chunilal SD, Harper PL, Tran H, Wood EM, Gallus AS.  An update of consensus guidelines for warfarin reversal.  MJA 2013;198(4);198–199