Omar AlsuhaibaniOmar AlsuhaibaniTransfusion MedicineTransfusion Medicine

Journal ClubJournal ClubFebruary 2, 2010February 2, 2010

BackgroundBackground

Transfusion therapy is common in trauma Transfusion therapy is common in trauma patients.patients.

Massive transfusion is defined as 10 or Massive transfusion is defined as 10 or more RBC units in a 24 hour periodmore RBC units in a 24 hour period

Massive transfusion occurs in up to 15% of Massive transfusion occurs in up to 15% of civilian trauma patients and is associated civilian trauma patients and is associated with a mortality rate of 20-50%with a mortality rate of 20-50%

Most patients requiring massive Most patients requiring massive transfusion die within 6 hours of admissiontransfusion die within 6 hours of admission

May 2005May 2005 international expert conference on massive international expert conference on massive

transfusion at the US Army's Institute of Surgical transfusion at the US Army's Institute of Surgical Research Research

concept of “damage control” should be expanded concept of “damage control” should be expanded to include what has subsequently come to be to include what has subsequently come to be known as “damage control resuscitation.”known as “damage control resuscitation.”

addresses the immediate need for coagulation addresses the immediate need for coagulation components as well as for oxygen delivery in the components as well as for oxygen delivery in the severely injured patient severely injured patient

specifies decreasing, to the extent possible, the specifies decreasing, to the extent possible, the use of crystalloids as volume replacementuse of crystalloids as volume replacement

matching RBC transfusion on a 1:1:1 ratio with matching RBC transfusion on a 1:1:1 ratio with plasma and platelets.plasma and platelets.

Borgman and coworkers - 2007Borgman and coworkers - 2007

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

Duchesne and colleagues - 2008Duchesne and colleagues - 2008

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

Maegele and colleagues - 2008Maegele and colleagues - 2008

retrospectively analyzed their trauma retrospectively analyzed their trauma registryregistry

improved mortality with a improved mortality with a RBC:plasma ratio of less than 0.9 RBC:plasma ratio of less than 0.9 compared to 0.9-1.1 and greater compared to 0.9-1.1 and greater than 1.1than 1.1

higher amounts of plasma-to-RBC higher amounts of plasma-to-RBC ratio were associated with increased ratio were associated with increased length of stay and increased rates of length of stay and increased rates of multiorgan failure.multiorgan failure.

Sperry and coworkers - 2008Sperry and coworkers - 2008

Multicenter prospective cohort study of 415 Multicenter prospective cohort study of 415 blunt-injured adults with hemorrhagic shock blunt-injured adults with hemorrhagic shock who required 8 or more units of RBCs within who required 8 or more units of RBCs within the first 12 hoursthe first 12 hours

1:1.50 or more versus less than 1:1.50 1:1.50 or more versus less than 1:1.50 plasma:RBC ratio was associated with plasma:RBC ratio was associated with improved mortality only after adjusting for improved mortality only after adjusting for confounders,confounders,

strongly associated with the development of strongly associated with the development of acute respiratory distress syndrome (ARDS).acute respiratory distress syndrome (ARDS).

Holcomb and colleagues - 2008Holcomb and colleagues - 2008 retrospective study of 466 massively retrospective study of 466 massively

transfused (10 units of RBCs in 24 hr) civilian transfused (10 units of RBCs in 24 hr) civilian patientspatients

the group with a high plasma- and PLT to- RBC the group with a high plasma- and PLT to- RBC ratio (1 unit of PLTs and plasma to 2 units of ratio (1 unit of PLTs and plasma to 2 units of RBCs) had the highest rate of 30-day survival RBCs) had the highest rate of 30-day survival (73%) compared to patients who received high (73%) compared to patients who received high plasma and low PLT (54%),low plasma and plasma and low PLT (54%),low plasma and high PLT (67%), and low plasma and low PLT high PLT (67%), and low plasma and low PLT (<1 unit of PLTs and plasma to 2 units of (<1 unit of PLTs and plasma to 2 units of RBCs;43%) ratios (p < 0.001).RBCs;43%) ratios (p < 0.001).

the higher 6-hour plasma:RBC and PLT:RBC the higher 6-hour plasma:RBC and PLT:RBC ratios were also correlated with survival.(2009)ratios were also correlated with survival.(2009)

Teixeira and coworkers - 2009Teixeira and coworkers - 2009

retrospective study of 484 trauma retrospective study of 484 trauma patients who received 10 or more patients who received 10 or more RBCs during 24 hoursRBCs during 24 hours

plasma:RBC ratio of higher than 1:3 plasma:RBC ratio of higher than 1:3 was associated with survival, but a was associated with survival, but a ratio of greater than 1:2 was no ratio of greater than 1:2 was no better than 1:2 or less to more than better than 1:2 or less to more than 1:3.1:3.

Snyder and coworkers - 2009Snyder and coworkers - 2009 the plasma:RBC ratio (1:2 vs.<1:2) was the plasma:RBC ratio (1:2 vs.<1:2) was

associated with survival (40% vs. 58% in-hospital associated with survival (40% vs. 58% in-hospital mortality rate) adjusting for multiple variablesmortality rate) adjusting for multiple variables

Similar to previous studies, an association Similar to previous studies, an association between higher FFP:PRBC ratios at 24 hours and between higher FFP:PRBC ratios at 24 hours and improved survival was observed. improved survival was observed.

However, after adjustment for survival bias in the However, after adjustment for survival bias in the analysis, the association was no longer analysis, the association was no longer statistically significant.statistically significant.

Prospective trials are necessary to evaluate Prospective trials are necessary to evaluate whether hemostatic resuscitation is clinically whether hemostatic resuscitation is clinically beneficialbeneficial

Varying definitions were used for Varying definitions were used for massive transfusion ranging from ≥8 massive transfusion ranging from ≥8 units in 12 h to >10 units in the first units in 12 h to >10 units in the first 6 h and varying ratios of component 6 h and varying ratios of component therapy were examined therapy were examined

Owing to the nature of severe Owing to the nature of severe trauma requiring high-volume blood trauma requiring high-volume blood product resuscitation, significant product resuscitation, significant survivor biassurvivor bias is highly likely. is highly likely.

Within these limitations, available Within these limitations, available literature demonstrates a clear literature demonstrates a clear survival benefit associated with early survival benefit associated with early delivery of FFP and platelets in delivery of FFP and platelets in exsanguinating traumaexsanguinating trauma

high ratio therapy may be associated high ratio therapy may be associated with a higher incidence of organ with a higher incidence of organ failure, ARDS and infection failure, ARDS and infection

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

Materials and MethodsMaterials and Methods Patient information was derived from a Patient information was derived from a

prospectively entered trauma registry that prospectively entered trauma registry that is maintained at Grady Health System. is maintained at Grady Health System.

Massive transfusion was defined as Massive transfusion was defined as transfusion of 10 or more units of RBC transfusion of 10 or more units of RBC products in the first 24-hour period of the products in the first 24-hour period of the hospital stay. hospital stay.

Non-trauma patients were excluded from Non-trauma patients were excluded from this data set. this data set.

This study combines two cohorts of This study combines two cohorts of patients: one after implementation of a patients: one after implementation of a massive transfusion protocol (MTP) and one massive transfusion protocol (MTP) and one before implementation.before implementation.

Patient inclusionPatient inclusion

MTP groupMTP group

The MTP group was defined as The MTP group was defined as trauma patients requiring massive trauma patients requiring massive transfusion and who received the transfusion and who received the MTP at Grady Memorial Hospital from MTP at Grady Memorial Hospital from February 1, 2007, to January February 1, 2007, to January 31,2009.31,2009.

Patient inclusionPatient inclusion

Pre-MTP groupPre-MTP group

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

MTP designMTP design

derived from military recommendations, derived from military recommendations, with some modifications.with some modifications.

the protocol is designed to ensure the protocol is designed to ensure immediate availability of aggressive and immediate availability of aggressive and early component therapy and is activated early component therapy and is activated with a phone call to the blood bank.with a phone call to the blood bank.

Activation of the protocol is restricted to Activation of the protocol is restricted to an attending or fellow from surgery, an attending or fellow from surgery, anesthesia, emergency medicine, or anesthesia, emergency medicine, or critical carecritical care

MTP designMTP design reserved for patients who have massive reserved for patients who have massive

hemorrhage in difficult to control anatomic hemorrhage in difficult to control anatomic locations, who use emergency issue RBCs (RBC locations, who use emergency issue RBCs (RBC products are available in the emergency room products are available in the emergency room and operating room), with ongoing blood loss of and operating room), with ongoing blood loss of more than 150 mL/minute or with blood loss of more than 150 mL/minute or with blood loss of 50% of blood volume in 4 hours or one blood 50% of blood volume in 4 hours or one blood volume in 24 hours.volume in 24 hours.

The blood bank responds to the call for protocol The blood bank responds to the call for protocol activation by immediately placing 6 units of group activation by immediately placing 6 units of group O RBCs and 6 units of group AB plasma in a O RBCs and 6 units of group AB plasma in a cooler as the “initiation package.”cooler as the “initiation package.”

The blood bank maintains an adequate inventory The blood bank maintains an adequate inventory of thawed plasma products for immediate of thawed plasma products for immediate distribution.distribution.

MTP designMTP design The blood bank then continues to prepare The blood bank then continues to prepare

pre-designated “packages” of components pre-designated “packages” of components to be picked up every 30 minutes with a to be picked up every 30 minutes with a ratio of plasma:RBC of 1:1 in addition to set ratio of plasma:RBC of 1:1 in addition to set amounts of platelets and cryoprecipitate.amounts of platelets and cryoprecipitate.

The protocol suggests transfusion of blood The protocol suggests transfusion of blood products in the appropriate amounts, but products in the appropriate amounts, but does not mandate it. does not mandate it.

if bleeding is uncontrolled, the trauma if bleeding is uncontrolled, the trauma service can request a recombinant factor service can request a recombinant factor VIIa (rFVIIa) after Package 2 with a second VIIa (rFVIIa) after Package 2 with a second dose if needed 30 minutes later.dose if needed 30 minutes later.

Data collectionData collection For the pre-MTP cohort, clinical and blood bank data were For the pre-MTP cohort, clinical and blood bank data were

retrospectively collected, and for the MTP patient cohort retrospectively collected, and for the MTP patient cohort prospective data were collected. prospective data were collected.

Clinical data collected included patient demographics Clinical data collected included patient demographics includingincluding

- 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 - lengths of stay (hospital length of stay, intensive

care unit length of stay, and ventilator days)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 collectionData collection

Laboratory data were collected including Laboratory data were collected including Hb/Hct, base deficit, and coagulation Hb/Hct, base deficit, and coagulation variables (PT, INR, aPTT, fibrinogen level, variables (PT, INR, aPTT, fibrinogen level, and PLT count) upon arrival to the and PLT count) upon arrival to the emergency department and on arrival to the emergency department and on arrival to the intensive care unit.intensive care unit.

Blood bank data collected included the Blood bank data collected included the number of units transfused of RBCs, plasma, number of units transfused of RBCs, plasma, platelets, and cryoprecipitate in the first 6 platelets, and cryoprecipitate in the first 6 hours, first 24 hours, and entire hospital hours, first 24 hours, and entire hospital stay.stay.

Definition of ratiosDefinition of ratios

plasma:RBC ratio of 1:1 was defined as one plasma product plasma:RBC ratio of 1:1 was defined as one plasma product per one RBC productper one RBC product

PLT:RBC ratio of 1:1 was defined as one apheresis PLT unit PLT:RBC ratio of 1:1 was defined as one apheresis PLT unit per 10 RBC products per 10 RBC products

cryoprecipitate:RBC ratio of 1:1 was defined as 1 cryoprecipitate:RBC ratio of 1:1 was defined as 1 cryoprecipitate unit per 1 RBC unit (cryoprecipitate was cryoprecipitate unit per 1 RBC unit (cryoprecipitate was administered in pools of 10 units).administered in pools of 10 units).

A number value for the ratios was created byA number value for the ratios was created by - dividing the number of plasma products by RBC products - dividing the number of plasma products by RBC products

(plasma:RBC)(plasma:RBC) - dividing the number of apheresis platelet products by 10 - dividing the number of apheresis platelet products by 10

RBC products (PLT:RBC)RBC products (PLT:RBC) - dividing the number of cryoprecipitate products by RBC - dividing the number of cryoprecipitate products by RBC

products (cryoprecipitate:RBC).products (cryoprecipitate:RBC).

Statistical analysisStatistical analysis

Blood product usage at 24 hours was Blood product usage at 24 hours was used for all transfusion variables.used for all transfusion variables.

Variables were selected from age, Variables were selected from age, base deficit, ISS, PT, PTT, RBCs, base deficit, ISS, PT, PTT, RBCs, gender, plasma:RBC ratio, PLT:RBC gender, plasma:RBC ratio, PLT:RBC ratio, and cryoprecipitate:RBC ratio ratio, and cryoprecipitate:RBC ratio by univariate logistic regression of by univariate logistic regression of alive 30 days after admission, which alive 30 days after admission, which are significant at an alpha level of are significant at an alpha level of 0.1.0.1.

RESULTSRESULTS

MTP versus pre-MTP cohortsMTP versus pre-MTP cohorts

Between February 1, 2007, and January 31, 2009, 132 Between February 1, 2007, and January 31, 2009, 132 patients met the inclusion criteria for the MTP cohort.patients met the inclusion criteria for the MTP cohort.

84 historic controls (pre-MTP) received 10 or more units of 84 historic controls (pre-MTP) received 10 or more units of RBCs in the first 24 hours of their hospital stay and were RBCs in the first 24 hours of their hospital stay and were treated between February 1, 2005, and January 31, 2007. treated between February 1, 2005, and January 31, 2007.

no difference in any demographic information or injury no difference in any demographic information or injury severity between the two cohorts: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)

RESULTSRESULTS

No patient had any documented existing use of No patient had any documented existing use of anticoagulants.anticoagulants.

Blood product usage was similar between the two cohorts, Blood product usage was similar between the two cohorts, except increase in plasma with the MTP cohort: 24 hr RBC except increase in plasma with the MTP cohort: 24 hr RBC products (p = 0.85), 24 hr plasma (p < 0.01), 24 hr products (p = 0.85), 24 hr plasma (p < 0.01), 24 hr apheresis PLTs (p = 0.56), and 24 hr cryoprecipitate units apheresis PLTs (p = 0.56), and 24 hr cryoprecipitate units (p = 0.79).(p = 0.79).

The blood product ratios at 24 hrs were similar except a The blood product ratios at 24 hrs were similar except a higher plasma:RBC ratio in the MTP cohort: plasma:RBC (p higher plasma:RBC ratio in the MTP cohort: plasma:RBC (p 0.001), PLT:RBC (p = 0.74), cryoprecipitate:RBC (p = 0.46). 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 Patient outcomes were similar: 24-hour and 30-day

survival rates (p = 0.28 and p = 0.47, respectively) survival rates (p = 0.28 and p = 0.47, respectively) intensive care unit and hospital length of stay intensive care unit and hospital length of stay

( p = 0.62 and p = 0.23, respectively). ( p = 0.62 and p = 0.23, respectively).

RESULTSRESULTS

Blood product ratio and survivalBlood product ratio and survival The MTP and pre-MTP cohorts were The MTP and pre-MTP cohorts were

combined to investigate the effect of combined to investigate the effect of the plasma, PLT, and cryoprecipitate the plasma, PLT, and cryoprecipitate on RBC products transfused in the on RBC products transfused in the first 24 hours on patient outcome.first 24 hours on patient outcome.

The plasma:RBC ratio, PLT:RBC ratio, The plasma:RBC ratio, PLT:RBC ratio, and cryoprecipitate:RBC ratio all had and cryoprecipitate:RBC ratio all had an effect on survivalan effect on survival

RESULTSRESULTS

the final model had five explanatory the final model had five explanatory variables;variables;

plasma:RBC, PLT:RBC, ISS, age, and plasma:RBC, PLT:RBC, ISS, age, and total RBCs as independent variables and total RBCs as independent variables and 30-day survival as a dependent variable30-day survival as a dependent variable

a total of 202 records over 214 overall a total of 202 records over 214 overall records were used in building the records were used in building the model, of which 102 survived after 30 model, of which 102 survived after 30 daysdays

LimitationsLimitations

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

Survival BiasSurvival Bias

All of the studies regarding plasma:RBC All of the studies regarding plasma:RBC

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

Survival BiasSurvival Bias

The strongest survival bias is likely seen in The strongest survival bias is likely seen in the plasma:RBC ratio because the 24-hour the plasma:RBC ratio because the 24-hour and 30-day mortality were unchanged in and 30-day mortality were unchanged in the groups who received the least amount the groups who received the least amount of plasma (i.e., these patients died early in of plasma (i.e., these patients died early in their hospital course).their hospital course).

Correction for survival bias eliminates the Correction for survival bias eliminates the apparent survival benefit of the “high” apparent survival benefit of the “high” ratio group suggesting that death was the ratio group suggesting that death was the cause, not the effect of the low ratiocause, not the effect of the low ratio

ConclusionConclusion

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

ConclusionConclusion

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

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