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Blood Transfusion, Independent of Shock Severity, Is Associated with Worse Outcome in Trauma

Malone, Debra L. MD; Dunne, James MD; Tracy, J. Kathleen MA; Putnam, A. Tyler MD; Scalea, Thomas M. MD; Napolitano, Lena M. MD

The Journal of Trauma: Injury, Infection, and Critical Care: May 2003 - Volume 54 - Issue 5 - p 898-907
doi: 10.1097/01.TA.0000060261.10597.5C
ORIGINAL ARTICLES
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Background  We have previously shown that blood transfusion in the first 24 hours is an independent predictor of mortality, intensive care unit (ICU) admission, and increased ICU length of stay in the acute trauma setting when controlling for Injury Severity Score, Glasgow Coma Scale score, and age. Indices of shock such as base deficit, serum lactate level, and admission hemodynamic status (systolic blood pressure, heart rate) and admission hematocrit were considered potential confounding variables in that study. The objectives of this study were to evaluate admission anemia and blood transfusion within the first 24 hours as independent predictors of mortality, ICU admission, ICU length of stay (LOS), and hospital LOS, with serum lactate level, base deficit, and shock index (heart rate/systolic blood pressure) as covariates.

Methods  Prospective data were collected on 15,534 patients admitted to a Level I trauma center over a 3-year period (1998–2000) and stratified by age, gender, race, Glasgow Coma Scale score, and Injury Severity Score. Admission anemia and blood transfusion were assessed as independent predictors of mortality, ICU admission, ICU LOS, and hospital LOS by logistic regression analysis, with base deficit, serum lactate, and shock index as covariates.

Results  Blood transfusion was a strong independent predictor of mortality (odds ratio [OR], 2.83; 95% confidence interval [CI], 1.82–4.40;p < 0.001), ICU admission (OR, 3.27; 95% CI, 2.69–3.99;p < 0.001), ICU LOS (p < 0.001), and hospital LOS (Coef, 4.37; 95% CI, 2.79–5.94;p < 0.001) when stratified by indices of shock (base deficit, serum lactate, shock index, and anemia). Patients who underwent blood transfusion were almost three times more likely to die and greater than three times more likely to be admitted to the ICU. Admission anemia (hematocrit < 36%) was an independent predictor of ICU admission (p = 0.008), ICU LOS (p = 0.012), and hospital LOS (p < 0.001).

Conclusion  Blood transfusion is confirmed as an independent predictor of mortality, ICU admission, ICU LOS, and hospital LOS in trauma after controlling for severity of shock by admission base deficit, lactate, shock index, and anemia. The use of other hemoglobin-based oxygen-carrying resuscitation fluids (such as human or bovine hemoglobin substitutes) in the acute postinjury period warrants further investigation.

From the Departments of Surgery (D.L.M., J.D., A.T.P., T.M.S., L.M.N.) and Epidemiology (J.K.T.), University of Maryland School of Medicine and R Adams Cowley Shock Trauma Center, Baltimore, Maryland.

Submitted for publication February 23, 2002.

Accepted for publication January 23, 2003.

Presented at the 15th Annual Meeting of the Eastern Association for the Surgery of Trauma, January 16–19, 2002, Orlando, Florida.

Address for reprints: Lena M. Napolitano, MD, Department of Surgery, 10 North Greene Street, Room 5C-122, Baltimore, MD 21201; email: lnapolitano@smail.umaryland.edu.

Research performed over the past decade has demonstrated that allogeneic blood transfusion is potentially associated with detrimental immunomodulation. 1 This effect may include decreased immune cell proliferation with subsequent decrease in T-cell–mediated immunity. 2 Numerous studies have associated blood transfusion with an increase in serum and soft tissue tumor necrosis factor-α, interleukin (IL)-1β, IL-6, IL-8, and other cytokines along with their soluble cytokine receptors. 3–7

Two recent clinical studies documented that blood transfusions are also associated with the induction and enhancement of an acute inflammatory response. 4,5 Incubation of normal neutrophils with plasma from stored blood was associated with a significant increase in inflammatory cytokine release, which was amplified with older (> 14 days) stored blood. 8 Plasma from aged stored red blood cells has also been documented to delay neutrophil apoptosis and prime neutrophils for cytotoxicity as measured by superoxide release. 9

Clinical studies have demonstrated an increased risk for cancer recurrence and decreased disease-free survival when blood transfusion is administered during operations intended to be curative. 10 Mynster and Nielsen documented that perioperative blood transfusion in colorectal cancer surgery patients was associated with a significant reduction in overall survival (3.0 years for 452 transfused patients vs. 4.6 years for 266 nontransfused patients, p = 0.004). Furthermore, the relative risk of disease recurrence was 1.5-fold higher in transfused patients (95% confidence interval [CI], 1.1–2.2) after multivariate correction for patient age, gender, tumor location, Dukes classification, blood loss, and postoperative infectious complications. 11

In trauma patients, blood transfusions have been shown to be an independent risk factor for death, perioperative infection, postinjury multiple organ failure (MOF), and admission to the intensive care unit (ICU). 12–16 We have previously documented 17 that blood transfusion within 24 hours of admission was a significant independent predictor of mortality, ICU admission, and ICU length of stay (LOS) in the acute trauma setting (n = 9,569) when controlling for Injury Severity Score (ISS), Glasgow Coma Scale (GCS) score, and age by logistic regression analysis. Blood transfusion was also associated with increased risk for the systemic inflammatory response syndrome (SIRS) in that study. A significant limitation of that study was the lack of inclusion of indices of shock such as base deficit, serum lactate level, admission hemodynamic status (systolic blood pressure [SBP], heart rate [HR]), and admission hematocrit as potential confounding variables. We therefore sought to reevaluate blood transfusion as an independent predictor of outcome in trauma using a larger patient cohort, and incorporated indices of shock as covariates. Anemia was also evaluated as an independent predictor of trauma outcome in this current study, and hospital LOS was included as an outcome variable.

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MATERIALS AND METHODS

Prospective data were collected on all trauma admissions (n = 15,534) to the R Adams Cowley Shock Trauma Center over a 3-year period (January 1998–December 2000). In this retrospective analysis of the data, patients were stratified by age, gender, race, GCS score, and ISS. Inclusion criteria included age ≥ 18 years. Blood product use at the time of admission was based on Advanced Trauma Life Support guidelines 18 for the initial resuscitation of trauma patients. Blood transfusion within the first 24 hours was based on clinical grounds (e.g., ongoing hemorrhage) and for treatment of anemia in the presence of concomitant hypovolemia and/or hemodynamic instability, and in attempts to normalize blood lactate concentration as a surrogate endpoint of resuscitation. There is no formal transfusion policy or hospital transfusion trigger that is used for blood transfusion in trauma. There was no specific effort to provide leukocyte-reduced blood to these trauma patients. During this period of time, the blood bank provided either non–leukocyte-reduced or leukocyte-reduced blood as it was available. The trauma registry does not collect information regarding whether blood transfusions were leukocyte-reduced or not.

Admission anemia and blood transfusion within the first 24 hours were assessed as independent predictors of the SIRS, mortality, ICU admission, ICU LOS, and hospital LOS by logistic and linear regression analysis, with admission base deficit, serum lactate, and shock index (HR/SBP) as covariates. The SIRS score was calculated at the time of admission, and was derived by assigning one point for each of the following findings: fever or hypothermia (temperature > 38°C or < 36°C), tachycardia (heart rate > 90 beats/min), tachypnea (respiratory rate > 20 breaths/min or Paco2 < 32 mm Hg), and abnormal white blood cell count (> 12,000/mm3 or < 4,000/mm3). A patient has SIRS if the SIRS score is ≥ 2. An abnormal shock index is > 0.6. The ISS was used to quantify extent and severity of injury. 19 The study was approved by the Institutional Review Board of the University of Maryland at Baltimore.

Anemia (defined at our institution as hematocrit < 36%, or hemoglobin < 12 g/dL), shock index, base deficit, and serum lactate as indices of shock were also evaluated as independent predictors of the outcome variables mortality, ICU admission, and LOS and hospital LOS. Shock index, base deficit, serum lactate, age, gender, race, GCS score, and ISS were studied to determine whether each individual variable was associated with an increased risk for anemia at admission or blood transfusion within the first 24 hours. Data are presented as mean ± SD. Categorical variables were compared using Pearson’s χ2 and contingency table analysis. Multiple logistic regression analyses were used for binary outcomes, using the covariates age, gender, race, and ISS as adjusters. Continuous variables were compared using t test (to compare differences between transfused and nontransfused patients) and multiple linear regression analysis, using the same covariates as adjusters (Stata, Release 6.0, Stata Corp., College Station, TX).

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RESULTS

The study cohort consisted of 15,534 trauma patients (Table 1) who were primarily men (n = 10,997 [71%]), involved more frequently in blunt trauma (n = 12,460 [80%]) than penetrating trauma (n = 2,291 [15%]). The study population was 58% Caucasian and 37% African-American. The mean age was 37 ± 18 years, and patients were moderately injured, with a mean ISS of 10 ± 10 and a mean GCS score of 14 ± 3. SIRS, defined as an admission SIRS score ≥ 2, was present in 23% of patients. The mean hospital LOS was 4 ± 8 days.

Table 1

Table 1

The study population was then divided into patients that received blood transfusion (Blood Transfusion group, n = 1,703) in the first 24 hours after injury, and those that did not (No Blood Transfusion group, n = 13,831). Transfused patients received a mean of 6.8 ± 6.7 units of blood postinjury. Massive transfusion (> 10 units of blood) was required in 421 of the 1,703 transfused patients (24.7%).

Patients in the Blood Transfusion group were significantly older (42 vs. 36 years, p < 0.001), had increased injury severity as measured by ISS (mean ISS, 22 vs. 8;p < 0.001), and had decreased admission GCS score (12 vs. 14, p < 0.001) (Table 1). SIRS was present in 47% of patients who underwent blood transfusion within the first 24 hours (p < 0.001 vs. total study cohort). No gender- or race-related differences in blood transfusion were identified. Penetrating trauma was associated with an increased incidence of blood transfusion (p < 0.001).

All indices of shock evaluated in this study were associated with an increased risk for blood transfusion (Table 2). Patients who received blood transfusion within the first 24 hours had significantly lower admission hematocrit, increased serum lactate concentration, worse base deficit, and increased incidence of SIRS compared with nontransfused patients (Table 2). The mean admission hematocrit was significantly lower (34 ± 7) in the Blood Transfusion group compared with 41 ± 5 for the No Blood Transfusion group (p < 0.001). Logistic regression analysis confirmed that elevated serum lactate, base deficit, and anemia were strong independent predictors for blood transfusion within the first 24 hours (Table 3). Trauma patients with a base deficit < −2.0 mmol/L were more likely to need a blood transfusion (odds ratio [OR], 3.35; 95% CI, 2.72–4.11;p < 0.001), although admission base deficit was available in a smaller cohort of trauma patients (n = 2,904). Trauma patients with an admission hematocrit < 36% were more likely to receive a blood transfusion (OR, 5.17; 95% CI, 4.37–6.10;p < 0.001) compared with patients without anemia (hematocrit > 36%). In addition, patients with physiologic evidence of shock, manifested by an abnormal shock index, were more likely to be transfused (OR, 2.54; 95% CI, 1.92–3.34;p < 0.001).

Table 2

Table 2

Table 3

Table 3

The Blood Transfusion group demonstrated a significant increase in both 24-hour mortality (11.4% vs. 0.8%, p < 0.001) and hospital mortality rates (22.1% vs. 2.3%, p < 0.001) (Table 4). Of patients with a length of stay < 24 hours, 2.2% died, and 63% of the patients who died within the first 24 hours had received a blood transfusion for treatment of hemorrhagic shock. Logistic regression analysis documented a significantly increased risk for mortality in Blood Transfusion patients (OR, 2.83; 95% CI, 1.82–4.40) (Table 5) after controlling for all other confounding variables that affect trauma mortality (including ISS, GCS score, age, and race) and all available shock variables (including lactate, base deficit, and shock index). Blood transfusion was therefore confirmed as a significant independent predictor of adverse trauma outcome, characterized by increased mortality. Furthermore, patients who required massive transfusion (> 10 units of blood) had a greater increase in mortality (OR, 3.65; 95% CI, 1.97–6.75;p < 0.001) compared with patients that received < 10 units of blood, after controlling for all other variables in the model.

Table 4

Table 4

Table 5

Table 5

Blood transfusion was also associated with an increased risk for ICU admission (Table 6). Of the 3,511 patients in the study cohort who were admitted to the ICU, 1,015 (29%) received a blood transfusion within the first 24 hours. Patients who received a blood transfusion within the first 24 hours were more likely to be admitted to the ICU (59.6% vs. 18.0%, p < 0.001) and had longer ICU LOS than nontransfused patients (17 ± 16 vs. 12 ± 12, p < 0.001) (Table 4). Linear regression analysis demonstrated that blood transfusion was an independent predictor of ICU LOS (Table 7) and determined that transfused patients spent greater than 4 more days in the ICU than nontransfused patients. ICU LOS was not significantly different (OR, 2.40; 95% CI, 1.22–6.02;p = 0.193) in patients who required massive transfusion (> 10 units of blood) compared with those who received < 10 units of blood postinjury.

Table 6

Table 6

Table 7

Table 7

Blood transfusion within the first 24 hours after trauma was also an independent predictor of increased hospital LOS by linear regression analysis (Table 7), confirming that transfused patients had greater than 6 more hospital days than nontransfused patients. The mean hospital length of stay for transfused patients was 14 ± 16 days compared with 3 ± 6 days for those patients who were not transfused.

Anemia (hematocrit < 36%) at the time of admission was associated with increased age, increased injury severity (reflected by increased ISS and lower GCS score), and female gender (Table 8). Patients who were anemic at the time of admission had significantly higher serum lactate levels, more abnormal base deficit and shock index scores, and an increased incidence of SIRS (SIRS score ≥ 2). Anemia was an independent predictor of ICU admission, ICU LOS, and hospital LOS, but was not an independent predictor of mortality.

Table 8

Table 8

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DISCUSSION

Blood transfusion is presently a major component of the treatment of acute traumatic hemorrhagic shock. The incorporation of blood transfusion in resuscitation protocols for acute trauma is supported in the Advanced Trauma Life Support guidelines of the American College of Surgeons, 18 which are adhered to in trauma treatment centers worldwide. Recent literature has documented severe immunologic responses to blood transfusion with resultant adverse outcomes.

Fransen et al. studied 114 consecutive cardiac surgery patients to evaluate the systemic inflammatory response and outcome associated with blood transfusion. 4 Blood samples were taken at induction of anesthesia; at the start of aortic cross-clamping; at aortic unclamping; and then at 0.5, 4, 8, and 18 hours thereafter. Bactericidal permeability increasing protein and IL-6 serum concentrations were significantly higher in patients who received intraoperative blood transfusions. Furthermore, serum bactericidal permeability increasing protein levels increased with the number of packed cells transfused. Patients who received blood transfusions were also noted to have worse postoperative clinical outcome.

In vitro studies 8 documented that incubation of normal neutrophils with plasma from blood stored for 21 and 42 days induced a significant increase in production of IL-8, IL-1β, tumor necrosis factor-α, and secretory phospholipase compared with plasma from fresh (day 0) blood. Another recent study examined the effect of blood transfusion on immune cells. 9 Neutrophils from healthy volunteers were incubated with plasma from unmodified, leukoreduced, or saline-washed red blood cell units. They documented that neutrophil apoptosis was delayed by blood stored for 21 and 42 days. Furthermore, poststorage washing with saline, but not prestorage leukoreduction, abrogated this effect. These data confirm that stored blood induces an inflammatory response in normal neutrophils.

Additional studies have suggested that universal leukodepletion of packed red blood cells may be a rational approach to preventing the adverse immunologic and inflammatory response to blood transfusion. 20,21 These studies document the deleterious effects of the highly active leukocyte enzymes, including increased in vitro deterioration of red blood cells during storage. These deleterious effects are preventable by prior leukodepletion of the stored blood. Conflicting data exist, however, and the additional costs of leukodepletion may not uniformly be associated with improved clinical outcomes. 22,23

Recent trauma literature has focused extensively on blood transfusion and adverse outcome in trauma. A 55-month inception cohort study evaluating 513 consecutive trauma patients (ISS > 15, survival greater than 48 hours) admitted to the ICU of a Level I trauma center demonstrated a dose-response relationship between blood transfusion and the development of MOF. 16 This effect was present independent of the other indices of shock that were examined. Further evaluation of this finding documented that the age of packed red blood cells transfused within the first 6 hours after trauma, the number of units older than 14 days, and the number of units older than 21 days were independent risk factors for MOF by multiple logistic analysis in trauma patients. 24

Purdy et al. also reported a correlation of mortality with the age of blood transfused in patients admitted to the ICU with a diagnosis of severe sepsis. 25 The median age of blood transfused to survivors was 17 days versus 25 days for nonsurvivors (p < 0.0001). A negative correlation was found between increasing age of blood transfused and survival (r = −0.73). We were unable to evaluate the age of blood as an independent risk factor in this current study, because this information is not currently collected routinely during trauma resuscitation and is not included in our trauma registry information. All future studies investigating blood transfusion and outcome after trauma should therefore include age of blood in the analysis.

Blood transfusion has also been associated with increased risk for bacterial infection in recent studies. A retrospective cohort study of 9,598 consecutive hip fracture patients who underwent surgical repair evaluated the effect of allogeneic blood transfusion on infectious outcomes. 13 Blood transfusion was associated with a 1.35-fold increased risk for bacterial infection and a 1.52-fold increased risk for pneumonia. A dose-response relationship for blood and serious bacterial infection (p = 0.001) and pneumonia (p = 0.001) was established. These investigators concluded that bacterial infection may be the most common life-threatening adverse effect of allogeneic blood transfusion.

Allogeneic blood transfusion was confirmed as an independent predictor for postoperative bacterial infection by multiple logistic regression (p = 0.007) in a prospective analysis of 1,349 patients who underwent colorectal surgery in 11 centers across Canada. 26 There was a higher frequency of wound infections and intra-abdominal sepsis in the 282 patients who had received blood transfusions (25.9 vs. 14.2%, p = 0.001), and a significant dose-response relationship between transfusion and infection was demonstrated. The mortality rate was significantly higher in the transfused group as well.

Most recently, Taylor et al. studied 1,717 patients admitted to a medical-surgical ICU to compare the rates of nosocomial infection between transfused (n = 416) and nontransfused (n = 1,301) patients. 14 Patients were stratified for severity of illness using Mortality Probability Model scores at admission, age, and gender. Nosocomial infection occurred in 5.94% of the entire cohort, but the transfused group had a significantly higher rate (sixfold increase) of nosocomial infection (15.38% vs. 2.92%, p < 0.05). Furthermore, a dose-response relationship between the number of units of red blood cells transfused and risk for nosocomial infection was identified. For each unit of blood administered, the odds of infection were increased by a factor of 1.5 (p < 0.0001). The transfusion group also had a significantly higher mortality rate (24.0% vs. 10.2%, p < 0.05).

Claridge and colleagues examined the relationship between infections in trauma patients and the transfusion of packed red blood cells within the first 48 hours of admission. 15 The overall blood transfusion rate in 1,593 trauma patients was 19.4%, ranging from 0 to 46 units. The infection rate in patients who received at least one blood transfusion was significantly higher (p < 0.0001) at 33.0% versus 7.6% in patients receiving no blood transfusion. This study confirmed a clear dose-dependent correlation between blood transfusion and the development of infection in trauma patients. Multivariate analysis further demonstrated that blood transfusion was an independent risk factor for infection.

We postulate that the increased mortality and ICU resource use identified in transfused trauma patients in this study may, in part, be related to an increased risk for nosocomial infection, but these data were not available for this current study. Future studies that investigate increased mortality and morbidity associated with blood transfusion in trauma should aim to assess this important variable.

The association between blood transfusion and risk for SIRS and worse outcome in trauma patients (n = 9,569) was the focus of a previous study at our institution. 17 Blood transfusion was found to be an independent predictor of mortality, ICU admission, and ICU LOS by logistic regression, with age, ISS, gender, and GCS score held constant. As in the present study, transfused patients were significantly older, had higher ISS, and had lower GCS scores. Patients who received blood transfusions had a 3- to 5-fold increased risk for SIRS, a 10-fold increased risk for mortality, a greater than 3-fold increased risk for ICU admission, and a 6-fold increase in mean ICU LOS. This previous study did not control for indices of shock such as abnormal physiology (represented in this study as shock index [HR/SBP], shown to be more predictive of shock than either HR or SBP alone), base deficit, elevated serum lactate, and anemia, all of which are potential confounding variables.

In the study presented in this article, we sought to validate these previous findings in a larger cohort of trauma patients (n = 15,534) and expanded the analysis to control for race and indices of shock as covariates. This current study confirmed that blood transfusion was a strong independent predictor of SIRS, mortality, ICU admission, ICU LOS, and hospital LOS by multiple logistic and linear regression. Anemia was also examined as an independent outcome variable, and was identified as an independent predictor of ICU admission, ICU LOS, and hospital LOS, but not mortality. Anemic trauma patients were older, had higher ISS, and had lower GCS score, and a higher proportion of anemic patients were female patients. The recognition that anemia, in this study defined as a hematocrit of 36% or hemoglobin concentration < 12 g/dL, was an independent predictor of worse outcome after trauma could lend support to the concept that correction of anemia should be initiated at admission in the acute trauma setting. The question that remains, however, is what hematocrit should be used as the transfusion trigger in the treatment of acute trauma victims, or whether blood transfusion should be reserved only for physiologic indications. A transfusion trigger was not used in the present study but should be considered for future study in trauma when the clinical scenario permits time for hemoglobin measurement.

A randomized, controlled, clinical trial in 25 ICUs (n = 838) randomized patients to a transfusion hemoglobin trigger of 7 g/dL (restrictive strategy) or 10 g/dL (liberal strategy 27). A 54% reduction was achieved in the restrictive group (2.5 vs. 5.6 units of blood). Furthermore, no blood transfusions were required in 33% of the restrictive group. No significant differences in mortality were identified, and organ failure was significantly reduced in the restrictive group. Subgroup analyses favored the restrictive blood transfusion strategy, with a significant decrease in 30-day mortality in patients younger than 55 years (6% vs. 13%, p = 0.02) and less severely ill patients (9% vs. 16%, p = 0.02). This study confirmed that critically ill patients can safely tolerate a lower hemoglobin concentration, and that blood transfusions to achieve a higher transfusion hemoglobin trigger may be associated with worse outcome.

The results of the present study would suggest that although anemia at admission in the acute trauma setting is associated with adverse outcome, blood transfusion for treatment of the anemia may not be the ideal resuscitative fluid with which to correct the deficit in hemoglobin. The hemoglobin concentration used to define anemia in this study is well above the levels defined as the recommended transfusion trigger in most current critical care studies, yet it is clear that this level of anemia at admission after trauma in this study was significantly associated with worse outcome.

Higher hemoglobin levels may indeed be more desirable in the acute trauma scenario for the treatment of hemorrhagic shock, but transfusion of stored blood may not be the best resuscitative fluid for achieving that goal. This finding may support the use of blood or hemoglobin substitutes or other oxygen-carrying fluids such as perfluorocarbons in this clinical scenario.

Initial investigations regarding the utility of human polymerized hemoglobin have been promising. The initial phase II clinical trial (n = 39) using Polyheme (Northfield Labs, Evanston, IL) documented no safety issues related to the use in trauma patients requiring emergent transfusion. 28 The first randomized trial of Polyheme in trauma (mean ISS, 21 ± 10) and emergent surgery documented that Polyheme was safe in acute blood loss, maintained total hemoglobin in lieu of blood despite the marked decrease in red blood cell hemoglobin, and reduced the use of allogeneic blood. 29 Resuscitation with this blood substitute has also been documented to abrogate pathologic postinjury neutrophil cytotoxicity in a recent small study. 30 Injured patients requiring urgent transfusion were given either Polyheme or packed red blood cells, and neutrophils were harvested from peripheral blood. Neutrophils from the patients resuscitated with blood showed increased priming as measured by beta-2 integrin expression, superoxide, and elastase release. In contrast, no such priming was evident with patients resuscitated with the blood substitute Polyheme. 29

In addition, phase III trials with polymerized bovine hemoglobin (hemoglobin-based oxygen carrier; HBOC-201, Biopure, Cambridge, MA) are completed, documenting that infusion of HBOC-201 can avoid or reduce allogeneic blood transfusion needs in specific perioperative settings. 31,32 Recent investigations have documented that hemoglobin-based oxygen carriers are not only simple erythrocyte transfusion substitutes but are highly effective in improving tissue oxygenation. 33 Other studies suggest that leukoreduction of blood (either prestorage at the time of donation or poststorage at the time of administration) or poststorage saline washing of blood may be potential methods for abrogating the adverse effects of blood transfusion.

This current study clearly documents that transfusion of blood in the first 24 hours after injury is associated with worse outcome in trauma after stratification for other factors that affect outcome, including age, gender, race, GCS score, and ISS, and admission shock variables (including admission base deficit, serum lactate, and shock index [HR/SBP]). Two possible explanations of this finding are plausible: blood transfusion increases the trauma patient’s risk of adverse outcome, or trauma patients who require blood transfusion have increased severity of illness that is not reflected in the static measures used in this study, and blood transfusion is simply a marker of increased severity of illness that has been inadequately quantified. Future studies that attempt to further investigate this association between blood transfusions and adverse outcome in trauma should include serial measurements of shock severity, which were not available for analysis in this study.

The results of this current study, and others, urge us to perform future prospective, randomized, clinical trials to investigate modifications (such as leukocyte reduction, saline washing) of blood transfusion and alternatives to blood transfusion in trauma. Furthermore, the development of transfusion protocols based on physiologic indications, to minimize overtransfusion of blood products, should be considered in trauma resuscitation. Future research should be actively engaged in the search for safe, efficacious alternatives to blood transfusion and modification of transfusion practices in the acute treatment and resuscitation of trauma patients.

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DISCUSSION

Dr. Erik S. Barquist (Miami, Florida): In the past 15 years, several critical changes in the management of trauma patients have taken place. These changes include, but of course are not limited to, damage control, open abdomens, much shorter courses of antibiotic therapy, and use of cell scavenging and fewer blood transfusions.

In fact, in the past 6 years, we have reduced red blood cell use in my home trauma center, mostly by changing our transfusion trigger in the ICU, by nearly 50% with no adverse effect on outcomes. This article by Malone et al. suggests that we should be similarly cautious about transfusing our acute trauma patients in the resuscitation bay.

This article used trauma registry data to assess the impact of blood transfusion on mortality in ICU length of stay. It is a well-performed registry study including over 15,000 patients and three years of data.

The data are taken from a previously established trauma registry database. The article is well written and easy to follow. There are many tables that make the data easy to digest. The discussion covers the pertinent articles and the references are complete. Statistical methods included control for covariables such as hypotension, lactate, and base deficit.

The authors tell us that the transfusion patients were older, had a higher ISS and a lower GCS score, and were more likely to have had penetrating trauma and higher SIRS scores. They also had lower admission hematocrits, higher lactates, and more negative base deficits. Risk factors for a transfusion included increasing age, increasing ISS, increased lactate base deficit, shock index, and decreasing GCS score.

Surprisingly, the greatest risk factor was so-called admission anemia, or hematocrit of greater than 36%. Similarly surprising was that female patients seemed to have a lower hematocrit at admission after relatively short transport times than male patients.

The authors report that there was a 22% death rate in those who were transfused early and only a 2.2% death rate in those who were not transfused. Although the authors don’t report the numbers in this fashion, the data aren’t available in the article to determine that of those that died in the ICU after 24 hours, which would presumably exclude those with massive head injury or exsanguination, there was a 14% death rate in those transfused early versus a 9% death rate in those who were not transfused in the first 24 hours. Those are more impressive data.

After stratification for every variable, including shock index, blood pressure, lactate, and base deficit, a statistically significant difference remains. The authors conclude that early blood transfusion is associated in this patient data set with higher mortality and longer lengths of stay.

However, because this is a class II data set, that is, use of a prospectively gathered but retrospectively analyzed trauma data registry, causation remains unclear. Put another way, we know that early blood transfusion in the trauma patient is associated with increased mortality, but we can’t be certain that it was the transfusion that caused the increased mortality.

Transfusion may be a marker for other diseases. A few comments: the extensive tables that accompany the article allow the reader to follow the analysis and conclusions; however, some of the entries are confusing and could be better clarified.

Second, the Materials and Methods section does not clearly state that this is a trauma registry study, and it should. Third, it would be interesting to look at those who died after more than 72 hours in the ICU because, once again, this would eliminate those patients who are destined to die no matter what we do to try and prevent that event from happening. Other than these minor points, however, this is a solid and well-written article, which I enjoyed reading.

Some questions for the authors: did the excess mortality in the early transfusion group occur because of multiple organ disfunction or because of overwhelming infection? Either of these results could be supported by the experimental in vitro data that you listed, supplied by your colleagues at the University of Colorado and other laboratories.

Why were so many patients anemic on presentation to the trauma center? Your trauma center is located in a relatively small state with one of the best prehospital systems in the country. Is this anemia assigned to prolong transporting some patients in hemodilution with crystalloid? Is it a marker of previous disease causing previously existing anemias, or is it perhaps that some sort of patient-aggressive transcapillary refill is a marker of bad disease?

Should transfusion be used if the patient can be volume-resuscitated with other fluids such as crystalloid? How anemic should we allow our acute trauma patients to become before we should worry about them dying from cellular hypoxia rather than in the late stage from multiple organ dysfunction syndrome?

Can you separate out those who are autotransfused using a cell scavenging technology from those who received allogeneic blood transfusion? Does this attenuate the survival disadvantage of transfusion as it has been shown to do in elective surgery?

Finally, have you changed your practice in your busy trauma environment? Do you allow “more anemia” and transfuse for lower hematocrits? Once again, thank you very much. I enjoyed reading the article very much.

Dr. James G. Tyburski (Detroit, Michigan): I want to congratulate Dr. Malone and the group at Maryland for a nice study. I have two questions. Basically, you talk a lot about how the blood would infect the immunologic system in your opening, but you really didn’t talk about infection rate.

Can you break that down a little bit more? Nothing better than infection will increase the length of stay, both in the hospital and in the ICU.

Also, was there any difference in the massive transfusion patients in penetrating trauma? That is, penetrating trauma, again, and the infection rates if there were hollow viscus injuries that could easily influence the lengths of stay. Thank you.

Dr. Carl J. Hauser (Newark, New Jersey): It’s said that there are lies, goddamn lies, and statistics. I would like to suggest that an alternative explanation for the data seen here is that our measurements of shock, things such as shock index, lactate, and base deficit, are just so poor that they don’t really predict the need for transfusion and resuscitation in these patients well.

This is a difficult problem, and I think that we have to be very, very cautious here. I would be very cautious about suggesting withholding transfusions from patients on the basis of the hypothetic danger of inflammation and SIRS associated with old units of blood.

It’s true. It works in the laboratory. It works on neutrophils, but we see a lot of patients here in whom the ongoing resuscitation with blood is necessary. There’s no question about it. If we don’t do it, they won’t live to see SIRS and MOF, so this needs to be looked at with great caution.

Dr. Bill Bromberg (Allentown, Pennsylvania): I had a question about the shock index and the fact that that was a measurement at one point in time. I was wondering whether it’s possible to actually see whether there was more shock over a longer period of time in those people that required transfusion rather than that one point in time. I was wondering whether they looked at that, because if people had ongoing bleeding, obviously, they were going to get transfused.

Dr. Debra L. Malone (closing): Thank you, Dr. Barquist, for your comments and your questions. You wondered, as a few of you other physicians did, what our excess mortality was attributable to.

We, too, wondered that and we have since collected data in that regard. We just have not analyzed that yet statistically, but we are looking at complications, for example, such as infection and now and then how infection may impact on the outcome of mortality.

I don’t know why we have so many anemic patients at shock trauma. I wonder, in part, whether it’s because of the way the main system triages patients and that shock trauma tends to get a greater percentage of sicker patients.

How anemic would I let my patient get before I would transfuse, and would I withhold blood transfusion? No. As of this day, right now, if I had a patient who was hemodynamically unstable because of hemorrhagic shock, I would be the first one in the trauma bay to hang the blood.

However, I would also do that recognizing that I might pay a price down the road. We did look at the number of units that were matched versus unmatched, autotransfused, and so forth.

We have some interesting preliminary data, but before reporting those data we want to perform further analyses. For example, we’re working very closely now with our blood bank, because we would like to know how many of our trauma patients may have received leukodepleted blood and how this may have had an impact on outcome as well.

Dr. Barquist did talk about trauma registry data. Yes, indeed, this is a trauma registry database study. We are in the process of validating our blood transfusion information from the trauma registry with our blood bank.

When I have that information, I will be very quick to pass that along. I cannot tell you statistically what the difference was regarding mechanism of injury in the patients that received massive transfusion. We did not actually break that down. We just saw that those who did receive massive transfusion had worse outcome.

Yes, I think that the measurements of shock are potentially problematic. I think they are limited in their ability at this point in time to assess severity of shock.

I do believe that we need to repeat studies like this and perform other studies so that we can better identify indices that might better clarify patients who are in shock. The shock index is a simple, easily performed, rapidly available tool. It’s a physiologic measure that we find correlates very nicely with the other known indices of shock available to us today.

We have a very busy trauma center, essentially 48 critical care bays that are always full to the brim, and we are always looking for ways to use our resources better. That is why we study shock index, and we hope that with further studies we might be able to quantify its validity as a measurement of shock. Thank you, again, for the opportunity to present this work.

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Keywords:

Blood transfusion; Trauma; Injury; Hemorrhage; Anemia; Shock; Nosocomial infection

© 2003 Lippincott Williams & Wilkins, Inc.