Hippokratia 2016, 20(3):179-186
Petrou A1, Tzimas P1, Siminelakis S2
1Department of Anesthesiology and Postoperative Intensive Care, 2Department of Cardiothoracic Surgery, Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, Hellas
Background: Severe or massive bleeding in cardiac surgery is an uncommon but important clinical scenario. Its existing definitions are diverse. Its characteristics constantly change during an active hemorrhage and, thus is difficult to define appropriately.
Methods: In this narrative, non-systematic review, we performed a literature search to retrieve data that could contribute to answering clinical questions on the definition and grading of severe hemorrhage and massive transfusion, identifying factors that predict and affect bleeding and transfusion-related mortality and describing the risks of re-exploration and the economic impact of severe bleeding in cardiac surgery.
Results: Massive perioperative bleeding is currently described by indices of its rate and extent and the magnitude of the consequent blood products transfusion. It has a significant impact on mortality, service logistics, and hospital financing. Proper and early identification of a massive bleeding is possible. Among other factors, patient’s co-morbidities, bleeding severity and transfusion volume seem to predict the associated mortality. Consequent to severe bleeding, re-exploration, is also a potentially hazardous adverse event that also affects morbidity and mortality.
Conclusions: Severe perioperative hemorrhage in cardiac surgery carries significant morbidity and mortality. Currently, prediction and identification of massive bleeding is a feasible but incomplete clinical task despite the availability of effective treatment regimens. A still missing, compact definition of massive perioperative bleeding in cardiac surgery that incorporates all phases of treatment could augment clinical preparedness, allow for the development of accurate prediction tools and permit the application of well-validated protocols of management. Hippokratia 2016, 20(3): 179-186.
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Key words: Massive bleeding, severe bleeding, massive transfusion, cardiac surgery, adult
Severe or massive hemorrhage in cardiac surgery is an infrequent but clinically significant event. Estimations vary considerably (2-10 %) depending on the definition of massive hemorrhage but are nevertheless associated with high mortality1-5.
Failed or delayed treatment of a massive bleeding can result in irreversible end-organ damage (e.g., renal failure), cardiovascular events (e.g., stroke, myocardial injury) or death, accompanied by significantly increased costs6,7. Massive transfusion protocols are effective in reducing large volume [>five units of red blood cells (RBC)] transfusion rate (from 15.9 % to 8.5 %) as well as massive (>10 units of RBC) transfusion incidence and re-exploration rate (4.6 % to 2.6 % and 5.6 % to 3.4 % respectively)8-12. But they are usually anchored on various definitions of massive bleeding and thus are quite often incomparable regarding triggers, timing, and extent of intervention.
Conforming with the need for appropriate identification of a potentially lethal massive bleeding episode13, we performed a review of the literature in order to contribute to the following objectives: How do we currently define massive bleeding and transfusion in cardiac surgery? Can we predict massive bleeding? Does massive bleeding affect mortality? Can we make any predictions about it? Is re-exploration risky? Is there an economic impact of such a bleeding event?
We aimed at describing the existing definitions of massive bleeding and massive transfusion in cardiac surgery and comment on their diversity. So, we searched PubMed for articles defining massive bleeding, massive transfusion, and massive transfusion protocols in adult cardiac surgery, focusing on the last ten years (2006-2016). We used the following search words: massive or severe bleeding, massive or severe hemorrhage, massive transfusion, cardiac surgery. We then expanded this search to guidelines on bleeding in cardiac surgery and retracted additional literature to support our statements in the text. Duplicate and irrelevant articles were excluded from further analysis (Figure 1).
Figure 1: Flow chart of the recovered and analyzed studies in PubMed regarding articles defining massive bleeding, massive transfusion, and massive transfusion protocols in adult cardiac surgery, focusing on literature of the last ten years (2006-2016).
We proceeded in discussing the various predictors of massive bleeding and transfusion and collected data on the existing prediction models. Then we tried to retrieve data on the bleeding associated mortality, the impact of massive bleeding and re-exploration on patient mortality rates and describe its implications on hospital finances. Retrieved studies that do not refer in detail to the rates of blood volumes lost perioperatively or amounts and ratios of blood products transfused to confirm fitting to any massive bleeding definition, were not used in the reporting of definitions of massive bleeding and transfusion that we were seeking.
The descriptive nature of the answers in search and the lack of homogeneity of the collected data precluded a structured systematic review and meaningful statistical analysis of the retrieved data. Thus, a narrative but comprehensive review of the declared topics is presented.
From the 226 articles retrieved, only a few deal with the definition of massive transfusion in cardiac surgery and most studies use arbitrarily chosen custom definitions (Figure 1, supplementary Table 1AS, supplementary Table 1BS)3,7,10,14-25. Twenty-two articles provide sufficient data on bleeding rates and transfusion of blood products in cases of severe or massive bleeding3,7,10,14-32. Among them, five case reports on massive bleeding were judged useful for their reporting data28-32. Six other studies although not providing adequate data for comparison, offer useful details on outcomes of severely or massively bleeding patient groups (supplementary Table 1AS, supplementary Table 1BS)1,33-37. We also retrieved three recent guideline articles from the major Anesthesiologist and Cardiothoracic Surgeon Societies38-40 and we commented on their contribution.
What is massive bleeding?
As clinicians recognize that measurement of actual blood loss in the setting of a massive bleeding episode is unreliable41, many of the given definitions of massive bleeding are based on the resultant transfusion of blood products42.
According to the Hemostasis Score10,42, intraoperativemassive hemorrhage is present when operating field blood loss exceeds 600 ml/h necessitating, among other measures, the intermittent application of packing and when the chest drains poor out >300 mL/h or 150 ml/h of blood for two hours postoperatively (67 % positive predictive value)10.The PLASMACARD study defined excessive bleeding as abnormal diffuse or microvascular bleeding that cannot be controlled by compression and electrocoagulation, necessitates >two or three units of RBC transfusion or >400 or 600 mL of cell salvage blood depending on patient’s weight (less or more than 60 kg, respectively) and a postoperative drain output of >1.5 mL/kg/h for at least three hours or a need for surgical re-exploration for hemostasis during the first 48 hours15.
The universal definition of perioperative bleeding in cardiac surgery (UDPB)2 attempted a more holistic approach. It uses five classes of bleeding (0: insignificant, 1: mild, 2: moderate, 3: severe, 4: massive) and considers a bleeding as severe when sternal closure is delayed (left open or packed for hemostatic issues), or five to ten units of RBC or fresh frozen plasma (FFP) have been transfused to the patient after chest closure, or the chest drains exceed 1,000 ml/12h or surgical re-exploration has already been applied. Massive bleeding occurs when more than ten units of RBC or FFP have been transfused, or drains exceed 2,000 ml/12h or when the administration of recombinant activated factor VII (rFVIIa) was judged compulsory to stop bleeding. Perioperative RBC transfusions for compensation for the extracorporeal circulation hemodilution were not included in the definition2.
The BART study and the BRiSc (Papworth Bleeding Risk Score) use only postoperative indices for massive or excessive bleeding (BART: chest drainage of >1.5 L within any eight-hour-period postoperatively - approximating a mean rate of 200 ml/h, the evolution of cardiac tamponade, re-exploration for or death from bleeding; BRiSc: mean blood loss exceeding 2 ml/kg/h between arrival in ICU and the earliest of the following events: the elapse of three hours; the start of transfusion of any one of FFP, PLT or cryoprecipitate; return to theatre or death)37. Of note, intraoperative bleeding and the consequent transfusion of blood products were considered “standard surgical practice” and were not taken into account in this study1. Karkouti et al consider the administration of more than five units of RBC within 24 hours as the cutoff point for identifying massive bleeding and confirmed this transfusion to correspond to one blood volume substitution (considering a normal preoperative Hb concentration of 16 g/dL, a blood volume of 70 ml/kg and a trigger of 8 g/dL of Hb to transfuse RBC)43. Some studies identify massive bleeding in the transfusion of four or more RBC during hospitalization33 while others as a chest tube drainage of more than 1,000 ml either at discharge from ICU or until removal of drains26.
What is massive transfusion?
Despite the fact that huge amounts of blood products can be transfused in complex cardiac surgery [for instance 29.4 RBC units, 27.7 FFP units and 39 platelet (PLT) units in patients undergoing heart transplant or implantation of heart/lung support devices]44, current definitions of massive transfusions are far less impressive. In a transfusion cohort of 104 cardiothoracic surgery patients who received massive transfusions per three different definitions (5/4h, 6/6h, 10/24h, meaning the administration of equal or more than five, six or ten units of RBC within any four-, six- or 24-hour-period) found that those in the 5/4h definition had significantly better survival rates compared to those who met 6/6h and 10/24h definitions (88.4 % vs 71.1 % respectively)45. The BART study used the 10/24h criterion as an indication for massive transfusion37.
The most recent European Society of Anesthesiologists (ESA) guidelines on severe perioperative bleeding, the Society of Thoracic Surgeons (STS) blood conservation clinical practice guidelines and the American Society of Anesthesiologists (ASA) practice guidelines for perioperative blood management recommend the incorporation of indices that reflect oxygen availability in the mixed venous blood (mixed venous oxygen saturation) and the cerebral tissue (near infrared spectrometry) into the decision making for RBC transfusion but detail neither cutoff values nor appropriate combinations of them with other indices38-40.
Predictors of massive bleeding and transfusion
There are quite many transfusion prediction scores available in the literature. Most of them have been produced in the last decade, have been validated accordingly and possibly predict even massive transfusion events (Table 1, supplementary Table 2S)1,33,46-49.
Age, female gender, somatometric data [weight, height or Body Mass Index (BMI)], and renal function (mainly as serum creatinine levels), left ventricle ejection fraction, a preoperative shock state [defined either clinically or with the use of intra-aortic balloon pump (IABP)], logistic EuroSCORE (European System for Cardiac Operative Risk Evaluation), preoperative hemoglobin, cardiopulmonary bypass time, emergency status of the operation, recent cardiac catheterization, other co-morbidities [recent myocardial infarction (MI), congestive heart failure, non-smoker, New York Heart Association (NYHA) classification], coagulation defect [elevated international normalized ratio (INR), elevated bleeding time], preoperative heparin, preoperative antiplatelet drugs, lowest temperature during cardio pulmonary bypass (CPB), protamine insufficiency or excess, the use of antifibrinolytic drugs, large volumes of intraoperative salvaged cells transfused, multiple coronary anastomoses, special types of surgery (namely heart transplant or the implantation of mechanical circulatory support devices), prior cardiac surgery with significant blood loss and the lactate levels when admitted to the intensive care unit (ICU) postoperatively, have all previously been associated with an increased risk of postoperative bleeding in general or for severe postoperative bleeding2,25,26,2250-53. In one study, recent intake of clopidogrel or dual antiplatelet therapy led to increased incidence of re-exploration (10.2 and 8.2 vs 3.9 %, p <0.005) and increased the probability of transfusion (54.2 % and 57.5 % vs 29.8 %, p <0.0001)26.
In a few but important studies, BRiSc seems to perform poorly in severe bleeding1,54,55. while the Transfusion Risk Score (TRS) presented adequate discrimination ability [Area Under the Curve (AUC): 0.7827 at the validation]49. The Transfusion Risk Understanding Scoring Tool (TRUST) score presented excellent calibration (Hosmer-Lemeshow χ2 2.192, p =0.70 at external validation) whereas the LITMATHE and the TRS achieved low discrimination indices (Hosmer-Lemeshow χ2 12.6, p =0.049 and 21.8, p <0.001, respectively)46.
A few scores have been produced specifically for prediction of severe or massive perioperative bleeding (Table 2, supplementary Table 3S). The Karkouti et al score has negative predictive value for low risk of transfusion at 95 % and a positive predictive value for the high-risk group over 60 %25. The large volume blood transfusion score (LVBT) was developed and tested on a multicenter study population (n =27,353)33. It presented excellent calibration and discrimination (AUC: 0.8 at validation) and performed better that the other three, all transfusion category models (TRUST: AUC: 0.71, TRACK: AUC: 0.71, BRiSc: AUC: 0.69)33, but it should be noted that multiple parameters can distort prediction models calibration33.
Viscoelastic methods like the Sonoclot® test (Sienco Inc., Arvada, CO, USA), performed after heparin reversal can effectively identify bleeders (those with >800 ml/4h drain output) in cardiac surgery12,14,whereas thromboelastometry guidance decreases the total number of blood products transfused as well as the total number of patients suffering massive transfusion20,34.
Given that surgeon’s skills (some surgeons perform better than others in the average blood loss during a certain operation), contribute statistically significantly to perioperative bleeding, it seems that the entire setting, within which any procedure is carried out, affects considerably either clinical or investigational outcomes26,55. Research has discovered significant correlation of genes rs1799809 (related to protein C activity), rs27646 (related to glycoprotein Ia) and rs1062535 (which codes for the alpha chain of the platelet collagen receptor integrin α2β1), rs630014 (in the ABO gene), and rs6048 (which codes for the coagulation factor IX pre-protein) with excessive postoperative bleeding (defined either as drain output >2 ml/kg/h or according to the universal definition)56.
Independent predictors of mortality in massive bleeding and transfusion
Perioperative transfusion (irrespective of its magnitude or kind of blood products transfused) was found to be a significant contributor to short and long-term (one to five years) postoperative mortality with a sharp effect during the first six months (risk ratio of 2.4, 95 % confidence interval: 2.0 to 2.8; p <0.001)57,58.In another study, each RBC unit increased the probability of death by 77 % and the risk of infection by 23 %5,59. The TRACS study found that the transfusion of more than six units of RBC had a hazard ratio (HR) of 9.7 for mortality despite comparable mortality rates in the groups with restricted vs liberal transfusion policies60. The coexistence of massive bleeding (exceeding 900 ml/12h or undergoing surgical revision for bleeding), RBC transfusions (of any amount) and preoperative anemia (hematocrit <36 %) correlates with significantly higher mortality (7.5 % adjusted, 24.2 % unadjusted) than any other combination of these three variables and constitute the “deadly triad” in cardiac surgery that is associated with increased thromboembolic events, postoperative infections, and re-exploration61.
There are only a few studies dealing with the prediction of mortality after a massive bleeding in cardiac surgery (Table 3, supplementary Table 4S). EuroSCORE, severity of transfusion and hemostatic indices [PLT, INR, activated Partial Thromboplastin Time (aPTT) ratio] seem to predict perioperative mortality after a massive bleeding (supplementary Table 4S)2,25,43, but INR prolongation carries decreased specificity in identifying patients with low factor VII activity and aPTT also has low positive predictive value for clotting factor deficiencies peri-operatively62.
The risks of re-exploration
Multiple studies have proven that re-exploration for bleeding carries an increased risk of morbidity and mortality, irrespective of the magnitude of accompanying transfusion63-66. A very recent one describes a mean re-exploration rate of 6 % for elective [4.5 % for coronary artery bypass grafting (CABG), 5.5 % for single valve surgery, 9.6 % for combined surgery and 7.9 % for the rest of their cardiac surgery cohort] and 15 % for emergency surgery67. Re-exploration is significantly associated with increased mortality (7.6 % vs 2.4 % for those without re-exploration, unadjusted rate) and more perioperative stroke, renal dysfunction, prolonged mechanical ventilation and increased need for mechanical circulatory support63,67. Unfortunately, almost one-third to one-half of all re-explorations fail to discover the source of bleeding65,67. Low BMI, high EuroSCORE, low preoperative fibrinogen plasma concentration, long extracorporeal circulation time, combined heart valve and coronary artery bypass operations, and dual antiplatelet therapy within five days are considered independent risk factors for re-exploration65,67.
The Bedside Risk Score accurately predicts the need for re-exploration due to hemorrhage55. It reveals decreasing mortality from re-operation for bleeding over time but predicts increasing rates for severe bleeding due to the new oral anticoagulants administration55.
The economic impact of severe bleeding.
Perioperative bleeding seems to be quite costly, independent of the costs of agents used to treat it68. In complex cardiac surgery the cost of care for transfused patients (receiving at least one unit of RBC, FFP, PLT or cryoprecipitate) is 133.2 % greater compared with those not transfused ($50,344 vs $21,590, for RBC, FFP, PLT as well as fibrin sealants, tranexamic acid, protamine, rFVIIa and cell saver use)68,69. One study attempted to evaluate the economic impact of severe postoperative bleeding7. It found that patients that bled severely (1,669 ± 1,170 ml) required almost double the cost of treatment compared with those without severe bleeding (€15,404 ± €8,986 vs €8,027 ± €7,557). When adjusting for potential confounding factors, the incremental costs of excessive postoperative hemorrhage was determined at €6,251 (95 % confidence interval, €4,594-7,909)7. These costs compare to those reported in an older study in CABG patients that required re-exploration for bleeding (or bled >800 ml/4h postoperatively)69.
The current concept of early coagulation support during bleeding by adopting structured, monitored and targeted coagulation factor administration has been proven effective in treating perioperative bleeding in cardiac surgery70,71. Cases that do not respond to treatment eventually end up in massive bleeding (up to 8.3 % in complex cardiac surgery, or from one in 50 up to one in 10 patients)24.
Unquestionably, severe or massive bleeding imposes additive morbidity and mortality burden in cardiac surgery patients (an eight-fold increase of death probability), just next to low cardiac output syndrome, perioperative stroke, and acute and chronic renal failure18,43.
Massive bleeding and massive transfusion are not identical entities and should not be used interchangeably. The deleterious effects of massive bleeding (acute anemia, hypovolemia, hypotension, end-organ ischemia, compensatory stress reaction) are different in origin and effect from those arising from massive transfusion (immunological reaction, blood storage lesion, dilution effect)42. Additionally, very high bleeding rates (>150 ml/min) sometimes last only for a few minutes and then cease due to prompt surgical intervention, so the rate of bleeding cannot be used as the sole indicator for a massive transfusion.
The universal definition of perioperative bleeding seems to be quite inclusive for most cases of severe bleeding2. The Hemostasis Score more effectively describes an intraoperative bleeding episode, albeit with increased complexity in estimating the true blood loss in the operating field. To the contrary, some of the proposed extended time frame observations (such as 2,000 ml/12 hours which equals approximately to 170 ml/h)2 might delay the identification of a true massive bleeding24,37,43.So, it seems imperative to further improve the definition of massive bleeding in a more comprehensive way.
Some prediction models (like the TRS and TRUST or LVBT for massive bleeding) perform quite satisfactory and perhaps could be implemented in identifying patients with a potentially severe bleeding. But most available data indicate that we currently cannot effectively predict which patient is going to bleed significantly. This is probably due to the dual nature of postoperative bleeding that cannot be adequately depicted in the proposed predictors: an initial systemic hypo-coagulation phase, secondary to excessive consumption and/or dilution of both clotting factors and platelet-mediated hemostasis and a subsequent phase of a more persistent, regional fibrinolytic bleeding in the mediastinum72.
The point of care testing with elastometric and other analog techniques seem to contribute significantly to the perioperative management of severe bleeding. In cardiac surgery, thromboelastometry and thromboelastography, as well as other point-of-care methods of coagulation monitoring, have proven quite effective in predicting excessive hemorrhage, reducing perioperative bleeding, transfused blood products and associated morbidity, but their effect on mortality is still debatable11,14,73-75.
The main limitation of this review is its narrative nature. A structured, systematic review and a consequent meaningful meta-analysis was hindered by the heterogeneity of the studies regarding massive bleeding definition and lack of adequate available data on perioperative transfusions.
Massive bleeding in cardiac surgery is a dynamic clinical entity that requires a more accurate definition due to its temporally fluctuating nature and etiology. It contributes to significant perioperative mortality, impacts blood banks and pharmacy logistics and heightens hospital expenses. Given that multiple and sometimes interrelated factors are responsible for its appearance and clinical course, a definition of massive perioperative bleeding in cardiac surgery that incorporates all leading aspects and phases of the event could allow for adequate clinical preparedness and hopefully augment management efficacy.
Conflict of interest
No author has any conflict of interest with the material presented in this review.
We would like to thank Dr Georgios Papadopoulos, Professor of Anesthesiology and Intensive Care, and Dr Efstratios Apostolakis, Professor of Cardiothoracic Surgery for their comprehensive guidance and tireless support in the preparation of the manuscript.
In the electronic version of the paper supplementary material is provided that contains detailed data on the studies reviewed. Supplementary Table 1AS and Table 1BS summarize the twenty-two articles that provide sufficient data on bleeding rates and transfusion in cases of severe or massive bleeding in cardiac surgery. Supplementary Table 2S and Table 3S summarize the prediction models for perioperative bleeding in cardiac surgery while Supplementary Table 4S summarizes the few studies dealing with the prediction of mortality after massive bleeding in cardiac surgery. Also a separate reference list is provided regarding the papers included in the supplementary Tables as some studies presented in these Tables are not detailed in the Review and the original reference list.
1. Vuylsteke A, Pagel C, Gerrard C, Reddy B, Nashef S, Aldam P, et al. The Papworth Bleeding Risk Score: a stratification scheme for identifying cardiac surgery patients at risk of excessive early postoperative bleeding. Eur J Cardiothorac Surg. 2011; 39: 924-930.
2. Dyke C, Aronson S, Dietrich W, Hofmann A, Karkouti K, Levi M, et al. Universal definition of perioperative bleeding in adult cardiac surgery. J Thorac Cardiovasc Surg. 2014; 147: 1458-1463.e1.
3. Karkouti K, Beattie WS, Arellano R, Aye T, Bussieres JS, Callum JL, et al. Comprehensive Canadian review of the off-label use of recombinant activated factor VII in cardiac surgery. Circulation. 2008; 118: 331-338.
4. Christensen MC, Dziewior F, Kempel A, von Heymann C. Increased chest tube drainage is independently associated with adverse outcome after cardiac surgery. J Cardiothorac Vasc Anesth. 2012; 26: 46-51.
5. Koch CG, Li L, Duncan AI, Mihaljevic T, Cosgrove DM, Loop FD, et al. Morbidity and mortality risk associated with red blood cell and blood-component transfusion in isolated coronary artery bypass grafting. Crit Care Med. 2006; 34: 1608-1616.
6. Ranucci M. Hemostatic and thrombotic issues in cardiac surgery. Semin Thromb Hemost. 2015; 41: 84-90.
7. Christensen MC, Krapf S, Kempel A, von Heymann C. Costs of excessive postoperative hemorrhage in cardiac surgery. J Thorac Cardiovasc Surg. 2009; 138: 687-693.
8. Pearse BL, Smith I, Faulke D, Wall D, Fraser JF, Ryan EG, et al. Protocol guided bleeding management improves cardiac surgery patient outcomes. Vox Sang. 2015; 109: 267-279.
9. Gross I, Seifert B, Hofmann A, Spahn DR. Patient blood management in cardiac surgery results in fewer transfusions and better outcome. Transfusion. 2015; 55: 1075-1081.
10. Greilich PE, Edson E, Rutland L, Jessen ME, Key NS, Levy JH, et al. Protocol adherence when managing massive bleeding following complex cardiac surgery: a study design pilot. J Cardiothorac Vasc Anesth. 2015; 29: 303-310.
11. Görlinger K, Dirkmann D, Hanke AA, Kamler M, Kottenberg E, Thielmann M, et al. First-line therapy with coagulation factor concentrates combined with point-of-care coagulation testing is associated with decreased allogeneic blood transfusion in cardiovascular surgery: a retrospective, single-center cohort study. Anesthesiology. 2011; 115: 1179-1191.
12. Weber CF, Görlinger K, Meininger D, Herrmann E, Bingold T, Moritz A, et al. Point-of-care testing: a prospective, randomized clinical trial of efficacy in coagulopathic cardiac surgery patients. Anesthesiology. 2012; 117: 531-547.
13. Mitra B, Rainer TH, Cameron PA. Predicting massive blood transfusion using clinical scores post-trauma. Vox Sang. 2012; 102: 324-330.
14. Bischof DB, Ganter MT, Shore-Lesserson L, Hartnack S, Klaghofer R, Graves K, et al. Viscoelastic blood coagulation measurement with Sonoclot predicts postoperative bleeding in cardiac surgery after heparin reversal. J Cardiothorac Vasc Anesth. 2015; 29: 715-722.
15. Doussau A, Perez P, Puntous M, Calderon J, Jeanne M, Germain C, et al; PLASMACARD Study Group. Fresh-frozen plasma transfusion did not reduce 30-day mortality in patients undergoing cardiopulmonary bypass cardiac surgery with excessive bleeding: the PLASMACARD multicenter cohort study. Transfusion. 2014; 54: 1114-1124.
16. Tanaka KA, Egan K, Szlam F, Ogawa S, Roback JD, Sreeram G, et al. Transfusion and hematologic variables after fibrinogen or platelet transfusion in valve replacement surgery: preliminary data of purified lyophilized human fibrinogen concentrate versus conventional transfusion. Transfusion. 2014; 54: 109-118.
17. Andersen ND, Bhattacharya SD, Williams JB, Fosbol EL, Lockhart EL, Patel MB, et al. Intraoperative use of low-dose recombinant activated factor VII during thoracic aortic operations. Ann Thorac Surg. 2012; 93: 1921-1928; discussion 1928-1929.
18. Chapman AJ, Blount AL, Davis AT, Hooker RL. Recombinant factor VIIa (NovoSeven RT) use in high risk cardiac surgery. Eur J Cardiothorac Surg. 2011; 40: 1314-1318; discussion 1318-1319.
19. Williams JB, Phillips-Bute B, Bhattacharya SD, Shah AA, Andersen ND, Altintas B, et al. Predictors of massive transfusion with thoracic aortic procedures involving deep hypothermic circulatory arrest. J Thorac Cardiovasc Surg. 2011; 141: 1283-1288.
20. Girdauskas E, Kempfert J, Kuntze T, Borger MA, Enders J, Fassl J, et al. Thromboelastometrically guided transfusion protocol during aortic surgery with circulatory arrest: a prospective, randomized trial. J Thorac Cardiovasc Surg. 2010; 140: 1117-1124.e2.
21. Willis C, Bird R, Mullany D, Cameron P, Phillips L. Use of rFVIIa for critical bleeding in cardiac surgery: dose variation and patient outcomes. Vox Sang. 2010; 98: 531-537.
22. Masud F, Bostan F, Chi E, Pass SE, Samir H, Stuebing K, et al. Recombinant factor VIIa treatment of severe bleeding in cardiac surgery patients: a retrospective analysis of dosing, efficacy, and safety outcomes. J Cardiothorac Vasc Anesth. 2009; 23: 28-33.
23. Wasowicz M, Meineri M, McCluskey SM, Mitsakakis N, Karkouti K. The utility of thromboelastography for guiding recombinant activated factor VII therapy for refractory hemorrhage after cardiac surgery. J Cardiothorac Vasc Anesth. 2009; 23: 828-834.
24. Trowbridge C, Stammers A, Klayman M, Brindisi N, Woods E. Characteristics of uncontrolled hemorrhage in cardiac surgery. J Extra Corpor Technol. 2008; 40: 89-93.
25. Karkouti K, O’Farrell R, Yau TM, Beattie WS; Reducing Bleeding in Cardiac Surgery Research Group. Prediction of massive blood transfusion in cardiac surgery. Can J Anaesth. 2006; 53: 781-794.
26. Kremke M, Tang M, Bak M, Kristensen KL, Hindsholm K, Andreasen JJ, et al. Antiplatelet therapy at the time of coronary artery bypass grafting: a multicentre cohort study. Eur J Cardiothorac Surg. 2013; 44: e133-e140.
27. Chen L, Bracey AW, Radovancevic R, Cooper JR Jr, Collard CD, Vaughn WK, et al. Clopidogrel and bleeding in patients undergoing elective coronary artery bypass grafting. J Thorac Cardiovasc Surg. 2004; 128: 425-431.
28. Stein P, Bosshart M, Brand B, Schlicker A, Spahn DR, Bettex D. Dabigatran anticoagulation and Stanford type A aortic dissection: lethal coincidence: Case report with literature review. Acta Anaesthesiol Scand. 2014; 58: 630-637.
29. Warkentin TE, Margetts P, Connolly SJ, Lamy A, Ricci C, Eikelboom JW. Recombinant factor VIIa (rFVIIa) and hemodialysis to manage massive dabigatran-associated postcardiac surgery bleeding. Blood. 2012; 119: 2172-2174.
30. Barua A, Rao VP, Ramesh B, Barua B, El-Shafei H. Salvage use of activated recombinant factor VII in the management of refractory bleeding following cardiac surgery. J Blood Med. 2011; 2: 131-134.
31. Bishop CV, Renwick WE, Hogan C, Haeusler M, Tuckfield A, Tatoulis J. Recombinant activated factor VII: treating postoperative hemorrhage in cardiac surgery. Ann Thorac Surg. 2006; 81: 875-879.
32. van de Garde EM, Bras LJ, Heijmen RH, Knibbe CA, van Dongen EP, Wiltink EH, et al. Low-dose recombinant factor VIIa in the management of uncontrolled postoperative hemorrhage in cardiac surgery patients. J Cardiothorac Vasc Anesth. 2006; 20: 573-575.
33. Goudie R, Sterne JA, Verheyden V, Bhabra M, Ranucci M, Murphy GJ. Risk scores to facilitate preoperative prediction of transfusion and large volume blood transfusion associated with adult cardiac surgery. Br J Anaesth. 2015; 114: 757-766.
34. Karkouti K, McCluskey SA, Callum J, Freedman J, Selby R, Timoumi T, et al. Evaluation of a novel transfusion algorithm employing point-of-care coagulation assays in cardiac surgery: a retrospective cohort study with interrupted time-series analysis. Anesthesiology. 2015; 122: 560-570.
35. Bolliger D, Dell-Kuster S, Seeberger MD, Tanaka KA, Gregor M, Zenklusen U, et al. Impact of loss of high-molecular-weight von Willebrand factor multimers on blood loss after aortic valve replacement. Br J Anaesth. 2012; 108: 754-762.
36. Gill R, Herbertson M, Vuylsteke A, Olsen PS, von Heymann C, Mythen M, et al. Safety and efficacy of recombinant activated factor VII: a randomized placebo-controlled trial in the setting of bleeding after cardiac surgery. Circulation. 2009; 120: 21-27.
37. Fergusson DA, Hébert PC, Mazer CD, Fremes S, MacAdams C, Murkin JM, et al; BART Investigators. A comparison of aprotinin and lysine analogues in high-risk cardiac surgery. N Engl J Med. 2008; 358: 2319-2331.
38. Kozek-Langenecker SA, Afshari A, Albaladejo P, Santullano CA, De Robertis E, Filipescu DC, et al. Management of severe perioperative bleeding: guidelines from the European Society of Anaesthesiology. Eur J Anaesthesiol. 2013; 30: 270-382.
39. Society of Thoracic Surgeons Blood Conservation Guideline Task Force, Ferraris VA, Brown JR, Despotis GJ, Hammon JW, Reece TB, et al; Society of Cardiovascular Anesthesiologists Special Task Force on Blood Transfusion; International Consortium for Evidence Based Perfusion. 2011 Update to The Society of Thoracic Surgeons and the Society of Cardiovascular Anesthesiologists blood conservation clinical practice guidelines. Ann Thorac Surg. 2011; 91: 944-982.
40. American Society of Anesthesiologists Task Force on Perioperative Blood Management. Practice guidelines for perioperative blood management: an updated report by the American Society of Anesthesiologists Task Force on Perioperative Blood Management*. Anesthesiology. 2015; 122: 241-275.
41. Brecher ME, Monk T, Goodnough LT. A standardized method for calculating blood loss. Transfusion. 1997; 37: 1070-1074.
42. van de Watering L, Brand A. Independent association of massive blood loss with mortality in cardiac surgery. Transfusion. 2005; 45: 1235; author reply 1235-1236.
43. Karkouti K, Wijeysundera DN, Yau TM, Beattie WS, Abdelnaem E, McCluskey SA, et al. The independent association of massive blood loss with mortality in cardiac surgery. Transfusion. 2004; 44: 1453-1462.
44. Geissler RG, Rotering H, Buddendick H, Franz D, Bunzemeier H, Roeder N, et al. Utilisation of blood components in cardiac surgery: a single-centre retrospective analysis with regard to diagnosis-related procedures. Transfus Med Hemother. 2015; 42: 75-82.
45. Zatta AJ, McQuilten ZK, Mitra B, Roxby DJ, Sinha R, Whitehead S, et al; Massive Transfusion Registry Steering Committee. Elucidating the clinical characteristics of patients captured using different definitions of massive transfusion. Vox Sang. 2014; 107: 60-70.
46. Ranucci M, Castelvecchio S, Frigiola A, Scolletta S, Giomarelli P, Biagioli B. Predicting transfusions in cardiac surgery: the easier, the better: the Transfusion Risk and Clinical Knowledge score. Vox Sang. 2009; 96: 324-332.
47. Alghamdi AA, Davis A, Brister S, Corey P, Logan A. Development and validation of Transfusion Risk Understanding Scoring Tool (TRUST) to stratify cardiac surgery patients according to their blood transfusion needs. Transfusion. 2006; 46: 1120-1129.
48. Litmathe J, Boeken U, Feindt P, Gams E. Predictors of homologous blood transfusion for patients undergoing open heart surgery. Thorac Cardiovasc Surg. 2003; 51: 17-21.
49. Magovern JA, Sakert T, Benckart DH, Burkholder JA, Liebler GA, Magovern GJ Sr, et al. A model for predicting transfusion after coronary artery bypass grafting. Ann Thorac Surg. 1996; 61: 27-32.
50. Lopes CT, Brunori EF, Cavalcante AM, Moorhead SA, Swanson E, Lopes Jde L, et al. Factors associated with excessive bleeding after cardiac surgery: A prospective cohort study. Heart Lung. 2016; 45: 64-69.e2.
51. Ranucci M, Baryshnikova E, Simeone F, Ranucci M, Scolletta S. Moderate-degree acidosis is an independent determinant of postoperative bleeding in cardiac surgery. Minerva Anestesiol. 2015; 81: 885-893.
52. Nuttall GA, Henderson N, Quinn M, Blair C, Summers L, Williams BA, et al. Excessive bleeding and transfusion in a prior cardiac surgery is associated with excessive bleeding and transfusion in the next surgery. Anesth Analg. 2006; 102: 1012-1017.
53. Görlinger K, Bergmann L, Dirkmann D. Coagulation management in patients undergoing mechanical circulatory support. Best Pract Res Clin Anaesthesiol. 2012; 26: 179-198.
54. Greiff G, Pleym H, Stenseth R, Berg KS, Wahba A, Videm V. Prediction of bleeding after cardiac surgery: comparison of model performances: a prospective observational study. J Cardiothorac Vasc Anesth. 2015; 29: 311-319.
55. Mehta RH, Sheng S, O’Brien SM, Grover FL, Gammie JS, Ferguson TB, et al; Society of Thoracic Surgeons National Cardiac Surgery Database Investigators. Reoperation for bleeding in patients undergoing coronary artery bypass surgery: incidence, risk factors, time trends, and outcomes. Circ Cardiovasc Qual Outcomes. 2009; 2: 583-590.
56. Greiff G, Pleym H, Stenseth R, Wahba A, Videm V. Genetic variation influences the risk of bleeding after cardiac surgery: novel associations and validation of previous findings. Acta Anaesthesiol Scand. 2015; 59: 796-806.
57. Mikkola R, Heikkinen J, Lahtinen J, Paone R, Juvonen T, Biancari F. Does blood transfusion affect intermediate survival after coronary artery bypass surgery? Scand J Surg. 2013; 102: 110-116.
58. Bhaskar B, Dulhunty J, Mullany DV, Fraser JF. Impact of blood product transfusion on short and long-term survival after cardiac surgery: more evidence. Ann Thorac Surg. 2012; 94: 460-467.
59. Horvath KA, Acker MA, Chang H, Bagiella E, Smith PK, Iribarne A, et al. Blood transfusion and infection after cardiac surgery. Ann Thorac Surg. 2013; 95: 2194-2201.
60. Hajjar LA, Vincent JL, Galas FR, Nakamura RE, Silva CM, Santos MH, et al. Transfusion requirements after cardiac surgery: the TRACS randomized controlled trial. JAMA. 2010; 304: 1559-1567.
61. Ranucci M, Baryshnikova E, Castelvecchio S, Pelissero G; Surgical and Clinical Outcome Research (SCOPE) Group. Major bleeding, transfusions, and anemia: the deadly triad of cardiac surgery. Ann Thorac Surg. 2013; 96: 478-485.
62. Thorell SE, Nash MJ, Thachil J. Clinical implications of clotting screens. Int J Lab Hematol. 2015; 37: 8-13.
63. Haneya A, Diez C, Kolat P, Suesskind-Schwendi M, Ried M, Schmid C, et al. Re-exploration for bleeding or tamponade after cardiac surgery: impact of timing and indication on outcome. Thorac Cardiovasc Surg. 2015; 63: 51-57.
64. Kristensen KL, Rauer LJ, Mortensen PE, Kjeldsen BJ. Reoperation for bleeding in cardiac surgery. Interact Cardiovasc Thorac Surg. 2012; 14: 709-713.
65. Biancari F, Mikkola R, Heikkinen J, Lahtinen J, Airaksinen KE, Juvonen T. Estimating the risk of complications related to re-exploration for bleeding after adult cardiac surgery: a systematic review and meta-analysis. Eur J Cardiothorac Surg. 2012; 41: 50-55.
66. Vivacqua A, Koch CG, Yousuf AM, Nowicki ER, Houghtaling PL, Blackstone EH, et al. Morbidity of bleeding after cardiac surgery: is it blood transfusion, reoperation for bleeding, or both? Ann Thorac Surg. 2011; 91: 1780-1790.
67. Fröjd V, Jeppsson A. Reexploration for Bleeding and Its Association With Mortality After Cardiac Surgery. Ann Thorac Surg. 2016: 102: 109-117.
68. Zbrozek A, Magee G. Cost of Bleeding in Trauma and Complex Cardiac Surgery. Clin Ther. 2015; 37: 1966-1974.
69. Herwaldt LA, Swartzendruber SK, Zimmerman MB, Scholz DA, Franklin JA, Caldarone CA. Hemorrhage after coronary artery bypass graft procedures. Infect Control Hosp Epidemiol. 2003; 24: 44-50.
70. Despotis G, Eby C, Lublin DM. A review of transfusion risks and optimal management of perioperative bleeding with cardiac surgery. Transfusion. 2008; 48: 2S-30S.
71. Görlinger K, Shore-Lesserson L, Dirkmann D, Hanke AA, Rahe-Meyer N, Tanaka KA. Management of hemorrhage in cardiothoracic surgery. J Cardiothorac Vasc Anesth. 2013; 27: S20-S34.
72. Nielsen VG. Coagulation crystal ball: why can’t we predict bleeding after cardiac surgery? Anesth Analg. 2012; 115: 490-492.
73. Deppe AC, Weber C, Zimmermann J, Kuhn EW, Slottosch I, Liakopoulos OJ, et al. Point-of-care thromboelastogra-phy/thromboelastometry-based coagulation management in cardiac surgery: a meta-analysis of 8332 patients. J Surg Res. 2016; 203: 424-433.
74. Wikkelsoe AJ, Afshari A, Wetterslev J, Brok J, Moeller AM. Monitoring patients at risk of massive transfusion with Thrombelastography or Thromboelastometry: a systematic review. Acta Anaesthesiol Scand. 2011; 55: 1174-1189.
75. Ranucci M, Baryshnikova E, Pistuddi V, Menicanti L, Frigiola A; Surgical and Clinical Outcome REsearch (SCORE) Group. The effectiveness of 10 years of interventions to control postoperative bleeding in adult cardiac surgery. Interact Cardiovasc Thorac Surg. 2017; 24: 196-202.