Hemostatic resuscitation in postpartum hemorrhage a supplement to surgery

A C TA Obstetricia et Gynecologica AOGS REVIEW ARTICLE Hemostatic resuscitation in postpartum hemorrhage a supplement to surgery KIM EKELUND 1, GABRIELE HANKE 1, JAKOB STENSBALLE 2,3, ANNE WIKKELSØE 4, CHARLOTTE KREBS ALBRECHTSEN 1 & ARASH AFSHARI 1 1 Department of Anesthesia, Juliane Marie Center, Copenhagen University Hospital, Rigshospitalet, Copenhagen, 2 Department of Anesthesia, Center of Head and Orthopedics, Copenhagen University Hospital, Rigshospitalet, Copenhagen, 3 Section for Transfusion Medicine, Capital Region Blood Bank, Copenhagen University Hospital, Rigshospitalet, Copenhagen, and 4 Department of Anesthesiology, Copenhagen University Hospital, Herlev Hospital, Herlev, Denmark Key words Postpartum hemorrhage, standard laboratory tests, viscoelastic hemostatic assays, fibrinogen, tranexamic acid, transfusion strategy, maternal morbidity Correspondence Kim Ekelund, Department of Anesthesia, Juliane Marie Center, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 3, 2100 Copenhagen, Denmark. E-mail: kimekelund@gmail.com Please cite this article as: Ekelund K, Hanke G, Stensballe J, Wikkelsøe A, Albrechtsen CK, Afshari A. Hemostatic resuscitation in postpartum hemorrhage a supplement to surgery. Acta Obstet Gynecol Scand 2015; 94: 680 692. Received: 9 March 2014 Accepted: 14 October 2014 DOI: 10.1111/aogs.12607 Abstract Background. Postpartum hemorrhage is a potentially life-threatening albeit preventable condition that persists as a leading cause of maternal death. Identification of safe and cost-effective hemostatic treatment options remains crucial as a supplement to surgery and uterotonic agents. Objective. This review summarizes the background, current evidence and recommendations with regard to the role of fibrinogen, tranexamic acid, prothrombin complex concentrate, desmopressin, and recombinant factor VIIa in the treatment of patients with postpartum hemorrhage. The benefits and evidence behind traditional standard laboratory tests and viscoelastic hemostatic assays, i.e. thromboelastography TEG â and thromboelastometry ROTEM â, are discussed. In addition we assess and elaborate on the current paradigm and evidence for transfusion of these patients. Data sources. Publications between 1994 and 2014 were identified from PubMed, EMBASE, Cochrane Library databases, and ClinicalTrial.gov. Results. Viscoelastic hemostatic assays were found to provide a real-time continuum of coagulation and fibrinolysis when introduced as a supplement in transfusion management of postpartum hemorrhage. Fibrinogen should be considered when hypofibrinogenemia is identified. Early administration of 1 2 g tranexamic acid is recommended, followed by an additional dose in cases of ongoing bleeding. Uncontrolled hemorrhage requires early balanced transfusion. Conclusion. Despite the lack of conclusive evidence for optimal hemostatic resuscitation in postpartum hemorrhage, the use of viscoelastic hemostatic assays, fibrinogen, tranexamic acid and balanced transfusion therapy may prove to be potentially pivotal in the treatment of postpartum hemorrhage. Abbreviations: DDAVP, desmopressin (1-deamino-8-D-arginine vasopressin); FFP, fresh frozen plasma; PCC, prothrombin concentrate complex; PPH, postpartum hemorrhage; PRBC, packed red blood cells; RCT, randomized clinical trial; rfviia, recombinant factor VIIa; ROTEM â, rotational thromboelastometry; TEG â, thromboelastograph; TXA, tranexamic acid; VHA, viscoelastic hemostatic assays. Introduction Obstetric hemorrhage remains a potentially preventable leading cause of maternal death throughout the world and has been estimated to cause 13 34% of all maternal deaths, particularly in low-resource countries (1). An increasing trend in the incidence of postpartum hemorrhage (PPH) has also been noticed in high-resource countries (2). Some have proposed a correlation to an 680

K. Ekelund et al. Hemostatic resuscitation in PPH increased incidence of cesarean section with a subsequent rise in the risk of abnormal placentation. Others have proposed increased rates of maternal obesity, a change in maternal age distribution, an increased use of induction of labor and a rising frequency of multiple pregnancies, as explanations (2). Still, the majority of women who develop PPH do not present with any such risk factors (3). PPH is often described as having four main causal components: uterine atony (tone), trauma of the birth canal (trauma), retained placental tissue (tissue) and impaired hemostasis (thrombin), collectively abbreviated to TTTT (4). Although the best treatment for ongoing bleeding may consist of surgical measures, PPH may equally result in an acute coagulopathy leading to persistent hemorrhage despite the use of uterotonics, controlled cord traction, uterine massage, intrauterine balloon tamponade, uterine artery embolization or surgical procedures (5). Fortunately, several treatment options are available to obtain the overall goal: hemostasis. We reviewed the current evidence in obstetrics for treatment strategies considered supplementary to surgery and uterotonic agents. We also describe ways in which to recognize and target impaired hemostasis by application of standard laboratory tests and viscoelastic hemostatic assays, how to target impaired hemostasis using fibrinogen concentrate, tranexamic acid, prothrombin complex concentrate, desmopressin and recombinant factor VII, and finally how to replace the blood loss with intravenous fluids, blood component therapy and the use of cell saver, and provide recommendations for each of these modalities. Material and methods We performed an electronic search using PubMed, EMBASE, Cochrane Library databases, and the Clinical- Trial.gov files, using combinations of the keyword postpartum hemorrhage, with one of the following: standard laboratory tests, thromboelastography, thromboelastometry, fibrinogen, tranexaminc acid, prothrombin complex concentrate, desmopressin, recombinant factor VII, transfusion strategy or cell saver. English-language articles published between 1994 and 2014 were retrieved. A total of 1161 publications were identified (date of search August 2014). After exclusion of non-english, non-pph and duplicate articles, 180 publications were retrieved. Fifteen of these were of high quality, i.e. randomized clinical trials (RCTs), controlled clinical trials, systematic reviews or meta-analyses (Supporting information Table S1). If relevant articles were identified as a supplement to the retrieved publications, they were included in the review. Results Recognizing and targeting impaired hemostasis and coagulopathy Standard laboratory tests usually comprise coagulation and fibrinolytic factors, platelet counts and hemoglobin assessment (Table 1). Pregnancy is associated with increased clotting and a decrease of fibrinolytic capacity. This state of hypercoagulability is evident when reference values of standard laboratory tests obtained from the non-pregnant population are applied (Table 1) (6 10). Changes in the standard laboratory tests during pregnancy normalize within 4 8 weeks after delivery (7,8). The risk of PPH prior to bleeding can not be quantified by any standard laboratory test (11). Charbit et al. found in a multicenter study of 128 women with PPH that the positive predictive value of a fibrinogen concentration <2 g/l among women with PPH was 100% when examining the occurrence of severe bleeding (12). During a normal pregnancy the fibrinogen level will increase to an average of 5.3 g/l at term (13). Several publications and guidelines recommend that fibrinogen levels of 2 g/ L should be considered a threshold for fibrinogen substitution, whereas others argue that a level <1 g/l is mandatory for fibrinogen replenishment (5,14 18). However, caution is warranted as the fibrinogen level may be significantly overestimated when plasma is diluted with colloids (19). Standard laboratory tests, including hemoglobin, platelet count, activated partial prothrombin time, prothrombin time, international normalized ratio, and fibrinogen may be justified in patients with a prior history of bleeding, a known bleeding disorder or when there is an increased risk of hemostatic deficiency caused by preeclampsia, such as in HELLP syndrome (hemolysis, elevated liver enzymes, low platelets), or in women with Key Message Goal-directed hemostatic resuscitation based on viscoelastic hemostatic assays, i.e. thromboelastography TEG â or thromboelastometry ROTEM â, can be pivotal in the treatment of postpartum hemorrhage. The role of fibrinogen, tranexamic acid, prothrombin complex concentrate, desmopressin, and recombinant factor VIIa, and the existing evidence in favor or against these agents are described in detail as supplements to surgery, uterotonic agents and blood products in the management of women with postpartum hemorrhage. 681

Hemostatic resuscitation in PPH K. Ekelund et al. Table 1. Changes in coagulation and fibrinolysis parameters at term gestation (6 10). Blood coagulation factors Factor I (fibrinogen) Factor II (prothrombin) Factor V (proaccelerin) Factor VII (proconvertin) Factor VIII (antihemophilic factor) Factor IX (Christmas factor) Factor X (Stuart-Power factor) Factor XI (thromboplastin antecedent) Factor XII (Hageman factor) Factor XIII (fibrin stabilizing factor) Von Willebrand factor Tissue factor Other coagulation parameters Platelet count Prothrombin time Activated partial thromboplastin time Fibrin degradation products Blood coagulation inhibitors Antithrombin III Protein C Protein S Thrombomodulin Tissue factor pathway inhibitor Fibrinolysis Plasminogen Tissue-type plasminogen activator Plasminogen activator inhibitor-1 (produced in endothelial cells) Plasminogen activator inhibitor-2 (produced in placenta) pre-existing liver disease or inherited hemostatic deficiencies (17). Abnormal test results have a low predictive capacity in the general obstetric population and may vary according to time of testing, i.e. during pregnancy, prelabor, in labor or at the onset of bleeding (8). The standard laboratory tests may equally be considered at an early stage of a bleeding episode in high-risk patients (11). However, standard laboratory tests have several general and practical limitations, such as delays in test result availability, lack of real-time monitoring, inability to assess hemostatic functionality of whole blood, including clot strength and platelet dysfunction, and inadequate clinical validation (20). Hence, standard laboratory tests are of limited use in diagnosis, risk assessment and transfusion algorithms in patients with PPH (20). Viscoelastic hemostatic assays No change or decreased No change or decreased Shortened Shortened No change or decreased or decreased Decreased Viscoelastic hemostatic assays (VHAs) test the hemostatic properties of whole blood and provide a real-time examination of clot initiation, propagation, maximum strength and dissolution. The overall principle of VHAs consists of whole blood being placed into a cup while a pin is immersed. Oscillation is introduced and the viscoelasticity of the sample is measured via movement of the pin and the cup. As the blood clots, fibrin polymerization progressively changes the viscoelasticity (21 24). Therefore, VHA coagulation assays are more representative of in vivo coagulation than conventional laboratory tests. The Thrombelastograph (TEG â ; Haemonetics Corp., Braintree, MA, USA) and Rotational Thromboelastometry (ROTEM â ; Tem International GmbH, Munich, Germany) are two different, well established and commonly used VHAs; both are transformed to a specific signature tracing (21 24) (Figure 1). A strong correlation has been identified between standard coagulation parameters and ROTEM â variables in women shortly after delivery (25,26). The hypercoagulability of pregnancy can be confirmed using either TEG â and ROTEM â (7,27 30) (Table 2). Nonetheless, a direct comparison of TEG â and ROTEM â has not been made in obstetrics (25,27,29,30). ROTEM â analyses could potentially be used as guidance for pre- and peri-operative administration of fibrinogen (16,31). The FIBTEM is a ROTEM â assay that evaluates the fibrinogen component and seems to be well correlated with the standard laboratory fibrinogen levels (32). The fibrinogen plasma level has been identified as an early independent predictor of the later development of severe PPH (12) and a prospective observational PPH study recently showed FIB- TEM to be an independent predictor of blood loss of >2500 ml (33). A new TEG â -based functional fibrinogen Figure 1. Schematic TEG â /ROTEM â trace, including the most frequently used variables: reaction time (R)/clotting time (CT), clot formation time (K, CFT), alpha angle (a), maximum amplitude (MA)/ maximum clot firmness (MCF) and lysis (Ly)/clot lysis (CL). The R-value/ CT is the time from the start of the test to the initial fibrin formation. The K value is the clot formation time to reach a specific level of clot strength. The a angle represents the acceleration (kinetics) of fibrin build up and cross-linking (clot strengthening). The MA/MCF reflects the ultimate strength of the clot, which depends on the number and function of platelets and their interaction with fibrin. Lysis or clot lysis can be indicated to a certain time, e.g. 30 min, and represents the lysis index at 30 min after MA. Ly is increased with fibrinolysis (146). 682

K. Ekelund et al. Hemostatic resuscitation in PPH Table 2. Changes in thromboelastography (TEG â ) and thromboelastometry (ROTEM â ) parameters at term gestation (7,27 30). ROTEM â TEG â EXTEM INTEM FIBTEM APTEM R, min Shortened CT, min No changes No changes/shortened No changes No changes K, min Shortened CTF, min Shortened Shortened ( ) No changes/shortened Angle, degree Angle, degree No changes No changes No changes/increased No changes MA, min MCF, min No changes/increased LY30, % Decreased CL30, % No changes No changes No changes No changes Angle a angle, angle of a tangent to the curve at 2 mm amplitude; K/CTF, clot formation time; Ly30/CL30: percentage of lysis/clot lysis at 30 min after MA/MCF; MA/MCF, maximum amplitude/maximum clot firmness; R/CT, reaction time/clotting time. test could potentially provide diagnostic accuracy similar to that of FIBTEM (16). Several publications have established thromboelastography to be useful in diagnosing and treating coagulopathies in obstetrics, including in preeclampsia, disseminated intravascular coagulation, dilutional coagulopathy, amniotic fluid embolism and placental abruption (28,29,34 40). A Cochrane review assessed efficacy of guiding transfusions using VHA compared with standard laboratory tests and included nine RCTs (no obstetric study) (41). No statistically significant effect on mortality or surgical re-intervention was found, but the use of fresh frozen plasma (FFP) and platelets was reduced, with reduced blood loss (41). In updated reviews on cardiac surgery it has been concluded that the use of VHAs with a standardized management algorithm are important components of blood resource management (42,43). In a similar way, VHAs should be used in PPH to diagnose coagulopathy and goal-direct therapy (16,17). Improving clot strength: fibrinogen Fibrinogen (coagulation factor I) is an acute phase reactant produced in the liver and essential for effective hemostasis (44). The fibrinogen level is the most sensitive coagulation parameter to indicate hemostatic compromise during severe PPH (20). It remains to be established whether low fibrinogen levels contribute to the pathogenesis of PPH or merely reflect the severity of the PPH (5,15,20). Several studies (12, 45 51) have indicated a potential benefit of fibrinogen substitution in normalizing standard laboratory tests and TEG â /ROTEM â variables in PPH associated with hypofibrinogenemia. FFP, cryoprecipitate and human fibrinogen concentrate are the available options for fibrinogen substitution. They contain approximately 2.5, 15 and 20 g/l of fibrinogen, respectively (44,52 54). Both FFP and cryoprecipitate require thawing and cross-matching before infusion, with known potential transfusion-related complications and risks (55,56). Cryoprecipitate remains unavailable in many European countries (57). In contrast, pasteurized fibrinogen concentrate is a sterile, lyophilized concentrate made from pooled human plasma and thus transfusionrelated complications are avoided (44,52). The efficacy of fibrinogen substitution is primarily determined from cardiac surgery and trauma studies (47,56,58). There is only one published RCT assessing the efficacy and safety of fibrinogen in PPH. In the recently published FIB-PPH trial, pre-emptive treatment with 2 g of fibrinogen concentrate in women with severe PPH and normofibrinogenemia was not found to reduce rates of transfusion or to provide any clear benefit (59). An ongoing trial by Ahonen et al. (60) aims to compare prothrombin complex concentrate (PCC) and fibrinogen with FFP in PPH (ClinicalTrial.gov Identifier: NCT01910675). In a recent systematic review the use of fibrinogen concentrate was investigated in seven RCTs including 268 patients undergoing elective non-obstetrical surgery (60). Fibrinogen concentrate seemed to reduce the need for red blood cell transfusions but the included studies were of poor quality, underpowered and provided weak evidence supporting the use of fibrinogen in bleeding patients (61). These conclusions are in line with a previous systematic review (62). Thus, much of the evidence supporting the benefit of fibrinogen concentrate for PPH is based on case series, retrospective register investigations or uncontrolled, non-randomized studies. Despite this, early administration of fibrinogen has already been included in some guidelines (63). Although fibrinogen concentrate is associated with reduced bleeding and a decreased need for transfusions in non-obstetric settings, the fibrinogen concentrate cannot as yet be considered a standard treatment in PPH; however, it may be given if hypofibrinogenemia (<1 g/l) is identified as part of a goal-directed approach. The latter approach aims at reducing the rate and amount of blood products transfused, preferably guided by VHA monitoring to detect existing and/or developing coagulopathy. This goal-directed approach ideally enables rapid reversal of coagulation impairment due to dilution and consumption, by initiation and implementation of protocolized strategies that may involve the use of coagulation factor concentrates (24). 683

Hemostatic resuscitation in PPH K. Ekelund et al. Reducing clot dissolution: tranexamic acid During the coagulation process a clot is formed, consisting of fibrin strings and activated platelets. At the same time this process is counterbalanced by the fibrinolytic system to avoid thrombosis. To balance the pro-coagulant effects which occur naturally during pregnancy, fibrinolysis is increased (8). Early tissue hypoperfusion, such as with acute blood loss or in preeclampsia, may lead to endothelial up-regulation of thrombomodulin, a thrombin receptor. This receptor interacts with thrombin, leading to activation of the protein C pathway. Protein C is a natural anticoagulant that irreversibly inhibits factors Va and VIIIa, and also enhances fibrinolysis through inhibition of plasminogen activator inhibitor 1 (64). Tranexamic acid (TXA) competitively inhibits fibrinolysis by blocking lysine binding sites on plasminogen molecules, thereby preventing the activation of plasmin to plasminogen (65). Limiting the hyperfibrinolysis has been suggested as the first step in a treatment algorithm for acquired coagulopathy in PPH (34). Prophylactic use of TXA in doses of 1 g or 10 15 mg/kg has been reported in several RCTs, in order to reduce blood loss without major complications, both with regard to elective cesarean section and vaginal delivery, compared with placebo (66 75). A Cochrane review based on two of these studies (453 women) (74,75) showed that there was insufficient evidence to confirm or refute a clinically important treatment effect from TXA in PPH (76). In a subsequent open-label unblinded RCT with 144 women, TXA administration reduced blood loss and maternal morbidity parameters among women with PPH >800 ml (77). A loading dose of 4 g TXA was administered over one hour with a subsequent infusion of 1 g/h over the course of 6 h. TXA is considered to be a safe option in obstetric, trauma- and surgery-related bleeding (76,78 80). A recent review of 34 articles (including five RCTs) adds to the body of evidence in support of the use of TXA (81). In an ongoing large international multicenter RCT of TXA scheduled to include 15 000 women diagnosed with PPH (the WOMAN trial), an initial fixed dose of 1 g TXA followed by an additional 1 g is administered in the case of continuous bleeding (82). Recommendations from the 2012 World Health Organization guidelines for the management of PPH and retained placenta, advise that TXA may be offered as a treatment for PPH if: (i) administration of oxytocin followed by second-line treatment options and prostaglandins fails to stop bleeding or (ii) it is thought that the bleeding may be partly due to trauma (78). Although some guidelines suggest administration of 2 g TXA (63), we consider that the current recommendation for TXA in PPH justifies early administration of 1 g TXA, followed by an additional dose if bleeding persists. Reducing the time to initial clot formation: prothrombin complex concentrate PCC contains four vitamin K-dependent clotting factors [factors II (prothrombin), VII, IX and X] and is obtained as a highly purified concentrate from pooled plasma, thus providing a much higher hemostatic activity than the same volume of FFP. Originally, the main indication for PCC was reversal of the effect of vitamin K antagonists (83). PCCs are now also used to treat congenital or acquired factor II or factor X deficiencies, and are useful in treating massive traumatic hemorrhage (84). No published RCTs have compared PCCs with FFP in major PPH but, as previously mentioned, a trial is registered on ClinicalTrial.gov (NCT0190675) (60). Furthermore a Cochrane review on PCC for patients with vitamin K antagonists undergoing emergency surgery is anticipated to be published (85). At this stage PCCs seem to carry a minimal thromboembolic risk (86,87). So far, one case report has described the beneficial use of PCC in PPH in a patient with a non-inherited deficiency of coagulation (34). In a retrospective study of 14 obstetrical cases with disseminated intravascular coagulation (DIC), the use of PCCs failed to alter outcome (88). The use of PCCs cannot be considered as a part of standard clinical practice for PPH. Improving platelet function: desmopressin Desmopressin, 1-deamino-8-D-arginine vasopressin (DDAVP) is a synthetic analogue of the antidiuretic pituitary hormone, arginine vasopressin. In vivo, it causes increased factor VIII levels and stimulates the release of von Willebrand factor from endothelial cells, which promotes platelet adhesion to wound sites. DDAVP can been used to correct the anti-hemostatic effect of aspirin and clopidogrel (89), and can also be applied as part of the treatment for platelet dysfunction or von Willebrand s disease. A recent study indicated reduced levels of fibrinogen following DDAVP administration despite consistent fibrin polymerization. As such it seems reasonable to monitor fibrinogen levels when considering DDAVP for perioperative bleeding (90). A meta-analysis of 38 RCTs (2488 non-obstetric patients) investigated the role of DDAVP in surgery and found a minimal reduced perioperative blood loss and transfusion requirements without reduction in the proportion of patients receiving transfusions (91). The same conclusion was reached in a later published Cochrane review investigating the requirement of blood transfusions for liver resections (92). A recent review concluded that DDAVP in selected cases is effective in reducing bleeding complications associated with pregnancy and childbirth 684

K. Ekelund et al. Hemostatic resuscitation in PPH with a good safety profile (93). Further research is needed to confirm the latter approach, as these recommendations are currently based on findings from small studies and case series. DDAVP is warranted when dysfunctional platelet activity is monitored and suspected to contribute to the PPH, but cannot be considered part of standard treatment. Improving the fibrin clot: recombinant factor VIIa Recombinant factor VIIa (rfviia) (NovoSeven â ; Novo Nordisk A/S, Bagsvaerd, Denmark) was licensed for treatment of bleeding episodes in patients with congenital hemophilia A or B, with factor VII deficiency or with Glanzmann s thrombasthenia with anti-gpiib/iiia antibodies (94,95). rfviia was introduced as an off-label drug for intracerebral hemorrhage and trauma patients (96,97). Supra-normal levels of rfviia cause a thrombin burst following generation of a prothrombinase complex (98,99). The fibrin clot formed in the presence of high thrombin concentration is stronger and more resistant to degradation by fibrinolytic enzymes compared with a normal clot. This clot formation requires the presence of adequate amounts of fibrinogen and platelets (100). The evidence regarding the benefit of rfviia for PPH with excessive microvascular bleeding (i.e. coagulopathy) is based on a few case series, retrospective register investigations and uncontrolled, non-randomized studies (101 109). Currently rfviia is not recommended for routine treatment of PPH (78,110), but off-label use of rfviia (60 90 lg/kg) is suggested in a few guidelines as a last resort (17,18,63,111,112). At ClinicalTrial.gov, a RCT is registered with the aim to evaluate the potential of a unique early infusion of rfviia (60 lg/kg) compared to standard therapy (NCT00370877) (113). Recruitment was completed in February 2012, but no data have been published. In a systematic review evaluating benefits and harms of in-hospital use of rfviia for off-label indications (intracranial hemorrhage, cardiac surgery, trauma, liver transplantation, prostatectomy), the authors found no reduction in mortality, whereas rfviia increased the risk of thromboembolism (114). Similar increased risks of arterial thromboembolism were found in 35 RCTs (4468 non-obstetrical patients) for off-label indications (115). In obstetrics, thromboembolic events were registered in 2.5% of 272 women with PPH and treated with rfviia (104). rfviia should only be considered for use as a rescue drug, and cannot be recommended as part of standard PPH treatment. Hypofibrogenemia, thrombocytopenia, hypothermia and acidosis should be treated by a standard protocol, before considering administration of rfviia. Balanced transfusion therapy to ensure circulation, oxygenation and hemostasis There are currently no data from RCTs on optimal transfusion strategy in PPH. The published incidence of PPH where transfusion is required has been reported as 0.26 2.7% of pregnancies (5). PPH has traditionally been termed as severe, massive or major to describe the seriousness of the clinical situation (14,102,108,116,117). Instead, it seems more sensible to differentiate between controlled and uncontrolled hemorrhage in an acute clinical setting. How to manage uncontrolled hemorrhage Uncontrolled bleeding is a life-threatening condition and requires emergency intervention due to hemodynamic instability (118). Based on a extrapolation of knowledge from trauma management to the PPH situation, and before transfusing packed red blood cells (PRBCs), the initial treatment of uncontrolled PPH is often administration of intravenous fluids (crystalloids or colloids), since anemia is better tolerated than hypovolemia, regardless of the cause of fluid loss (119). Crystalloids are often the preferred choice, since colloids may induce coagulopathy and hypocoagulability (120). Likewise, infusion of excessive amounts may increase hemorrhage and mortality due to the so-called dilutional coagulopathy (121,122). Transfusion with O Rh (D) negative blood must be prioritized, prior to obtaining the initial hemoglobin count, or other standard laboratory tests. Transfusion of PRBC, FFP and platelets should follow a transfusion protocol in accordance with national or international transfusion guidelines (123). In the PROMMTT study, early and balanced transfusions were associated with decreased mortality in trauma patients within six hours of admission (124). The management of uncontrolled hemorrhage with blood products has evolved from increasing evidence gained in the management of civilian and military trauma. Current practice from the USA and UK military is to treat massive hemorrhage after trauma with FFP and PRBC in a 1:1 ratio (125,126). Likewise, administration of platelets is recommended in a 1:1 ratio with PRBC (127). Transfusion of PRBC:plasma:platelets in a 1:1:1 ratio, resembling the ratio found in fresh whole blood, has been compared with a 1:1:2 ratio in a multicenter RCT setting among trauma patients (128). The study was completed in December 2013 but no results have been published. In PPH, a high ratio of FFP:PRBC is associated with fewer hemostatic interventional procedures (129). Lessons learned from trauma settings seem equally applicable for the management of uncontrolled PPH (129 131). Transfusion practices should be evaluated criti- 685

Hemostatic resuscitation in PPH K. Ekelund et al. cally since higher mortality has been reported in association with increased transfusion requirements among trauma patients. How to manage a controlled hemorrhage Despite the ongoing debate on how to manage a controlled PPH setting, there seems to be a general acceptance of the need for early transfusion, but without solid evidence in favor of a golden transfusion strategy or an optimal PRBC, FFP and platelet ratio such as 1:1:1 (118). Retrospective or descriptive studies support a tendency towards administration of higher ratios of PRBC units in PPH, often empirically and without guidance from paraclinical and laboratory tests (132 134). The implementation of hemostatic control strategies in acute but controlled bleeding settings based on the use of transfusion packages with PRBCs, FFPs and platelets, guided by TEG â or ROTEM â, appears to be associated with reduced transfusion requirements in the peri- and postoperative period, with reduced mortality (135). In addition, rapid early replacement of coagulation factors and platelets has gained importance in the management of bleeding patients (101). Noticeably, in a recent RCT a restrictive postoperative transfusion strategy was well tolerated compared with a liberal strategy in PPH (136). A systematic review has shown reduced health care-associated infection risks in association with a restricted RBC transfusion strategy, compared with a liberal approach (137). Transfusion-related complications Approximately 1 in 30 000 transfused RBC units are ABOincompatible, and 1 in 500 000 deaths is due to ABO incompatibility (138). Other immune-mediated causes of transfusion-related morbidity and mortality identified, include hemolytic transfusion reactions, allergic and anaphylactic reactions, transfusion-related acute lung injury and transfusion-associated graft-versus-host disease (136). Transfusion-related complications are not restricted to giving PRBC (139 141). Despite increased safety strategies, transfusion complications remain a major concern in the management of the bleeding patient (142). It is essential to emphasize that human errors are the most common cause of incorrect blood component transfusion (142). Alternative to allogeneic red blood cell transfusions: cell savers Intraoperative cell salvage offers a technique for possible reduction of homologous blood transfusions. Blood is aspirated from the surgical field and filtered into a collecting reservoir. Up-concentrated washed packed red cells can be re-infused. Although evidence is limited (143,144), the use of cell salvage is recommended in the UK. A theoretical concern with the use of cell salvage in obstetrics is the occurrence of iatrogenic amniotic fluid embolism, but no adverse events have been published (143,145). Although the safety and efficacy of cell salvage appears promising, there is still no high-level evidence to support its use in obstetrics. Discussion PPH requires early recognition, immediate control of the bleeding (including medical, mechanical and surgical interventions), rapid stabilization of the patient, and early activation and involvement of multi-professional and multi-disciplinary clinical management. In recent years, there has been an increasing emphasis on treatment of PPH to include potential use of fibrinogen and TXA and the introduction of VHA-guided strategies and protocols as important supplements to uterotonic agents and surgery. In several international PPH guidelines, early administration of fibrinogen and TXA has already been introduced. However, solid evidence supporting this is lacking, and the results from an on-going randomized trial have not yet been published (59,82). In the uncontrolled PPH situation, early adminstration of intravenous crystalloids, O Rhesus-negative blood should be initiated together with plasma and platelet transfusions in a balanced 1:1:1 ratio (PRC:FFP:platelets). Transfusions should be halted as soon as bleeding is controlled, with a shift towards a restrictive and goal-directed use of blood components. VHA-guided transfusion or supplement therapy may be preferred. Although VHAguided transfusion strategies lead to reduced bleeding and a decreased need for hemostatic transfusions, large RCTs of PPH are needed to confirm benefits in terms of morbidity and mortality. Ideally, VHAs should be performed by designated authorized personnel instead of using bedside analyses done by the clinicians themselves. Such a set-up can ensure valid VHA interpretation of results and support patient-focused clinicians who receive professional guidance. Most importantly, in a global perspective, we urgently need evidence and knowledge to improve the treatment of women in impoverished undeveloped countries where basic blood transfusion practices are nearly non-existent and where considerable effort and innovation is required. Conclusion It is essential that clinicians are aware of the content of local, national and international guidelines for management of PPH in order to provide the best possible patient 686

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