Omar Alsuhaibani Transfusion Medicine Journal Club February 2, 2010

Background Transfusion therapy is common in trauma patients. Transfusion therapy is common in trauma patients. Massive transfusion is defined as 10 or more RBC units in a 24 hour period Massive transfusion is defined as 10 or more RBC units in a 24 hour period Massive transfusion occurs in up to 15% of civilian trauma patients and is associated with a mortality rate of 20-50% Massive transfusion occurs in up to 15% of civilian trauma patients and is associated with a mortality rate of 20-50% Most patients requiring massive transfusion die within 6 hours of admission Most patients requiring massive transfusion die within 6 hours of admission

May 2005 international expert conference on massive transfusion at the US Army's Institute of Surgical Research international expert conference on massive transfusion at the US Army's Institute of Surgical Research concept of “damage control” should be expanded to include what has subsequently come to be known as “damage control resuscitation.” concept of “damage control” should be expanded to include what has subsequently come to be known as “damage control resuscitation.” addresses the immediate need for coagulation components as well as for oxygen delivery in the severely injured patient addresses the immediate need for coagulation components as well as for oxygen delivery in the severely injured patient specifies decreasing, to the extent possible, the use of crystalloids as volume replacement specifies decreasing, to the extent possible, the use of crystalloids as volume replacement matching RBC transfusion on a 1:1:1 ratio with plasma and platelets. matching RBC transfusion on a 1:1:1 ratio with plasma and platelets.

Borgman and coworkers significant reduction in mortality in 246 massively transfused (10 units of RBCs in 24 hr) trauma patients (65% reduced to 19%, p < 0.001), with an optimal plasma to RBC product ratio of 1.4. significant reduction in mortality in 246 massively transfused (10 units of RBCs in 24 hr) trauma patients (65% reduced to 19%, p < 0.001), with an optimal plasma to RBC product ratio of 1.4.

Duchesne and colleagues improved survival in 135 massively transfused (defined as >10 units of RBCs during and after initial surgical intervention) trauma patients who received less than 2 units of RBCs per unit of plasma versus 2 or more units of RBCs per unit of plasma (12% vs. 21% died at discharge). improved survival in 135 massively transfused (defined as >10 units of RBCs during and after initial surgical intervention) trauma patients who received less than 2 units of RBCs per unit of plasma versus 2 or more units of RBCs per unit of plasma (12% vs. 21% died at discharge).

Maegele and colleagues retrospectively analyzed their trauma registry retrospectively analyzed their trauma registry improved mortality with a RBC:plasma ratio of less than 0.9 compared to and greater than 1.1 improved mortality with a RBC:plasma ratio of less than 0.9 compared to and greater than 1.1 higher amounts of plasma-to-RBC ratio were associated with increased length of stay and increased rates of multiorgan failure. higher amounts of plasma-to-RBC ratio were associated with increased length of stay and increased rates of multiorgan failure.

Sperry and coworkers Multicenter prospective cohort study of 415 blunt-injured adults with hemorrhagic shock who required 8 or more units of RBCs within the first 12 hours Multicenter prospective cohort study of 415 blunt-injured adults with hemorrhagic shock who required 8 or more units of RBCs within the first 12 hours 1:1.50 or more versus less than 1:1.50 plasma:RBC ratio was associated with improved mortality only after adjusting for confounders, 1:1.50 or more versus less than 1:1.50 plasma:RBC ratio was associated with improved mortality only after adjusting for confounders, strongly associated with the development of acute respiratory distress syndrome (ARDS). strongly associated with the development of acute respiratory distress syndrome (ARDS).

Holcomb and colleagues retrospective study of 466 massively transfused (10 units of RBCs in 24 hr) civilian patients retrospective study of 466 massively transfused (10 units of RBCs in 24 hr) civilian patients the group with a high plasma- and PLT to- RBC ratio (1 unit of PLTs and plasma to 2 units of RBCs) had the highest rate of 30-day survival (73%) compared to patients who received high plasma and low PLT (54%),low plasma and high PLT (67%), and low plasma and low PLT (<1 unit of PLTs and plasma to 2 units of RBCs;43%) ratios (p < 0.001). the group with a high plasma- and PLT to- RBC ratio (1 unit of PLTs and plasma to 2 units of RBCs) had the highest rate of 30-day survival (73%) compared to patients who received high plasma and low PLT (54%),low plasma and high PLT (67%), and low plasma and low PLT (<1 unit of PLTs and plasma to 2 units of RBCs;43%) ratios (p < 0.001). the higher 6-hour plasma:RBC and PLT:RBC ratios were also correlated with survival.(2009) the higher 6-hour plasma:RBC and PLT:RBC ratios were also correlated with survival.(2009)

Teixeira and coworkers retrospective study of 484 trauma patients who received 10 or more RBCs during 24 hours retrospective study of 484 trauma patients who received 10 or more RBCs during 24 hours plasma:RBC ratio of higher than 1:3 was associated with survival, but a ratio of greater than 1:2 was no better than 1:2 or less to more than 1:3. plasma:RBC ratio of higher than 1:3 was associated with survival, but a ratio of greater than 1:2 was no better than 1:2 or less to more than 1:3.

Snyder and coworkers the plasma:RBC ratio (1:2 vs.<1:2) was associated with survival (40% vs. 58% in-hospital mortality rate) adjusting for multiple variables the plasma:RBC ratio (1:2 vs.<1:2) was associated with survival (40% vs. 58% in-hospital mortality rate) adjusting for multiple variables Similar to previous studies, an association between higher FFP:PRBC ratios at 24 hours and improved survival was observed. Similar to previous studies, an association between higher FFP:PRBC ratios at 24 hours and improved survival was observed. However, after adjustment for survival bias in the analysis, the association was no longer statistically significant. However, after adjustment for survival bias in the analysis, the association was no longer statistically significant. Prospective trials are necessary to evaluate whether hemostatic resuscitation is clinically beneficial Prospective trials are necessary to evaluate whether hemostatic resuscitation is clinically beneficial

Varying definitions were used for massive transfusion ranging from ≥8 units in 12 h to >10 units in the first 6 h and varying ratios of component therapy were examined Varying definitions were used for massive transfusion ranging from ≥8 units in 12 h to >10 units in the first 6 h and varying ratios of component therapy were examined Owing to the nature of severe trauma requiring high-volume blood product resuscitation, significant survivor bias is highly likely. Owing to the nature of severe trauma requiring high-volume blood product resuscitation, significant survivor bias is highly likely.

Within these limitations, available literature demonstrates a clear survival benefit associated with early delivery of FFP and platelets in exsanguinating trauma Within these limitations, available literature demonstrates a clear survival benefit associated with early delivery of FFP and platelets in exsanguinating trauma high ratio therapy may be associated with a higher incidence of organ failure, ARDS and infection high ratio therapy may be associated with a higher incidence of organ failure, ARDS and infection

This study investigates the improvement in survival with higher plasma:RBC, platelet:RBC, and cryoprecipitate:RBC transfusion ratios in a civilian Level 1 trauma center.

Materials and Methods Patient information was derived from a prospectively entered trauma registry that is maintained at Grady Health System. Patient information was derived from a prospectively entered trauma registry that is maintained at Grady Health System. Massive transfusion was defined as transfusion of 10 or more units of RBC products in the first 24-hour period of the hospital stay. Massive transfusion was defined as transfusion of 10 or more units of RBC products in the first 24-hour period of the hospital stay. Non-trauma patients were excluded from this data set. Non-trauma patients were excluded from this data set. This study combines two cohorts of patients: one after implementation of a massive transfusion protocol (MTP) and one before implementation. This study combines two cohorts of patients: one after implementation of a massive transfusion protocol (MTP) and one before implementation.

Patient inclusion MTP group The MTP group was defined as trauma patients requiring massive transfusion and who received the MTP at Grady Memorial Hospital from February 1, 2007, to January 31,2009. The MTP group was defined as trauma patients requiring massive transfusion and who received the MTP at Grady Memorial Hospital from February 1, 2007, to January 31,2009.

Patient inclusion Pre-MTP group The pre-MTP group was created by querying the prospectively entered trauma registry and identifying all patients in the 2 years before the institution of the MTP (February 1, 2005-January 31, 2007) who received 10 or more units of RBCs in the first 24 hours of their hospital stay. The pre-MTP group was created by querying the prospectively entered trauma registry and identifying all patients in the 2 years before the institution of the MTP (February 1, 2005-January 31, 2007) who received 10 or more units of RBCs in the first 24 hours of their hospital stay.

MTP design derived from military recommendations, with some modifications. derived from military recommendations, with some modifications. the protocol is designed to ensure immediate availability of aggressive and early component therapy and is activated with a phone call to the blood bank. the protocol is designed to ensure immediate availability of aggressive and early component therapy and is activated with a phone call to the blood bank. Activation of the protocol is restricted to an attending or fellow from surgery, anesthesia, emergency medicine, or critical care Activation of the protocol is restricted to an attending or fellow from surgery, anesthesia, emergency medicine, or critical care

MTP design reserved for patients who have massive hemorrhage in difficult to control anatomic locations, who use emergency issue RBCs (RBC products are available in the emergency room and operating room), with ongoing blood loss of more than 150 mL/minute or with blood loss of 50% of blood volume in 4 hours or one blood volume in 24 hours. reserved for patients who have massive hemorrhage in difficult to control anatomic locations, who use emergency issue RBCs (RBC products are available in the emergency room and operating room), with ongoing blood loss of more than 150 mL/minute or with blood loss of 50% of blood volume in 4 hours or one blood volume in 24 hours. The blood bank responds to the call for protocol activation by immediately placing 6 units of group O RBCs and 6 units of group AB plasma in a cooler as the “initiation package.” The blood bank responds to the call for protocol activation by immediately placing 6 units of group O RBCs and 6 units of group AB plasma in a cooler as the “initiation package.” The blood bank maintains an adequate inventory of thawed plasma products for immediate distribution. The blood bank maintains an adequate inventory of thawed plasma products for immediate distribution.

MTP design The blood bank then continues to prepare pre- designated “packages” of components to be picked up every 30 minutes with a ratio of plasma:RBC of 1:1 in addition to set amounts of platelets and cryoprecipitate. The blood bank then continues to prepare pre- designated “packages” of components to be picked up every 30 minutes with a ratio of plasma:RBC of 1:1 in addition to set amounts of platelets and cryoprecipitate. The protocol suggests transfusion of blood products in the appropriate amounts, but does not mandate it. The protocol suggests transfusion of blood products in the appropriate amounts, but does not mandate it. if bleeding is uncontrolled, the trauma service can request a recombinant factor VIIa (rFVIIa) after Package 2 with a second dose if needed 30 minutes later. if bleeding is uncontrolled, the trauma service can request a recombinant factor VIIa (rFVIIa) after Package 2 with a second dose if needed 30 minutes later.

Data collection For the pre-MTP cohort, clinical and blood bank data were retrospectively collected, and for the MTP patient cohort prospective data were collected. For the pre-MTP cohort, clinical and blood bank data were retrospectively collected, and for the MTP patient cohort prospective data were collected. Clinical data collected included patient demographics including Clinical data collected included patient demographics including - a history of anticoagulant use - a history of anticoagulant use - mechanism of injury - mechanism of injury - type and severity of anatomic injury - type and severity of anatomic injury - injury severity score (ISS) - injury severity score (ISS) - lengths of stay (hospital length of stay, intensive care unit length of stay, and ventilator days) - lengths of stay (hospital length of stay, intensive care unit length of stay, and ventilator days) - mortality rate (24 hr, 30 day, and hospital stay) - mortality rate (24 hr, 30 day, and hospital stay) - time to and length of first operation - time to and length of first operation - use of a damage control procedure - use of a damage control procedure - presenting vital signs. - presenting vital signs.

Data collection Laboratory data were collected including Hb/Hct, base deficit, and coagulation variables (PT, INR, aPTT, fibrinogen level, and PLT count) upon arrival to the emergency department and on arrival to the intensive care unit. Laboratory data were collected including Hb/Hct, base deficit, and coagulation variables (PT, INR, aPTT, fibrinogen level, and PLT count) upon arrival to the emergency department and on arrival to the intensive care unit. Blood bank data collected included the number of units transfused of RBCs, plasma, platelets, and cryoprecipitate in the first 6 hours, first 24 hours, and entire hospital stay. Blood bank data collected included the number of units transfused of RBCs, plasma, platelets, and cryoprecipitate in the first 6 hours, first 24 hours, and entire hospital stay.

Definition of ratios plasma:RBC ratio of 1:1 was defined as one plasma product per one RBC product plasma:RBC ratio of 1:1 was defined as one plasma product per one RBC product PLT:RBC ratio of 1:1 was defined as one apheresis PLT unit per 10 RBC products PLT:RBC ratio of 1:1 was defined as one apheresis PLT unit per 10 RBC products cryoprecipitate:RBC ratio of 1:1 was defined as 1 cryoprecipitate unit per 1 RBC unit (cryoprecipitate was administered in pools of 10 units). cryoprecipitate:RBC ratio of 1:1 was defined as 1 cryoprecipitate unit per 1 RBC unit (cryoprecipitate was administered in pools of 10 units). A number value for the ratios was created by A number value for the ratios was created by - dividing the number of plasma products by RBC products (plasma:RBC) - dividing the number of plasma products by RBC products (plasma:RBC) - dividing the number of apheresis platelet products by 10 RBC products (PLT:RBC) - dividing the number of apheresis platelet products by 10 RBC products (PLT:RBC) - dividing the number of cryoprecipitate products by RBC products (cryoprecipitate:RBC). - dividing the number of cryoprecipitate products by RBC products (cryoprecipitate:RBC).

Statistical analysis Blood product usage at 24 hours was used for all transfusion variables. Blood product usage at 24 hours was used for all transfusion variables. Variables were selected from age, base deficit, ISS, PT, PTT, RBCs, gender, plasma:RBC ratio, PLT:RBC ratio, and cryoprecipitate:RBC ratio by univariate logistic regression of alive 30 days after admission, which are significant at an alpha level of 0.1. Variables were selected from age, base deficit, ISS, PT, PTT, RBCs, gender, plasma:RBC ratio, PLT:RBC ratio, and cryoprecipitate:RBC ratio by univariate logistic regression of alive 30 days after admission, which are significant at an alpha level of 0.1.

RESULTS MTP versus pre-MTP cohorts Between February 1, 2007, and January 31, 2009, 132 patients met the inclusion criteria for the MTP cohort. Between February 1, 2007, and January 31, 2009, 132 patients met the inclusion criteria for the MTP cohort. 84 historic controls (pre-MTP) received 10 or more units of RBCs in the first 24 hours of their hospital stay and were treated between February 1, 2005, and January 31, historic controls (pre-MTP) received 10 or more units of RBCs in the first 24 hours of their hospital stay and were treated between February 1, 2005, and January 31, no difference in any demographic information or injury severity between the two cohorts: no difference in any demographic information or injury severity between the two cohorts: - age (p = 0.28), - age (p = 0.28), - Gender (p = 0.82), - Gender (p = 0.82), - trauma mechanism (p = 0.27) - trauma mechanism (p = 0.27) - ISS (p = 0.49) - ISS (p = 0.49) - initial base deficit (p = 0.51) - initial base deficit (p = 0.51)

RESULTS No patient had any documented existing use of anticoagulants. No patient had any documented existing use of anticoagulants. Blood product usage was similar between the two cohorts, except increase in plasma with the MTP cohort: 24 hr RBC products (p = 0.85), 24 hr plasma (p < 0.01), 24 hr apheresis PLTs (p = 0.56), and 24 hr cryoprecipitate units (p = 0.79). Blood product usage was similar between the two cohorts, except increase in plasma with the MTP cohort: 24 hr RBC products (p = 0.85), 24 hr plasma (p < 0.01), 24 hr apheresis PLTs (p = 0.56), and 24 hr cryoprecipitate units (p = 0.79). The blood product ratios at 24 hrs were similar except a higher plasma:RBC ratio in the MTP cohort: plasma:RBC (p 0.001), PLT:RBC (p = 0.74), cryoprecipitate:RBC (p = 0.46). The blood product ratios at 24 hrs were similar except a higher plasma:RBC ratio in the MTP cohort: plasma:RBC (p 0.001), PLT:RBC (p = 0.74), cryoprecipitate:RBC (p = 0.46). rFVIIa usage was similar (p = 0.31). rFVIIa usage was similar (p = 0.31). Patient outcomes were similar: 24-hour and 30-day survival rates (p = 0.28 and p = 0.47, respectively) Patient outcomes were similar: 24-hour and 30-day survival rates (p = 0.28 and p = 0.47, respectively) intensive care unit and hospital length of stay ( p = 0.62 and p = 0.23, respectively). intensive care unit and hospital length of stay ( p = 0.62 and p = 0.23, respectively).

RESULTS Blood product ratio and survival The MTP and pre-MTP cohorts were combined to investigate the effect of the plasma, PLT, and cryoprecipitate on RBC products transfused in the first 24 hours on patient outcome. The MTP and pre-MTP cohorts were combined to investigate the effect of the plasma, PLT, and cryoprecipitate on RBC products transfused in the first 24 hours on patient outcome. The plasma:RBC ratio, PLT:RBC ratio, and cryoprecipitate:RBC ratio all had an effect on survival The plasma:RBC ratio, PLT:RBC ratio, and cryoprecipitate:RBC ratio all had an effect on survival

RESULTS the final model had five explanatory variables; the final model had five explanatory variables; plasma:RBC, PLT:RBC, ISS, age, and total RBCs as independent variables and 30-day survival as a dependent variable plasma:RBC, PLT:RBC, ISS, age, and total RBCs as independent variables and 30-day survival as a dependent variable a total of 202 records over 214 overall records were used in building the model, of which 102 survived after 30 days a total of 202 records over 214 overall records were used in building the model, of which 102 survived after 30 days

Limitations relatively small sample size relatively small sample size the use of historic controls the use of historic controls

Survival Bias All of the studies regarding plasma:RBC ratios and massive transfusion outcome have survival bias in the data because those who survive longer are more likely to receive more coagulation factor therapies versus patients who die early after admission who may receive less coagulation factors due to delay in coagulation product transfusion.

Survival Bias The strongest survival bias is likely seen in the plasma:RBC ratio because the 24-hour and 30- day mortality were unchanged in the groups who received the least amount of plasma (i.e., these patients died early in their hospital course). The strongest survival bias is likely seen in the plasma:RBC ratio because the 24-hour and 30- day mortality were unchanged in the groups who received the least amount of plasma (i.e., these patients died early in their hospital course). Correction for survival bias eliminates the apparent survival benefit of the “high” ratio group suggesting that death was the cause, not the effect of the low ratio Correction for survival bias eliminates the apparent survival benefit of the “high” ratio group suggesting that death was the cause, not the effect of the low ratio

Conclusion “ current data support early and aggressive coagulation factor replacement through transfusion of plasma, PLT, and cryoprecipitate products. Although the optimal ratio is not precisely defined, these reports, including this study, support an aggressive approach to transfusion.” “ current data support early and aggressive coagulation factor replacement through transfusion of plasma, PLT, and cryoprecipitate products. Although the optimal ratio is not precisely defined, these reports, including this study, support an aggressive approach to transfusion.”

Conclusion “ higher ratios of plasma, PLT, and cryoprecipitate to RBC transfusion were associated with markedly improved patient survival. Therefore, MTPs with blood administration ratios that recapitulate whole blood should be adopted by centers routinely taking care of trauma patients in an effort to improve the early resuscitations of these critically injured patients with a resulting decrease in mortality.”

PRBC PLASMA

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