ORIGINAL ARTICLE

The Association Between Anemia and the Mortality of Severe Traumatic Brain Injury in Emergency Department
Chia-Jung Yang, MD, Kuang-Yu Hsiao, MD, I-Chun Su, MD, and I-Chuan Chen, MD

Background: Anemia is a common medical problem for critically ill patients. Blood transfusion to augment oxygen delivery for these patients has been a traditional therapy. However, few studies have identied the impact of anemia on individuals suffering from severe traumatic brain injury (TBI). Hence, this study aims to evaluate the effects of initial anemia on patients with severe TBI admitted to the Emergency Unit. Methods: We reviewed the medical records of patients with isolated severe TBI admitted to the Emergency Unit of a university hospital from July 2003 to June 2008. Patients were divided into two groups based on their initial anemia data taken while in the Emergency Unit. The anemia datum is dened as hemoglobin (Hb) 10 mg/dL. The t test was used to identify the differences between the two groups, while logistic regression was applied to determine any signicant differences found in the statistical analysis. Results: A total of 234 patients were signed up in our study. Based on their initial hemoglobin at emergency department, 23 patients (9.8%) comprised the anemia group, 17 patients (7.3%) comprised the nonanemia group, whereas 112 patients (47.9%) belonging to the nonanemia group were deceased. There is no signicant difference between the two groups (p 0.076; odds ratio, 0.97; condence interval, 0.78 1.05). Conclusion: This study shows that initial anemia is not a mortality risk factor for patients with isolated severe blunt TBI. Key Words: Anemia, Traumatic brain injury, Transfusion, Emergency department. (J Trauma. 2011;71: E132E135)

evere traumatic brain injury (TBI), according to populationbased epidemiologic studies, causes 30% to 54% mortality.1 4 Every year, 50,000 deaths, 235,000 hospitalizations and 60,000 to 90,000 cases of severe disability result
Submitted for publication October 23, 2010. Accepted for publication January 5, 2011. Copyright 2011 by Lippincott Williams & Wilkins From the Department of Emergency Medicine (C.-J.Y., K.-Y.H., I.-C.S., I.-C.C.), Chang Gung Memorial Hospital, Puzih City, Chiayi County, Taiwan; and Department of Medicine (C.-J.Y., K.-Y.H., I.-C.S., I.-C.C.), Chang Gung University College of Medicine, Gueishan Township, Taoyuan County, Taiwan. I.-C.C., K.-Y.H., and C.-J.Y. conceived the study and designed the method. I.-C.C., C.-J.Y., K.-Y.H., and I.-C.S. supervised the conduct of the data collection. C.-J.Y., K.-Y.H., and I.-C.S. undertook recruitment of participating centers and patients and managed the data, including quality control. C.-J.Y. and I.-C.C. provided statistical advice on study design and analyzed the data; K.-Y.H. chaired the data oversight committee. I.-C.C. and C.-J.Y. drafted the manuscript, and all authors contributed substantially to its revision. I.-C.C. takes responsibility for the article as a whole. Address for reprints: I-Chuan Chen, MD, Department of Emergency Medicine, Chang Gung Memorial Hospital, No. 6, W. Sec., Jiapu Rd., Puzih City, Chiayi County 613, Taiwan; email: giomacky@gmail.com. DOI: 10.1097/TA.0b013e31820ea36b

from TBI in the United States.5,6 Anemia, a common medical complication noted in critically injured patients, occurs quite often in severe TBI patients as well. There is evidence to imply that anemia is harmful to the brain. The association between anemia and worsened neurologic status in both adults and children during cardiopulmonary bypass has been demonstrated.7,8 In TBI patients, the occurrence of jugular venous desaturation has been associated with neurologic outcome, and anemia has been known to contribute to jugular venous desaturation.9,10 In a study by Carlson et al., the lowest measured hematocrit is signicantly associated with all lower outcome scores in the hospital discharge outcome data.11 However, the association between transfusion and poor outcome also appear in other observational studies, and transfusions seem to be a stronger contributor than anemia itself.1115 The decision to perform a blood transfusion in anemic TBI patients could be a challenge for clinical physicians due to scarce clinical guidelines and the need to observe balance between injury to the brain and to other organ systems. Trauma patients with or without TBI are often liberally transfused because of the concern for ongoing bleeding in the acute resuscitation phase. Once acute resuscitation phase has passed, moderate anemia is considered safe in most hemodynamically stable trauma patients.16 Most studies have focused on the effects of anemia and transfusion on outcomes after the initial acute phase. However, the role of anemia and transfusion in initial resuscitation in severe TBI patients has not been discussed. Thus, our study aims to investigate the association between initial anemia and blood transfusion for patients admitted to the emergency department (ED), and the corresponding outcomes in severe TBI patients.

PATIENTS AND METHODS General Design

This is a retrospective medical record review study. The research subject is comprised of patients with isolated severe TBI who were treated in the ED from July 2003 to June 2008. This study has been approved by Chang Gung Memorial Hospital Institute Reviewing Board with serial number 98-0876B. The informed consents of the patients were not obtained because of the retrospective design.

Patient Selection
The hospital selected for this study is a university hospital located at the heart of Taiwan. It provides neurosurgeon consultations and operating room service on a 24-hour basis, and admits referred patients with severe brain injury

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from within the region. There are approximately 70,000 visits to their emergency room every year. Patients with severe TBI during the time period selected were included in this research. However, all patients younger than 16 years, with penetrating injury, multiple trauma or no vital signs on ED arrival were excluded. Multiple trauma is dened as patients with a non-head abbreviated injury score of 2 or a sum of nonhead abbreviated injury score 3. Severe TBI is dened as Glasgow Coma Scale (GCS) score 8 at ED triage. A total 234 patients were signed; of which, 23 patients with hemoglobin 10 g/dL were classied as the anemia group, whereas the other 211 patients were classied as nonanemia group. Data were collected from the clinical information, such as all vital signs checked during the ED stay, initial laboratory data collected in the ED, amount of blood transfusion performed at ED, length of ICU stay, length of hospitalization, the lowest hemoglobin during the entire hospital admission, amount of blood transfusion during ICU stay, and survival status. Hypotension is dened as the lowest systolic pressure checked during ED stay, that is, 90 mm Hg. Bradycardia is dened as the lowest heart rate checked during ED stay, that is, 60 beat per minute. A body temperature of 36.0C is dened as hypothermia and a body temperature of 38.0C is dened as hyperthermia.

Data Analysis
Enrolled patients were divided into two groups. Those with hemoglobin of 10 at ED were classied as group I, and those with hemoglobin of 10 at ED were classied as group II. The demographic characteristics, clinical presentations, underlying disease, and hospital courses were analyzed. In addition, the differences in mortality, length of hospitalization, and the amount of blood transfusion between these two groups were compared. Statistical analysis was performed using the software SPSS version 17.0 (SPSS Inc., Chicago, IL). Mann-Whitney U test and a Students t test were used to compare the statistically signicant differences between the two groups. The difference was considered signicant if p 0.05. Stepwise backward logistic regression model was developed. All variables with a p 0.05 in the univariate analysis were selected for the stepwise backward elimination model. Continuous cycles of repeated operations were performed until all covariates with a multivariate p 0.1 were eliminated from the model. Hospital mortality was used as the dependent variable in the model, whereas p 0.05 indicated a signicant contribution of the variable in the model.

transfusion in ED had similar length of ICU stay (anemic vs. nonanemic: 8.3 9.9; 8.6 10.2; p 0.9, respectively; blood transfusion at ED vs. no transfusion: 8.7 10.3; 5.4 6.6; p 0.227, respectively) and similar length or hospital stay (anemic vs. nonanemic: 11.9 16.3, 17.6 21.7; p 0.22, respectively; blood transfusion at ED vs. no transfusion: 17.6 21.7; 9.0 11.9; p 0.128, respectively). Twentyeight patients (12.0%) had uid resuscitation with normal saline or lactate ringer at ED. Pressor had been used in 17 patients (7.3%) at ED to maintain adequate blood pressure. Seventy-two patients (30.8%) received emergent operation (i.e. patients were sent to the operation room directly from ED). In the intensive care unit (ICU), 81 patients (34.6%) had hemoglobin 10 g/dL and 88 (37.6%) had been transfused with PRBC. Patients who were anemic or transfused with blood in the ICU had a longer ICU stay (anemic vs. nonanemic: 6.0 8.0; 13.2 11.9; p 0.0001, respectively; blood transfusion during ICU vs. no transfusion: 6.1 8.4; 12.5 11.6; p 0.0001, respectively) and longer hospital stay (anemic vs. nonanemic: 12.7 17.5; 25.1 25.3; p 0.0001, respectively; blood transfusion during ICU vs. no transfusion: 11.9 16.8; 25.6 25.1; p 0.0001, respectively). The mean lowest hemoglobin during the whole stay of these 234 patients was 11.07 2.99. The mean ICU stay was 8.5 days 10.1 days and the mean hospital stay was 17.1 days 21.3 days. Table 1 showed that demographic characteristics, clinical features, ICU length of stay, hospital length of stay of the anemic and nonanemic patients. Univariate analysis (Table 2) showed that initial anemia at ED, hypothermia, hypothermia and blood transfusion at ED were not risk factors of mortality. Blood transfusion and anemia in ICU, the lowest hemoglobin during hospital stay were also not risk factors of mortality. Initial hypotension, bradycardia, uid, and pressor use at ED were all risk factors of mortality. Age and GCS at triage were also risk factors. Logistic regression for the risk factor of mortality of the 234 TBI patients showed that hypotension (odds ratio [OR], 18.8; 95% condence interval [CI], 4.1 86.6; p 0.0001) and age (OR, 1.03; 95% CI,
TABLE 1. Comparison of Characteristics and Outcomes in Anemic (Hb 10) and Nonanemic (Hb 10) Severe Traumatic Brain Injury Patients
Anemic at ED (n 23) Nonanemic at ED (n 211)

Variables

RESULTS
A total of 234 patients with severe TBI were enrolled and analyzed. Of which, 129 patients (55.1%) died. Thirtyfour patients (14.5%) had hypotension episode during ED stay, whereas 25 patients (10.7%) experienced bradycardia. Fifty-six patients (23.9%) had hypothermia and 27 patients (11.5%) suffered from hyperthermia. The mean age of the enrolled patients was 52.0 17.9. Twenty-three patients (9.8%) had initial hemoglobin of 10 g/dL at ED and 15 patients (6.4%) had blood transfusion with packed red blood cell (PRBC) at ED. Patients who were anemic or had a blood
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Age (yr) 58.86 18.29 51.27 17.77 0.053 GCS score 4.56 1.97 5.54 1.76 0.026 Hypotension 10 (43.5) 24 (11.4) 0.0001 Bradycardia 4 (17.4) 21 (9.9) 0.283 Fluid resuscitation 7 (30.4) 24 (11.4) 0.011 Pressor use 7 (30.4) 10 (4.7) 0.0001 Total unit of transfused PRBC 5.2 5.2 2.3 4.7 0.02 ICU length of stay 8.3 10.0 8.6 10.2 0.91 Hospital length of stay 11.8 16.3 17.6 21.8 0.22 Mortality 17 (73.9) 112 (53.1) 0.076
Values are expressed as mean SD and n (%).

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TABLE 2. Univariate Analysis for Risk Factors of Mortality in Severe Traumatic Brain Injury Patients
Variables Age (yr) GCS score Hypotension Bradycardia Hypothermia hyperthermia Fluid resuscitation Anemia (Hb 10) at ED Blood transfusion at ED Pressor use at ED Anemia (Hb 10) during ICU Blood transfusion during ICU Lowest hemoglobin during hospital stay Nonmortality (n 105) 47.6 16.9 6.35 1.42 2 (1.9) 6 (5.7) 26 (24.8) 12 (11.4) 5 (4.8) 6 (5.7) 4 (3.8) 1 (1.0) 43 (41.0) 46 (43.8) 10.7 2.3 Mortality (n 129) 55.6 18.0 4.54 1.67 32 (24.8) 19 (14.7%) 30 (23.3) 15 (11.6) 23 (17.8) 17 (13.2) 11 (8.5) 16 (12.4) 38 (29.5) 42 (33.3) 11.3 3.4 p 0.001 0.0001 0.0001 0.026 0.878 0.96 0.002 0.076 0.183 0.0001 0.074 0.103 0.08

Values are expressed as mean SD and n (%).

1.011.04; p 0.0001) were associated with higher mortality. Better GCS at triage (OR, 0.484; 95% CI, 0.388 0.604; p 0.0001) was associated with lower mortality.

DISCUSSION
The causes of ischemia inducing secondary brain injury seem to vary for different neurocritical care conditions. For example, cerebral vasospasm and delayed infarction are major causes of neurologic deterioration in the 2 weeks after a ruptured cerebral aneurysm.17,18 In contrast, the frequency and relevance of cerebral ischemia in the pathophysiology of TBI or intracerebral hemorrhage continue to be debated.19,20 Avoidance of secondary brain injury caused by hypoxia and hypotension has been the classical management of TBI. Importantly, anemia in TBI patients may be a risk factor of poor outcomes. Liberal transfusion to increase oxygen capacity and oxygen delivery has been the standard therapy for TBI patients. However, transfusion itself has been associated with increased infectious risk, complications, and mortality in critically ill patient.2123 In some studies, transfusion proved to be a stronger risk factor of mortality than anemia.1115 Most current reports have focused on anemia and transfusion in the ICU care. However, patient care is a continuous process and should be initiated as soon as possible. ED is a main entrance of health care system for most patients, especially for the critically ill ones. This study aims to examine the impact of initial anemia and transfusion at ED, and anemia and transfusion in the ICU on the outcomes in TBI patients. In our study, only 23 patients (9.8%) were initially anemic at ED and only 15 patients (6.4%) had been transfused with PRBC. In contrast, 81 patients (34.6%) were anemic and 88 (37.6%) had been transfused with PRBC during ICU stay. Anemia, either at ED or during ICU stay, is not associated with mortality. Anemia and blood transfusion during ICU stay are associated with longer ICU stay and longer hospital stay. Decreased organ function, immune reE134

action, infections, and increased mortality have been associated with blood transfusion in intensive care unit patients.24,25 Interestingly, our study revealed blood transfusion either at ED or during ICU stay was not associated with mortality. The benet of transfusion in TBI patient has still remained uncertain. Leal-Noval et al.26 recently found that only those patients having received RBCs 14 days old had a statistically signicant improvement in PbtO2 1 hour after transfusion. On the contrary, Zygun et al.27 found no improvement in cerebral lactate to pyruvate ratio (a marker of ischemia and metabolic distress) in response to transfusion, despite an increment in PbtO2. In a retrospective study of 169 patients with TBI, Carlson et al.11 found nadir hematocrit levels to be associated with a worse Glasgow Outcome Scale at hospital discharge. Initial anemia at ED, anemia during ICU stay and the lowest hemoglobin level during hospital stay were not associated with mortality in our results. Our ndings suggested that the role of anemia and transfusion were uncertain to TBI patients. In the acute resuscitation phase, transfusion with blood to avoid hypotension but not to avoid anemia is indicated. However, once the patient has been in the ICU and passed the acute phase, the indication for transfusion should be more restrictive and individualized. The TRICC trial enrolled only 67 patients with severe TBI. Although no statistically signicant benet from a liberal transfusion strategy was observed, this subgroup was too small to reach meaningful conclusions.28 Thus, the optimal use of RBCs in patients with severe TBI remains unclear. A recent survey found that most clinicians think a threshold of 7 g/dL for blood transfusion to be too restrictive, especially in the presence of intracranial hypertension.29 Our study provided information about anemia is not a risk factor of mortality in TBI patients. Furthermore, hypotension episode during ED stay is a main risk factor of mortality in TBI patients. George et al.15 demonstrated that in the acute setting it is safe to use a lower red blood cell transfusion threshold in patients with anemia and severe isolated TBI. However, the importance of hypotension to the outcome of TBI patients was not mentioned. Our study emphasized that in acute resuscitation stage, uid resuscitation and blood transfusion to avoid hypotension is necessary. Once the patient is hemodynamic stable, blood transfusion for only anemia correction should be cautious because the role of anemia on the mortality of TBI patients is equivocal and transfusion itself may not be benecial. Hypotension has been associated with poor outcome and high mortality in trauma patients.30,31 The impact of hypotension on mortality of TBI patients has been demonstrated, too.32,33 Our report revealed the association between hypotension and mortality in TBI patients, consistent with the ndings of other studies. The retrospective nature of our study is one of the major limitations. We are aware that reviewed medical charts may not contain all variables of interest and may have inconsistent descriptions. To overcome these issues, we had all the charts reviewed by two principal investigators. Furthermore, we used standardized chart review procedures to
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ensure the quality of data collection and to increase the validity and reliability of the data collected. In summary, hypotension, lower GCS, and older age were risk factors of mortality in TBI patients in our study. In contrast, no signicant association between initial anemia at ED, anemia during ICU stay, the lowest hemoglobin during hospital stay, and mortality were demonstrated. Either transfusion at ED or during ICU stay was not a risk factor of mortality. Based on our ndings, transfusion with blood to avoid hypotension is still warranted in the acute resuscitation phase. However, once the patient has been in the ICU and passed the acute phase, the indication for transfusion should be more cautious and individualized. REFERENCES
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