ORIGINAL ARTICLE
Blood component transfusion increases the risk of death in children with traumatic brain injury Shannon N. Acker, MD, David A. Partrick, MD, James T. Ross, BS, Nicole A. Nadlonek, MD, Michael Bronsert, PhD, and Denis D. Bensard, MD, Aurora, Colorado
Blood transfusion has been associated with worse outcomes in adult trauma patients with traumatic brain injury (TBI). However, the effects in injured children have not been evaluated. We hypothesize that blood transfusion is also associated with worse outcomes in children with TBI. METHODS: A retrospective review of the trauma database at two Level I pediatric trauma centers was performed. We reviewed all patients 18 years and younger with TBI, who survived at least 24 hours, from 2002 to 2011. Exclusion criteria include those who underwent craniotomy, thoracotomy, exploratory laparotomy, and any orthopedic procedure. RESULTS: A total of 1,607 children with TBI were included in the study population (mean age, 6.4 [5.7] years; 65% male), 178 of whom received a blood transfusion. Mean Injury Severity Score (ISS) was 16.5 (9.1). Patients who received a transfusion had a higher ISS than those who did not (26.7 vs. 15.3). After controlling for age, sex, ISS, Glasgow Coma Scale (GCS) score on presentation, and mechanism of injury, patients who received a blood transfusion were more likely to be admitted to the intensive care unit ( p G 0.0001), less likely to survive to hospital discharge ( p = 0.02), more likely to be discharged to a rehabilitation facility ( p = 0.01) and be dependent on caretakers at follow-up ( p G 0.0001), as well as more likely to develop urinary tract infection ( p = 0.02) and bacteremia ( p = 0.02) during their hospital stay. These differences in outcomes among those who did and did not receive a blood transfusion began to disappear in patients with a nadir hemoglobin of less than 8.0 g/dL. CONCLUSION: Pediatric patients sustaining TBI who receive blood transfusion and do not require operative intervention have worse outcomes compared with patients who do not receive transfusion. This includes an increased risk of death. These data suggest that a transfusion trigger of hemoglobin level at 8.0 g/dL in injured children with TBI may be beneficial. (J Trauma Acute Care Surg. 2014;76: 1082Y1088. Copyright * 2014 by Lippincott Williams & Wilkins) LEVEL OF EVIDENCE: Epidemiologic study, level III. Therapeutic study, level IV. KEY WORDS: Traumatic brain injury; blood transfusion; anemia; children. BACKGROUND:
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nemia is a common clinical problem in injured and other critically ill patients. Recent reviews of the literature reveal that anywhere from 20% to 53% of adult patients admitted to the intensive care unit (ICU) and 14% to 50% of children admitted to the pediatric ICU will receive a transfusion of packed red blood cells (PRBCs).1Y3 Despite the frequent use of blood transfusion, this is not a benign intervention. Recent data have begun to elucidate the risks associated with blood product transfusion. These include transmission of microorganisms; transfusionrelated immunomodulation, which can lead to an increased risk of infection; transfusion-related acute lung injury (TRALI); and human errors leading to transfusion of the wrong type or cross-match leading to hemolytic reactions.1 These risks are well documented in the adult population with multiple studies demonstrating that critically ill adult patients who receive blood Submitted: August 1, 2013, Revised: October 18, 2013, Accepted: October 18, 2013. From the Department of Pediatric Surgery (S.N.A., D.A.P., J.T.R., N.A.N., D.D.B.), Children’s Hospital Colorado; and Department of Surgery, Surgical Outcomes and Applied Research (M.B.), University of Colorado School of Medicine, Aurora; and Department of Surgery (D.D.B.), Denver Health and Hospital Authority, Denver, Colorado. This study was presented as a quickshot presentation at the 72nd annual meeting of the American Association for the Surgery of Trauma, September 18Y21, 2013, in San Francisco, California. Address for reprints: Shannon Acker, MD, University of Colorado School of Medicine, 12631 E 17th Ave, C302, Aurora, CO 80045; email: shannon.acker@ ucdenver.edu. DOI: 10.1097/TA.0000000000000095
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transfusions have increased hospital and ICU lengths of stay as well as increased mortality rates.4Y8 These findings have also been specifically demonstrated in adult trauma patients.9 Traumatic brain injury (TBI) remains an area of controversy as traditional neurosurgical teaching recommends transfusion to a hematocrit greater than 30% for patients with TBI.10 However, recent data from adult patients with TBI suggest that blood transfusion in this group of patients is associated with worse outcomes.11Y13 The optimal transfusion trigger in patients with TBI is unknown. Furthermore, the effects of blood transfusion on outcomes in children with TBI have not been evaluated. Children differ from adults with regard to metabolic requirements, presence of chronic disease, underlying cardiac function, response to anemia, and possibly even the response to brain ischemia and hypoxia.14,15 For these reasons, it is important to investigate the effects of blood transfusion on children with TBI. We hypothesize that blood transfusion is also associated with worse outcomes in children with TBI, similar to what has been demonstrated in adults. The aim of the current work was to investigate the association between blood transfusion and infectious complications and outcomes in children with TBI.
PATIENTS AND METHODS Patients Following the approval of the Colorado Multi-Institutional Review Board, we performed a retrospective review of the J Trauma Acute Care Surg Volume 76, Number 4
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trauma databases at two Level I urban pediatric trauma centers as follows: Children’s Hospital Colorado and Denver Health Medical Center. Each of these hospitals maintains a prospective trauma registry of all patients presenting to the hospital with traumatic injury. We reviewed all patients 18 years and younger who were admitted to the hospital and survived greater than 24 hours with a diagnosis of TBI from 2002 to 2011. We included all patients with TBI, not just those with isolated head injuries. Patients were identified from the trauma registries based on the diagnosis of TBI. Children who underwent a craniotomy, thoracotomy, exploratory laparotomy, or any orthopedic procedure during their hospitalization were excluded from the data analysis to eliminate confounding factors related to intraoperative blood loss. There were no other exclusion criteria. Predictor variables include age, sex, Injury Severity Score (ISS), presentation Glasgow Coma Scale (GCS) score, and cause of injury. Dependent variables include survival to hospital discharge, discharge to rehabilitation facility, dependence on caretakers at the time of follow-up, admission to the ICU, and infectious complications including bacteremia, pneumonia, urinary tract infection (UTI), and sepsis. Data not contained within the trauma databases were collected via retrospective review of the medical record. Dependent variables were compared between those children who received any type of blood product transfusion during hospitalization and those who did not. Analysis was then repeated comparing those patients who received a transfusion of PRBCs and those who did not. Analysis was repeated a third time comparing those patients with a nadir hemoglobin of less than 10 who received a PRBC transfusion with those who did not receive a transfusion, and then again for nadir hemoglobin of less than 9 and less than 8.
Statistical Analysis Statistical analysis was performed using SAS 9.3 (SAS Institute, Inc., Cary, NC). A two-side p G 0.05 was considered statistically significant. Continuous variables are expressed as mean (SD). Categorical data are expressed as number and percentages. Continuous variables were compared with an unpaired t test. All predictor variables were converted to categorical variables to facilitate statistical analysis. Patients were divided into the following three categories based on age: younger than 5 years, 5 years to 12 years, and older than 12 years. GCS scores were also used to divide patients into three groups as follows: presentation GCS of less than 9, 9 to 12, and greater than 12. Injury causes were grouped as follows: motor vehicle related, fall, nonaccidental trauma (NAT), sports related, and others. These categorical variables were compared using Pearson’s W2 or Fisher’s exact test. Logistic regression was used for multivariate analysis.
RESULTS During the 10-year study period, a total of 1,681 children with a diagnosis of TBI who did not meet any exclusion criteria were identified. Seventy-four children (4.4%) were excluded secondary to missing predictor variables, leaving 1,607 patients included in the analysis. Demographic data are presented in Table 1. One hundred seventy-eight children received a transfusion of either PRBCs (n = 164), fresh frozen plasma
TABLE 1. Demographic Characteristics Characteristics
Total (n = 1,607)
Transfusion No Transfusion (n = 178) (n = 1,429)
Age, mean (SD), y 6.4 (5.7) 4.3 (5.5) Age category, n (%), y G5 764 (47.5) 119 (66.9) 5Y12 500 (31.1) 32 (18.0) 912 343 (21.3) 27 (15.2) Male, n (%) 1,060 (66.0) 120 (67.4) ISS, mean (SD) 16.5 (9.1) 26.7 (8.8) GCS score, n (%) G9 312 (19.4) 118 (66.3) 9Y12 151 (9.4) 123 (8.6) 912 1,144 (71.2) 1,112 (77.8) Cause of injury, n (%) Motor vehicle 438 (27.3) 363 (25.4) related Falls 499 (31.1) 447 (33.4) NAT 339 (21.1) 265 (18.5) Sports related 230 (14.3) 229 (16.0) Other 101 (6.3) 95 (6.7)
6.6 (5.6)
645 (45.1) 468 (32.8) 316 (22.1) 940 (65.8) 15.3 (8.3)
P* G0.0001 G0.0001
0.6641 G0.0001 G0.0001
194 (13.6) 123 (8.6) 1,112 (77.8) G0.0001 75 (45.1) 22 (12.4) 74 (41.6) 1 (0.6) 6 (3.4)
*p values are for testing across transfusion status with t test for continuous and W2 test for categorical variables.
(FFP) (n = 50), platelets (n = 11), or cryoprecipitate (n = 5) during their hospitalization. The mean (SD) age of these children was 6.4 (5.7) years. Patients who received a transfusion were significantly younger than those who did not (4.3 years vs. 6.6 years). This is reflected in the fact that patients in the transfusion group were more likely to be either younger than 5 years or 5 years to 12 years compared with patients who did not receive a transfusion. A total of 1,060 patients (66.0%) were male, and this did not differ between the two groups. Mean (SD) ISS was 16.5 (9.1). Patients who received a transfusion had a higher ISS than those who did not (26.7 vs. 15.3). GCS score on presentation also differed between the two groups. The majority of patients who received a transfusion presented with a GCS score of less than 9 (66.3%), while the majority of patients who did not receive a transfusion presented with a GCS greater than 12 (77.8%). Patients in the transfusion group had a lower systolic blood pressure on presentation (107.5 [23.7] vs. 114.0 [17.1], p G 0.001). The most common cause of injury was falls (n = 499, 31.1%), followed by motor vehicle related (n = 438, 27.3%), NAT (n = 339, 21.1%), sports related (n = 230, 14.3%), and other (n = 101, 6.3%). On univariate analysis, multiple dependent variables were found to be more likely to occur in patients who received a blood transfusion (Table 2). Survival rate in the no-transfusion group was 98.9%; however, survival to hospital discharge was only 80.3% in those who received a transfusion ( p G 0.0001). In addition, patients who received a transfusion were more likely to be admitted to the ICU (97.2% vs. 46.6%, p G 0.0001) and more likely to be discharged to a rehabilitation facility (42.1% vs. 8.2%, p G 0.0001). Follow-up data were available for 1,449 patients who survived to hospital discharge (93.2%). When analyzing only those patients who survived to hospital discharge,
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TABLE 2. Univariate and Multivariate Analyses Stratified by Any Blood Transfusion Univariate Analysis Outcome
No Transfusion (n = 1,429)
Survived to hospital discharge† Discharge to rehabilitation† Dependence on caretaker‡ ICU stay Positive blood culture Pneumonia UTI Sepsis
Multivariate Analysis*
Any Transfusion (n = 178)
p**
OR (95% CI)
p**
143 (80.3) 75 (42.1) 48 (35.3) 173 (97.2) 7 (3.9) 23 (15.9) 12 (6.7) 3 (1.7)
G0.0001 G0.0001 G0.0001 G0.0001 G0.0001 G0.0001 G0.0001 0.005
2.414 (1.163Y5.009) 1.813 (1.141Y2.882) 3.545 (2.056Y6.110) 10.14 (3.875Y26.546) 6.949 (1.427Y33.832) 1.667 (0.796Y3.491) 4.358 (1.272Y14.928) 21.96 (0.631Y764.5)
0.0180 0.0119 G0.0001 G0.0001 0.0164 0.1758 0.0191 0.0881
1,411 (98.9) 117 (8.2) 76 (5.8) 666 (46.6) 3 (0.2) 19 (1.3) 8 (0.6) 1 (0.1)
*Multivariate model also included GCS score, age category, male, and ISS. **Univariate p values were from the W2 test or Fisher’s exact test and multivariate were from logistic regression. †There were two patients missing vital and rehabilitation status in the no-transfusion category. ‡This was based on a subset of patients who did not die (1,313 with no transfusion and 136 with any transfusion). CI, confidence interval; OR, odds ratio.
patients who received a blood transfusion were more likely to be dependent on caretakers at the time of follow-up (35.3% vs. 5.8%, p G 0.0001). Blood transfusion was also associated with multiple infectious complications including bacteremia (3.0% vs. 0.2%, p G 0.0001), pneumonia (15.9% vs. 1.3%, p G 0.0001), UTI (6.7% vs. 0.6%, p G 0.0001), and sepsis (1.7% vs. 0.1%, p = 0.005). In addition, depicted in Table 2 are the results of multivariate logistic regression. After controlling for age, sex, ISS, GCS score on presentation, and mechanism of injury, patients who received a blood transfusion had worse outcomes. On multivariate analysis, patients who received a transfusion were less likely to survive to hospital discharge ( p = 0.02). In addition, they were more likely to be admitted to the ICU ( p G 0.0001), be discharged to a rehabilitation facility ( p = 0.01), and be dependent on caretakers at follow-up ( p G 0.0001). Children who received a transfusion were also more likely to develop UTI ( p = 0.02) and bacteremia ( p = 0.02). Sepsis as a dependent variable was not included in the multivariate analysis given the low incident number (only one case documented in those patients who did not receive a transfusion and three cases among those who did).
We also sought to identify the nadir hemoglobin below which these differences in outcomes were eliminated. We began by repeating the previously mentioned analysis comparing those patients who received a transfusion of PRBCs to those patients who did not. We found that the results were identical to those found when comparing patients who received any transfusion with those who did not (data not shown). On multivariate analysis, patients who received transfusion of PRBCs were more likely to die, more likely to be discharged to a rehabilitation facility, more likely to be dependent on caretakers at the time of follow-up, more likely to require ICU stay, and more likely to develop pneumonia or UTI or have a positive blood culture ( p G 0.05 for all variables). We then repeated this analysis for various nadir hemoglobin levels recorded during hospitalization. Among patients with a nadir hemoglobin of less than 10.0 g/dL, we compared those who received a PRBC transfusion with those who did not and again found similar results (Table 3). On multivariate analysis, patients who received a transfusion were more likely to be dependent on caretakers at follow-up, more likely to be admitted to the ICU, and more likely to be discharged to a rehabilitation facility ( p G 0.05 for all variables), and there was a trend toward an increased risk of bacteremia ( p = 0.8). The
TABLE 3. Univariate and Multivariate Analyses of PRBC Transfusion for Those Patients With Nadir Hemoglobin of Less Than 10.0 g/dL Univariate Analysis Outcome Survived to hospital discharge Discharge to rehabilitation Dependence on caretaker† ICU stay Positive blood culture Pneumonia UTI Sepsis
Multivariate Analysis*
No PRBC Transfusion (n = 269)
PRBC Transfusion (n = 146)
p**
Patients With Nadir G 10, OR (95% CI)
256 (95.2) 52 (19.3) 33 (13.4) 184 (68.4) 1 (0.4) 14 (5.2) 7 (2.6) 0 (0)
123 (84.3) 67 (45.9) 46 (39.7) 141 (96.6) 5 (3.4) 19 (13.0) 10 (6.9) 1 (0.7)
G0.001 G0.0001 G0.0001 G0.0001 0.0221 0.005 0.0371 0.3518
1.377 (0.622Y3.050) 1.703 (1.004Y2.888) 3.166 (1.738Y5.769) 4.666 (1.708Y12.748) 7.663 (0.757Y77.536) 1.012 (0.461Y2.224) 2.022 (0.656Y6.230) NA
p** 0.4307 0.0481 0.0002 0.0027 0.0846 0.9754 0.2203
*Multivariate model also included GCS score, age category, male, and ISS. **Univariate p values were from the W2 test or Fisher’s exact test and multivariate were from logistic regression. †This was based on a subset of patients who did not die (247 with no PRBC transfusion and 116 with transfusion. CI, confidence interval; OR, odds ratio.
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TABLE 4. Univariate and Multivariate Analyses of PRBC Transfusion for Those Patients With Nadir Hemoglobin of Less Than 9.0 g/dL Univariate Analysis Outcome
Multivariate Analysis*
No PRBC Transfusion (n = 155)
PRBC Transfusion (n = 126)
p**
Patients with Nadir G 9, OR (95% CI)
145 (93.6) 34 (21.9) 25 (17.9) 116 (74.8) 1 (0.7) 9 (5.8) 6 (3.4) 0 (0)
108 (85.7) 57 (45.2) 40 (39.6) 122 (96.8) 4 (3.2) 18 (14.3) 8 (6.4) 1 (0.8)
0.0292 G0.0001 G0.001 G0.0001 0.1771 0.0165 0.3423 0.4484
1.240 (0.506Y3.039) 1.711 (0.938Y3.120) 2.372 (1.231Y4.569) 4.400 (1.401Y13.824) 4.563 (0.427Y48.745) 1.335 (0.540Y3.300) 1.376 (0.413Y4.584) NA
Survived to hospital discharge Discharge to rehabilitation Dependence on caretaker† ICU stay Positive blood culture Pneumonia UTI Sepsis
p** 0.6378 0.0799 0.0098 0.0112 0.2091 0.5321 0.6031
*Multivariate model also included GCS score, age category, male, and ISS. **Univariate p values were from the W2 test or Fisher’s exact test and multivariate were from logistic regression. †This was based on a subset of patients who did not die (140 with no pack RBC transfusion and 101 with transfusion. CI, confidence interval; OR, odds ratio.
increased risks associated with transfusion were less striking among patients with a nadir hemoglobin of less than 9.0 g/dL (Table 4). Patients in this group who received a transfusion did have an increased risk of dependence on caretakers at follow-up and ICU admission ( p G 0.01) and a trend toward increased risk of discharge to a rehabilitation facility ( p = 0.08); however, the risks associated with the other variables did not differ between the two groups. Among patients with a nadir hemoglobin of less than 8.0 g/dL, those who received a transfusion were more likely to be discharged to a rehabilitation facility ( p = 0.03) and be admitted to the ICU ( p G 0.01), and there was a trend toward increased dependence on caretakers at follow-up ( p = 0.07) (Table 5). Unfortunately, there were only 7 patients with a nadir hemoglobin of less than 7.0 g/dL who did not receive a transfusion.7 Figure 1 depicts the composite odds of a complication, death, increased risk of ICU admission, discharge to rehabilitation, dependence on caretakers at follow-up, or any infectious complication, relative to patients who did not receive a PRBC transfusion.
DISCUSSION Our data demonstrate that in pediatric patients with TBI, blood product transfusion is associated with worse outcomes. This includes a higher risk of admission to the ICU, a higher risk
of being dependent on caretakers at follow-up, and a higher risk of death. In addition, blood product transfusion is associated with an increased risk of multiple infectious complications including UTI and bacteremia. There has been one previous report describing the epidemiology and early predictive factors of mortality and outcome in children experiencing TBI.16 This group similarly found that blood transfusion was independently predictive of death in this population. However, this previous report looked only at transfusion within the first 6 hours, indicating the severity of trauma, not the effect of blood transfusion independently. For this reason, the analysis could not be repeated among this group of patients. Ours is the first report describing the adverse effects of blood transfusion in children with TBI. Similar to what has been shown in adult patients with TBI, blood transfusion is associated with worse outcomes in the pediatric population. Children in our series who received a blood transfusion had an increased risk of a variety of complications, including death, compared with those who did not receive a transfusion. Salim et al.11 performed a similar review in adult patients with TBI and found that those who received blood transfusion had higher mortality rates, poorer long-term functional outcomes, and increased rates of acute renal failure, acute respiratory failure, bacteremia or fungemia, multisystem organ
TABLE 5. Univariate and Multivariate Analyses of PRBC Transfusion for Those Patients With Nadir Hemoglobin of Less Than 8.0 g/dL Univariate Analysis Outcome
Multivariate Analysis*
No PRBC Transfusion (n = 58)
PRBC Transfusion (n = 91)
p**
Patients with Nadir G 8, OR (95% CI)
53 (91.4) 10 (17.2) 12 (23.1) 40 (69.0) 0 (0) 4 (6.9) 3 (5.2) 0 (0)
79 (86.8) 40 (44.0) 31 (42.5) 88 (96.7) 2 (2.2) 12 (13.2) 8 (8.8) 0 (0)
0.3927 0.0008 0.0245 G0.0001 0.5213 0.2266 0.5296 NA
1.072 (0.324Y3.544) 2.662 (1.078Y6.569) 2.227 (0.931Y5.328) 9.971 (2.202Y45.14) NA 1.273 (0.359Y4.508) 1.438 (0.337Y6.130) NA
Survived to hospital discharge Discharge to rehabilitation Dependence on caretaker† ICU stay Positive blood culture Pneumonia UTI Sepsis
p** 0.9098 0.0337 0.0721 0.0028 0.7086 0.6233
*Multivariate model also included GCS score, age category, male, and ISS. **Univariate p values were from the W2 test or Fisher’s exact test and multivariate were from logistic regression. †This was based on a subset of patients who did not die (52 with no PRBC transfusion and 73 with transfusion).
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Figure 1. Composite odds of a complication, ICU admission, discharge to rehabilitation, dependence on caretakers at follow-up, and any infectious complication for patients who received a blood transfusion at each nadir hemoglobin. The odds of any complication decrease as the nadir hemoglobin decreases. Reference patients who did not receive a blood transfusion. Of note, there was no complication that occurred at an increased rate (with p G 0.15) among patients with nadir hemoglobin of less than 7.0 who did or did not receive transfusion.
failure, pneumonia, and sepsis. While the focus of the work of Salim et al. has been the relationship among anemia, blood transfusion, and outcomes in TBI, other groups have also looked at the effect of platelet and plasma transfusion in this same group of patients. Anglin et al.12 found that in patients with TBI and moderate coagulopathy, those who received transfusion of FFP alone or in combination with PRBCs had worse long-term functional outcomes. However, in this recent study, platelet transfusion was not found to be associated with adverse outcomes. In our current work, we found that children who received transfusions of any type of blood product had significantly worse outcomes than those who received no transfusions. Given the relatively small number of patients in our series who received a cryoprecipitate5 or platelet11 transfusion, it is not possible to determine if either of these is independently associated with poorer outcomes. Of note, each of these patients did however also receive transfusion of PRBC and/or FFP. When considered as a whole, our data demonstrate that children with TBI who receive any type of blood product transfusion have worse outcomes. While this is the first report focusing specifically on outcomes following blood transfusion in pediatric patients with TBI, previous work has described other consequences of blood transfusion in critically ill and injured children. A recent report from our institution compared pediatric trauma patients who received a blood transfusion to age- and ISS-matched controls and found that those patients who received a transfusion had increased ICU and ventilator days.17 Other groups have similarly shown blood transfusion to be associated with death in pediatric 1086
trauma patients.18 In a prospective observational study of critically injured children, Karam et al.19 found that plasma transfusions were independently associated with increased incidence of new or progressive multiple-organ dysfunction syndrome, nosocomial infections, and increased length of stay. A recent review of the Canadian Blood Service database revealed that children develop TRALI at similar rates and with similar outcomes as adult patients.20 While these data do not originate only from injured children, it does further support the growing body of evidence demonstrating that the adverse effects of blood transfusions, which have been consistently shown in adults, are also present in the pediatric population. Poor outcome in patients who received blood transfusions is thought to result from transfusion-related immunomodulation.21 While the precise mechanisms are unknown, blood transfusion has been shown to lead to immune activation, leading to clinical syndromes that include transfusion-associated graft-versus-host disease, TRALI, alloimmunization, and the possibility of future development of autoimmune diseases.22 Immunosuppression associated with blood transfusion is known to increase a patient’s predisposition to nosocomial and postoperative infections.23,24 The immunomodulatory risks associated with blood transfusion must be weighed against the risks of anemia in patients with TBI. Studies in adults have consistently shown that a restrictive transfusion policy is associated with decreased mortality in critically ill adults.4 The Transfusion Requirements in Critical Care (TRICC) trial, a prospective randomized trial of 838 critically ill adults, showed that a restrictive transfusion strategy (waiting to transfuse until the hemoglobin dropped to G7.0 g/dL) lead to a decrease in hospital mortality, except in those patients with significant cardiac disease.4 Among pediatric patients, Rouette et al.25 found no difference in mortality or development of multiple-organ dysfunction syndrome among children who were randomized to either a liberal or a restrictive transfusion strategy. The advantages of a restrictive transfusion strategy have also been demonstrated among adult patients with TBI.26 Our data also support the judicious use of blood transfusion in the setting of pediatric patients with TBI. In addition, we have attempted to identify a hemoglobin level below which the adverse effects associated with blood transfusion are eliminated. While our analysis is limited by its retrospective nature, we have shown that among injured children who received a transfusion of PRBCs, one or more outcomes are significantly better when compared with patients who did not receive a blood transfusion. This holds true among all levels of nadir hemoglobin. For all levels of nadir hemoglobin evaluated, patients who did not receive a transfusion had improved neurologic outcomes. In addition, all infectious complications recorded occurred more frequently among those who received a transfusion. While the numbers are too small to report statistical significance, this trend should not be overlooked. We found that as nadir hemoglobin decreased, the composite odds associated with blood transfusion and the complications we evaluated also tended to decrease. The trend seems to be that around a nadir hemoglobin of 7.0 g/dL to 8.0 g/dL, the rates of adverse consequences begin to equilibrate between those who have and have not received a transfusion. Our data suggest that a hemoglobin of 8.0 g/dL be used as a transfusion trigger among children with TBI. This * 2014 Lippincott Williams & Wilkins
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conclusion is certainly limited by the retrospective nature of the data; however, the current work does provide a guideline by which to initiate future study. The data presented here are limited by the retrospective nature of the study. While our observations describe associations and provide no evidence for cause and effect, our study brings focus to an important group of critically injured children. Given the ongoing controversy regarding the appropriate transfusion cutoff among critically ill patients, particularly those with TBI, our current work further delineates the risks to these children associated with blood transfusion. Therefore, in children with TBI, transfusion of any blood product is associated with a number of risks including an increased risk of death. Furthermore, children who receive a blood transfusion are more likely to be admitted to the ICU, more likely to be discharged to a rehabilitation facility, and more likely to be dependent on caretakers at the time of follow-up. In addition, we provide further evidence describing the infectious risks associated with blood transfusion including pneumonia, UTI, and bacteremia. Our data suggest that a restrictive transfusion policy with a hemoglobin of 8.0 g/dL used as a transfusion trigger is appropriate among children with TBI. AUTHORSHIP S.N.A., D.A.P., and D.D.B. contributed in the conception and design of the research. S.N.A., J.T.R., and N.A.N. contributed in the collection of data. S.N.A., M.B., and D.D.B. contributed in the analysis of data. S.N.A. and D.D.B. contributed in the interpretation of the results. S.N.A. drafted the manuscript. S.N.A., D.A.P., J.T.R., N.A.N., M.B., and D.D.B. edited and revised the manuscript.
ACKNOWLEDGMENT We thank Lucinda Giblin, RN, and Kristine Hansen, RN, from the Children’s Hospital Colorado and Craig Gravitz, RN, from Denver Health Medical Center for their help in obtaining trauma registry data.
DISCLOSURE The authors declare no conflicts of interest.
REFERENCES 1. Vincent L, Piagnerelli M. Transfusion in the intensive care unit. Crit Care Med. 2006;34:S96YS101. 2. Armano R, Gauvin F, Ducruet T, Lacroix J. Determinants of red blood cell transfusions in a pediatric critical care unit: a prospective, descriptive epidemiological study. Crit Care Med. 2005;33:2637Y2644. 3. Morris KP, Naqvi N, Davies P, Smith M, Lee PW. A new formula for blood transfusion volume in the critically ill. Arch Dis Child. 2005;90:724Y728. 4. Hebert PC, Wells G, Blajchman MA, Marshall J, Martin C, Pagliarello G Tweeddale M, Schweitzer I, Yetisir E, and the Transfusion Requirements in Critical Care Investigators for the Canadian Critical Care Trials Group. A multicenter, randomized controlled clinical trial of transfusion requirements in critical care. N Engl J Med. 1999;340:409Y417. 5. Vincent JL, Baron JF, Reinhart K, Gattinoni L, Thijs L, Webb A, MeierHellermann A, Nollet G, Peres-Bota D, ABC (Anemia and Blood Transfusion in Critical Care) Investigators. Anemia and blood transfusion in critically ill patients. JAMA. 2002;288:1499Y1507. 6. Corwin HL, Gettinger A, Pearl RG, Frank MP, Levy MM, Abraham E, MacIntyre NR, Shabot M, Duh MS, Shapiro MJ. The CRIT study: anemia and blood transfusion in the critically illVcurrent clinical practice in the United States. Crit Care Med. 2004;32:39Y52.
7. Spinella PC, Perkins JG, Grathwohl KW, Beekley Ac, Niles SE, McLaughlin DF, Wade CE, Holcomb JB. Effect of plasma and red blood cell transfusion on survival in patients with combat related traumatic injuries. J Trauma. 2008;64:S69YS78. 8. Marik PE, Corwin HL. Efficacy of red blood cell transfusion in the critically ill: a systematic review of the literature. Crit Care Med. 2008;36: 2667Y2674. 9. Malone DL, Dunn J, Tracy JK, Putman AT, Scaleea TM, Napolitano LM. Blood transfusion, independent of shock severity, is associated with worse outcome in trauma. J Trauma. 2003;54:898Y905. 10. Winn HR. Youmans Neurological Surgery. 5th ed. Philadelphia, PA: WB Saunders Company; 2004. 11. Salim A, Hadjizacharia P, DuBose J, Brown C, Inaba K, Chan L, Margulies DR. Role of anemia in traumatic brain injury. J Am Coll Surg. 2008;207: 398Y406. 12. Anglin CO, Spence JS, Warner MA, Paliotta C, Harper C, Moore C, Sarode R, Madden C, Diaz-Arrastia R. Effects of platelet and plasma transfusion on outcome in traumatic brain injury patients with moderate bleeding diatheses. J Neurosurg. 2013;11:676Y686. 13. Elterman J, Brasel K, Brown S, Bulger E, Christenson J, Kerby JD, Kannas D, Lin S, Minei JP, Rixoli S, et al., the Resuscitation Outcomes Consortium Investigators. Transfusion of red blood cells in patients with a prehospital Glasgow Coma Scale score of 8 or less and no evidence of shock is associated with worse outcomes. J Trauma Acute Care Surg. 2013;75:8Y14. 14. Yager JY, Thornhill JA. The effect of age on susceptibility to hypoxicischemic brain damage. Neurosci Biobehav Rev. 1997;21:167Y174. 15. Desmet L, Lacroix J. Transfusion in pediatrics. Crit Care Clin. 2004;20: 299Y311. 16. Ducrocq SC, Meyer PG, Orliaguet GA, Blanot S, Laurent-Vannier A, Carli P. Epidemiology and early predictive factors of mortality and outcome in children with traumatic severe brain injury: experience of a French pediatric trauma center. Pediatr Crit Care Med. 2006;7:461Y467. 17. Pieracci FM, Witt J, Moore EE, Burlew CC, Johnson J, Biffle WL, Barnett CC Jr, Bensard DD. Early death and late morbidity after blood transfusion of injured children: a pilot study. J Pediatr Surg. 2012;47:1587Y1591. 18. Orliaguet GA, Meyer PG, Blanot S, Jarreau MM, Charron B, Buisson C, Carli PA. Predictive factors of outcome in severely traumatized children. Anesth Analg. 1998;87:537Y542. 19. Karam O, Lacroix J, Robitaille N, Rimesberger PC, Tucci M. Association between plasma transfusions and clinical outcome in critically ill children: a prospective observational study. Vox Sang. 2013;104:342Y349. 20. Lieberman L, Petraszko T, Yi QL, Hannach B, Skeate R. Transfusionrelated lung injury in children: a case series and review of the literature. Transfusion. 2013 Jun 13. doi: 10.1111/trf.12249 [Epub ahead of print]. 21. Blajchman MA. Immunomodulation and blood transfusion. Am J Ther. 2002;9:389Y395. 22. Raghavan M, Marik PE. Anemia, allogenic blood transfusion, and immunomodulation in the critically ill. Chest. 2005;127:295Y307. 23. Vamvakas EC, Carven JH. Allogeneic blood transfusion, hospital charges, and length of hospitalization: a study of 487 consecutive patients undergoing colorectal cancer resection. Arch Pathol Lab Med. 1998;122: 145Y151. 24. Moore FA, Moore EE, Sauaia A. Blood transfusion: an independent risk factor for postinjury multiple organ failure. Arch Surg. 1997;132:620Y624. 25. Rouette J, Trottier H, Ducruet T, Beaunoyer M, Lacroix J, Tucci M, Canadian Critical Care Trials Group, PALISI Network. Red blood cell transfusion threshold in postsurgical pediatric intensive care patients: a randomized clinical trial. Ann Surg. 2010;25:421Y427. 26. Carlson AP, Schermer CR, Lu SW. Retrospective evaluation of anemia and transfusion in traumatic brain injury. J Trauma. 2006;61:567Y571.
DISCUSSION Dr. David Notrica (Phoenix, Arizona): The authors have done a retrospective review of non-craniotomy TBI children accumulated over a 10-year period. This is a nice follow-up to their pilot study showing late morbidity after blood transfusions in children.
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I have two questions. In the multivariate analysis, the authors have chosen to control for age, sex, ISS, GCS, and mechanism of injury. Are these factors adequate to control for confounders? Specifically, could other important factors such as hypotension, or anemia, itself, be a confounder? The second question is, this is a young cohort with a mean age of 6.5 years with abusive head trauma as the most common mechanism at 24%. Non-accidental trauma is a very different disease than acute trauma. Often these children have multiple prior injuries before the injury that sends them to the hospital as well as significant delays in care. Is it reasonable to include these same patients in the multivariate analysis, especially in the light of the recent Western Pediatric Trauma paper that showed abusive head trauma patients are more likely to be anemic? Dr. Shannon Acker (Denver, Colorado): Thank you for your questions. I appreciate your comments. With regards to
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the first question, did we adequately control for confounders, other things we could certainly look at include blood pressure and anemia, like you stated. I think that we have adequately controlled for confounders but I think that it would be certainly worth our while to go back and reevaluate the data again, controlling for anemia. Blood pressure is a little bit more difficult in our patient population. Given the varying age, normal systolic is going to be a little bit harder to control for. But I think it would certainly be worthwhile to look at that as well. And then with regard to your second question, including the non-accidental trauma patients, our overall goal with this was to look at the global effect of traumatic brain injury in the pediatric population so that is why we chose to include all patients. I think it would be interesting to go back and look at our data and piece out the different causes of brain injury and see if those effects do differ among those different causes of injury.
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Blood component transfusion increases the risk of death in children with traumatic brain injury Shannon N. Acker, MD, David A. Partrick, MD, James T. Ross, BS, Nicole A. Nadlonek, MD, Michael Bronsert, PhD, and Denis D. Bensard, MD, Aurora, Colorado
Blood transfusion has been associated with worse outcomes in adult trauma patients with traumatic brain injury (TBI). However, the effects in injured children have not been evaluated. We hypothesize that blood transfusion is also associated with worse outcomes in children with TBI. METHODS: A retrospective review of the trauma database at two Level I pediatric trauma centers was performed. We reviewed all patients 18 years and younger with TBI, who survived at least 24 hours, from 2002 to 2011. Exclusion criteria include those who underwent craniotomy, thoracotomy, exploratory laparotomy, and any orthopedic procedure. RESULTS: A total of 1,607 children with TBI were included in the study population (mean age, 6.4 [5.7] years; 65% male), 178 of whom received a blood transfusion. Mean Injury Severity Score (ISS) was 16.5 (9.1). Patients who received a transfusion had a higher ISS than those who did not (26.7 vs. 15.3). After controlling for age, sex, ISS, Glasgow Coma Scale (GCS) score on presentation, and mechanism of injury, patients who received a blood transfusion were more likely to be admitted to the intensive care unit ( p G 0.0001), less likely to survive to hospital discharge ( p = 0.02), more likely to be discharged to a rehabilitation facility ( p = 0.01) and be dependent on caretakers at follow-up ( p G 0.0001), as well as more likely to develop urinary tract infection ( p = 0.02) and bacteremia ( p = 0.02) during their hospital stay. These differences in outcomes among those who did and did not receive a blood transfusion began to disappear in patients with a nadir hemoglobin of less than 8.0 g/dL. CONCLUSION: Pediatric patients sustaining TBI who receive blood transfusion and do not require operative intervention have worse outcomes compared with patients who do not receive transfusion. This includes an increased risk of death. These data suggest that a transfusion trigger of hemoglobin level at 8.0 g/dL in injured children with TBI may be beneficial. (J Trauma Acute Care Surg. 2014;76: 1082Y1088. Copyright * 2014 by Lippincott Williams & Wilkins) LEVEL OF EVIDENCE: Epidemiologic study, level III. Therapeutic study, level IV. KEY WORDS: Traumatic brain injury; blood transfusion; anemia; children. BACKGROUND:
A
nemia is a common clinical problem in injured and other critically ill patients. Recent reviews of the literature reveal that anywhere from 20% to 53% of adult patients admitted to the intensive care unit (ICU) and 14% to 50% of children admitted to the pediatric ICU will receive a transfusion of packed red blood cells (PRBCs).1Y3 Despite the frequent use of blood transfusion, this is not a benign intervention. Recent data have begun to elucidate the risks associated with blood product transfusion. These include transmission of microorganisms; transfusionrelated immunomodulation, which can lead to an increased risk of infection; transfusion-related acute lung injury (TRALI); and human errors leading to transfusion of the wrong type or cross-match leading to hemolytic reactions.1 These risks are well documented in the adult population with multiple studies demonstrating that critically ill adult patients who receive blood Submitted: August 1, 2013, Revised: October 18, 2013, Accepted: October 18, 2013. From the Department of Pediatric Surgery (S.N.A., D.A.P., J.T.R., N.A.N., D.D.B.), Children’s Hospital Colorado; and Department of Surgery, Surgical Outcomes and Applied Research (M.B.), University of Colorado School of Medicine, Aurora; and Department of Surgery (D.D.B.), Denver Health and Hospital Authority, Denver, Colorado. This study was presented as a quickshot presentation at the 72nd annual meeting of the American Association for the Surgery of Trauma, September 18Y21, 2013, in San Francisco, California. Address for reprints: Shannon Acker, MD, University of Colorado School of Medicine, 12631 E 17th Ave, C302, Aurora, CO 80045; email: shannon.acker@ ucdenver.edu. DOI: 10.1097/TA.0000000000000095
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transfusions have increased hospital and ICU lengths of stay as well as increased mortality rates.4Y8 These findings have also been specifically demonstrated in adult trauma patients.9 Traumatic brain injury (TBI) remains an area of controversy as traditional neurosurgical teaching recommends transfusion to a hematocrit greater than 30% for patients with TBI.10 However, recent data from adult patients with TBI suggest that blood transfusion in this group of patients is associated with worse outcomes.11Y13 The optimal transfusion trigger in patients with TBI is unknown. Furthermore, the effects of blood transfusion on outcomes in children with TBI have not been evaluated. Children differ from adults with regard to metabolic requirements, presence of chronic disease, underlying cardiac function, response to anemia, and possibly even the response to brain ischemia and hypoxia.14,15 For these reasons, it is important to investigate the effects of blood transfusion on children with TBI. We hypothesize that blood transfusion is also associated with worse outcomes in children with TBI, similar to what has been demonstrated in adults. The aim of the current work was to investigate the association between blood transfusion and infectious complications and outcomes in children with TBI.
PATIENTS AND METHODS Patients Following the approval of the Colorado Multi-Institutional Review Board, we performed a retrospective review of the J Trauma Acute Care Surg Volume 76, Number 4
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trauma databases at two Level I urban pediatric trauma centers as follows: Children’s Hospital Colorado and Denver Health Medical Center. Each of these hospitals maintains a prospective trauma registry of all patients presenting to the hospital with traumatic injury. We reviewed all patients 18 years and younger who were admitted to the hospital and survived greater than 24 hours with a diagnosis of TBI from 2002 to 2011. We included all patients with TBI, not just those with isolated head injuries. Patients were identified from the trauma registries based on the diagnosis of TBI. Children who underwent a craniotomy, thoracotomy, exploratory laparotomy, or any orthopedic procedure during their hospitalization were excluded from the data analysis to eliminate confounding factors related to intraoperative blood loss. There were no other exclusion criteria. Predictor variables include age, sex, Injury Severity Score (ISS), presentation Glasgow Coma Scale (GCS) score, and cause of injury. Dependent variables include survival to hospital discharge, discharge to rehabilitation facility, dependence on caretakers at the time of follow-up, admission to the ICU, and infectious complications including bacteremia, pneumonia, urinary tract infection (UTI), and sepsis. Data not contained within the trauma databases were collected via retrospective review of the medical record. Dependent variables were compared between those children who received any type of blood product transfusion during hospitalization and those who did not. Analysis was then repeated comparing those patients who received a transfusion of PRBCs and those who did not. Analysis was repeated a third time comparing those patients with a nadir hemoglobin of less than 10 who received a PRBC transfusion with those who did not receive a transfusion, and then again for nadir hemoglobin of less than 9 and less than 8.
Statistical Analysis Statistical analysis was performed using SAS 9.3 (SAS Institute, Inc., Cary, NC). A two-side p G 0.05 was considered statistically significant. Continuous variables are expressed as mean (SD). Categorical data are expressed as number and percentages. Continuous variables were compared with an unpaired t test. All predictor variables were converted to categorical variables to facilitate statistical analysis. Patients were divided into the following three categories based on age: younger than 5 years, 5 years to 12 years, and older than 12 years. GCS scores were also used to divide patients into three groups as follows: presentation GCS of less than 9, 9 to 12, and greater than 12. Injury causes were grouped as follows: motor vehicle related, fall, nonaccidental trauma (NAT), sports related, and others. These categorical variables were compared using Pearson’s W2 or Fisher’s exact test. Logistic regression was used for multivariate analysis.
RESULTS During the 10-year study period, a total of 1,681 children with a diagnosis of TBI who did not meet any exclusion criteria were identified. Seventy-four children (4.4%) were excluded secondary to missing predictor variables, leaving 1,607 patients included in the analysis. Demographic data are presented in Table 1. One hundred seventy-eight children received a transfusion of either PRBCs (n = 164), fresh frozen plasma
TABLE 1. Demographic Characteristics Characteristics
Total (n = 1,607)
Transfusion No Transfusion (n = 178) (n = 1,429)
Age, mean (SD), y 6.4 (5.7) 4.3 (5.5) Age category, n (%), y G5 764 (47.5) 119 (66.9) 5Y12 500 (31.1) 32 (18.0) 912 343 (21.3) 27 (15.2) Male, n (%) 1,060 (66.0) 120 (67.4) ISS, mean (SD) 16.5 (9.1) 26.7 (8.8) GCS score, n (%) G9 312 (19.4) 118 (66.3) 9Y12 151 (9.4) 123 (8.6) 912 1,144 (71.2) 1,112 (77.8) Cause of injury, n (%) Motor vehicle 438 (27.3) 363 (25.4) related Falls 499 (31.1) 447 (33.4) NAT 339 (21.1) 265 (18.5) Sports related 230 (14.3) 229 (16.0) Other 101 (6.3) 95 (6.7)
6.6 (5.6)
645 (45.1) 468 (32.8) 316 (22.1) 940 (65.8) 15.3 (8.3)
P* G0.0001 G0.0001
0.6641 G0.0001 G0.0001
194 (13.6) 123 (8.6) 1,112 (77.8) G0.0001 75 (45.1) 22 (12.4) 74 (41.6) 1 (0.6) 6 (3.4)
*p values are for testing across transfusion status with t test for continuous and W2 test for categorical variables.
(FFP) (n = 50), platelets (n = 11), or cryoprecipitate (n = 5) during their hospitalization. The mean (SD) age of these children was 6.4 (5.7) years. Patients who received a transfusion were significantly younger than those who did not (4.3 years vs. 6.6 years). This is reflected in the fact that patients in the transfusion group were more likely to be either younger than 5 years or 5 years to 12 years compared with patients who did not receive a transfusion. A total of 1,060 patients (66.0%) were male, and this did not differ between the two groups. Mean (SD) ISS was 16.5 (9.1). Patients who received a transfusion had a higher ISS than those who did not (26.7 vs. 15.3). GCS score on presentation also differed between the two groups. The majority of patients who received a transfusion presented with a GCS score of less than 9 (66.3%), while the majority of patients who did not receive a transfusion presented with a GCS greater than 12 (77.8%). Patients in the transfusion group had a lower systolic blood pressure on presentation (107.5 [23.7] vs. 114.0 [17.1], p G 0.001). The most common cause of injury was falls (n = 499, 31.1%), followed by motor vehicle related (n = 438, 27.3%), NAT (n = 339, 21.1%), sports related (n = 230, 14.3%), and other (n = 101, 6.3%). On univariate analysis, multiple dependent variables were found to be more likely to occur in patients who received a blood transfusion (Table 2). Survival rate in the no-transfusion group was 98.9%; however, survival to hospital discharge was only 80.3% in those who received a transfusion ( p G 0.0001). In addition, patients who received a transfusion were more likely to be admitted to the ICU (97.2% vs. 46.6%, p G 0.0001) and more likely to be discharged to a rehabilitation facility (42.1% vs. 8.2%, p G 0.0001). Follow-up data were available for 1,449 patients who survived to hospital discharge (93.2%). When analyzing only those patients who survived to hospital discharge,
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TABLE 2. Univariate and Multivariate Analyses Stratified by Any Blood Transfusion Univariate Analysis Outcome
No Transfusion (n = 1,429)
Survived to hospital discharge† Discharge to rehabilitation† Dependence on caretaker‡ ICU stay Positive blood culture Pneumonia UTI Sepsis
Multivariate Analysis*
Any Transfusion (n = 178)
p**
OR (95% CI)
p**
143 (80.3) 75 (42.1) 48 (35.3) 173 (97.2) 7 (3.9) 23 (15.9) 12 (6.7) 3 (1.7)
G0.0001 G0.0001 G0.0001 G0.0001 G0.0001 G0.0001 G0.0001 0.005
2.414 (1.163Y5.009) 1.813 (1.141Y2.882) 3.545 (2.056Y6.110) 10.14 (3.875Y26.546) 6.949 (1.427Y33.832) 1.667 (0.796Y3.491) 4.358 (1.272Y14.928) 21.96 (0.631Y764.5)
0.0180 0.0119 G0.0001 G0.0001 0.0164 0.1758 0.0191 0.0881
1,411 (98.9) 117 (8.2) 76 (5.8) 666 (46.6) 3 (0.2) 19 (1.3) 8 (0.6) 1 (0.1)
*Multivariate model also included GCS score, age category, male, and ISS. **Univariate p values were from the W2 test or Fisher’s exact test and multivariate were from logistic regression. †There were two patients missing vital and rehabilitation status in the no-transfusion category. ‡This was based on a subset of patients who did not die (1,313 with no transfusion and 136 with any transfusion). CI, confidence interval; OR, odds ratio.
patients who received a blood transfusion were more likely to be dependent on caretakers at the time of follow-up (35.3% vs. 5.8%, p G 0.0001). Blood transfusion was also associated with multiple infectious complications including bacteremia (3.0% vs. 0.2%, p G 0.0001), pneumonia (15.9% vs. 1.3%, p G 0.0001), UTI (6.7% vs. 0.6%, p G 0.0001), and sepsis (1.7% vs. 0.1%, p = 0.005). In addition, depicted in Table 2 are the results of multivariate logistic regression. After controlling for age, sex, ISS, GCS score on presentation, and mechanism of injury, patients who received a blood transfusion had worse outcomes. On multivariate analysis, patients who received a transfusion were less likely to survive to hospital discharge ( p = 0.02). In addition, they were more likely to be admitted to the ICU ( p G 0.0001), be discharged to a rehabilitation facility ( p = 0.01), and be dependent on caretakers at follow-up ( p G 0.0001). Children who received a transfusion were also more likely to develop UTI ( p = 0.02) and bacteremia ( p = 0.02). Sepsis as a dependent variable was not included in the multivariate analysis given the low incident number (only one case documented in those patients who did not receive a transfusion and three cases among those who did).
We also sought to identify the nadir hemoglobin below which these differences in outcomes were eliminated. We began by repeating the previously mentioned analysis comparing those patients who received a transfusion of PRBCs to those patients who did not. We found that the results were identical to those found when comparing patients who received any transfusion with those who did not (data not shown). On multivariate analysis, patients who received transfusion of PRBCs were more likely to die, more likely to be discharged to a rehabilitation facility, more likely to be dependent on caretakers at the time of follow-up, more likely to require ICU stay, and more likely to develop pneumonia or UTI or have a positive blood culture ( p G 0.05 for all variables). We then repeated this analysis for various nadir hemoglobin levels recorded during hospitalization. Among patients with a nadir hemoglobin of less than 10.0 g/dL, we compared those who received a PRBC transfusion with those who did not and again found similar results (Table 3). On multivariate analysis, patients who received a transfusion were more likely to be dependent on caretakers at follow-up, more likely to be admitted to the ICU, and more likely to be discharged to a rehabilitation facility ( p G 0.05 for all variables), and there was a trend toward an increased risk of bacteremia ( p = 0.8). The
TABLE 3. Univariate and Multivariate Analyses of PRBC Transfusion for Those Patients With Nadir Hemoglobin of Less Than 10.0 g/dL Univariate Analysis Outcome Survived to hospital discharge Discharge to rehabilitation Dependence on caretaker† ICU stay Positive blood culture Pneumonia UTI Sepsis
Multivariate Analysis*
No PRBC Transfusion (n = 269)
PRBC Transfusion (n = 146)
p**
Patients With Nadir G 10, OR (95% CI)
256 (95.2) 52 (19.3) 33 (13.4) 184 (68.4) 1 (0.4) 14 (5.2) 7 (2.6) 0 (0)
123 (84.3) 67 (45.9) 46 (39.7) 141 (96.6) 5 (3.4) 19 (13.0) 10 (6.9) 1 (0.7)
G0.001 G0.0001 G0.0001 G0.0001 0.0221 0.005 0.0371 0.3518
1.377 (0.622Y3.050) 1.703 (1.004Y2.888) 3.166 (1.738Y5.769) 4.666 (1.708Y12.748) 7.663 (0.757Y77.536) 1.012 (0.461Y2.224) 2.022 (0.656Y6.230) NA
p** 0.4307 0.0481 0.0002 0.0027 0.0846 0.9754 0.2203
*Multivariate model also included GCS score, age category, male, and ISS. **Univariate p values were from the W2 test or Fisher’s exact test and multivariate were from logistic regression. †This was based on a subset of patients who did not die (247 with no PRBC transfusion and 116 with transfusion. CI, confidence interval; OR, odds ratio.
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TABLE 4. Univariate and Multivariate Analyses of PRBC Transfusion for Those Patients With Nadir Hemoglobin of Less Than 9.0 g/dL Univariate Analysis Outcome
Multivariate Analysis*
No PRBC Transfusion (n = 155)
PRBC Transfusion (n = 126)
p**
Patients with Nadir G 9, OR (95% CI)
145 (93.6) 34 (21.9) 25 (17.9) 116 (74.8) 1 (0.7) 9 (5.8) 6 (3.4) 0 (0)
108 (85.7) 57 (45.2) 40 (39.6) 122 (96.8) 4 (3.2) 18 (14.3) 8 (6.4) 1 (0.8)
0.0292 G0.0001 G0.001 G0.0001 0.1771 0.0165 0.3423 0.4484
1.240 (0.506Y3.039) 1.711 (0.938Y3.120) 2.372 (1.231Y4.569) 4.400 (1.401Y13.824) 4.563 (0.427Y48.745) 1.335 (0.540Y3.300) 1.376 (0.413Y4.584) NA
Survived to hospital discharge Discharge to rehabilitation Dependence on caretaker† ICU stay Positive blood culture Pneumonia UTI Sepsis
p** 0.6378 0.0799 0.0098 0.0112 0.2091 0.5321 0.6031
*Multivariate model also included GCS score, age category, male, and ISS. **Univariate p values were from the W2 test or Fisher’s exact test and multivariate were from logistic regression. †This was based on a subset of patients who did not die (140 with no pack RBC transfusion and 101 with transfusion. CI, confidence interval; OR, odds ratio.
increased risks associated with transfusion were less striking among patients with a nadir hemoglobin of less than 9.0 g/dL (Table 4). Patients in this group who received a transfusion did have an increased risk of dependence on caretakers at follow-up and ICU admission ( p G 0.01) and a trend toward increased risk of discharge to a rehabilitation facility ( p = 0.08); however, the risks associated with the other variables did not differ between the two groups. Among patients with a nadir hemoglobin of less than 8.0 g/dL, those who received a transfusion were more likely to be discharged to a rehabilitation facility ( p = 0.03) and be admitted to the ICU ( p G 0.01), and there was a trend toward increased dependence on caretakers at follow-up ( p = 0.07) (Table 5). Unfortunately, there were only 7 patients with a nadir hemoglobin of less than 7.0 g/dL who did not receive a transfusion.7 Figure 1 depicts the composite odds of a complication, death, increased risk of ICU admission, discharge to rehabilitation, dependence on caretakers at follow-up, or any infectious complication, relative to patients who did not receive a PRBC transfusion.
DISCUSSION Our data demonstrate that in pediatric patients with TBI, blood product transfusion is associated with worse outcomes. This includes a higher risk of admission to the ICU, a higher risk
of being dependent on caretakers at follow-up, and a higher risk of death. In addition, blood product transfusion is associated with an increased risk of multiple infectious complications including UTI and bacteremia. There has been one previous report describing the epidemiology and early predictive factors of mortality and outcome in children experiencing TBI.16 This group similarly found that blood transfusion was independently predictive of death in this population. However, this previous report looked only at transfusion within the first 6 hours, indicating the severity of trauma, not the effect of blood transfusion independently. For this reason, the analysis could not be repeated among this group of patients. Ours is the first report describing the adverse effects of blood transfusion in children with TBI. Similar to what has been shown in adult patients with TBI, blood transfusion is associated with worse outcomes in the pediatric population. Children in our series who received a blood transfusion had an increased risk of a variety of complications, including death, compared with those who did not receive a transfusion. Salim et al.11 performed a similar review in adult patients with TBI and found that those who received blood transfusion had higher mortality rates, poorer long-term functional outcomes, and increased rates of acute renal failure, acute respiratory failure, bacteremia or fungemia, multisystem organ
TABLE 5. Univariate and Multivariate Analyses of PRBC Transfusion for Those Patients With Nadir Hemoglobin of Less Than 8.0 g/dL Univariate Analysis Outcome
Multivariate Analysis*
No PRBC Transfusion (n = 58)
PRBC Transfusion (n = 91)
p**
Patients with Nadir G 8, OR (95% CI)
53 (91.4) 10 (17.2) 12 (23.1) 40 (69.0) 0 (0) 4 (6.9) 3 (5.2) 0 (0)
79 (86.8) 40 (44.0) 31 (42.5) 88 (96.7) 2 (2.2) 12 (13.2) 8 (8.8) 0 (0)
0.3927 0.0008 0.0245 G0.0001 0.5213 0.2266 0.5296 NA
1.072 (0.324Y3.544) 2.662 (1.078Y6.569) 2.227 (0.931Y5.328) 9.971 (2.202Y45.14) NA 1.273 (0.359Y4.508) 1.438 (0.337Y6.130) NA
Survived to hospital discharge Discharge to rehabilitation Dependence on caretaker† ICU stay Positive blood culture Pneumonia UTI Sepsis
p** 0.9098 0.0337 0.0721 0.0028 0.7086 0.6233
*Multivariate model also included GCS score, age category, male, and ISS. **Univariate p values were from the W2 test or Fisher’s exact test and multivariate were from logistic regression. †This was based on a subset of patients who did not die (52 with no PRBC transfusion and 73 with transfusion).
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Figure 1. Composite odds of a complication, ICU admission, discharge to rehabilitation, dependence on caretakers at follow-up, and any infectious complication for patients who received a blood transfusion at each nadir hemoglobin. The odds of any complication decrease as the nadir hemoglobin decreases. Reference patients who did not receive a blood transfusion. Of note, there was no complication that occurred at an increased rate (with p G 0.15) among patients with nadir hemoglobin of less than 7.0 who did or did not receive transfusion.
failure, pneumonia, and sepsis. While the focus of the work of Salim et al. has been the relationship among anemia, blood transfusion, and outcomes in TBI, other groups have also looked at the effect of platelet and plasma transfusion in this same group of patients. Anglin et al.12 found that in patients with TBI and moderate coagulopathy, those who received transfusion of FFP alone or in combination with PRBCs had worse long-term functional outcomes. However, in this recent study, platelet transfusion was not found to be associated with adverse outcomes. In our current work, we found that children who received transfusions of any type of blood product had significantly worse outcomes than those who received no transfusions. Given the relatively small number of patients in our series who received a cryoprecipitate5 or platelet11 transfusion, it is not possible to determine if either of these is independently associated with poorer outcomes. Of note, each of these patients did however also receive transfusion of PRBC and/or FFP. When considered as a whole, our data demonstrate that children with TBI who receive any type of blood product transfusion have worse outcomes. While this is the first report focusing specifically on outcomes following blood transfusion in pediatric patients with TBI, previous work has described other consequences of blood transfusion in critically ill and injured children. A recent report from our institution compared pediatric trauma patients who received a blood transfusion to age- and ISS-matched controls and found that those patients who received a transfusion had increased ICU and ventilator days.17 Other groups have similarly shown blood transfusion to be associated with death in pediatric 1086
trauma patients.18 In a prospective observational study of critically injured children, Karam et al.19 found that plasma transfusions were independently associated with increased incidence of new or progressive multiple-organ dysfunction syndrome, nosocomial infections, and increased length of stay. A recent review of the Canadian Blood Service database revealed that children develop TRALI at similar rates and with similar outcomes as adult patients.20 While these data do not originate only from injured children, it does further support the growing body of evidence demonstrating that the adverse effects of blood transfusions, which have been consistently shown in adults, are also present in the pediatric population. Poor outcome in patients who received blood transfusions is thought to result from transfusion-related immunomodulation.21 While the precise mechanisms are unknown, blood transfusion has been shown to lead to immune activation, leading to clinical syndromes that include transfusion-associated graft-versus-host disease, TRALI, alloimmunization, and the possibility of future development of autoimmune diseases.22 Immunosuppression associated with blood transfusion is known to increase a patient’s predisposition to nosocomial and postoperative infections.23,24 The immunomodulatory risks associated with blood transfusion must be weighed against the risks of anemia in patients with TBI. Studies in adults have consistently shown that a restrictive transfusion policy is associated with decreased mortality in critically ill adults.4 The Transfusion Requirements in Critical Care (TRICC) trial, a prospective randomized trial of 838 critically ill adults, showed that a restrictive transfusion strategy (waiting to transfuse until the hemoglobin dropped to G7.0 g/dL) lead to a decrease in hospital mortality, except in those patients with significant cardiac disease.4 Among pediatric patients, Rouette et al.25 found no difference in mortality or development of multiple-organ dysfunction syndrome among children who were randomized to either a liberal or a restrictive transfusion strategy. The advantages of a restrictive transfusion strategy have also been demonstrated among adult patients with TBI.26 Our data also support the judicious use of blood transfusion in the setting of pediatric patients with TBI. In addition, we have attempted to identify a hemoglobin level below which the adverse effects associated with blood transfusion are eliminated. While our analysis is limited by its retrospective nature, we have shown that among injured children who received a transfusion of PRBCs, one or more outcomes are significantly better when compared with patients who did not receive a blood transfusion. This holds true among all levels of nadir hemoglobin. For all levels of nadir hemoglobin evaluated, patients who did not receive a transfusion had improved neurologic outcomes. In addition, all infectious complications recorded occurred more frequently among those who received a transfusion. While the numbers are too small to report statistical significance, this trend should not be overlooked. We found that as nadir hemoglobin decreased, the composite odds associated with blood transfusion and the complications we evaluated also tended to decrease. The trend seems to be that around a nadir hemoglobin of 7.0 g/dL to 8.0 g/dL, the rates of adverse consequences begin to equilibrate between those who have and have not received a transfusion. Our data suggest that a hemoglobin of 8.0 g/dL be used as a transfusion trigger among children with TBI. This * 2014 Lippincott Williams & Wilkins
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conclusion is certainly limited by the retrospective nature of the data; however, the current work does provide a guideline by which to initiate future study. The data presented here are limited by the retrospective nature of the study. While our observations describe associations and provide no evidence for cause and effect, our study brings focus to an important group of critically injured children. Given the ongoing controversy regarding the appropriate transfusion cutoff among critically ill patients, particularly those with TBI, our current work further delineates the risks to these children associated with blood transfusion. Therefore, in children with TBI, transfusion of any blood product is associated with a number of risks including an increased risk of death. Furthermore, children who receive a blood transfusion are more likely to be admitted to the ICU, more likely to be discharged to a rehabilitation facility, and more likely to be dependent on caretakers at the time of follow-up. In addition, we provide further evidence describing the infectious risks associated with blood transfusion including pneumonia, UTI, and bacteremia. Our data suggest that a restrictive transfusion policy with a hemoglobin of 8.0 g/dL used as a transfusion trigger is appropriate among children with TBI. AUTHORSHIP S.N.A., D.A.P., and D.D.B. contributed in the conception and design of the research. S.N.A., J.T.R., and N.A.N. contributed in the collection of data. S.N.A., M.B., and D.D.B. contributed in the analysis of data. S.N.A. and D.D.B. contributed in the interpretation of the results. S.N.A. drafted the manuscript. S.N.A., D.A.P., J.T.R., N.A.N., M.B., and D.D.B. edited and revised the manuscript.
ACKNOWLEDGMENT We thank Lucinda Giblin, RN, and Kristine Hansen, RN, from the Children’s Hospital Colorado and Craig Gravitz, RN, from Denver Health Medical Center for their help in obtaining trauma registry data.
DISCLOSURE The authors declare no conflicts of interest.
REFERENCES 1. Vincent L, Piagnerelli M. Transfusion in the intensive care unit. Crit Care Med. 2006;34:S96YS101. 2. Armano R, Gauvin F, Ducruet T, Lacroix J. Determinants of red blood cell transfusions in a pediatric critical care unit: a prospective, descriptive epidemiological study. Crit Care Med. 2005;33:2637Y2644. 3. Morris KP, Naqvi N, Davies P, Smith M, Lee PW. A new formula for blood transfusion volume in the critically ill. Arch Dis Child. 2005;90:724Y728. 4. Hebert PC, Wells G, Blajchman MA, Marshall J, Martin C, Pagliarello G Tweeddale M, Schweitzer I, Yetisir E, and the Transfusion Requirements in Critical Care Investigators for the Canadian Critical Care Trials Group. A multicenter, randomized controlled clinical trial of transfusion requirements in critical care. N Engl J Med. 1999;340:409Y417. 5. Vincent JL, Baron JF, Reinhart K, Gattinoni L, Thijs L, Webb A, MeierHellermann A, Nollet G, Peres-Bota D, ABC (Anemia and Blood Transfusion in Critical Care) Investigators. Anemia and blood transfusion in critically ill patients. JAMA. 2002;288:1499Y1507. 6. Corwin HL, Gettinger A, Pearl RG, Frank MP, Levy MM, Abraham E, MacIntyre NR, Shabot M, Duh MS, Shapiro MJ. The CRIT study: anemia and blood transfusion in the critically illVcurrent clinical practice in the United States. Crit Care Med. 2004;32:39Y52.
7. Spinella PC, Perkins JG, Grathwohl KW, Beekley Ac, Niles SE, McLaughlin DF, Wade CE, Holcomb JB. Effect of plasma and red blood cell transfusion on survival in patients with combat related traumatic injuries. J Trauma. 2008;64:S69YS78. 8. Marik PE, Corwin HL. Efficacy of red blood cell transfusion in the critically ill: a systematic review of the literature. Crit Care Med. 2008;36: 2667Y2674. 9. Malone DL, Dunn J, Tracy JK, Putman AT, Scaleea TM, Napolitano LM. Blood transfusion, independent of shock severity, is associated with worse outcome in trauma. J Trauma. 2003;54:898Y905. 10. Winn HR. Youmans Neurological Surgery. 5th ed. Philadelphia, PA: WB Saunders Company; 2004. 11. Salim A, Hadjizacharia P, DuBose J, Brown C, Inaba K, Chan L, Margulies DR. Role of anemia in traumatic brain injury. J Am Coll Surg. 2008;207: 398Y406. 12. Anglin CO, Spence JS, Warner MA, Paliotta C, Harper C, Moore C, Sarode R, Madden C, Diaz-Arrastia R. Effects of platelet and plasma transfusion on outcome in traumatic brain injury patients with moderate bleeding diatheses. J Neurosurg. 2013;11:676Y686. 13. Elterman J, Brasel K, Brown S, Bulger E, Christenson J, Kerby JD, Kannas D, Lin S, Minei JP, Rixoli S, et al., the Resuscitation Outcomes Consortium Investigators. Transfusion of red blood cells in patients with a prehospital Glasgow Coma Scale score of 8 or less and no evidence of shock is associated with worse outcomes. J Trauma Acute Care Surg. 2013;75:8Y14. 14. Yager JY, Thornhill JA. The effect of age on susceptibility to hypoxicischemic brain damage. Neurosci Biobehav Rev. 1997;21:167Y174. 15. Desmet L, Lacroix J. Transfusion in pediatrics. Crit Care Clin. 2004;20: 299Y311. 16. Ducrocq SC, Meyer PG, Orliaguet GA, Blanot S, Laurent-Vannier A, Carli P. Epidemiology and early predictive factors of mortality and outcome in children with traumatic severe brain injury: experience of a French pediatric trauma center. Pediatr Crit Care Med. 2006;7:461Y467. 17. Pieracci FM, Witt J, Moore EE, Burlew CC, Johnson J, Biffle WL, Barnett CC Jr, Bensard DD. Early death and late morbidity after blood transfusion of injured children: a pilot study. J Pediatr Surg. 2012;47:1587Y1591. 18. Orliaguet GA, Meyer PG, Blanot S, Jarreau MM, Charron B, Buisson C, Carli PA. Predictive factors of outcome in severely traumatized children. Anesth Analg. 1998;87:537Y542. 19. Karam O, Lacroix J, Robitaille N, Rimesberger PC, Tucci M. Association between plasma transfusions and clinical outcome in critically ill children: a prospective observational study. Vox Sang. 2013;104:342Y349. 20. Lieberman L, Petraszko T, Yi QL, Hannach B, Skeate R. Transfusionrelated lung injury in children: a case series and review of the literature. Transfusion. 2013 Jun 13. doi: 10.1111/trf.12249 [Epub ahead of print]. 21. Blajchman MA. Immunomodulation and blood transfusion. Am J Ther. 2002;9:389Y395. 22. Raghavan M, Marik PE. Anemia, allogenic blood transfusion, and immunomodulation in the critically ill. Chest. 2005;127:295Y307. 23. Vamvakas EC, Carven JH. Allogeneic blood transfusion, hospital charges, and length of hospitalization: a study of 487 consecutive patients undergoing colorectal cancer resection. Arch Pathol Lab Med. 1998;122: 145Y151. 24. Moore FA, Moore EE, Sauaia A. Blood transfusion: an independent risk factor for postinjury multiple organ failure. Arch Surg. 1997;132:620Y624. 25. Rouette J, Trottier H, Ducruet T, Beaunoyer M, Lacroix J, Tucci M, Canadian Critical Care Trials Group, PALISI Network. Red blood cell transfusion threshold in postsurgical pediatric intensive care patients: a randomized clinical trial. Ann Surg. 2010;25:421Y427. 26. Carlson AP, Schermer CR, Lu SW. Retrospective evaluation of anemia and transfusion in traumatic brain injury. J Trauma. 2006;61:567Y571.
DISCUSSION Dr. David Notrica (Phoenix, Arizona): The authors have done a retrospective review of non-craniotomy TBI children accumulated over a 10-year period. This is a nice follow-up to their pilot study showing late morbidity after blood transfusions in children.
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I have two questions. In the multivariate analysis, the authors have chosen to control for age, sex, ISS, GCS, and mechanism of injury. Are these factors adequate to control for confounders? Specifically, could other important factors such as hypotension, or anemia, itself, be a confounder? The second question is, this is a young cohort with a mean age of 6.5 years with abusive head trauma as the most common mechanism at 24%. Non-accidental trauma is a very different disease than acute trauma. Often these children have multiple prior injuries before the injury that sends them to the hospital as well as significant delays in care. Is it reasonable to include these same patients in the multivariate analysis, especially in the light of the recent Western Pediatric Trauma paper that showed abusive head trauma patients are more likely to be anemic? Dr. Shannon Acker (Denver, Colorado): Thank you for your questions. I appreciate your comments. With regards to
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the first question, did we adequately control for confounders, other things we could certainly look at include blood pressure and anemia, like you stated. I think that we have adequately controlled for confounders but I think that it would be certainly worth our while to go back and reevaluate the data again, controlling for anemia. Blood pressure is a little bit more difficult in our patient population. Given the varying age, normal systolic is going to be a little bit harder to control for. But I think it would certainly be worthwhile to look at that as well. And then with regard to your second question, including the non-accidental trauma patients, our overall goal with this was to look at the global effect of traumatic brain injury in the pediatric population so that is why we chose to include all patients. I think it would be interesting to go back and look at our data and piece out the different causes of brain injury and see if those effects do differ among those different causes of injury.
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