Clinical Opinion

ajog.org

OBSTETRICS

An update on the use of massive transfusion protocols in obstetrics Luis D. Pacheco, MD; George R. Saade, MD; Maged M. Costantine, MD; Steven L. Clark, MD; Gary D. V. Hankins, MD

Obstetrical hemorrhage remains a leading cause of maternal mortality worldwide. New concepts involving the pathophysiology of hemorrhage have been described and include early activation of both the protein C and fibrinolytic pathways. New strategies in hemorrhage treatment include the use of hemostatic resuscitation, although the optimal ratio to administer the various blood products is still unknown. Massive transfusion protocols involve the early utilization of blood products and limit the traditional approach of early massive crystalloid-based resuscitation. The evidence behind hemostatic resuscitation has changed in the last few years, and debate is ongoing regarding optimal transfusion strategies. The use of tranexamic acid, fibrinogen concentrates, and prothrombin complex concentrates has emerged as new potential alternative treatment strategies with improved safety profiles. Key words: hemostatic resuscitation, massive transfusion, obstetrical hemorrhage

H

emorrhage remains a major cause of maternal mortality worldwide. In 2005, in the United States, hemorrhage was the third leading cause of maternal death caused by obstetric factors.1 Current trends in obstetrical practice (increased cesarean delivery rate and decreased vaginal birth after cesarean delivery) have resulted in an increased prevalence of placental anomalies (both placenta previa and accreta), placing peripartum hemorrhage as one of the most important potential causes for maternal mortality.2

From the Departments of Obstetrics and Gynecology (Drs Pacheco, Saade, Constantine, and Hankins) and Anesthesiology (Dr Pacheco), The University of Texas Medical Branch at Galveston, Galveston, TX; and Department of Obstetrics and Gynecology, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX (Dr Clark). Received May 20, 2015; revised Aug. 14, 2015; accepted Aug. 31, 2015. The authors report no conflict of interest. Corresponding author: Luis D. Pacheco, MD. [email protected] 0002-9378/$36.00 ª 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajog.2015.08.068

Recent literature suggests that alternative pathways may play a key role in the pathophysiology of massive hemorrhage. Limited evidence suggests that early aggressive blood product replacement (hemostatic resuscitation) in the setting of massive hemorrhage can improve outcomes when compared with traditional resuscitation involving the use of large amounts of crystalloids and blood therapy replacement based on laboratory parameters.3,4 Despite limited prospective data, many level I trauma centers and obstetrical units in the United States have adopted the use of massive transfusion protocols to treat patients with severe hemorrhage.5 The main objective of massive transfusion protocols is to administer blood products early in the resuscitation process. These protocols, if adopted, require a multidisciplinary approach involving obstetricians, anesthesiologists, hematologists, and blood bank personnel. The idea is that once it is activated, blood bank personnel will provide blood products (packed red blood cells, fresh frozen plasma, cryoprecipitate, platelets) at a predefined ratio without waiting for laboratory test results. Since our last publication on the topic, the evidence has evolved

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and new pharmacological agents have become available for the management of severe hemorrhage.4 The purpose of this review is to address new updates regarding the use of massive transfusion protocols and their applicability to obstetrical hemorrhage.

Fresh frozen plasma and platelets Classically, resuscitation in hemorrhage has been centered on the administration of crystalloids and packed red blood cells (PRBCs). Use of other blood products like fresh frozen plasma, cryoprecipitate, and platelets was traditionally withheld until there was laboratory evidence of developing coagulopathy (eg, platelet count <50,000/mm3, fibrinogen <100e150 mg/dL, prothrombin time (PT), or activated partial thromboplastin time >1.5  normal). These transfusion guidelines fail to prevent early coagulopathy in massive bleeding.6 Patients with crystalloid/ PRBC-based resuscitation will frequently develop dilution of clotting factors and platelets, leading to dilutional coagulopathy. Massive crystalloid resuscitation may further worsen bleeding prior to achieving the surgical control of hemorrhage by increasing intravascular hydrostatic pressures and dislodging fresh clots at sites of endothelial injury.7 Excessive amounts of crystalloids have been associated with third spacing, leading to cerebral, cardiac, and pulmonary edema.7 Third spacing from massive crystalloid-based resuscitation may also worsen hemodynamics and renal perfusion by increasing intraabdominal pressures, leading to abdominal compartment syndrome.8 Furthermore, recent evidence suggests that excessive administration of crystalloids in the setting of acute kidney injury (not uncommon in massive hemorrhage) results in interstitial kidney edema with renal vein obliteration

ajog.org delaying the recovery of kidney function.9 Chlorine-rich fluids (eg, 0.9% saline) worsen kidney function because chloride induces renal vasoconstriction.10 Recent evidence advocates the use of balanced crystalloid solutions such as lactated Ringers and Plasmalyte.11 Prior to surgical control of hemorrhage, permissive hypotension with systolic blood pressures between 80 and 100 mm Hg may be optimal to limit ongoing blood loss.7 Permissive hypotension may be considered in patients with postpartum hemorrhage. However, there are no data regarding permissive hypotension prior to delivery of the fetus, when the risks and benefits need to take into account the effect on uterine perfusion. Early coagulopathy may occur prior to hemodilution and before the consumption of clotting factors takes place. This mechanism of early coagulopathy has mainly been studied in trauma; however, obstetrical hemorrhage may share some of the mechanisms involved.7 Hypoperfusion results in an up-regulation of thrombomodulin receptors on endothelial cells. These receptors interact with thrombin, leading to the activation of the protein C pathway. Protein C will irreversibly inhibit factors Va and VIIIa and enhance fibrinolysis through inhibition of plasminogen activator inhibitor 1.12 Similarly, endothelial ischemia results in increased production of tissue plasminogen activator, resulting in increased fibrinolysis. Increased fibrinolytic activity has been described in obstetrical hemorrhage secondary to uterine atony, placental abruption, and accretism.7 Early use of antifibrinolytic agents (eg, epsilonaminocarpoic acid or tranhexamic acid) has been shown to decrease bleeding and mortality among trauma victims.13 Following placental separation, the fibrinolytic pathway is activated for up to 10 hours into the postpartum period.14 Hemostatic resuscitation has emerged as an option to overcome the previously described shortcomings. The key concept of this approach is to limit the administration of crystalloids and

Obstetrics instead make blood products the cornerstone of resuscitation.3 In hemostatic resuscitation, packed red blood cells are administered in a 1:1:1 ratio with fresh frozen plasma (FFP) and platelets. The administration of these products is given, regardless of laboratory values. Theoretically, clotting factor dilution and third spacing are minimized with this approach. One unit of platelets will increase the platelet count by 5000e10,000/mm3. When administering platelets, the typical dose used is 1 U per 10 kg of weight. One unit of FFP contains all clotting factors including 2 g of fibrinogen for each 1000 mL. One unit of FFP (200e250 mL) increases serum fibrinogen by 10 mg/dL. Overall, the evidence behind the use of hemostatic resuscitation is limited. Retrospective studies have demonstrated absolute mortality reductions between 15% and 62% with the use of high ratios of FFP:PRBC (eg, 1:1).15,16 A limitation of the available literature is the presence of survival bias. On average, the median time for obtaining the first unit of PRBC is 18 minutes, as opposed to more than 1 hour for fresh frozen plasma (needs to be thawed).17 It is likely that the patients who received fresh frozen plasma were not as sick as those who died before the fresh frozen plasma was available. Patients’ ability to survive until fresh frozen plasma was available to be included in the group who received it may have biased the analysis in favor of high FFP:PRBC ratios. A limited number of studies have specifically addressed the survivorship bias in high FFP:PRBC studies. When early deaths were excluded, no survival benefit for higher ratios was noted.18 A recent randomized clinical trial among patients with severe traumaassociated hemorrhages found no difference in mortality at 24 hours or 30 days when comparing the use of plasma, platelets, and red cells at a 1:1:1 ratio to a 1:1:2 ratio. In a subgroup analysis, patients assigned to the 1:1:1 ratio had lower deaths from exsanguination in the first 24 hours, and more patients in the 1:1:1 ratio achieved hemostasis.19 Importantly, despite more use of

Clinical Opinion

plasma and platelets in the 1:1:1 ratio group, there was no difference in adverse outcomes, including sepsis, acute kidney injury, acute lung injury, febrile transfusion reactions, or multiorgan failure. This latest trial provides the best available evidence to date favoring the use of hemostatic resuscitation.

Recombinant activated factor VII Early administration of recombinant activated factor VII (rFVIIa) was typically included in massive transfusion protocols if bleeding persisted after administration of a predetermined number of blood products. rFVIIa is licensed for use in patients with hemophilia and inhibitory alloantibodies against factors VIII or IX.20 It has increasingly been used for off-license indications, including trauma, heart surgery after cardiopulmonary bypass, warfarin reversal, and obstetrical hemorrhage. Despite having a very short half-life, concerns about thrombotic events as a complication are real. A recent study found an increased risk of arterial thrombosis among recipients of recombinant activated factor VII.21 rFVIIa is not a first-line treatment for bleeding, and it is effective only after major sources of bleeding have been controlled. The use of this product should be combined with best practice use of blood products.22 Ideally, the patient should have a platelet count >50,000/mm3, fibrinogen >50e100 mg/dL, temperature >32 C (pH > 7.2), and normal ionized calcium prior to administration.22 Randomized controlled trials addressing the use of rFVIIa in massive hemorrhage have found an overall reduction in transfusion requirements or blood loss, but none has reported a survival benefit.5,23 In obstetrics, the available evidence is mostly from case reports and case series. In cases of amniotic fluid embolism, the use of this agent has been associated with increased mortality.24 At this time, given the wellknown adverse effects of recombinant activated factor VII, its extremely high cost, and its lack of survival benefit, it is difficult to justify the routine use of this agent in massive transfusion protocols.

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The use of other pharmacological approaches with a more favorable profile, including tranexamic acid (TXA), fibrinogen concentrates, and prothrombin complex concentrates, may be preferable.

Fibrinogen and cryoprecipitates In the setting of massive hemorrhage, fibrinogen is the first clotting factor to fall to critically low levels.25 Fibrinogen plays a pivotal role in clotting by serving as the substrate for thrombin to generate fibrin and also by interacting with the glycoprotein IIb/IIIa on the platelet surface.26 Achieving specific fibrinogen levels is now considered an important target during massive transfusion. Whereas previous guidelines recommended maintaining a level above 100 mg/dL during a bleeding episode, currently it is recommended that levels above 150e200 mg/dL be targeted.27 During normal pregnancy, fibrinogen levels increase to values as high as 400e500 mg/dL so that low values may represent a more severe coagulopathy compared with nonpregnant individuals.27 In the setting of obstetrical hemorrhage, a serum fibrinogen level below 200 mg/dL had a positive predictive value for progression to severe hemorrhage of 100%.28 It is, therefore, reasonable to target a fibrinogen level of at least 150e200 mg/dL during obstetrical hemorrhage. In the United States, most of the fibrinogen replacement is done in the form of cryoprecipitates (100 mL of cryoprecipitate contain approximately 2 g of fibrinogen). Each unit of cryoprecipitate will increase the serum fibrinogen by 10 mg/dL. The usual adult dose of cryoprecipitate is 10 U, which is expected to raise the serum fibrinogen by 100 mg/dL.29 Disadvantages with the use of cryoprecipitate include the necessity to thaw prior to use and the risk of virus transmission. Fibrinogen concentrates have emerged as an extremely effective agent in recent years and have been used in trauma, cardiovascular surgery, and obstetrics.30 The safety profile of this product is favorable because viral inactivation and removal of multiple antigens and antibodies is part of the manufacturing

process. Fibrinogen concentrates are stored at room temperature, are available for immediate use, and come in small volumes with high fibrinogen concentrations (2 g of fibrinogen in 100 mL).30 The recommended initial dose is 2e3 g intravenously with subsequent doses adjusted according to serum fibrinogen levels. Multiple case reports and case series attest to the efficacy of fibrinogen concentrates in the management of obstetrical hemorrhage.31,32 Similarly, the use of fibrinogen concentrates in trauma victims with severe hemorrhage has been effective, with a significant decrease in blood product requirements.33 Most clinical data to date suggest that fibrinogen concentrates play a key role as a hemostatic agent resulting in reduced requirements of allogeneic blood product transfusions without evidence of harmful effects.30 We believe that fibrinogen concentrates will play a major role in the management of obstetrical hemorrhage in the near future. Unfortunately, fibrinogen concentrates are not yet widely available in the United States.

Tranexamic acid Increased fibrinolytic activity has been described in trauma, cardiovascular surgery, liver transplantation, and obstetrical hemorrhage. A recent clinical randomized placebo-controlled multicenter study found increased survival among trauma patients with severe hemorrhage who received TXA within 3 hours of injury.34 Interestingly, the latter trial did not find any evidence that the use of TXA was associated with an increased risk of thrombotic events. TXA has also been used in the setting of obstetrical hemorrhage.35 When utilized for prophylaxis of peripartum bleeding, a reduction in blood loss and transfusion requirements has been described. The evidence supporting the use of TXA for the treatment of established postpartum hemorrhage is limited. One small randomized controlled trial found that patients who received TXA after a diagnosis of postpartum hemorrhage was established had less blood loss compared with patients who did not received it.36

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ajog.org Importantly, so far there is no evidence that the use of TXA in obstetrical patients is associated with increased risk of thrombotic events. It appears that TXA is a potentially safe and effective treatment of postpartum hemorrhage. Most of the cited studies have administered TXA without the use of viscoelastic tests (eg, thromobelastography) designed to diagnose hyperfibrinolysis. Because the latter is not widely available in obstetrical units, we recommend that if TXA is to be used in the setting of postpartum hemorrhage that it be administered without the requirement of a viscoelastic test. The combined use of TXA and cryoprecipitates has been described to improve outcomes in trauma victims.37 More high-quality data are required before TXA can be universally recommended in the obstetrical setting.

Prothrombin complex concentrates Prothrombin complex concentrates (PCCs) are human plasma-derived concentrates of vitamin K-dependent clotting factors. Currently PCCs are the first-line treatment modality for the emergent reversal of warfarin.38 Different preparations of PCCs are available. A 3-factor product known as Profilnine contains only factors II, IX, and X. Two products with 4-factor concentrates are also available: Kcentra and FEIBA. The latter 2 contain all 4 vitamin K-dependent clotting factors with the difference that factors are inactivated in Kcentra, whereas factor VII is activated in FEIBA. The usual dose used for warfarin reversal (only current approved indication in the United States) is 30e50 U/kg. PCCs have been used off label in cases of intractable hemorrhage in the setting of trauma and cardiovascular surgery.39 Studies have shown that PCCs reduce bleeding and the need for blood transfusions under such circumstances. Unfortunately, available data so far mainly consist of small observational trials, and no information is yet available regarding the risk of thrombotic complications. Data in obstetrical hemorrhage are equally limited. We believe that PCCs should not be used first line during

Obstetrics

ajog.org life-threatening obstetrical hemorrhage but may be considered as a last resort in refractory cases. The ideal dose for hemorrhage is not known but appears to be lower than that recommended for warfarin reversal.

Drawbacks of massive transfusion protocols The economic repercussions of utilizing multiple blood products and thawing fresh-frozen plasma are significant. Once plasma is thawed, it must be used within the next 5 days. It is of utmost importance that as soon as the transfusion requirements decrease, the blood bank be notified to stop further preparation of blood products that would otherwise be wasted. Early administration of multiple blood products could lead to a higher incidence of transfusion-related complications like transfusion-related acute lung injury and transfusion-related immunomodulation.40 Excessive use of blood products could also increase the risk of transfusion-related infectious diseases, allergic and febrile reactions, transfusion-related acute kidney injury, transfusion-related circulatory overload, and metabolic complications, including hyperkalemia, hypocalcemia, iron overload, and citrate toxicity.41 Some argue the opposite with the rationale that early administration of fresh-frozen plasma and platelets achieves hemostasis earlier, thus decreasing the total number of blood products given.4 A recently published randomized clinical trial found no evidence of adverse reactions associated with increased ratios of FFP:PRBC.19 Proposed massive transfusion protocol Controversy still surrounds the optimal ratio of packed red blood cells, freshfrozen plasma, and platelets that needs to be administered. The combination of early recognition and intervention may be more important than a specific administration ratio of blood products. The Table depicts an updated massive transfusion protocol for use in obstetrical practice based on new available evidence. Although there are various guidelines that have been proposed for

Clinical Opinion

TABLE

Massive transfusion protocol in obstetrics PRBCs

FFP

Platelets

Cryoprecipitate

Round 1

6U

6U

6U

10 U

Round 2

6U

6U

6U

10 U

Round 3

Tranexamic acid 1 g intravenously over 10 min

Round 4

6U

6U

6U

Consider activating the protocol when hemorrhage is expected to be massive (anticipated need to replace 50% or more of blood volume within 2 hours), bleeding continues after the transfusion of 4 U of packed red blood cells within a short period of time (1e2 hours), or systolic blood is pressure below 90 mm Hg and heart rate is above 120 beats per minute in the presence of uncontrolled bleeding. Once activated, blood bank personnel will continue preparing blood products until the surgical team inactivates the protocol. After round 4, if not inactivated, the protocol will start again from round 1. FFP, fresh-frozen plasma; PRBC, packed red blood cell; Adapted from Pacheco et al.4 Pacheco. Massive transfusion protocols in obstetrics. Am J Obstet Gynecol 2016.

nonobstetrical patients, the precise threshold to activate the protocol in obstetrical patients is difficult to establish. In practice, the decision is based on a clinical evaluation by the surgeon and/or anesthesiologist involved in the case. Criteria that would have an impact on the decision include the estimated blood already lost, the anticipated further blood loss, and the likelihood the bleeding will be controlled any time soon. An experienced physician who is leading the resuscitation efforts should initiate the protocol. We suggest the activation of the massive transfusion protocol when hemorrhage is expected to be massive (anticipated need to replace 50% or more of blood volume within 2 hours), bleeding continues after the transfusion of 4 U of packed red blood cells within a short period of time (1e2 hours), or the systolic blood pressure is below 90 mm Hg and the heart rate is above 120 beats per minute in the presence of uncontrolled bleeding. Once activated, the blood bank will prepare and send blood products to the operating room in the order depicted in the Table. Blood bank personnel will send the first round of products that will include 6 U of PRBCs, 6 U of FFP, 6 U of platelets, and 10 U of cryoprecipitate. Unless inactivated, the blood bank will start preparing the products for round 2 (6 U of PRBCs, 6 U of FFP, and 10 U of cryoprecipitate) and send them to the operating room as soon as they are ready. The sequence will continue until round

4. If not inactivated, and if the patient still has uncontrolled hemorrhage, the protocol will start again from round 1. Coagulation parameters (complete blood cell count, including platelet counts, fibrinogen level, activated partial prothrombin time, prothrombin time, and a basic metabolic panel) should be obtained periodically as clinically indicated. Fibrinogen levels should be maintained above 150e200 mg/dL. We have replaced the use of activated rFVII with TXA. As discussed previously, activated rFVII has not been shown to improve survival, whereas the evidence of potential harm in the form of arterial thrombosis is real.21 TXA has been shown to decrease mortality in traumarelated hemorrhage and ameliorate obstetrical hemorrhage and has not been associated with thrombotic complications. The use of PCCs should be limited to refractory cases until more data regarding safety are available.

Conclusions Hemostatic resuscitation has emerged as a new concept, albeit based on limited prospective data. Massive transfusion protocols could improve outcomes in the bleeding patient not only because of early blood product administration but also secondarily to an early and aggressive multidisciplinary intervention. The availability of new and safer pharmacological options, such as TXA, fibrinogen concentrates, and prothrombin complex concentrates, will continue to modify the components of the ideal

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massive transfusion protocol. Hospitals that institute massive transfusion protocols should ideally include a quality/ peer review committee to guarantee periodic revisions of the available protocol with modifications according to new guidelines. ACKNOWLEDGMENT For editorial and graphic assistance, we thank obstetrics-gynecologist publication, grant, and media support director and staff. The office is supported by the Department of Obstetrics and Gynecology at The University of Texas Medical Branch.

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ajog.org of the severity of postpartum hemorrhage. J Thromb Haemost 2007;5:266-73. 29. Nascimento B, Goodnough LT, Levy JH. Cryoprecipitate therapy. Br J Anaesth 2014;113:922-34. 30. Levy JH, Welsby I, Goodnough LT. Fibrinogen as a therapeutic target for bleeding: a review of critical levels and replacement therapy. Transfusion 2014;54:1389-405. 31. Bell SF, Rayment R, Collins PW, Collis RE. The use of fibrinogen concentrate to correct hypofibrinogenemia rapidly during obstetric hemorrhage. Int J Obstet Anesth 2010;19: 218-23. 32. Kikuchi M, Itakura A, Miki A, Nishibayashi M, Ikebuchi K, Ishihara O. Fibrinogen concentrate substitution therapy for obstetric hemorrhage complicated by coagulopathy. J Obstet Gynaecol Res 2013;39:770-6. 33. Schochl H, Forster L, Woidke R, Solomon C, Voelckel W. Use of rotation thromboelastometry (ROTEM) to achieve successful treatment of polytrauma with fibrinogen concentrate and prothrombin complex concentrate. Anaesthesia 2010;65:199-203. 34. CRASH 2 trial collaborators, Shakur H, Roberts I, et al. Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial. Lancet 2010;376: 23-32. 35. Heesen M, Bohmer J, Klohr S, et al. Prophylactic tranexamic acid in parturients at low risk for post partum hemorrhage: systematic review and meta-analysis. Acta Anaesthesiol Scand 2014;58:1075-85. 36. Ducloy-Bouthors AS, Jude B, Duhamel A, et al. High-dose tranexamic acid reduces blood loss in postpartum haemorrhage. Crit Care 2011;15:R117. 37. Morrison JJ, Ross JD, Dubose JJ, Jansen JO, Midwinter MJ, Rasmussen TE. Association of cryoprecipitate and tranexamic acid with improved survival following wartime injury: findings from the MATTERs II Study. JAMA Surg 2013;148:218-25. 38. Gordon HG, Akl EA, Crowther M, Gutterman DD, Schuünemann HJ; the American College of Chest Physicians Antithrombotic Therapy and Prevention of Thrombosis Panel. Executive summary: antithrombotic therapy and prevention of thrombosis, 9th edition: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2012;141(Suppl 2): 7s-47s. 39. Grottke O, Levy JH. Prothrombin complex concentrates in trauma and perioperative bleeding. Anesthesiology 2015;122:923-31. 40. Gonzalez EA, Moore FA, Halcomb JB, et al. Fresh frozen plasma should be given earlier to patients requiring massive transfusion. J Trauma 2007;62:112-9. 41. Gilliss BM, Looney MR, Gropper MA. Reducing noninfectious risks of blood transfusion. Anesthesiology 2011;115:635-46.