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Table 8.2 Consequences of liver disease on coagulation [80]

1. Thrombocytopenia

2. Accelerated or decreased brinolysis

3. Qualitative defects in platelets function

4. Predisposition to brinolysis

has usually been associated with massive bleeding and requires a considerable amount of blood transfusion. The etiologies of liver transplantation-associated bleeding can be multifactorial including preoperative liver failure, cirrhosis, cholestasis, and splenomegaly; intraoperative transaction of the fragile collateral vessels, release of heparin-like factors from the allograft, coagulopathy; and postoperative leaking at vascular anastomosis, graft-versus-host disease, thrombocytopenia, and coagulopathy [5]. Intraoperative management-related issues such as massive volume load and subsequent hypothermia & hypocalcemia secondary to citrate toxicity can also signicantly worsen the pre-existing coagulopathy, thus further increase the perioperative hemorrhage [6]. Excessive blood loss and a large quantity of blood transfusion during orthotopic liver transplant are unfortunately associated with signicantly decreased graft survival and markedly increased episodes of sepsis and prolonged ICU stay [6]. In principle, the degree of hemorrhage can be estimated based on the severity of preoperative liver disease and coagulation function, quality of the donor’s liver, recipient’s overall clinical status, and surgical skills and experience of the transplantation team [7]. There is a strong correlation between Model for End-Stage Liver Disease (MELD) score and transfusion requirements in patients undergoing orthotopic liver transplantation. Higher MELD scores (>30) were found to be signicantly associated with increased bleeding and transfusion requirements when compared to patients with lower MELD scores (< 30) [8]. Massive bleeding may result from multiple clinical consequences, as illustrated in Table8.2.

Cardiothoracic andMajor Vascular Surgery

In cardiothoracic or major vascular surgeries, surgeons deal with main blood vessels like aorta, coronaries, femoral, tibial, brachial, or vertebral arteries. These procedures usually involve vascular anastomosis, therefore, there are higher chances of intraoperative and postoperative severe hemorrhage leading to signicant adverse outcome.

Major Cancer andSpine Surgery

Reconstructive and multilevel procedures like spine surgery and spine fusion procedures are potentially complicated by signicant intraoperative blood loss and the need for allogeneic blood transfusion. The unique prone position for spine surgery likely leads to increased intraabdominal pressure, which increases epidural venous pressure and consequently exacerbates intraoperative surgical bleeding. Raised

intraabdominal pressure can be measured via a urinary bladder catheter [9]. The total blood loss is proportionate with the intraabdominal pressure, also proportionate with the patient’s body mass index (BMI) [9]. In another study, the effects of prone versus jackknife position on intraabdominal pressure and intraoperative bleeding during lumbar disc herniation surgery were conducted, and intraabdominal pressure came out to be signicantly higher in a prone position [10]. Anesthetic agents in spine and cancer surgeries can play an important role in exacerbating intraoperative blood loss like sevourane results in signicantly greater intraoperative blood loss than Propofol [11]. Certain cancer surgeries also cause massive perioperative bleeding due to extensive intratumor blood vessel networks that lead to unpredictable internal bleeding during surgery. A case report of metastatic prostate adenocarcinoma described a patient who developed hyperbrinolysis leading to widespread ecchymosis and disseminated intravascular coagulation (DIC). Any surgical attempt to resect this type of cancer can potentially lead to massive perioperative hemorrhage and other complications [

12].

Coagulation Abnormalities

Acute Traumatic Coagulopathy

It could mainly be an iatrogenic or secondary coagulopathy, a condition in which various elements are thought to play a role, including consumption of clotting factors, hemodilution from a large quantity of crystalloid infusion, acidosis, and hypothermia. The exact mechanism of coagulopathy is still unknown. One theory believes that actual injury causes a release of certain tissue factors that result in thrombin and brin generation and utilization, leading to DIC [13]. Another theory describes that trauma-induced hypoperfusion and ischemia lead to a release of activated protein C, which leads to consumption of plasminogen activator inhibitor, inhibition of the clotting cascade, systemic anticoagulation, and hyperbrinolysis [14].

Clotting Factors Deciencies

Clotting factors deciencies may be congenital or acquired. Congenital coagulation factor deciency includes factor VIII deciency called hemophilia A disease and deciency of factor IX called hemophilia B.Another congenital bleeding disorder is Von Willebrand’s disease caused by a deciency of Von Willebrand’s Factor (vWF). Acquired clotting factors deciency also develops in selective individuals because of the autoantibodies affecting the activity or accelerating the clearance of clotting factors [15]. Such antibodies are usually directed against factor VIII and vWF. These acquired antibodies are IgG4 type targeting several epitopes of clotting factors [16].

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Dilutional Coagulopathy

Dilutional coagulopathy is dened as a coagulation abnormality due to “loss, consumption, or dilution of coagulation factors that occurs when blood is replaced with uids that do not contain adequate coagulation factors” [17]. This hemostatic disturbance is further deteriorated by continuous crystalloid administration, acidosis, brinolysis, and hypothermia. It is a multifaceted change that affects thrombin generation, clot rmness, and brinolysis. Acquired brinogen deciency is considered the leading cause of dilutional coagulopathy [18]. High-molecular weight dextran is also linked to severe disturbances of clot formation [19]. This impact on clot formation was signicantly reduced by introducing new low-molecular weight starches, but depending on the amount of uid given, marked impairment of hemostasis can still be observed. Rotation Thromboelastometry (ROTEM) is the test of choice to evaluate perioperative coagulation status. Fresh frozen plasma (FFP) transfusion 30ml/kg is the treatment of choice for dilutional coagulopathy and in massive transfusion scenarios [20].

Obstetric Diseases

Denition of massive obstetric hemorrhage includes a fall in hemoglobin concentration of >40 g/L or blood loss of >2500 mL or transfusion of >4 units of RBCs [21]. Postpartum hemorrhage (PPH) means more than 1000mL blood loss from the genital tract within 24 hours of birth [22]. Common etiologies include uterine atony, placenta previa, placenta accreta, placental abruption, uterine rupture, or embryonic emboli-associated DIC.In parturient, brinogen levels are 4–6g/L, almost twice the level when compared to nonpregnant females. And the concurrent drop in protein C and S promotes prothrombotic state resulting in shorter PT and aPTT values. Thus, the combined results may come out normal in massive hemorrhage [23].

Amniotic uid embolism leading to DIC usually occurs at term pregnancy or immediate postpartum period [24]. Amniotic uid contains surfactants and various pro and anticoagulants. Surfactant, a lipoprotein produced by fetal lungs and present in increasing amounts in amniotic uid with increasing gestational age, is structurally like tissue thromboplastin and possesses signicant thromboplastic activity. It also contains cysteine protease that directly activates factor X, and it directly inhibits the PLTs [25]. Newborn may develop tachypnea and cyanosis. A patient shows signs of hypotension, brief-generalized seizures, profuse vaginal bleeding followed by unconsciousness. PT, aPTT, and bleeding time all are prolonged while brinogen

level falls drastically. Treatment strategy comprises of blood component replacement, including RBC, FFP, PLT, cryoprecipitate, and possibly brinogen concentrate. Recombinant-activated factor VIIa (rFVIIa) use is associated with increased mortality as compared to the patients who do not receive rFVIIa [26].

Massive Transfusion Protocol

The damage control resuscitation concept was rst proposed in the mid-2000s as an alternative approach to manage the hemorrhagic shock. Damage control resuscitation components are shown in Table8.3 [17, 27].

An MTP has been developed to provide a standard set of blood products to the unstable trauma patients immediately and in a sustained manner [28]. MTPs may have a predened ratio of RBC, FFP, and PLT units in each pack for transfusion which is usually set to what would be found in whole blood [29, 30]. A set ratio of each component should be tailored to individual institution’s needs that commonly deal with trauma, obstetrics, cardiac, and other major vascular surgeries.

While most institutions have developed own MTPs, the common theme of all such protocols is determining specic triggers for activation of an MTP, transfusion end targets, the logistics of blood product, and adjunct availability [31]. Once the protocol is adopted, it is necessary to approach as a multidisciplinary team, including surgeons, anesthesiologists, hematologists, and blood bank personnel [28]. A common component of MTP is shown in Table8.4.

Table 8.3 Components of damage control resuscitation [80]

1. Rapid control of surgical bleeding

Early and increased use of red blood cells, plasma, and platelets in

a 1:1:1 ratio

3. Hypotensive resuscitation strategies

4. Prevention and treatment of hypothermia, hypocalcemia, and acidosis

5. Limitation of excessive crystalloid use

Table 8.4 Common component of massive transfusion protocol

[39, 68]

Common component of MTP

1. An MTP activation and deactivation process

2. Communication between the patient area and blood bank

3. Transfusion services processes for delivery of blood products

4. Consistent blood component packs

5. Disposition of unused blood components

6. Activation of adjunct therapies

7. Consistent and timely laboratory testing

8. Performance improvement monitoring

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The Purpose ofMTP

The main purpose of MTP is to provide blood products early in the resuscitation and to treat coagulopathy in an immediate and sustained manner [28, 32]. The hemostatic resuscitation can be achieved by providing a predened ratio of RBC: FFP: PLT.Hemostatic resuscitation has been reported to be benecial in the trauma setting. Although the evidence of benets with a high transfusion ratio of plasma to RBC, this practice has spread to the nontrauma setting as well [33, 34].

Generally, MTP is activated after replacement of total blood volume in 24h needing ≥10units of packed RBCs, replacement of >4 units of packed RBCs in 1h with the anticipation of continuous need for blood products or replacement of 50% of the total blood volume within 3h. Blood loss up to 1.5ml/kg/min for more than 20min. In children, this is activated after transfusion of 4–10 units [35].

Emergency release of blood products can be universally compatible (i.e., group O, Rh(D) negative RBCs or AB plasma) or type-specic, if the patient’s blood type is known [36]. Upon activation of MTP, sufcient types and volume of the blood can be delivered with short turnaround times [37]. Time delay in receiving blood products can signicantly impact the resuscitation of massive hemorrhage and contribute to morbidity and mortality [38]. Protocols should include periodical laboratory tests to monitor coagulation status and hemostatic resuscitation. In some instances, point of care coagulation (POC) testing can provide the guidance to assess ongoing hemorrhage [39].

Optimal Ratios andComponents ofBlood Products

insufcient evidence of a difference in mortality and morbidity outcomes with a 2:1:1 (RBC: FFP: PLT) or 1:1:1 ratio of MTP [

42]. In spite of the limited evidence of recommenda-

tion with 1:1:1 over 2:1:1 (RBC: FFP: PLT), most of the trauma centers of academic facilities in the United States use 1:1 ratio of RBC: FFP [43].

Fibrinogen Component

Low-plasma brinogen level has been observed in critical bleeding and associated with a risk of massive transfusion [33, 42, 44]. Fibrinogen supplementation during massive hemorrhage may be considered in addition to conventional MTP with RBCs, FFP, and PLTs. However, there is limited evidence of brinogen supplementation in terms of improving patient outcome. According to randomized controlled trials (RCTs) to determine the feasibility of cryoprecipitate or brinogen concentrates, RCTs did not show any difference in mortality or morbidity outcomes between the patients receiving brinogen components in addition to MTP [45, 46].

Whole Blood Compared toComponent Therapy

Based on the experience in the military setting, whole blood use is associated with improved mortality outcome instead of component therapy with RBCs:FFP: PLT in a 1:1:1 ratio [47,

48]. One RCT to compare whole blood therapy with compo-

nent therapy did not report any difference in 24-hour or 30-day mortality or morbidity outcomes between two groups. According to this study, the authors used leukodepleted cold stored whole blood which can reduce the safety concerns regarding whole blood transfusion [30].

Since the extensive military experience suggesting possible survival benet, it may be warranted to conduct a multicenter RCT to evaluate the outcomes and adverse effect in massive hemorrhage [47].

RBC, FFP, andPLT

The majority of the institutions have massive transfusion protocols provide 1:1:1 ratio of RBC:FFP: PLT since the early-mid 2000s. Retrospectively, the survival data from military and civilian trauma patients showed the benet of transfusion with equal amounts of RBC, FFP, and PLT during the early phase of resuscitation [28, 40]. However, the optimal ratio of blood products remains debatable. Holcomb et al. conducted prospective cohort study which did not show that 1:1:1 or 2:1:1 has a clinical difference in mortality during the rst 24hours after admission [3]. This result was conrmed in a multisite, randomized clinical trial of 680 severely injured patients [41]. According to this study, there was no signicant difference in mortality at 24hours or at 30days among patients with severe trauma and major bleeding with 1:1:1 or 2:1:1 RBC: FFP: PLT ratios. A recent systemic review of 16 randomized controlled trials concluded there is

Prediction ofMassive Hemorrhage andInitiation ofProtocol

Predicting massive bleeding and the decision to initiate an MTP can be challengeable. Foster et al. reviewed societal guidelines from the American Society of Anesthesiologists (ASA), American College of Surgeons (ACS), and European Society for Advanced Bleeding Care in Trauma (ABCTrauma), and supporting literature with massive transfusion prediction scoring systems [49]. All three societies recommend using scoring systems to initiate a massive transfusion. The ASA and ACS recommend Assessment of Blood Consumption (ABC) Score Massive Hemorrhage and Initiation of Protocol, which is a 4-variable scoring system assessing massive transfusion risk in trauma patients shown in Table8.5 [39, 50, 51].

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Table 8.5 Assessment of bleeding consumption score [49]

Variable Value Points Systolic blood pressure (mm Hg) Heart rate (beats/min) Focused Assessment with Sonography for

Trauma examination (FAST) Mechanism of injury Penetrating 1 Score range Positive

Table 8.6 Shock index [52]

Shock index HR (beats/min)/SBP (mmHg) Positive-score

threshold

SI≥0.9 predicting massive hemorrhage (Olaussen) SI≥0.8 predicting MTP (El-Menya)

≤90 ≥120

Positive 1

score-threshold

1 1

0–49

While the American guidelines use ABC score activates the MTP, European guideline suggests that the shock index (SI) be used to assess the degree of hypovolemic shock [52]. SI is dened as the ratio of heart rate to systolic blood pressure, which has been used in massive transfusion risk assessments in the patients for critical bleeding [53–55]. SI with the prediction of massive transfusion is shown in Table8.6.

Continuation ofMassive Transfusion andMonitoring

Table 8.7 Limitations of PT/aPTT [80, 81]

1. PT and aPTT do not provide any clue about invivo interaction of platelets with coagulation factors

PT and aPTT remain prolonged even if thrombin generation is improved because of antithrombin or protein C deciency

PT/aPTT does not tell about the overall stability of a hemostatic thrombus because both tests are terminated at very low thrombin levels and before brin is polymerized

Table 8.8 Advantages/disadvantages of POC testing [80, 82]

Advantages of POC testing Disadvantages of POC testing Small sample volume Variation in performance between

Rapid test results Lack of detailed guidelines for

No transportation of samples Overpriced tests Portable devices and exibilities to move to labs or exam rooms

devices

performance and quality controls

Pre-existing coagulopathies or hypo/hyperthermia can affect the results

International Normalized Ratio (INR) of more than 1.5 times normal, PT demonstrates a sensitivity of 88% and a specicity of 88% in detecting at least one nonhemostatic coagulation factor level after trauma whereas prolongation of aPTT demonstrates a sensitivity of only 50% and a specicity of 100% because Factor VIII is often increased as an acute phase reactant in trauma and surgical patients [57]. The limitations of PT, aPTT are summarized in Table8.7.

In massive hemorrhage, clinicians should assess the extent of bleeding in consideration of the patient’s physiology, injury pattern, mechanism of hemorrhage, and the initial response to the resuscitation [56]. Majority of the MTPs based on the xed ratio of blood transfusion, however, it is necessary to reassess continuously ongoing changes and further resuscitation guided by hemodynamic monitoring and coagulation tests. Instead of focusing on applying one standardized protocol to all critical bleeding patients, MTP implementation should address specic factors of bleeding, source control, hemostatic monitoring, and physiologic responses following massive transfusion.

Laboratory Directed Transfusion Management inMTP

Prothrombin Time andActivated Partial Thromboplastin Time

Prothrombin Time (PT) is used to test Factor VII in the extrinsic factor pathway. Activated Partial Thromboplastin Time (aPTT) measures the integrity of the intrinsic system (Factor VIII, IX, XI, XII). Using the cut-off value of

Point ofCare Testing

POC testing is suggested in most of the trauma patients who have signicant injuries to provide valuable information promptly. The advantages and disadvantages of POC are summarized in Table8.8.

Thromboelastography andRotational Thromboelastometry

Because PT and aPTT tests are usually performed in central laboratories of the hospital, there is a substantial time delay in getting the results. TEG or ROTEM can be performed as a POC hemostasis monitoring test. Both tests evaluate the speed and strength of clot formation as well as clot stability, but also help to diagnose hemophilia, brinogen deciency, Factor XIII deciency, and brinolytic state [33, 58].

Arterial Blood Gas Analysis

It includes basic electrolytes, glucose level, lactate measurement, arterial hemoglobin level as well as blood gas analysis. Timely measurement of these parameters facilitates in assessment of occurrence and severity of any disturbance and helps its management accordingly [39].

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Termination oftheProtocol

Based on PROPPR trial [41], the decision to terminate an MTP should include control of bleeding anatomically and physiologic recovery such as stable hemodynamic status. Laboratory values should be used additionally to guide further transfusion requirements. Once the ongoing bleeding is controlled, the xed ratio MTP may be switched to the goal- directed protocol based on the laboratory nding. Frequent communication among the providers can facilitate the process of MTP to guide continuing blood transfusion, need for adjuncts, and determine the end of protocols [39].

Complications andDrawback ofMTPs

Massive transfusion can lead to some complications such as acid-base disturbances, electrolyte abnormalities, and hypothermia, in addition to acute trauma coagulopathy, which is reviewed in Table8.9.

The economic consequence of utilizing multiple blood products should be considered to minimize the wastage of unused products [32, 39]. It is crucial to ensure the MTP does not waste valuable resources by determining the initiation and termination process of the protocol [39].

MTP Strategies inTrauma andNonTrauma Settings

Hemostatic resuscitation with early transfusion with a higher ratio of plasma and PLTs to RBC has improved patient outcome, including mortality and morbidity in trauma setting [59]. Trauma-induced coagulopathy (TIC) is one of the com-

Table 8.9 Complications of massive transfusion [35]

Acute Dilutional coagulopathy Blood cells hemolysis Metabolic acidosis Electrolytes imbalances Hyperkalemia Hypocalcemia Hypomagnesemia Transfusion-related acute lung injury(TRALI) Transfusion-associated circulatory overload (TACO) Decreased oxygen distribution to tissues Delayed Postoperative bacterial infections Microchimerism Systemic inammatory response syndrome Immunosuppression Longer hospital stays Increased mortality

plex phenomena in trauma patients causing critical bleeding. Early correction of TIC by an MTP activation plays a vital role in the initial resuscitation of trauma patients [60].

Although an MTP also applied to the patients with critical bleeding in the trauma and nontrauma settings, there is limited evidence that implementation of trauma MPT improves the outcome in nontrauma patients [61, 62]. Patel etal. conducted retrospective study to characterize blood utilization in a trauma MTP (6 units of RBCs, 5 units of FFP, and 1 unit apheresis PLTs) and a nontrauma MPT (6 units of RBCs and 3 units of FFP). In the nontrauma MTP group, majority of the patients did not require to switch to a trauma MTP and received lower numbers of transfusion with less wastage of unused blood products. A nontrauma MTP can optimize blood utilization instead of using universal MTP in trauma and nontrauma settings [62].

Massive Transfusion Protocol forSpecic Patient Groups

Trauma

In trauma patients, MTPs have improved patient outcomes by providing blood product with the ratios closer to whole blood and early correction of coagulopathy. The implementation of MTPs improved efciency in initial resuscitation of severely injured trauma patients such as quicker access to the rst blood product, multidisciplinary team approach, and better communication among the providers. Based on PROPPR data, there is still benet to use RBCs, FFP, and PLT in a 1:1:1 ratio in exsanguination which is prominent cause of death in 24hours, however, there was no difference in mortality and morbidity compared to 2:1:1 group in mortality at 24hours and 30days [41]. Criteria to trigger the activation of the protocol and the subsequent process in trauma MTP are shown in Tables 8.10 and 8.11.

Major Hepatic Surgery andLiver Transplantation

Major hepatic surgery, including liver transplantation, is associated with massive hemorrhage during surgery. Hepatic surgery is performed in a mostly well-controlled setting and coagulation monitoring is available to guide transfusion.

Table 8.10 Criteria to trigger the activation of an MTP [39]

ABC score≥2 Persistent hemodynamic instability Activates bleeding requiring operation or angioembolization Blood transfusion in the trauma bay

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Table 8.11 Sample massive transfusion protocol in trauma [39]

Transfuse Universal RBCs and FFP in a ratio between 1:1 or 2:1 Add one single donor apheresis PLT or random donor pool PLT every 6 units of RBCs Automatically send a cooler with blood products in an established ratio by the blood bank Subsequent coolers should be sent at 15-minutes intervals until termination of an MTP Once major bleeding has been controlled, switch to a laboratory or POC-based transfusion Once laboratory data available, resuscitation should be goal-directed based on clinical assessment and laboratory ndings

POC coagulation monitors enable the accurate and rapid coagulation assessment intraoperatively to treat coagulopathy. In the uncontrolled hemorrhage, a xed ratio MTP is still considered as a feasible option. Tune etal. reported the utilization of an MTP during liver resection with acute vascular bleeding [63]. An MTP is allowed to reduce the processing and transport time of blood products, and improve administration time in uncontrolled hemorrhage.

Although there is still limited evidence whether goal driven resuscitation guided by laboratory tests or xed ratio MTPs, POC coagulation monitor-guided transfusion strategy would be recommended in the controlled setting such as major hepatic procedures. Ball etal. conducted a retrospective cohort study to evaluate the inuence of a high plasma ratio MTP in major hepatic injury patients [64]. Overall, there was no difference in mortality; however, in MTP cohort, the rate of primary abdominal fascial closure was signicantly higher than a preMTP cohort. The authors observed a decrease in crystalloid resuscitation following the use of an MTP.An MTP implementation and less crystalloid resuscitation led a decrease in both visceral and abdominal wall edema, which may improve the rate of denitive abdominal fascial closure [64].

Cardiac andMajor Vascular Surgery

hemorrhage in cardiac surgery. However, their effect on mortality is still debatable [

67].

Obstetric Hemorrhage

During pregnancy, the level of coagulation factors, including brinogen, vWF, and factor VIII, have increased that result in a prothrombotic state [68]. In obstetric hemorrhage, hemorrhage protocols or MTPs have been recommended to promote maternal safety [37, 69]. However, obstetric MTPs have been based on trauma experience without validating exclusively in obstetric hemorrhage. While ACOG recommended a xed ratio of hemorrhage protocol, CMQCC recommendations include the emergency release of blood package with laboratory-guided transfusion strategy if time permits [32, 70].

Fibrinogen level during obstetric hemorrhage has been described as a biomarker for severe postpartum hemorrhage (PPH). A serum brinogen level below 200 mg/dL had a positive predictive value for severe PPH of 100% [71]. Although the appropriate brinogen level to maintain during PPH is not dened clearly, most of the societal guidelines recommend to replace brinogen when the level is between 125 and 200mg/dL [22, 70, 72]. Cryoprecipitate (CRYO) is the most common form of brinogen replacement in the U.S.The usual dose of cryoprecipitates is 10 units expected to raise the serum brinogen 100mg/dL in adult. Early brinolysis has been observed during childbirth [73]. Based on the trials from trauma and surgery, antibrinolytic agent administration during PPH is recommended [32, 74]. The most recent international RCT to investigate the effect of early tranexamic acid (TXA) administration showed TXAreduced death caused by PPH when it was used within 3 hours of giving birth especially [74]. Laboratory tests should be obtained as clinically indicated during an MTP activation. A suggested obstetric MTP is shown in Table8.12.

Cardiac surgery is one of the surgical settings requiring massive transfusion. Massive bleeding during cardiac surgery is associated with PLT dysfunction induced by cardiopulmonary bypass. However, the component of massive transfusion during cardiac surgery is not investigated. Delaney etal. analyzed data from a prospective RCT whether massive transfusion with a high ratio of FFP: RBC (1:1 or higher) or PLT: RBC (1:5 or higher) can impact the clinical outcomes in patients undergoing complex cardiac surgery [65, 66]. According to this study, less organ dysfunction was observed in the patients with a high ratio of FFP: RBC or PLT: RBC, and lower mortality in high ratio FFP: RBC group. TEG and ROTEM have been used successfully to predict excessive

Table 8.12 Sample obstetric hemorrhage MTP [32, 70]

RBC

Round

(units) 1 6 6 6 2 6 6 6 3 6 6 6 8–10 repeat

Consider activating an MTP when 50% or more of blood volume needs to be replaced within 2hours, bleeding continues after the transfusion of 4units of RBCs within 1–2hours, or systolic blood pressure is below 90mm Hg and heart rate is above 120 beats per minute in the presence of uncontrolled bleeding. Cryoprecipitates may be considered to maintain the serum brinogen 150–200mg/dL.After third round, if an MTP is not terminated, will repeat from round 1

FFP (units)

PLT (units) CRYO (units) TXA

1 G IV over every third round

10min

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Pediatric Population

In most of the pediatric population, the adult MTP can be applied as RBC: FFP: PLT ratio of 1:1:1. However, for smaller children, this protocol should be adjusted as a weight-based system [75, 76]. Dehmer et al. reviewed the transfusion management in pediatric trauma patients and suggested sample pediatric MTP in their recent publication [76]. The authors recommend including the following elements in pediatric MTPs in Table8.13.

Outcomes, Performance, andComplication Monitoring

There is a good quality of evidence that the implementation of MTP improves patient outcomes, but also potential benets enhancing the efciencies of blood utilization, delivery of the care, and communication among the providers [33]. One study by Riskin etal. found a signicant reduction in mortality despite unchanged blood component ratio and numbers of transfusion after the MTP implementation [77]. The authors conclude the improved survival was mainly achieved by the blood product availability promptly, and multidisciplinary team approaches concurrently.

Since the beginning of the implementation of MTPs, performance, and quality improvement review by a multidisciplinary committee for compliance were strongly recommended [28]. Performance indicators should include the time from activation of MTP to rst RBC and plasma administration, adherence to a predetermined ratio or goal between 1–2hours after initiation, informing the transfusion service within 1hour of protocol termination, and wastage rate of blood products [39]. The example of performance indicators is shown in Table8.14. According to the literature

Table 8.13 Suggested sample pediatric MTP [76]

Initiation Persistent hemodynamic instability

Blood components

Monitoring Body temperature

rFVIIa In extreme cases (i.e., after 3 BV lost), consider dose

Ongoing bleeding after 40ml/kg of crystalloid infusion More than 40mL/kg packed red blood cells (PRBCs) transfused

≥30kg, 1:1:1 (RBC: FFP: PLT) with CRYO (4ml/ kg) in low-brinogen level (100–150mg/dL) or ongoing bleeding after rst round <30kg, Wt-based 30:20:20 ratio EBL (ml/kg) 20–40: Crystalloid IV 20–40ml/kg EBL 40 and above: RBC 30ml/kg After 1 BV lost: RBC 30ml/kg+FFP 20ml/kg After 2 BV lost: RBC 30ml/kg+FFP 20ml/

kg+PLT 20ml/kg+CRYO 4ml/kg

Laboratory data including serum calcium and blood pH

90mcg/kg

Table 8.14 An example of trauma massive transfusion protocol audit

lters [

28]

Initiation Activated by the trauma surgeon Blood product Timely acquired of blood samples for type and

Discontinuation MTP discontinued when the active hemorrhage has

screening process from ED PRBC: plasma administered in a ratio of 3:2 PRBC: Platelets administered in a ratio of 5:1 Timely response of required personnel and blood products from the blood bank Unused blood products are appropriately stored

been controlled

review, full compliance was signicantly associated with survival rate [78, 79]. Bawazzer etal. measured compliance of MTP with their protocol criteria including timely activation and deactivation of the protocol, laboratory assessment in the trauma bay, communication with the blood bank, and prevention of wasting blood products. Based on the result of the study, noncompliance was observed more commonly in sending a complete hemorrhage panel from the trauma bay and monitoring blood work periodically. Also, discontinuation of the protocol following compliance was associated with a reduction in blood product wastage [79].

Massive transfusion could lead to a higher incidence of transfusion-related complications, including transfusionrelated acute lung injury, immunomodulation, infectious disease, transfusion reactions, metabolic derangement, and circulatory overload. Therefore, it is recommended the trauma centers should review this massive transfusionrelated complications in addition to the performance indicators [39].

Summary

This chapter highlights the management of massive hemorrhage with MTPs. We discussed the implications of MTPs, including trauma, major hepatic, major vascular, cardiothoracic, spine surgery, and obstetric and pediatric patients. Activation and termination criteria of MTPs were discussed. Current evidence recommends using ratios either 2:1:1 or 1:1:1 of RBC:FFP:PLT, which is based on the trauma MTPs. Fibrinogen replacement is also indicated in obstetric hemorrhage and other uncontrolled, ongoing hemorrhage with brinogenemia. Initial massive transfusion with a xed ratio of blood products can be switched as a laboratory-based protocol by POC tests or other coagulation studies when critical hemorrhage is controlled. Outcomes and compliance measurement are necessary to improve the performance and quality of MTPs. The implementation of an MTP has impacted the patient outcomes, but also improved the efciencies in blood utilization and delivery of care. The multidisciplinary team approach plays a crucial role in the success of an MTPs.

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