Massive Transfusion : New Insights

Kristen C. Sihler and Lena M. Napolitano Chest 2009;136;1654-1667 DOI 10.1378/chest.09-0251 The online version of this article, along with updated information and services can be found online on the World Wide Web at: http://chestjournal.chestpubs.org/content/136/6/1654.full.html

Chest is the official journal of the American College of Chest Physicians. It has been published monthly since 1935. Copyright2009by the American College of Chest Physicians, 3300 Dundee Road, Northbrook, IL 60062. All rights reserved. No part of this article or PDF may be reproduced or distributed without the prior written permission of the copyright holder. (http://chestjournal.chestpubs.org/site/misc/reprints.xhtml) ISSN:0012-3692

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CHEST
New Insights

Postgraduate Education Corner

CONTEMPORARY REVIEWS IN CRITICAL CARE MEDICINE

Massive Transfusion
Kristen C. Sihler, MD, MS; and Lena M. Napolitano, MD, FCCP

Massive transfusion (MT) is used for the treatment of uncontrolled hemorrhage. Earlier definitive control of life-threatening hemorrhage has significantly improved patient outcomes, but MT is still required. A number of recent advances in the area of MT have emerged, including the use of hypotensive or delayed resuscitation for victims of penetrating trauma before hemorrhage is controlled and hemostatic resuscitation with increased use of plasma and platelet transfusions in an attempt to maintain coagulation. These advances include the earlier use of hemostatic blood products (plasma, platelets, and cryoprecipitate), recombinant factor VIIa as an adjunct to the treatment of dilutional and consumptive coagulopathy, and a reduction in the use of isotonic crystalloid resuscitation. MT protocols have been developed to simplify and standardize transfusion practices. The authors of recent studies have advocated a 1:1:1 ratio of packed RBCs to fresh frozen plasma to platelet transfusions in patients requiring MT to avoid dilutional and consumptive coagulopathy and thrombocytopenia, and this has been associated with decreased mortality in recent reports from combat and civilian trauma. Earlier assessment of the exact nature of abnormalities in hemostasis has also been advocated to direct specific component and pharmacologic therapy to restore hemostasis, particularly in the determination of ongoing fibrinolysis. (CHEST 2009; 136:1654 1667)
Abbreviations: FFP fresh frozen plasma; HR hazard ratio; ISS injury severity score; MT massive transfusion; OR odds ratio; PRBC packed RBC; rFVIIa recombinant factor VIIa; SBP systolic BP; TEG Thromboelastograph

number of of massive T here are a (MT) in the definitions(Table 1). transfusion literature
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Epidemiology and Identification Any causes of hemorrhagic shock may require MT. In most institutions, the most common reason for MT is trauma.8 MT is also frequently required as treatment for severe hemorrhage in patients with GI bleeding9 11 and surgical patients undergoing elective or emergent complex surgical procedures (abdominal aortic aneurysm repair, orthotopic liver transplantation).1214 Other causes of severe hemorrhage include cardiac and vascular surgery, ectopic pregnancy, major obstetric hemorrhage, and postpartum uterine bleeding.15 In a survey16 of blood use in the United States, England, Australia, and Denmark, two countries provided data relating RBC use of 50 units per episode. In Australia, RBC use of 50 units per episode was largely associated with multiple trauma, whereas in Denmark it was associated with GI hemorrhage.16 Early identification of the patient who may require MT is critically important, particularly in areas with limited blood product availability. In trauma, risk
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MT is commonly defined as the administration of 10 units of packed RBCs (PRBCs) to an individual patient or the transfusion of more than one blood volume in 24 h. Other dynamic definitions of MT have been used, particularly in order to initiate MT institutional protocols.

Manuscript received January 30, 2009; revision accepted June 17, 2009. Affiliations: From the University of Michigan School of Medicine, Ann Arbor, MI. Correspondence to: Lena M. Napolitano, MD, FCCP, Professor of Surgery, Division Chief, Acute Care Surgery (Trauma, Burn, Critical Care, Emergency Surgery), Associate Chair, Department of Surgery, University of Michigan Health System, Room 1C421 University Hospital, 1500 East Medical Dr, Ann Arbor, MI 48109-0033; e-mail: lenan@umich.edu 2009 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/site/ misc/reprints.xhtml). DOI: 10.1378/chest.09-0251
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Table 1MT Definitions

MT Replacement of Transfusion of Transfusion of Dynamic MT Transfusion of foreseeable6 Replacement of one entire blood volume within 24 h1,2 10 units of PRBCs in 24 h3,4 20 units of PRBCs in 24 h5 4 units of PRBCs in 1 h when ongoing need is 50% of total blood volume within 3 h7

sure, and biochemistry. Therefore, the additional administration of other blood components (in addition to PRBCs) is necessary for the prevention of dilutional coagulopathy and dilutional thrombocytopenia.

MT Outcomes Despite major advances in the treatment of hemorrhagic shock, hemorrhage remains a leading cause of early death in both civilian and military trauma. Massive postpartum hemorrhage is one of the worlds leading causes of maternal morbidity and mortality. Additionally, hemorrhage and the need for MT is a contributing cause of mortality in patients requiring major elective and emergent surgery. What is the outcome of patients requiring MT? Few data are available in general patient populations. In a single-center study9 of patients who had undergone MT ( 10 units of PRBCs) due to varied causes (trauma, 46%; GI bleeding, 21%; leaking abdominal aortic aneurysm, 14%), a total of 824 units of PRBCs, 457 units of fresh frozen plasma (FFP), and 370 units of platelets were transfused to 43 patients. These patients consumed 16% of the total blood products used in that year. The overall survival rate was 60%. Severe coagulopathy occurred in 44% of patients (mortality rate, 74%), and 13 (31%) had severe thrombocytopenia (platelet count, 50,000).9 Trauma patients requiring MT have high mortality rates, ranging from 19% to 84%. Data from recent studies document a significant reduction in mortality in these patients, with reported mortality rates of approximately 30% (Table 2). Mortality is directly related to the severity of the hemorrhagic shock and the total number of PRBC units transfused. In a single-center study, 8% of trauma patients (479 of 5,645 trauma patients) received PRBCs, using 5,219 total units with an overall mortality rate of 27%. The majority of PRBC units (62%) were given in the first 24 h of trauma care. Only 3% of patients (n 147) received MT ( 10 units of PRBCs), and these patients received 71% of all PRBCs administered. The mortality rate in the MT cohort was significantly higher, at 39%. In these patients who underwent MT, 90% also received FFP and 71% received platelet transfusions.21 Is there a point where MT is associated with futile care and excessive expense? In a single-center retrospective study21 of trauma patients requiring MT of 50 units of blood products in the first 24 h, the overall mortality rate was 57%. Interestingly, there was no significant difference in mortality rate between patients who received 75 units of blood products in the first day vs those who received 51 to
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factors for MT have been identified in a number of studies. In a retrospective study17 of two combat support hospitals in Iraq, 247 patients who underwent MT received 17.9 units of stored PRBCs and 2.0 units of fresh whole blood, compared with 1.1 units of PRBCs and 0.2 unit of whole blood in 311 patients who did not undergo MT (p 0.001). Mortality rates were significantly higher in patients who underwent MT (39% vs 1%, respectively). The following variables independently predicted the need for MT: hemoglobin 11 g/dL; international normalized ratio 1.5; and a penetrating mechanism.17 Another study using data from one combat support hospital in Iraq identified that patients who underwent MT had significantly higher mortality rates (29% vs 7%, respectively), and increased injury severity. The following four independent risk factors for MT were identified: heart rate 105; systolic BP (SBP) 110 mm Hg; pH 7.25; and hematocrit 32%. Although several scoring systems have been proposed to predict the need for MT, these scores require laboratory data, injury severity scores (ISSs), and significant mathematical computations.18,19 A more simplified score (assessment of blood consumption or ABC score; the following four parameters: penetrating mechanism; hypotension; tachycardia; and positive hemoperitoneum by ultrasound) has recently been demonstrated20 to be accurate (75% sensitive, 86% specific) for predicting MT in the civilian setting.

Aim of Treatment In the treatment of acute hemorrhage and hemorrhagic shock, the first priority is to stop hemorrhage and the second, albeit concurrent, priority is blood transfusion. The aim of hemorrhagic shock treatment is the rapid and effective restoration of an adequate blood volume to maximize tissue oxygen delivery. Furthermore, the goal of transfusion of blood and blood products is to maintain the patients blood composition within safe limits with regard to hemostasis, oxygen-carrying capacity, oncotic preswww.chestjournal.org

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Table 2MT and Outcome

Study Phillips et al
76

Year of Publication 1987

Patient Cohort 56 patients (blunt and penetrating trauma, emergency surgery) who sustained MT exceeding two times their estimated blood volume 92 patients (blunt trauma) who received 20 units of blood

Time Period/Location

Mean Transfusions 33 units of PRBCs

Hospital Mortality Rate 61% (100% mortality rate in victims of blunt trauma, cirrhotics, and nontrauma surgical emergencies)

Wudel et al5

1991

54-mo retrospective review/academic level 1 trauma center

33 units of PRBCs

48%

Cosgriff et al77 Velmahos et al78

1997 1998 141 trauma patients who received 20 units of blood 4-yr retrospective (19931997) review/academic level 1 trauma center 10-yr review/ academic level 1 trauma center 19881992 vs 19931997 5-yr (19952000) retrospective review/academic level 1 trauma center

24 units of PRBCs 32 units of PRBCs

43% 69.5%

Cinat et al79

1999

Vaslef et al22

2002

45 trauma patients who received 50 units of PRBCs or whole blood in 48 h following hospital admission 44 trauma patients who received 50 units of blood products on the first day

63.1 13.4 units of PRBCs

Overall, 71%; 19881992, 84%; 19931997, 55%

33

Como et al21

2004

147 trauma patients who received 10 units of PRBCs

HuberWagner et al80

2007

Mitra et al81

2007

1,062 trauma patients receiving 10 units of PRBCs; 661 (1019 units of PRBCs); 253 (2029 units of PRBCs); 148 ( 30 units of PRBCs); reference group 7,021 (09 units of PRBCs) 119 trauma patients who received 5 units of PRBCs in 4 h

Calendar yr 2000, retrospective review/academic level 1 trauma center Retrospective review (1993 2001)/Trauma Registry of German Trauma Society

14 units of PRBCs; 75 22 total units of blood products; 9 5 units of FFP; 25 12 units of cryoprecipitate; 8 6 units of platelets 25 units of PRBCs; 24 units of FFP; 16 units of platelets 19.5 units of PRBCs

57%

39%

35.1% (1019 units of PRBCs); 53.7% (2029 units of PRBCs); 60.4% ( 30 units of PRBCs); reference group, 14.8% (09 units of PRBCs)

Gonzalez et al39

2007

97 trauma patients receiving 10 units of PRBCs during hospital day 1

26-mo period (July 2002 to September 2004)/level 1 adult trauma center, Australia 51-mo period ending January 2003

Median No. of units of PRBCs in first 4 h was 8.0 (interquartile range, 614)

27.7%

30%

(Continued)

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Table 2Continued
Study Borgman et al33 Year of Publication 2007 Patient Cohort 246 trauma patients at a US Army combat support hospital each received MT ( 10 units of PRBCs in 24 h) 467 trauma patients from 16 level 1 trauma centers receiving MT ( 10 units of PRBC in 24 h) Time Period/Location November 2003 to September 2005, patients divided into groups based on FFP/RBC ratio July 2005 through June 2006 Mean Transfusions Hospital Mortality Rate Plasma/RBC ratio groups: 1:8, 65%; 1:2.5, 34%); 1:1.4, 19%

Holcomb et al40

2008

Scalea et al41

2008

Duchesne et al42

2008

Maegele et al43

2008

806 trauma patients who required ICU admission, single-center study; 365 patients received PRBCs in the first 24 h; 81 patients received MT ( 10 units of PRBCs in 24 h); 250 patients received PRBCs FFP (51 patients in 1:1 ratio) 135 trauma patients who required surgery and received 10 units of PRBCs and were alive to ICU 713 trauma patients with ISS 16 and MT ( 10 units of PRBCs)

July 2004 to November 2006

7.7 12 units of PRBC (total hospitalization); 7 8 units of PRBCs (24 h); 6.5 12 units of FFP (total hospitalization); 5 5 units of FFP (24 h)

Range, 26% to 59%; 30-d survival was increased in patients with a high plasma/RBC ratio ( 1:2) relative to those with a low plasma/RBC ratio ( 1:2) (low, 40.4%; high, 59.6%; p 0.01); similarly, 30-d survival was increased in patients with a high platelet/RBC ratio ( 1:2) relative to those with a low platelet/RBC ratio ( 1:2) (low, 40.1%; high, 59.9%; p 0.01) 14.0%; logistic regression in MT cohort for PRBC/FFP ratio of 1:1; OR, 1.49 (95% CI, 0.63 3.53); p 0.37

4-yr retrospective review (January 2002 to December 2006) Retrospective review (2002 2006)/Trauma Registry of German Trauma Society Of 713 patients, 484 patients had undergone MT with PRBC/FFP ratio 1.1, 114 with PRBC/FFP ratio 0.91.1 (1:1), and 115 with PRBC/FFP ratio 0.9

Sperry et al44

2008

415 trauma patients who required 8 units of PRBCs within the first 12 h postinjury; multicenter study, seven institutions, 3.5 yr

November 2003 to March 2007

The median blood transfusion requirement in first 12 h postinjury was 14 units (interquartile range, 1422) for the entire study cohort

55.5%; FFP/PRBC ratio 1:1, 26%; FFP/PRBC ratio 1:4, 87.5%; LR for mortality for 1:1 FFP/PRBC ratio; OR, 18.88 (95% CI, 6.32 56.36); p 0.001 Acute mortality ( 6 h) rates: PRBC/FFP ratio 1.1, 24.6%; PRBC/FFP ratio 0.91.1 (1:1), 9.6%; and PRBC/FFP ratio 0.9, 3.5% (p 0.0001) 24-h mortality rates: PRBC/FFP ratio 1.1, 32.6%; PRBC/FFP ratio 0.91.1 (1:1), 16.7%; and PRBC/FFP ratio 0.9, 11.3% (p 0.0001) 30-day mortality rates: PRBC/FFP ratio 1.1, 45.5; PRBC/FFP ratio 0.91.1 (1:1), 35.1%; and PRBC/FFP ratio 0.9, 24.3% (p 0.001) 33.5% High FFP/PRBC ratio group (1:1.5 or 1:1; n 102), 28.4%; low FFP/PRBC ratio group ( 1:2; n 313), 35.1% Cox regression: high FFP/PRBC ratio associated with a 52% lower risk of mortality (HR, 0.48; 95% CI, 0.3 0.8; p 0.002); high FFP/PRBC ratio associated with a twofold higher risk of ARDS (HR, 1.93; 95% CI: 1.233.02; p 0.004)

LR

likelihood ratio.
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75 units. Multiple logistic regression analysis identified only one independent risk factor (base deficit 12 mmol/L) that was associated with mortality (odds ratio [OR], 5.5; 95% CI, 1.44 to 20.95; p 0.013).22 The study by Como et al21 also could not identify a clear threshold beyond which MT was futile.

Severe Hemorrhage, MT, and Coagulopathy Patients who have sustained severe hemorrhage and require MT commonly have an early and profound coagulopathy that is present on hospital admission and worsens with PRBC transfusion because of dilutional and consumptive coagulopathy.23 Recent studies24 have documented that the acute coagulopathy of trauma is associated with systemic hypoperfusion and is characterized by anticoagulation and hyperfibrinolysis. Traditional resuscitation techniques using large amounts of crystalloid and PRBCs without other blood products can exacerbate this coagulopathy.25 The standard goal of MT in past years was to supply isotonic crystalloids and plasma-poor RBC concentrates to maintain normovolemia and tissue oxygen supply. This, however, frequently led to dilutional coagulopathy, which was aggravated and accelerated by hypothermia, acidosis, shock-induced impairment of hepatic function, disseminated intravascular coagulation due to tissue injury, and increased consumption of clotting factors and platelets at extensive wound sites in injured patients. Therefore, another key aim of modern MT protocols is the timely administration of plasma and platelet concentrates as required to halt microvascular bleeding induced by impaired hemostasis.26,27

Figure 1. The pathogenesis of the bloody vicious cycle following major torso trauma is multifactorial, but usually manifests as a triad of refractory coagulopathy, progressive hypothermia, and persistent metabolic acidosis. Adapted from Moore and Thomas.28

Recent Advances in MT and Resuscitation Hemostatic Resuscitation The authors of recent studies have reported that most severely injured patients are coagulopathic at hospital admission, before resuscitation interventions, and that traditional MT practices grossly underestimate the treatment that is needed to correct the coagulopathy. Since hemorrhage is a major cause of trauma deaths and coagulopathy exacerbates hemorrhage, prompt reversal of coagulopathy by using hemostatic resuscitation has been advocated as the optimal practice for MT in trauma patients.30 The reversal of coagulopathy involves the normalization of body temperature, hemorrhage control, and transfusion with FFP, platelets, and cryoprecipitate as needed. Some authors have advocated that coagulopathy can best be avoided or reversed when severe trauma victims are transfused with at least the equivalent of whole blood.31 Randomized, controlled trials of how best to administer coagulation factors (FFP, platelets, and cryoprecipitates) in the presence of ongoing severe traumatic hemorrhage are difficult to execute and have not been published.
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Lethal Triad of Acidosis, Hypothermia, and Coagulopathy Uncontrolled hemorrhage may ultimately result in the development of hypothermia, coagulopathy, and acidosis. Each of these life-threatening abnormalities exacerbates the others, contributing to a spiraling cycle that results in rapid death unless hemorrhage is stopped and the abnormalities are reversed. This bloody vicious cycle is depicted in Figure 1.28,29 A number of strategies, including early definitive control of hemorrhage, improved blood resuscitation, and more aggressive treatment of coagulopathy and hemostatic defects, have all been implemented in attempts to improve survival with MT.
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Figure 2. Mortality rates associated with low, medium, and high plasma/RBC ratios transfused at hospital admission. Ratios are reported as the median ratios per group and include units of fresh whole blood counted both as plasma and RBCs. Adapted from Borgman et al.33

A pharmacokinetic model to simulate the dilutional component of coagulopathy during hemorrhage confirmed that during trauma resuscitation, the equivalent of whole blood transfusion is required to correct or prevent dilutional coagulopathy. This pharmacokinetic model documented that once excessive deficiency of factors has developed and bleeding is unabated, 1 to 1.5 units of FFP must be administered for every unit of PRBCs transfused. If FFP transfusion starts before plasma factor concentration drops below

50% of normal, an FFP/PRBC transfusion ratio of 1:1 would prevent further dilution.32 Borgman et al33 performed a retrospective review of 246 patients who underwent MT ( 10 units PRBCs in 24 h) at a US Army combat support hospital and examined the FFP/PRBC ratio and associated mortality rates (Fig 2). The median ISS was 18 for all groups. For low (1:8), medium (1:2.5), and high (1:1.4) FFP/PRBC ratios, the overall mortality rates were 65%, 34%, and 19%, respectively (p 0.001); hemorrhage mortality rates were 92.5%, 78%, and 37%, respectively (p 0.001). Logistic regression analysis confirmed that FFP/PRBC ratio was independently associated with survival (OR, 8.6; 95% CI, 2.1 to 35.2). In patients with combat-related trauma requiring MT, a high 1:1.4 FFP/PRBC ratio was independently associated with improved survival to hospital discharge, primarily by decreasing death from hemorrhage. The authors concluded that MT protocols should utilize a 1:1 ratio of FFP/PRBC for all patients who are hypocoagulable with traumatic injuries.34 It should also be noted that some additional significant differences in these three patient cohorts are present. Patients in the high ratio group received recombinant factor VIIa (rFVIIa) more often, received less total isotonic crystalloid, and more cryoprecipitate and platelet transfusions (Table 3).

Table 3Crystalloid and Blood Products for Each Plasma to RBC Ratio Group
LowRatio Group (1:8; 0:221:5)* n 31 7.0 (2.09.6) 1.8 (0.364.2) 16 (1218) 4 (0.511.8) 0 (00) 0.1 0 (00) 0.01 2 (03) 0.1 (00.4) 0.57 None received None received 0 (00) 1.6 0 (00) 0.7 16% MediumRatio Group (1:2.5; 1:3.01:2.3) n 53 8.0 (4.411.5) 0.6 (0.31.5) 16 (1226) 0.9 (0.64.0) 0 (02) 1.1 0 (00.1) 0.15 # 6 (410)# 0.3 (0.21.4) 1.1 # 0 (00) 0.4 # 0 (00) 0.02 0 (010) 6.6 0 (01.3) 0.9 26% HighRatio Group (1:1.4; 1:1.71:1.2) n 162 9.6 (6.012.9) 0.5 (0.40.7) 17 (1224) 0.8 (0.61.3) 0 (04) 3.1 0 (00.2) 0.23 ** 12 (918)** 0.6 (0.41.0) 1.1 ** 0 (01) 0.8 ** 0 (00) 0.05 9 (010) 9.1 0.4 (00.8) 0.6 38%

Variables Crystalloid, L Crystalloid, L/h RBCs, units RBCs, units/h FWB, units FWB, units/h FFP and FWB, units FFP and FWB, units/h Apheresis platelet, units Apheresis platelet, units/h Cryoprecipitate, units Cryoprecipitate, units/h rFVIIa use

Data are presented as the median (interquartile range) mean . FWB fresh whole blood. *Ratio calculated as (FFP FWB)/(RBC FWB). Mann-Whitney U test. Crystalloid, liters of normal saline solution and lactated Ringers solution. Significantly different from the high-ratio group (p 0.05). Significantly different from the low-ratio group (p 0.05). Significantly different from the medium-ratio group and the high-ratio group (p 0.05). #Significantly different from the low-ratio group and the high-ratio group (p 0.05). **Significantly different from the low-ratio group and the medium-ratio group (p 0.05). Data presented as percentage used in each cohort (ie, rFVIIa use/total number in cohort) p
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Similarly, a recent study35 reported 16 patients who underwent MT with extensive injuries (blast, gunshot wounds, and vascular injuries) who were treated at a combat support hospital (mean [ SD] PRBCs, 23 18 units; mean FFP, 16 12 units; mean cryoprecipitate, 11 14 units; and mean platelets, 13 9 units) and who underwent vascular reconstruction. All patients survived their initial injuries and hemorrhagic shock treatment phase. The patients underwent hemostatic resuscitation including the use of rFVIIa and limited heparin use. No patient had a thrombotic failure of a graft even when given rFVIIa.35 The principles of hemostatic resuscitation, including the use of liberal blood products, reduced isotonic crystalloid resuscitation, and the use of rFVIIa represent an evolution in resuscitation for severe hemorrhagic shock that has been associated with significantly improved outcomes. The use of fresh whole blood has also been required in the combat casualty setting because of a lack of sufficient stored blood products.36 The efficacy of fresh whole blood in MT for severe hemorrhage continues to undergo evaluation with comparison to standard stored component therapy.37,38 The practice of hemostatic resuscitation was initiated in military combat casualty care, but has also been examined in civilian trauma, and the concept is now being applied to other patient populations requiring MT for severe hemorrhage. Multiple clinical studies in civilian trauma patient populations have addressed the topic of hemostatic resuscitation as well. Gonzalez et al39: This single-institution study identified 97 MT trauma patients ( 10 units of PRBCs during hospital day 1) with a hospital survival rate of 70%. Resuscitation followed a protocol by which FFP was not given until after 6 units of PRBCs. Prior to ICU admission, patients received on average 12 units of PRBCs and 5 units of FFP. In the first 24 h in the ICU, patients received an average of 13 units of FFP, six 6-pack platelets, and four 10-pack cryoprecipitate for coagulopathy as well as an average of 10 units of PRBCs. The severity of coagulopathy, as measured by the international normalized ratio at ICU admission, was associated with survival outcome (p 0.02; receiver operating characteristic, 0.71.). Acidosis and hypothermia were well managed, but the coagulopathy was extremely difficult to correct. Excessive crystalloid resuscitation and inadequate blood product resuscitation likely contributed to the coagulopathy. The authors have since revised their MT protocol so that PRBCs and FFP are administered in a 1:1 ratio early in the resuscitation.
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Holcomb et al40: This multicenter retrospective study documented and reviewed current MT practices at 16 major civilian level 1 trauma centers in the United States and the records of 466 MT trauma patients ( 10 units of PRBC in 24 h). Survival rates varied by center from 41% to 74%. The mean FFP/PRBC ratio varied from 0.32 to 0.87, while the platelets/PRBCs ratio varied from 0.10 to 1.06. The FFP/PRBC and platelet/PRBC ratios and ISS were independent predictors of 30-day mortality. Any FFP/PRBC ratio 1:2 was associated with an improved 30-day survival rate (61% vs 53%, respectively; p 0.01) as was a platelet/PRBC ratio 1:2 (70% vs 44%, respectively; p 0.01). A statistical model indicated that a mean FFP/PRBC ratio of 1:1 was optimal. This study documented that conventional MT practices vary widely at level 1 trauma centers, and survival after MT differs greatly. Scalea et al41: This single-institution study reviewed data on 365 patients admitted to the ICU over a period of 2 years who received PRBCs in the first 24 h. Two hundred fifty patients received both PRBCs and FFP. Patients received transfusions with a mean of 7 8 units of PRBCs and 5 5 units of FFP in the first 24 h. Only 81 patients received MT ( 10 units of PRBCs in 24 h), and, of the total number of patients in that cohort, 51 patients received transfusion in a 1:1 PRBC/FFP ratio. Logistic regression in the MT cohort documented that PRBC:FFP 1:1 ratio was not associated with decreased mortality (OR, 1.49; 95% CI, 0.63 to 3.53; p 0.37). The authors recommended reevaluating the early use of FFP in the civilian trauma population. This study, however, was limited by a small sample size in the MT cohort. Duchesne et al42: This was a single-institution, 4-year retrospective study of all trauma patients who underwent emergency surgery in an urban level 1 trauma center. The authors examined 135 patients who underwent MT ( 10 units of PRBCs), and all received FFP. In univariate analysis, a significant difference in mortality rate was found in patients who underwent MT with FFP/PRBC ratios of 1:1 vs 1:4 (26% vs 87.5%, respectively; p 0.0001). Multivariate analysis in patients who underwent MT showed that an FFP/PRBC ratio of 1:4 was consistent with increased mortality risk (relative risk, 18.88; 95% CI, 6.32 to 56.36; p 0.001) when compared with a ratio of 1:1. Patients who underwent MT had a trend toward increased mortality rate when the FFP/ PRBC ratio was 1:4 compared with 1:1 (21.2% vs 11.8%, respectively; p 0.06). This study documented that an FFP/PRBC ratio close to 1:1 confers a survival advantage in patients requiring MT.
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Figure 3. Early (at 6 h and 24 h) and 30-day mortality rates for patients transfused with different PRBC/FFP ratios. A PRBC/ FFP ratio 0.9 was associated with a significant reduction in 6-h and 24-h mortality rates (p 0.0001) and 30-day mortality rates (p 0.001). Adapted from Maegele et al.43

Maegele et al43: This was a multicenter retrospective analysis using the trauma registry founded by the German Society of Trauma Surgery. The registry documents the use of FFP since 2002, and this analysis spans from 2002 to 2006 with a total of 17,935 patients from 100 hospitals. Patients (n 713) with significant injury (ISS 16) who have received MT ( 10 units of PRBCs) were divided into three groups based on PRBCs/FFP ratios. Acute mortality rates (at 6 h and 24 h) and 30-day mortality rates were significantly lower in patients who received more FFP (Fig 3). Sperry et al44: This study reviewed data obtained from a multicenter prospective cohort study evaluating clinical outcomes in blunt injured adults with hemorrhagic shock, who required 8 units of PRBCs within the first 12 h postinjury (n 415).

Patients who received transfusion products with a high FFP/PRBC ratio ( 1:1.5; n 102) vs low FFP/PRBC ratio ( 1:1.5; n 313) required significantly less blood for transfusion at 24 h (16 9 units vs 22 17 units, respectively; p 0.001). The crude mortality rate differences between the groups did not reach statistical significance (high FFP/PRBC ratio, 28%; low FFP/PRBC ratio, 35%; p 0.202); however, there was a significant difference in early (24 h) mortality (high FFP/PRBC ratio, 3.9%; low FFP/PRBC ratio, 12.8%; p 0.012). Cox proportional hazard regression revealed that receiving treatment with a high FFP/PRBC ratio was independently associated with 52% lower risk of mortality after adjusting for important confounders (hazard ratio [HR], 0.48; 95% CI, 0.3 to 0.8; p 0.002) [Fig 4]. A high FFP/PRBC ratio was not associated with a higher risk of organ failure or nosocomial infection; however, it was associated with an almost twofold higher risk of ARDS (HR, 1.93; 95% CI, 1.23 to 3.02; p 0.004), after controlling for important confounders. These results suggest that the mortality risk associated with an FFP/PRBC ratio 1:1.5 may occur early, possibly secondary to ongoing coagulopathy and hemorrhage. This analysis provides further justification for a prospective trial investigation into the optimal FFP/PRBC ratio required in MT practice. Despite significant controversy, based on these studies reviewed above, an emerging consensus for hemostatic resuscitation in patients requiring MT is as follows: Expedite the control of hemorrhage to prevent consumptive coagulopathy and thrombocytopenia and reduce the need for blood products;

Figure 4. Data from the multicenter prospective cohort study in 415 patients requiring MT. A high FFP/PRBC ratio was associated with a 52% lower risk of mortality (HR, 0.48; 95% CI, 0.3 to 0.8; p 0.002) left but also with an almost twofold higher risk of ARDS (HR, 1.93; 95% CI, 1.23 to 3.02; p 0.004) right after controlling for important confounders. Adapted from Sperry et al.44
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 Limit isotonic crystalloid infusion to prevent dilutional coagulopathy and thrombocytopenia; Hypotensive resuscitation (SBP, 80 to 100 mm Hg) until definitive hemorrhage control has been established; Transfuse blood products in a 1:1:1 ratio of PRBCs/FFP/platelets (one five-pack of pooled platelets counted as 5 units); and Frequent laboratory monitoring (arterial lactate to assess adequacy of resuscitation, ionized calcium, and electrolytes). Despite emerging data with documented improved outcomes in trauma patients who receive hemostatic resuscitation, we must recognize that there are potential adverse effects associated with the transfusion of blood component therapy (FFP and platelets). The authors of several studies45 47 have documented the increased risk for acute lung injury and ARDS with blood and plasma transfusions. Transfusionrelated acute lung injury is now the leading cause of transfusion-associated mortality, even though it is underdiagnosed and underreported.48 50 Fibrinogen constitutes an important component of the hemostatic process, including its roles in the formation of platelet aggregates and the generation of a sufficiently stable fibrin network. Presently, the strategy to preserve adequate coagulation is strongly based on FFP and platelet replacement therapy. The need for cryoprecipitate (which contains factor VIII, fibrinogen, fibronectin, von Willebrand factor, and factor XIII) is usually managed by the measurement of serum fibrinogen concentrations and replacement therapy commonly initiated when the fibrinogen level is 100 mg/dL.51 Ten units of cryoprecipitate contain 2.5 g of fibrinogen in 100 mL of plasma, which is a significantly decreased volume compared with FFP.52 The benefits of maintaining normal fibrinogen concentrations in trauma patients requiring MT is not known at present. Recently, a pasteurized fibrinogen concentrate has demonstrated efficacy in Europe.53,54 Coagulation testing is an important component of MT treatment. Repeated and timely point-of-care coagulation testing is ideal. The time lapse for reporting results and insufficient identification of the hemostatic defect are significant obstacles with conventional laboratory coagulation testing. Evidence is growing that rotational thromboelastometry or modified thromboelastography is superior to routine laboratory tests in guiding coagulation management.13,55 MT Protocols MT protocols have long been in place at major trauma centers for the treatment of patients with severe hemorrhagic shock.4 In the past, MT proto1662

cols provided PRBCs, but still required the clinician to issue specific requests for other blood component therapy, including FFP and platelets. It was recommended that clinicians performing transfusions of additional blood components wait until laboratory evidence of dilutional and consumptive coagulopathy and thrombocytopenia were present. In the current era, MT protocols now focus on the prevention of coagulopathy and thrombocytopenia. A 1:1:1 ratio (ie, equal parts PRBCs, FFP, and platelets) for blood component therapy is now recommended for MT based on a more physiologic regimen similar to whole blood transfusion. This approach (called hemostatic resuscitation) focuses on the early correction of coagulopathy that is thought to be associated with improved survival. An institution that implemented a trauma exsanguination protocol (immediate release of blood products in a predefined ratio of 10 units of PRBCs to 4 units of FFP to 2 units of platelets [2 units of single-donor platelets or 2 apheresis packs, both equivalent to traditional 10-packs of pooled platelets] followed by continued release of 6 units of PRBCs to 4 units of FFP to 2 units of single donor platelets thereafter) compared it with a cohort preprotocol in patients who received MT ( 10 units of PRBCs in the first 24 h). Multivariate regression analysis confirmed a 74% reduction in mortality (p 0.001), and total blood product consumption was also significantly reduced.56 They also demonstrated a reduction in multiorgan failure and complications from infections, an increased number of ventilator-free days, and a dramatic reduction in the development of abdominal compartment syndrome.57 Another institution implemented transfusion packages (5 units of PRBCs, 5 units of FFP, and 2 platelet concentrates) to improve hemostatic competence after identifying that continued hemorrhage was a major cause of mortality in their patients who underwent MT in whom coagulopathy developed. They identified that 10% of patients received what they termed suboptimal transfusion therapy and that survivors had a higher platelet count than nonsurvivors. In addition, use of a hemostatic system (Thromboelastograph [TEG]; Hemoscope Corp; Niles, IL) was implemented to aid in the diagnosis and treatment of coagulopathy. The fraction of patients who were suboptimally transfused declined from 10% to 3%. The transfusion package administered intraoperatively to patients with ruptured abdominal aortic aneurysm resulted in decreased postoperative transfusions and improved 30-day survival rates (66% vs 44%, respectively).58 The TEG showed a 97% predictability in identifying a surgical cause of bleeding in postoperative patients; 10% of the trauma patients
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who underwent MT had hyperfibrinolysis as the major cause of bleeding, whereas 45% were hypercoagulable. This initiative significantly improved transfusion practices and survival in patients who underwent MT.59 In addition, it was documented that this early balanced transfusion strategy maintained hemostatic competence as measured by TEG in these patients who experienced massive bleeding.60

rFVIIa for Treatment of Coagulopathy Associated With MT The first step in hemostasis is the formation of a platelet aggregate. At the molecular level, this interaction of coagulation factors takes place on the surface of activated platelets. The tissue factor-FVIIa complex is the physiologic activator of normal hemostasis. rFVIIa, therefore, works via multiple mechanisms, including increased tissue factor binding, increased binding to activated platelets when administered in pharmacologic doses and factor X activation independent of tissue factor. It also bypasses inhibitors to factors VIII and IX and von Willebrand factor. Trauma patients with severe hemorrhage and tissue destruction commonly have an early and profound coagulopathy that may not be corrected by the administration of blood component therapy alone. rFVIIa may provide advantages over FFP when coagulopathy requires quick reversal without risk of volume overload. The use of rFVIIa in managing hemostatic abnormalities related to MT is still controversial, and there is a concern regarding potential thrombotic complications including the potential for an increased risk for venous thromboembolism. Two randomized, placebo-controlled, doubleblind trials61 in patients with blunt trauma (n 143) and penetrating trauma (n 134) were conducted simultaneously to evaluate the efficacy and safety of rFVIIa as adjunctive therapy for the control of bleeding in trauma patients. Trauma patients experiencing severe bleeding were randomly assigned to receive three doses of rFVIIa (200, 100, and 100 g/kg) or placebo (first dose immediately after transfusion of the eighth unit of PRBCs, and the second and third doses followed 1 h and 3 h, respectively, after the first dose) in addition to standard treatment. The first dose followed transfusion of the eighth unit of PRBCs, with additional doses 1 h and 3 h later. In blunt trauma patients, PRBC transfusion was significantly reduced by rFVIIa administration (reduction, 2.6 units of PRBCs; p 0.02), and the need for MT ( 20 units of PRBCs) was reduced (14% vs 33%, respectively; p 0.03). In patients with penetrating trauma, similar analyses showed trends toward rFVIIa reducing the PRBC transfusion (reducwww.chestjournal.org

tion of 1.0 units of PRBCs; p 0.10) and MT (7% vs 19%, respectively; p 0.08), reduced mortality and numbers of critical complications, and no difference in thromboembolic events. rFVIIa administration resulted in a significant reduction in PRBC transfusion in patients with severe blunt trauma but no significant reduction in mortality. The safety of rFVIIa administration was established in these trauma populations within the investigated dose range. A subgroup analysis of coagulopathic trauma patients from these two trials62 confirmed that the rFVIIa-treated coagulopathic subgroup consumed significantly fewer blood products (PRBCs, FFP, and platelets) and underwent significantly fewer MTs (29% vs 6%, respectively; p 0.01). rFVIIa reduced multiorgan failure and/or ARDS in the coagulopathic patients (3% vs 20%, respectively; p 0.004); thromboembolic events were equally present in both groups (3% vs 4%, respectively; p 1.00). The authors concluded that coagulopathic trauma patients appear to derive particular benefit from early adjunctive rFVIIa therapy. The authors of another study63 examined the efficacy of rFVIIa administered early (before 8 units of blood were transfused) vs late (after 8 units of blood were transfused) to combat casualty patients who had undergone MT. The early-rFVIIa group required significantly less blood (mean amount, 20.6 vs 25.7 units, respectively) and fewer stored PRBCs (mean amount, 16.7 vs 21.7 units, respectively). Early and late rates of mortality (33.3% vs 34.2%, respectively), ARDS (5.9% vs 6.8%, respectively), infection (5.9% vs 9.1%, respectively), and thrombotic events (0% vs 2.3%, respectively) were not statistically different. This study documented that the early administration of rFVIIa decreased PRBC use by 20% in trauma patients who underwent MT.63 However, the pharmacokinetics of rFVIIa in trauma patients who underwent MT have been noted to be quite variable,64 and some have advocated lower dosing strategies at earlier time points in blood resuscitation for the treatment of severe hemorrhage. The efficacy of this practice awaits additional controlled clinical trials. A number of reports65,66 have suggested a potential role for rFVIIa in treating patients with massive postpartum hemorrhage and other etiologies of massive hemorrhage that are refractory to standard therapy, but most suggestions have been derived from a few uncontrolled studies. Although clinical guidelines have been developed, further evidence is needed using welldesigned clinical trials to better assess the timing, optimal dose, efficacy, and safety of rFVIIa therapy under such critical bleeding conditions.65,66
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Reduced Crystalloid Resuscitation The initial treatment priority in trauma patients with hemorrhagic shock is the cessation of hemorrhage. Fluid resuscitation is the second priority, but avoidance of excessive crystalloid resuscitation is now recognized as an important component of hemostatic resuscitation. Aggressive crystalloid fluid resuscitation in patients with uncontrolled hemorrhagic shock may increase hemorrhage and mortality.67 Limited prehospital fluid resuscitation has been advocated by the Eastern Association for the Surgery of Trauma Practice Management Guidelines for Prehospital Fluid Resuscitation in the Injured Patient.68 This evidence-based guideline recommends the following: (1) IV fluids should be withheld in the prehospital setting in patients with penetrating torso injuries; (2) IV fluid resuscitation should be withheld until active bleeding/hemorrhage is addressed; and (3) IV fluid administration in the prehospital setting (regardless of the mechanism or transport time) should be titrated for palpable radial pulse by using small boluses of fluid (250 mL) rather than fixed volumes or continuous administration. The consensus algorithm of fluid resuscitation for combat casualties incorporated many of these concepts of limited resuscitation in bleeding patients, excluding those with traumatic brain injuries in which the maintenance of adequate mean arterial pressure is optimal for cerebral perfusion.69 The concept of delaying resuscitation or resuscitating to a low BP (hypotensive resuscitation) in the actively

hemorrhaging patient until definitive hemorrhage control has been advocated based on a number of preclinical studies70 that have documented that vigorous fluid resuscitation in patients with uncontrolled hemorrhagic shock was associated with increased hemorrhage and decreased survival. The data strongly suggest that hypotensive resuscitation may be preferable for the trauma victim with the potential for ongoing uncontrolled hemorrhage. In a randomized prospective trial71 of immediate vs delayed fluid resuscitation in patients (n 598) with penetrating torso trauma who presented with a prehospital SBP of 90 mm Hg with an overall mortality rate of 34%, there was a significantly increased mortality rate (38% vs 30%, respectively; p 0.04), length of stay, and postoperative complication rates in the immediate vs the delayed group. However, the study was limited to isolated torso injuries in a city with a single centralized system of prehospital emergency care and a single receiving trauma center with a very rapid response time such that most patients were in the operating room within 1 h of injury. Therefore, the results of this study may not be applicable to other injuries including blunt trauma, head injury, multiple sites of penetrating trauma, or to patients in remote locations requiring long transport times. The results are also difficult to interpret in the modern era of limiting the use of crystalloid for large volume resuscitations in favor of blood and blood products. A single-center study72 randomly assigned patients (n 110) presenting with hemorrhagic shock to one

Figure 5. Guidelines for transfusion in the trauma patient have been established as a standard operating procedure to guide PRBC transfusion therapy for critically ill patients after the immediate resuscitation phase and to minimize the adverse consequences of potentially unnecessary transfusions. Adapted from West et al.75
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of two fluid resuscitation protocols (target SBP, 100 mm Hg vs 70 mm Hg) until definitive hemostasis was achieved. No mortality benefit was identified with hypotensive resuscitation (survival rate in each group, 92.7%), but a number of study limitations were present, as follows: failure to achieve target mean SBP in the hypotensive group (100 mm Hg; control group, 114 mm Hg); small sample size; mix of blunt trauma patients (49%) and penetrating trauma patients (51%); and a lengthy duration of active hemorrhage (2.97 1.75 h vs 2.57 1.46 h, respectively; p 0.20).72 Despite the limitations of these clinical studies, hypotensive resuscitation (minimizing crystalloid administration in particular) has become increasingly accepted in the prehospital resuscitation phase of trauma and in the hospital setting prior to definitive hemorrhage control, since aggressive fluid resuscitation may increase bleeding and worsen coagulopathy.73 The guidelines for shock resuscitation used as the standard operating procedures for clinical care in the clinical studies being conducted by the Surgical Glue Grant, Inflammation and Host Response to Injury Large Scale Collaborative Project award from National Institute of General Medical Sciences recommend hypotensive resuscitation (goal SBP, 90 mm Hg; goal heart rate, 130 beats/min) with moderate fluid resuscitation until hemorrhage control is accomplished.74 Table 3 documents that patients in the high plamsa/PRBC ratio group had significantly reduced rates of crystalloid fluid resuscitation (high-ratio group, 0.5 L/h; low-ratio group, 1.8 L/h), highlighting the importance of reduced crystalloid use. The continuing controversy regarding whether it is preferable to administer fluids to restore perfusion to vital organs (risking hemodilution and disruption of early hemostatic clots) or to minimize fluid resuscitation until the control of hemorrhage (risking prolonged cellular shock to the extent that it becomes irreversible by the time hemorrhage control is accomplished) is ongoing, and will require further clinical studies to advance our knowledge.

citation has been completed, and the patient is stable in the ICU with no evidence of ongoing bleeding (Fig 5). This guideline advocates a trigger for PRBC transfusion of hemoglobin of 7 g/dL (hematocrit, 21%).75

Conclusions Transfusion of the bleeding patient with PRBCs and other blood products requires careful vigilance during the acute resuscitative and recovery phases. At present, blood transfusion is the only option for the treatment of severe hemorrhagic shock. Newer protocols using hemostatic resuscitation and rFVIIa reduce the coagulopathic effects of MT, and the authors of some studies have reported improved survival. This strategy has resulted in more liberal use of blood and blood products in resuscitation for acute massive hemorrhage. Additional prospective multicenter studies are warranted to confirm this survival benefit with hemostatic resuscitation. However, following the definitive cessation of hemorrhage, all efforts to minimize the use of blood transfusion is warranted.

Acknowledgments
Financial/nonfinancial disclosures: The authors have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

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Massive Transfusion : New Insights Kristen C. Sihler and Lena M. Napolitano Chest 2009;136; 1654-1667 DOI 10.1378/chest.09-0251 This information is current as of February 21, 2012
Updated Information & Services Updated Information and services can be found at: http://chestjournal.chestpubs.org/content/136/6/1654.full.html References This article cites 78 articles, 7 of which can be accessed free at: http://chestjournal.chestpubs.org/content/136/6/1654.full.html#ref-list-1 Permissions & Licensing Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://www.chestpubs.org/site/misc/reprints.xhtml Reprints Information about ordering reprints can be found online: http://www.chestpubs.org/site/misc/reprints.xhtml Citation Alerts Receive free e-mail alerts when new articles cite this article. To sign up, select the "Services" link to the right of the online article. Images in PowerPoint format Figures that appear in CHEST articles can be downloaded for teaching purposes in PowerPoint slide format. See any online figure for directions.

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