Safety and cost efficiency of a restrictive transfusion protocol in patients with traumatic brain injury

View More View Less
  • 1 Department of Neurological Surgery and
  • | 2 Brain and Spinal Injury Center, University of California, San Francisco, California
Full access

OBJECTIVE

Blood loss and moderate anemia are common in patients with traumatic brain injury (TBI). However, despite evidence of the ill effects and expense of the transfusion of packed red blood cells, restrictive transfusion practices have not been universally adopted for patients with TBI. At a Level I trauma center, the authors compared patients with TBI who were managed with a restrictive (target hemoglobin level > 7 g/dl) versus a liberal (target hemoglobin level > 10 g/dl) transfusion protocol. This study evaluated the safety and cost-efficiency of a hospital-wide change to a restrictive transfusion protocol.

METHODS

A retrospective analysis of patients with TBI who were admitted to the intensive care unit (ICU) between January 2011 and September 2015 was performed. Patients < 16 years of age and those who died within 24 hours of admission were excluded. Demographic data and injury characteristics were compared between groups. Multivariable regression analyses were used to assess hospital outcome measures and mortality rates. Estimates from an activity-based cost analysis model were used to detect changes in cost with transfusion protocol.

RESULTS

A total of 1565 patients with TBI admitted to the ICU were included in the study. Multivariable analysis showed that a restrictive transfusion strategy was associated with fewer days of fever (p = 0.01) and that patients who received a transfusion had a larger fever burden. ICU length of stay, ventilator days, incidence of lung injury, thromboembolic events, and mortality rates were not significantly different between transfusion protocol groups. A restrictive transfusion protocol saved approximately $115,000 annually in hospital direct and indirect costs.

CONCLUSIONS

To the authors’ knowledge, this is the largest study to date to compare transfusion protocols in patients with TBI. The results demonstrate that a hospital-wide change to a restrictive transfusion protocol is safe and cost-effective in patients with TBI.

ABBREVIATIONS

ABC = activity-based cost; ALI = acute lung injury; ARDS = acute respiratory distress syndrome; DVT = deep vein thrombosis; GCS = Glasgow Coma Scale; Hb = hemoglobin; ICU = intensive care unit; ISS = Injury Severity Score; LOS = length of stay; MTP = massive transfusion protocol; OR = operating room; PbtO2 = brain tissue oxygen; PE = pulmonary embolism; PRBCs = packed red blood cells; SFGH = San Francisco General Hospital; TBI = traumatic brain injury; UCSF = University of California, San Francisco.

OBJECTIVE

Blood loss and moderate anemia are common in patients with traumatic brain injury (TBI). However, despite evidence of the ill effects and expense of the transfusion of packed red blood cells, restrictive transfusion practices have not been universally adopted for patients with TBI. At a Level I trauma center, the authors compared patients with TBI who were managed with a restrictive (target hemoglobin level > 7 g/dl) versus a liberal (target hemoglobin level > 10 g/dl) transfusion protocol. This study evaluated the safety and cost-efficiency of a hospital-wide change to a restrictive transfusion protocol.

METHODS

A retrospective analysis of patients with TBI who were admitted to the intensive care unit (ICU) between January 2011 and September 2015 was performed. Patients < 16 years of age and those who died within 24 hours of admission were excluded. Demographic data and injury characteristics were compared between groups. Multivariable regression analyses were used to assess hospital outcome measures and mortality rates. Estimates from an activity-based cost analysis model were used to detect changes in cost with transfusion protocol.

RESULTS

A total of 1565 patients with TBI admitted to the ICU were included in the study. Multivariable analysis showed that a restrictive transfusion strategy was associated with fewer days of fever (p = 0.01) and that patients who received a transfusion had a larger fever burden. ICU length of stay, ventilator days, incidence of lung injury, thromboembolic events, and mortality rates were not significantly different between transfusion protocol groups. A restrictive transfusion protocol saved approximately $115,000 annually in hospital direct and indirect costs.

CONCLUSIONS

To the authors’ knowledge, this is the largest study to date to compare transfusion protocols in patients with TBI. The results demonstrate that a hospital-wide change to a restrictive transfusion protocol is safe and cost-effective in patients with TBI.

ABBREVIATIONS

ABC = activity-based cost; ALI = acute lung injury; ARDS = acute respiratory distress syndrome; DVT = deep vein thrombosis; GCS = Glasgow Coma Scale; Hb = hemoglobin; ICU = intensive care unit; ISS = Injury Severity Score; LOS = length of stay; MTP = massive transfusion protocol; OR = operating room; PbtO2 = brain tissue oxygen; PE = pulmonary embolism; PRBCs = packed red blood cells; SFGH = San Francisco General Hospital; TBI = traumatic brain injury; UCSF = University of California, San Francisco.

A restrictive transfusion protocol has yet to become standard of care in patients with traumatic brain injury (TBI). Blood transfusions are an integral part of health care. A transfusion of packed red blood cells (PRBCs) can be lifesaving in a hemodynamically unstable patient. Despite the lifesaving benefits of a transfusion, there are many risks. Blood transfusions are associated with morbidities, including fever, infection, thromboembolic events, multiple organ failure, and lung injury.2,12,14 Transfusions are also associated with an increase in hospital mortality rates.5 In addition, the acquisition of PRBCs, laboratory tests, quality control, and transfusion services contribute to increased hospital costs.10

It has been more than 15 years since the Transfusion Requirements in Critical Care trial demonstrated that when compared with a liberal strategy of transfusion when hemoglobin (Hb) levels decrease to < 10 g/dl, a restrictive transfusion protocol allowing an Hb of 7 g/dl is safe in critically ill patients.9 This restrictive protocol has been widely adopted as the standard of care in many populations of critically ill patients8 and has led to safer and more cost-effective transfusion guidelines.

Practitioners are reluctant to treat patients with TBI with a restrictive transfusion protocol due to concerns that a lower Hb target could lead to ischemia, secondary brain injury, and thus worse outcomes.6,11,16 It has been demonstrated that transfusion of PRBCs increases brain tissue oxygen (PbtO2); however, there is not an associated improvement in cerebral metabolism to support aggressive transfusion.21 Yamal et al.20 have shown that although PbtO2 was slightly lower in patients managed with a threshold of Hb 7 g/dl (compared with Hb 10 g/dl), there were no long-term differences in neurological outcome. Additional studies have not substantiated claims of worse outcomes with a lower Hb threshold.

A subgroup analysis of the Transfusion Requirements in Critical Care trial did not find a difference in outcomes between patients with TBI managed with a restrictive versus a liberal protocol.13 A study comparing outcomes from 2 Level I trauma centers with different transfusion thresholds for the management of patients with TBI did not find any adverse effects of withholding transfusion in moderately anemic patients.7 Recently, a randomized controlled trial also tested the hypothesis that maintaining an Hb level > 10 g/dl would lead to improved functional neurological outcome compared with a restrictive strategy that maintained Hb > 7 g/dl.15 This randomized controlled trial found no difference in outcome; instead, there was a significant increase in the incidence of thromboembolic events among patients in the group transfused to maintain Hb > 10 g/dl.

Despite this formidable body of evidence that a restrictive transfusion protocol is safe in patients with TBI, it has not been universally accepted. The reluctance of many practitioners to make system-wide changes based on these studies is in part due to the small number of subjects represented by these studies. The largest study to date included only 200 patients; thus a complementary study that is generalizable to the broader TBI population is needed.

In this retrospective study, we assessed hospital outcomes in 1565 patients with TBI who were managed with either a liberal or a restrictive transfusion protocol. To our knowledge, this is the largest study to date to compare transfusion protocols in patients with TBI. The results demonstrate that a hospital-wide change to a restrictive transfusion protocol is safe and cost-effective in patients with TBI.

Methods

Selection of Subjects

We examined records from 1907 consecutive patients with a diagnosis of TBI who were admitted to the intensive care unit (ICU) at San Francisco General Hospital (SFGH) between January 2011 and September 2015. Patients < 16 years of age and those who died within 24 hours of admission were excluded. This retrospective case review received a waiver of consent and was approved by the SFGH and University of California, San Francisco (UCSF) Committee on Human Research.

TBI Management

All patients were managed in accordance with strict TBI hospital guidelines as part of the neurotrauma program at SFGH. These guidelines were based on the recommendations of the Brain Trauma Foundation.3 In addition to maintaining intracranial pressure < 20 mm Hg, cerebral perfusion pressure > 60 mm Hg, and PbtO2 > 15 mm Hg, other routine aspects of critical care management were standardized. This included maintaining ventilator parameters to achieve PaO2 95–105 mm Hg and PaCO2 35–45 mm Hg, serum sodium 135–145 mEq/L, serum glucose 80–180 mg/dl, and temperature 36.0°C–38.0°C. Platelets were maintained at a level ≥ 75,000/µl and INR (International Normalized Ratio) was kept ≤ 1.4. The hospital-wide TBI guidelines were followed throughout the duration of the study by all physicians actively involved in the critical care management of patients with TBI, including neurosurgeons, trauma surgeons, and neurocritical care physicians. When patients were discharged from the ICU, TBI guidelines were maintained for the duration of their hospital stay.

Transfusion Protocols

As part of our institutional TBI treatment guidelines, patients received a transfusion when their Hb level fell below a target threshold. In 2011, the threshold for transfusion was an Hb < 10 g/dl; however, starting in January 2014, the threshold was changed to an Hb < 7 g/dl. We examined patient characteristics and outcomes in the patient groups before and after the hospital-wide change in this policy. During a 3-month transition (October 2013 to January 2014), patients were excluded from the study due to inconsistencies in patient management during that time (Fig. 1). Thus patients were designated to a transfusion group by the convenience sample of year of admission.

FIG. 1.
FIG. 1.

Patients included in the study. A: Diagram showing total number of patients with TBI admitted to the ICU between January 2011 and September 2015 and those excluded to yield the final number of 1565 patients. B: A schematic demonstrating the number of patients at each timeframe. The timeframes delineate the transfusion protocol by which the patients were managed.

Patient Characteristics and Outcome Measures

Demographic data and admission information were obtained from a review of medical records. We used our prospectively collected neurotrauma database, called Neurotracker, to identify patients who were admitted to the ICU with a diagnosis of TBI. We began to collect patient information in our Neurotracker database in 2011. Demographic data and injury information (including Glasgow Coma Scale [GCS] score) and discharge disposition data were obtained from the Neurotracker database and patient medical records. Hb data, temperature data, and transfusion history were obtained from an export of the medical records via the Integrated Data Repository at SFGH/UCSF.

Additional injury characteristics (including Injury Severity Score [ISS], number of visits to the operating room [OR], and activation of the massive transfusion protocol [MTP]) were obtained from the prospectively collected Trauma Registry at SFGH. Outcome measures included ICU length of stay (LOS), ventilator days, hospital mortality rate, and number of days of fever. The number of days of fever was calculated by collecting all documented temperatures from the medical record; a temperature > 38.5°C indicated fever.

In addition, lung injury was assessed by the incidence of acute respiratory distress syndrome or acute lung injury (ARDS/ALI), and thromboembolic events were accounted for by the occurrence of deep vein thrombosis or pulmonary embolism (DVT/PE). Lung and thromboembolic outcome measures were obtained from the medical records and from the Trauma Registry. Information was collected for all patients for the entirety of their hospital stay. If an admission or outcomes variable was missing due to incomplete data in the Trauma Registry or medical record, pairwise deletion was used for group means and listwise deletion was used for regression analysis.

Cost Analysis

At our institution, the cost of 1 unit of PRBCs was approximately $210 US. This cost included only the price of the blood from Red Cross. This amount excluded costs associated with product procurement and transport, hospital processing steps, laboratory work, and the costs associated with the personnel and equipment needed for transfusion. Because these operational costs are not available at our institution, we used results from the well-established activity-based cost (ABC) analysis by Shander et al.18 They estimated that the US surgical transfusion costs ranged from $726 to $1183 (in 2008 dollars) per PRBC unit transfused. This range included the costs associated with blood product procurement, in-hospital processing steps, and direct and indirect overhead fees, but excluded cost elements incurred as the result of donor recruitment, blood collection processes, and potential long-term adverse events. We adjusted this cost range to 2016 dollars (https://www.bls.gov/data/inflation_calculator.htm) to calculate the change in cost associated with change in transfusion threshold.

The total dollar amount of transfusion-associated costs per person in each transfusion group was estimated by multiplying the average number of PRBCs units transfused per person by the cost per unit transfused. The difference in cost was calculated by subtracting the per-person transfusion cost in the Hb 7-g/dl group from the per-person transfusion cost in the Hb 10-g/dl group.

Statistical Analysis

Demographic data and injury characteristics were compared between groups using univariate analysis (t-test or χ2 as appropriate). To assess for bias, characteristics were compared between those included versus those excluded from the study, as well as between transfusion groups. Individual multivariable linear regression analyses were done for the outcome variables of ICU LOS, days of fever, and ventilator days, while controlling for age, ISS, activation of MTP, number of OR visits, and total hospital days. Multivariable logistic regression was performed for each of the binary outcome variables, which included ARDS/ALI, DVT/PE, and mortality at discharge. All regression analysis was done using a standard listwise deletion approach for missing variables. Approximately 10% of patients were missing MTP activation data or ARDS/ALI and DVT/PE data; thus outcomes regression analysis was based on 1377 patients. To specifically address patients most at risk, those with an admission GCS score ≤ 8 underwent a separate subgroup analysis, using the same factors as above. For all analyses, differences were considered significant at p < 0.05.

Results

Subjects and Demographic Data

A total of 1907 consecutive patients were admitted to the ICU with a diagnosis of TBI between January 2011 and September 2015. Ninety-nine patients were excluded because of age < 16 years, and an additional 131 were excluded because they died within 24 hours of admission (Fig. 1A). Those who died were more frequently hypotensive on admission (48.8% vs 12.4%; p < 0.01), hypoxic (37.8% vs 6.8%; p < 0.01), had a lower GCS score (5.5 vs 12.0; p < 0.01), and a higher ISS (32.1 vs 18.9; p < 0.01). Patients who died within 24 hours were also more likely to receive a transfusion (67.1% vs 28.7%; p < 0.01) and more units of PRBCs (7.2 vs 1.8 units; p < 0.01). Nine hundred seventy-nine patients were managed with a liberal transfusion protocol of Hb 10 g/dl, and 586 patients were managed with a restrictive transfusion protocol of Hb 7 g/dl. One hundred twelve patients were excluded because they were admitted during the 3-month transition period. The transition group had a smaller percentage of patients with hypotension on admission (5.4% vs 12.9%; p = 0.02), and fewer total hospital days (p = 0.01). Otherwise, there were no differences in demographic data or injury characteristics between those excluded and those included in the study (Table 1). A total of 1565 patients remained in the study. Each time period averaged approximately 30 patients per month (Fig. 1B).

TABLE 1.

All patients eligible for inclusion in the study

VariableStudyTransitionp Value
No. of patients1565112
Demographic & admission data
 Mean age in yrs (SD)53.4 (21.7)57.2 (22.1)0.08
 Male, no. (%)1113 (71.1)77 (68.8)0.59
 Mean GCS score on admission (SD)12.0 (3.8)12.0 (3.9)0.97
 Mean ISS (SD)18.8 (11.2)19.7 (11.6)0.45
 Hypotension on admission, no. (%)201 (12.9)6 (5.4)0.02
 Hypoxia on admission, no. (%)106 (6.8)7 (6.3)0.82
 Mean Hb on admission, g/dl (SD)13.5 (2.0)13.6 (1.8)0.55
Inpatient characteristics
 Mean min Hb, g/dl (SD)10.6 (2.6)10.5 (2.5)0.68
 Mean Hb, g/dl (SD)11.9 (2.0)11.9 (2.0)0.75
 Received transfusion, no. (%)452 (28.9)30 (26.8)0.64
 Units of PRBC, mean (SD)1.8 (5.0)1.7 (4.6)0.89
 MTP activation, no. (%)83 (6.0)6 (5.8)0.94
 Mean no. of OR visits (SD)0.6 (1.2)0.5 (1.0)0.42
 Total hospital days, mean (SD)12.8 (20.3)9.7 (11.5)0.01

OR = operating room.

The Hb 7-g/dl group contained older patients, and those in the Hb 10-g/dl group were more severely injured, as reflected by the ISS. Otherwise, there were no differences between groups on admission (Table 2). During the hospital stay, the mean Hb was lower in the Hb 7-g/dl group. Because there were many patients in both groups who did not meet the criteria for transfusion, the mean minimum Hb is the average of each patient’s lowest reported Hb level, and is thus similar between groups. Significantly, there was a 25% decrease in the proportion of patients who received a transfusion in the Hb 7-g/dl group. There was also a difference in discharge disposition, with a higher percentage of patients deceased at discharge in the Hb 10-g/dl group.

TABLE 2.

All patients included in the study

VariableTransfusion Groupp Value
Hb 10 g/dlHb 7 g/dl
No. of patients979586
Demographic & admission data
 Mean age in yrs (SD)52.4 (21.8)55.0 (21.5)0.02
 Male, no. (%)680 (69.5)433 (73.9)0.06
 Mean GCS score on admission (SD)12.0 (3.8)12.0 (3.7)0.89
 Mean ISS (SD)19.3 (11.6)18.1 (10.6)0.04
 Hypotension on admission, no. (%)137 (14.1)64 (10.9)0.07
 Hypoxia on admission, no. (%)66 (6.8)40 (6.8)0.97
 Mean Hb on admission, g/dl (SD)13.5 (2.0)13.4 (2.1)0.15
Inpatient characteristics
 Mean min Hb, g/dl (SD)10.7 (2.6)10.5 (2.6)0.18
 Mean Hb, g/dl (SD)12.0 (2.0)11.8 (2.2)0.04
 Received transfusion, no. (%)310 (31.7)142 (24.2)0.00*
 Units of PRBC, mean (SD)1.9 (4.7)1.6 (5.5)0.24
 MTP activation, no. (%)44 (5.4)39 (7.0)0.23
 Mean no. of OR visits (SD)0.6 (1.1)0.6 (1.4)0.50
 Total hospital days, mean (SD)13.9 (23.3)10.9 (13.6)0.00
Discharge disposition, no. (%)0.00
 Home452 (46.2)253 (43.2)
 Rehab/SNF182 (18.6)166 (28.3)
 Acute care hospital176 (18.0)87 (14.8)
 Other66 (6.7)31 (5.3)
 Deceased101 (10.3)49 (8.4)

Rehab = rehabilitation facility; SNF = skilled nursing facility.

0.002.

≤ 0.001.

Outcomes and Complications Assessment in All Patients

Outcomes were controlled for age, total hospital days, and injury characteristics using multivariable regression statistics. There was no difference between transfusion groups in ICU LOS (p = 0.21) or days requiring mechanical ventilation (p = 0.40; Fig. 2A and B, respectively). However, the amount of time with fever was significantly less in the Hb 7-g/dl group (p = 0.01; Fig. 2C). Within each transfusion group, fever was more common among individuals who received a transfusion of PRBCs (Fig. 2D).

FIG. 2.
FIG. 2.

Estimated marginal (EM) mean values showing the ICU LOS (A), ventilator time (B), and fever time (C) in days. Error bars represent the 95% CI. Mean values were adjusted for age, ISS, MTP activation, number of OR visits, and total hospital days. Fever (D) was increased among patients who received a transfusion of PRBCs, irrespective of transfusion protocol. Mean values are shown; error bars represent standard error of the mean. *p < 0.05.

The occurrences of ARDS/ALI, DVT/PE, and hospital mortality were examined and no differences were found between transfusion groups. A total of 22 of 848 patients (2.6%) in the Hb 10-g/dl group and 7 of 561 patients (1.2%) in the Hb 7-g/dl group developed ARDS/ALI during their hospital stay. DVT/PE occurred in 46 of 848 patients (5.4%) in the Hb 10-g/dl group and in 38 of 561 patients (6.8%) in the Hb 7-g/dl group. Hospital mortality rates were comparable; 101 patients (10.3%) in the Hb 10-g/dl group and 49 patients (8.4%) in the Hb 7-g/dl group were deceased at discharge. In the final binary logistic regression models that controlled for age, total hospital days, number of OR visits, activation of MTP, and ISS, the transfusion group was not significantly associated with ARDS/ALI, DVT/PE, or hospital mortality.

Outcomes and Complications in Patients With GCS Score ≤ 8

Three hundred fifteen patients had a GCS score ≤ 8. Of these, 203 patients were in the Hb 10-g/dl protocol and 112 were in the Hb 7-g/dl protocol (Table 3). Similar to the total study population, more patients received a transfusion of PRBCs in the Hb 10-g/dl group compared with the Hb 7-g/dl group (55.2% vs 42.0%; p = 0.03). There was no significant difference in discharge disposition among patients with a GCS score ≤ 8. There was no significant relationship of transfusion group with ICU LOS, days of fever, or ventilator days (Table 4).

TABLE 3.

Patients with a GCS score ≤ 8

VariableTransfusion Groupp Value
Hb 10 g/dlHb 7 g/dl
No. of patients203112
Demographic & admission data
 Mean age in yrs (SD)45.2 (19.4)45.2 (19.6)1.00
 Male, no. (%)155 (76.4)85 (75.9)0.93
 Mean GCS score on admission (SD)5.4 (2.0)5.4 (2.1)0.99
 Mean ISS (SD)23.9 (14.9)21.4 (14.8)0.16
 Hypotension on admission, no. (%)57 (28.4)19 (17.0)0.02
 Hypoxia on admission, no. (%)31 (15.4)12 (10.7)0.25
 Mean Hb on admission, g/dl (SD)13.5 (2.2)13.2 (2.1)0.28
Inpatient characteristics
 Mean min Hb, g/dl (SD)9.6 (2.4)9.6 (2.6)1.00
 Mean Hb, g/dl (SD)11.4 (1.8)11.3 (2.1)0.49
 Received transfusion, no. (%)112 (55.2)47 (42.0)0.03
 Units of PRBC, mean (SD)4.1 (6.9)2.8 (5.4)0.10
 MTP activation, no. (%)22 (12.6)21 (19.1)0.13
 Mean no. of OR visits (SD)0.9 (1.5)0.9 (1.5)0.93
 Total hospital days, mean (SD)20.5 (31.3)15.6 (20.7)0.14
Discharge disposition, no. (%)0.16
 Home53 (26.1)34 (30.4)
 Rehab/SNF43 (21.2)35 (31.3)
 Acute care hospital38 (18.7)15 (13.4)
 Other12 (5.9)4 (3.6)
 Deceased57 (28.1)24 (21.4)
TABLE 4.

Effect of transfusion group on outcomes in patients with a GCS score ≤ 8

OutcomeTransfusion Groupp Value
Hb 10 g/dl*Hb 7 g/dl*
ICU LOS9.9 (1.0)10.6 (1.0)0.60
Ventilator days7.8 (0.8)6.8 (0.8)0.36
Days of fever0.5 (0.2)0.3 (0.2)0.47

Reported as the mean (standard error) adjusted for age, ISS, activation of MTP, no. of OR visits, & total hospital days.

The occurrences of ARDS/ALI, DVT/PE, and hospital mortality were also examined among patients with a GCS score ≤ 8. Although the incidence of complications was higher in this severe TBI group, no differences were found due to transfusion protocol. A total of 15 of 177 patients (8.5%) in the Hb 10-g/dl group and 5 of 110 patients (4.5%) in the Hb 7-g/dl group developed ARDS/ALI during their hospital stay. DVT/PE occurred in 18 of 177 patients (10.2%) in the Hb 10-g/dl group and in 13 of 110 patients (11.8%) in the Hb 7-g/dl group. Hospital mortality rates were similar, with 56 patients (27.6%) from the Hb 10-g/dl group and 24 (21.4%) from the Hb 7-g/dl group deceased at discharge. In the final binary logistic regression models that controlled for age, total hospital days, number of OR visits, activation of MTP, and ISS, the transfusion protocol was not significantly associated with ARDS/ALI, DVT/PE, or hospital mortality.

Cost Analysis

Using the range $726–$1183 (in 2008 US dollars) for the average cost per PRBC unit transfused, we estimated that a patient in the Hb 10-g/dl group had transfusion-associated costs between $1533 and $2499 compared with $1291–$2104 for a patient in the Hb 7-g/dl group, after adjusting for inflation to 2016 dollars. The change in Hb threshold from 10 to 7 g/dl is estimated to save $242–$394 per patient. Among patients with a GCS score ≤ 8, who were more likely to receive a transfusion, the savings per patient was $1049–$1710. At a hospital-wide level, assuming that approximately 30 patients with TBI were admitted to the ICU each month, the change in protocol saved between $87,156 and $142,020 (approximately $115,000) annually.

Discussion

We demonstrated that at a Level I trauma center, patients with TBI can be successfully managed with a restrictive transfusion protocol. The restrictive protocol resulted in fewer patients receiving a transfusion and a significantly lower mean Hb level during their hospital stay. This was done safely, i.e., outcomes were similar between transfusion groups. The adoption of a restrictive transfusion protocol resulted in fewer days of fever, no difference in hospital mortality rates, and an average savings of $115,000 annually.

A Restrictive Transfusion Protocol is Safe in TBI

Although some studies have suggested that the moderate anemia resulting from a lower transfusion threshold is associated with poor outcomes, the majority of studies have shown that the risks of transfusion outweigh the benefits. Sekhon et al.17 demonstrated that a mean 7-day Hb level of < 9 g/dl was associated with increased mortality. Other studies have similarly shown increased mortality rates with anemia, but admit that transfusion itself is a risk factor for morbidity and mortality.4,6,16 In a study of 139 patients with TBI, Warner et al.19 demonstrated that transfusion of PRBCs was associated with poor 6-month neurological outcome. In the only randomized controlled trial of transfusion threshold in TBI, Robertson et al.15 showed that there were no ill effects of an Hb threshold of 7 g/dl, and that there was increased presence of DVT in patients who were managed with an Hb threshold of 10 g/dl. The trial reported by Robertson and colleagues had 200 patients. Our study included 1565 patients, thus adding to the evidence supporting the safety of adopting a restrictive transfusion threshold in patients with TBI.

Study Limitations and Considerations

In our retrospective study, groups were determined on the basis of consecutive cases (i.e., patients were not randomly assigned), which is a limitation. Thus, there were some differences at baseline between the transfusion threshold groups. Notably, patients in the Hb 7-g/dl group were older and had fewer total hospital days. This probably reflects aging of the trauma population and improvements in hospital discharge management between 2011 and 2015. These variables were controlled for in the multivariable analyses of outcomes. All patients admitted to the ICU with a diagnosis of TBI were included in our study, including those with polytrauma.

At our institution, all trauma patients with TBI are treated according to the TBI transfusion protocol thresholds. Therefore, the nature of the study population includes heterogeneity in patient population, but not in patient management. This allows generalizability of the results to a larger TBI population. The subgroup analyses of patients with a GCS score ≤ 8 demonstrated no differences in outcome with a restrictive transfusion protocol, providing evidence that maintaining an Hb ≥ 7 g/dl is safe in the most vulnerable TBI patients.

A limitation of the study is that we did not specifically address other patient populations that may need a more aggressive transfusion protocol due to medical comorbidities. Of importance is that we did not disallow transfusions to be given to patients who arrived with signs of hemorrhagic shock. As shown in Table 2, approximately 5%–7% of patients met criteria for activation of the MTP during resuscitation. Our results do not suggest that resuscitation efforts should be thwarted in patients with TBI. Rather, we demonstrated that postresuscitation, patients with TBI should not constitute a special group and can be managed with the same restrictive transfusion thresholds as other patients in the ICU.

The advantages of our study include that, to our knowledge, this is the largest study to date to compare transfusion protocols in patients with TBI. Because of our standardized hospital guidelines for the management of patients with TBI, all patients received identical care throughout their hospital stay, including avoidance of hypoxia and hyperglycemia, which have been shown to be risk factors for poor outcome.11 Although this is a retrospective study, the large number of patients and the consistent clinical management enable these results to have a significant impact.

Restrictive Transfusion Protocol is Cost-Effective

We showed that a restrictive transfusion protocol also reduces cost. A blood transfusion can range from $807 to $1315 (in 2016 dollars) per unit after the acquisition and all activity-based costs are considered. Early transfusion cost analyses overlooked direct and indirect costs associated with hospital overhead, material, and service costs.10 To address the underestimation of transfusion costs, in 2003, the Cost of Blood Consensus Conference devised a standardized method for calculating the cost associated with blood transfusions.1 The ABC model accounts for technical, administrative, and clinical process steps, including consent and ordering procedures, laboratory services, and transfusion administration.18

We used the ABC estimate of the cost of a unit of surgical PRBCs in the United States,18 adjusted for inflation to 2016 dollars, to calculate our cost savings. Although our analysis was not limited to patients undergoing surgical interventions, the ABC cost estimate is the most accurate among those available. We gave transfusions to fewer patients as a result of our hospital-wide change in transfusion protocol, and estimated a savings of approximately $115,000 dollars annually at our Level I trauma center. This amount is a low estimate because we generalized to an entire ICU TBI population. The cost savings could be considerably increased when populations with multiple comorbidities and the cost associated with transfusion-related complications are included in the calculations.

Conclusions

In what is the largest study to date, to our knowledge, we showed that at a Level I trauma center, a restrictive transfusion protocol can be safely adopted in patients with TBI. We demonstrated no evidence of poor outcome, an improved fever profile, and cost savings. The benefits of restrictive transfusion outweigh the risks; thus a transfusion threshold of Hb < 7 g/dl should be considered standard policy for patients with TBI.

Acknowledgments

We acknowledge the UCSF Department of General Surgery at Zuckerberg SFGH and the staff of the Integrated Data Repository of the UCSF Department of Information Technology for their assistance in data collection.

Disclosures

The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

Author Contributions

Conception and design: Ngwenya, Tarapore, Manley, Huang. Acquisition of data: Ngwenya, Suen. Analysis and interpretation of data: Ngwenya, Suen, Huang. Drafting the article: Ngwenya, Suen. Critically revising the article: all authors. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: Ngwenya. Statistical analysis: Ngwenya.

Supplemental Information

Previous Presentations

A portion of this work was presented in poster form at the National Neurotrauma Symposium, Lexington, KY, June 28, 2016.

References

  • 1

    Aledort LM, Broder M, Busch MP, Custer BS, Fergusson DA, Goodnough LT, et al.: The cost of blood: multidisciplinary consensus conference for a standard methodology. Transfus Med Rev 19:6678, 2005

    • Search Google Scholar
    • Export Citation
  • 2

    Bernard AC, Davenport DL, Chang PK, Vaughan TB, Zwischenberger JB: Intraoperative transfusion of 1 u to 2 u packed red blood cells is associated with increased 30-day mortality, surgical-site infection, pneumonia, and sepsis in general surgery patients. J Am Coll Surg 208:931939, 937.e1–937.e2, 2009

    • Search Google Scholar
    • Export Citation
  • 3

    Bullock MR, Povlishock JT (eds): Guidelines for the management of severe traumatic brain injury. J Neurotrauma 24 (Suppl 1):S-1S-106, 2007

    • Search Google Scholar
    • Export Citation
  • 4

    Carlson AP, Schermer CR, Lu SW: Retrospective evaluation of anemia and transfusion in traumatic brain injury. J Trauma 61:567571, 2006

    • Search Google Scholar
    • Export Citation
  • 5

    Carson JL, Carless PA, Hebert PC: Transfusion thresholds and other strategies for guiding allogeneic red blood cell transfusion. Cochrane Database Syst Rev (4):CD002042, 2012

    • Search Google Scholar
    • Export Citation
  • 6

    Duane TM, Mayglothling J, Grandhi R, Warrier N, Aboutanos MB, Wolfe LG, et al.: The effect of anemia and blood transfusions on mortality in closed head injury patients. J Surg Res 147:163167, 2008

    • Search Google Scholar
    • Export Citation
  • 7

    George ME, Skarda DE, Watts CR, Pham HD, Beilman GJ: Aggressive red blood cell transfusion: no association with improved outcomes for victims of isolated traumatic brain injury. Neurocrit Care 8:337343, 2008

    • Search Google Scholar
    • Export Citation
  • 8

    Hébert PC, Carson JL: Transfusion threshold of 7 g per deciliter—the new normal. N Engl J Med 371:14591461, 2014

  • 9

    Hébert PC, Wells G, Blajchman MA, Marshall J, Martin C, Pagliarello G, et al.: A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. Transfusion Requirements in Critical Care Investigators, Canadian Critical Care Trials Group. N Engl J Med 340:409417, 1999

    • Search Google Scholar
    • Export Citation
  • 10

    Hofmann A, Ozawa S, Farrugia A, Farmer SL, Shander A: Economic considerations on transfusion medicine and patient blood management. Best Pract Res Clin Anaesthesiol 27:5968, 2013

    • Search Google Scholar
    • Export Citation
  • 11

    Jeremitsky E, Omert L, Dunham CM, Protetch J, Rodriguez A: Harbingers of poor outcome the day after severe brain injury: hypothermia, hypoxia, and hypoperfusion. J Trauma 54:312319, 2003

    • Search Google Scholar
    • Export Citation
  • 12

    Marik PE, Corwin HL: Efficacy of red blood cell transfusion in the critically ill: a systematic review of the literature. Crit Care Med 36:26672674, 2008

    • Search Google Scholar
    • Export Citation
  • 13

    McIntyre LA, Fergusson DA, Hutchison JS, Pagliarello G, Marshall JC, Yetisir E, et al.: Effect of a liberal versus restrictive transfusion strategy on mortality in patients with moderate to severe head injury. Neurocrit Care 5:49, 2006

    • Search Google Scholar
    • Export Citation
  • 14

    Moore FA, Moore EE, Sauaia A: Blood transfusion. An independent risk factor for postinjury multiple organ failure. Arch Surg 132:620625, 1997

    • Search Google Scholar
    • Export Citation
  • 15

    Robertson CS, Hannay HJ, Yamal JM, Gopinath S, Goodman JC, Tilley BC, et al.: Effect of erythropoietin and transfusion threshold on neurological recovery after traumatic brain injury: a randomized clinical trial. JAMA 312:3647, 2014

    • Search Google Scholar
    • Export Citation
  • 16

    Salim A, Hadjizacharia P, DuBose J, Brown C, Inaba K, Chan L, et al.: Role of anemia in traumatic brain injury. J Am Coll Surg 207:398406, 2008

    • Search Google Scholar
    • Export Citation
  • 17

    Sekhon MS, McLean N, Henderson WR, Chittock DR, Griesdale DE: Association of hemoglobin concentration and mortality in critically ill patients with severe traumatic brain injury. Crit Care 16:R128, 2012

    • Search Google Scholar
    • Export Citation
  • 18

    Shander A, Hofmann A, Ozawa S, Theusinger OM, Gombotz H, Spahn DR: Activity-based costs of blood transfusions in surgical patients at four hospitals. Transfusion 50:753765, 2010

    • Search Google Scholar
    • Export Citation
  • 19

    Warner MA, O’Keeffe T, Bhavsar P, Shringer R, Moore C, Harper C, et al.: Transfusions and long-term functional outcomes in traumatic brain injury. J Neurosurg 113:539546, 2010

    • Search Google Scholar
    • Export Citation
  • 20

    Yamal JM, Rubin ML, Benoit JS, Tilley BC, Gopinath S, Hannay HJ, et al.: Effect of hemoglobin transfusion threshold on cerebral hemodynamics and oxygenation. J Neurotrauma 32:12391245, 2015

    • Search Google Scholar
    • Export Citation
  • 21

    Zygun DA, Nortje J, Hutchinson PJ, Timofeev I, Menon DK, Gupta AK: The effect of red blood cell transfusion on cerebral oxygenation and metabolism after severe traumatic brain injury. Crit Care Med 37:10741078, 2009

    • Search Google Scholar
    • Export Citation
  • View in gallery

    Patients included in the study. A: Diagram showing total number of patients with TBI admitted to the ICU between January 2011 and September 2015 and those excluded to yield the final number of 1565 patients. B: A schematic demonstrating the number of patients at each timeframe. The timeframes delineate the transfusion protocol by which the patients were managed.

  • View in gallery

    Estimated marginal (EM) mean values showing the ICU LOS (A), ventilator time (B), and fever time (C) in days. Error bars represent the 95% CI. Mean values were adjusted for age, ISS, MTP activation, number of OR visits, and total hospital days. Fever (D) was increased among patients who received a transfusion of PRBCs, irrespective of transfusion protocol. Mean values are shown; error bars represent standard error of the mean. *p < 0.05.

  • 1

    Aledort LM, Broder M, Busch MP, Custer BS, Fergusson DA, Goodnough LT, et al.: The cost of blood: multidisciplinary consensus conference for a standard methodology. Transfus Med Rev 19:6678, 2005

    • Search Google Scholar
    • Export Citation
  • 2

    Bernard AC, Davenport DL, Chang PK, Vaughan TB, Zwischenberger JB: Intraoperative transfusion of 1 u to 2 u packed red blood cells is associated with increased 30-day mortality, surgical-site infection, pneumonia, and sepsis in general surgery patients. J Am Coll Surg 208:931939, 937.e1–937.e2, 2009

    • Search Google Scholar
    • Export Citation
  • 3

    Bullock MR, Povlishock JT (eds): Guidelines for the management of severe traumatic brain injury. J Neurotrauma 24 (Suppl 1):S-1S-106, 2007

    • Search Google Scholar
    • Export Citation
  • 4

    Carlson AP, Schermer CR, Lu SW: Retrospective evaluation of anemia and transfusion in traumatic brain injury. J Trauma 61:567571, 2006

    • Search Google Scholar
    • Export Citation
  • 5

    Carson JL, Carless PA, Hebert PC: Transfusion thresholds and other strategies for guiding allogeneic red blood cell transfusion. Cochrane Database Syst Rev (4):CD002042, 2012

    • Search Google Scholar
    • Export Citation
  • 6

    Duane TM, Mayglothling J, Grandhi R, Warrier N, Aboutanos MB, Wolfe LG, et al.: The effect of anemia and blood transfusions on mortality in closed head injury patients. J Surg Res 147:163167, 2008

    • Search Google Scholar
    • Export Citation
  • 7

    George ME, Skarda DE, Watts CR, Pham HD, Beilman GJ: Aggressive red blood cell transfusion: no association with improved outcomes for victims of isolated traumatic brain injury. Neurocrit Care 8:337343, 2008

    • Search Google Scholar
    • Export Citation
  • 8

    Hébert PC, Carson JL: Transfusion threshold of 7 g per deciliter—the new normal. N Engl J Med 371:14591461, 2014

  • 9

    Hébert PC, Wells G, Blajchman MA, Marshall J, Martin C, Pagliarello G, et al.: A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. Transfusion Requirements in Critical Care Investigators, Canadian Critical Care Trials Group. N Engl J Med 340:409417, 1999

    • Search Google Scholar
    • Export Citation
  • 10

    Hofmann A, Ozawa S, Farrugia A, Farmer SL, Shander A: Economic considerations on transfusion medicine and patient blood management. Best Pract Res Clin Anaesthesiol 27:5968, 2013

    • Search Google Scholar
    • Export Citation
  • 11

    Jeremitsky E, Omert L, Dunham CM, Protetch J, Rodriguez A: Harbingers of poor outcome the day after severe brain injury: hypothermia, hypoxia, and hypoperfusion. J Trauma 54:312319, 2003

    • Search Google Scholar
    • Export Citation
  • 12

    Marik PE, Corwin HL: Efficacy of red blood cell transfusion in the critically ill: a systematic review of the literature. Crit Care Med 36:26672674, 2008

    • Search Google Scholar
    • Export Citation
  • 13

    McIntyre LA, Fergusson DA, Hutchison JS, Pagliarello G, Marshall JC, Yetisir E, et al.: Effect of a liberal versus restrictive transfusion strategy on mortality in patients with moderate to severe head injury. Neurocrit Care 5:49, 2006

    • Search Google Scholar
    • Export Citation
  • 14

    Moore FA, Moore EE, Sauaia A: Blood transfusion. An independent risk factor for postinjury multiple organ failure. Arch Surg 132:620625, 1997

    • Search Google Scholar
    • Export Citation
  • 15

    Robertson CS, Hannay HJ, Yamal JM, Gopinath S, Goodman JC, Tilley BC, et al.: Effect of erythropoietin and transfusion threshold on neurological recovery after traumatic brain injury: a randomized clinical trial. JAMA 312:3647, 2014

    • Search Google Scholar
    • Export Citation
  • 16

    Salim A, Hadjizacharia P, DuBose J, Brown C, Inaba K, Chan L, et al.: Role of anemia in traumatic brain injury. J Am Coll Surg 207:398406, 2008

    • Search Google Scholar
    • Export Citation
  • 17

    Sekhon MS, McLean N, Henderson WR, Chittock DR, Griesdale DE: Association of hemoglobin concentration and mortality in critically ill patients with severe traumatic brain injury. Crit Care 16:R128, 2012

    • Search Google Scholar
    • Export Citation
  • 18

    Shander A, Hofmann A, Ozawa S, Theusinger OM, Gombotz H, Spahn DR: Activity-based costs of blood transfusions in surgical patients at four hospitals. Transfusion 50:753765, 2010

    • Search Google Scholar
    • Export Citation
  • 19

    Warner MA, O’Keeffe T, Bhavsar P, Shringer R, Moore C, Harper C, et al.: Transfusions and long-term functional outcomes in traumatic brain injury. J Neurosurg 113:539546, 2010

    • Search Google Scholar
    • Export Citation
  • 20

    Yamal JM, Rubin ML, Benoit JS, Tilley BC, Gopinath S, Hannay HJ, et al.: Effect of hemoglobin transfusion threshold on cerebral hemodynamics and oxygenation. J Neurotrauma 32:12391245, 2015

    • Search Google Scholar
    • Export Citation
  • 21

    Zygun DA, Nortje J, Hutchinson PJ, Timofeev I, Menon DK, Gupta AK: The effect of red blood cell transfusion on cerebral oxygenation and metabolism after severe traumatic brain injury. Crit Care Med 37:10741078, 2009

    • Search Google Scholar
    • Export Citation

Metrics

All Time Past Year Past 30 Days
Abstract Views 557 0 0
Full Text Views 751 257 23
PDF Downloads 469 166 18
EPUB Downloads 0 0 0